non-ipso attack electrophilic aromatic addition reaction ... · non-ipso 친전자성 방향족...
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1
理學碩士學位 請求論文
Non-Ipso 친전자성 방향족 첨가반응
안트라센의 첨과 반응과 첨가물의 재방향족 반응과 응용
Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
Rearomatization Reactions and Applications of Anthracene Adducts
2005 년 2 월
仁荷大學校 大學院
化學科 (化學專攻)
張 根 三
2
理學碩士學位 請求論文
Non-Ipso 친전자성 방향족 첨가반응
안트라센의 첨과 반응과 첨가물의 재방향족 반응과 응용
Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
Rearomatization Reactions and Applications of Anthracene Adducts
2005 년 2 월
指導敎授 池 大 潤
이 論文을 碩士學位 論文으로 提出함
仁荷大學校 大學院
化學科 (化學專攻)
張 根 三
3
이 論文을 張根三의 碩士學位論文으로 認定함
2005 년 2 월
主審 (인)
副審 (인)
副審 (인)
4
Contents
Abstract (English)
Abstract (Korean)
Part І Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
Introduction
The AdEAr in various conditions
Results and Discussion
Conclusion
Experimental Section
References
NMR Spectrum (1H NMR and 13C NMR)
Part II Rearomatization Reactions and Applications of Anthracene Adducts
Introduction
The Addition Reaction of Anthracene
Results and Discussion
Conclusion
Experimental Section
References
NMR Spectrum (1H NMR and 13C NMR)
5
List of Tables
Part І
Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various
Conditions
Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under
NaHCO3-Methanol Conditions
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various
Nucleophiles
Part ІІ
Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
Table-2 AdEAr Rate of Anthracene of the Various Conditions
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditions
6
Abstract
Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction
The electrophilic aromatic addition reaction (AdEAr) at H substituent position has been
extensive studied The bromomethoxylation of 1-methoxynaphthalene in various conditions
showed AdEAr at room temperature using bromine and other brominating agents The
addition reaction could be occurred in either 12-addition or 14-addition manner depend on
structure of starting material Treatments of the addition product 57-dibromo-88-
dimethoxy-2-methyl-78-dihydroquinoline with nucleophiles gave nucleophilic
substitution-rearomatization products which were considered as a new potential route for
synthesis of 7-substituted-8-methoxyquinaldine
Part II Rearomatization Reactions and Applications of Anthracene Adducts
Since the discovery of anticancer drugs such as daunomycin adriamycin and
mitoxantrone a variety of anthracene derivatives have been investigated for significant
activity in the relation to their biological activity and pharmacological properties especially
910-disubstituted anthracene derivatives possesses the DNA accessibility with antitumor
activity Bromination of anthracene with bromine in the basic methanolic gave the adduct
910-dimethoxy-910-dihydroanthracene 2 which is the cis and trans isomers by 14-addition
Formation of adduct on anthracene using 30 equiv bromine and 10 equiv pyridine at room
temperature for 15 min under basic methanolic condition gave 910-dimethoxy-910-
dihydroanthracene adduct 2 Interestingly during do the reaction in the some conditions we
obtained that oxidative demethylation compound such as anthraquinone instead of 910-
7
dimethoxy-910-dihydroanthracene adduct 2 Moreover we can control either methoxylation
or addition reaction or both reaction Also we can obtain both selective 9-methoxy
anthracene in the basic condition and 910-dimethoxyanthracene in the rearomatization
reaction from the 910-dihydro-910-dimethoxyanthracene adduct 2
8
요약문
Part I Non-Ipso 친전자성 방향족 첨가반응
H 치환기 위치에서 친전자성 방향족 첨가 반응(AdEAr)이 폭 넓게 연구되었다
1-메톡시나프탈렌의 브로모메톡시화반응이 다양한 조건에서 친전자성방향족
첨가반응(AdEAr)이 일어날 수 있는 것과 다른 브로민 물질로도 첨가반응이
일어난다는 것을 보여준다 첨가반응은 출발 물질에 따라서 12-첨가 또는 14-
첨가반응이 일어난다 첨가반응의 생성물 57-dibromo-88-dimethoxy-2-
methyl-78-dihydroquinoline을 다양한 친핵체들과 반응을 시키면 7번 위치에
다양한 치환기를 도입시킬 수 친핵성 치환반응을 통한 재방향족화 생성물인 7-
substituted-8-methoxyquinaldine을 합성하는 새로운 길이 될 것이다
Part II AdEAr 반응을 통한 Anthracene 첨가물의 재방향족 반응과 응
용
Daunomycin adriamycin 그리고 mitoxantrone의 anticancer drug을 발견된
이후로 다양한 안트라센 유도체들이 생물학적 활성과 약리학적 성질이 있다는
것을 알게 되었다 특히 910번 위치에 치환된 안트라센 유도체들은 antitumor
활성에 대해서 DNA에 결합하는 능력을 가지고 있다 메탄올 염기조건에서
안트라센의 브롬화반응은 14-첨가반응을 통해 시스 그리고 트랜스 형태로 된
아이소머 첨가물질인 910-dihydro-910-dimethoxyanthracene (2) 를 주
9
생성물로 얻게된다 특히 910 유도체들은 antitumor 활성에 대해서 DNA에
결합하는 능력을 가지고 있다 메탄올 염기조건에서 브로민 30 당량과 피리틴
10 당량을 사용해서 실온에서 15분 동안 반응을 시키면 910-dihydro-910-
dimethoxyanthracene의 첨가 생성물을 얻을 수가 있다 흥미로운 것은 어떤
다른 조건에서는 첨가 반응의 생성물이 아닌 산화탈 메틸반응으로 안트라퀴논
이 얻어지게 된다 더구나 이 반응을 통해서 치환반응의 메톡시반응과 첨가
반응을 조절할 수가 있다 또한 이 조건에서 얻은 첨가물을 가지고 선택적으로
치환되는 메톡시 위치를 조절할 수가 있게 된다 재방향성 반응을 통해서 910-
dimethoxyanthracene와 염기로 처리해서 9-methoxy anthracene 을 얻을
수가 있게 되었다
1
Part I Non-Ipso Attack Electrophilic Aromatic Addition
Reaction
2
Introduction
Unlike aliphatic compounds aromatic systems usually react with electrophiles resulting
substitution which occur via arenium ion mechanism by replacement at hydrogen
substituent In this mechanism the electrophile attacks in the first step giving rise to a
positively charged intermediate and the leaving group departs in the second step1 However
the nucleophilic capture is sometimes faster in the latter step leading to the formation of an
addition tetrahedral intermediate2 which was whether isolated or guessed from products
Electrophilic addition reaction of hetereocyclic compounds such as furan derivatives were
reported3 In bezenoid systems ipso attack addition reactions on aromatic ring by nitronium
ion at the position bearing the substiutents have been extensively studied4 With haloamine
amination of toluene which firstly addition take place and then followed by elimination of
HCl yielding m-methylaniline could be an example of addition reaction on aromatic
systems even though addition adduct was unable to isolated5
In our previous work we reported an unusual electrophilic aromatic addition reaction at H
substituent position and its mechanism of methoxyquinaldine derivatives and 1-
methoxynaphthalene by bromomethoxylation at rt6 The reaction proceeded via a stable
cation intermediate and gave 12-addition products in high yield Herein we investigated
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
2
理學碩士學位 請求論文
Non-Ipso 친전자성 방향족 첨가반응
안트라센의 첨과 반응과 첨가물의 재방향족 반응과 응용
Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
Rearomatization Reactions and Applications of Anthracene Adducts
2005 년 2 월
指導敎授 池 大 潤
이 論文을 碩士學位 論文으로 提出함
仁荷大學校 大學院
化學科 (化學專攻)
張 根 三
3
이 論文을 張根三의 碩士學位論文으로 認定함
2005 년 2 월
主審 (인)
副審 (인)
副審 (인)
4
Contents
Abstract (English)
Abstract (Korean)
Part І Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
Introduction
The AdEAr in various conditions
Results and Discussion
Conclusion
Experimental Section
References
NMR Spectrum (1H NMR and 13C NMR)
Part II Rearomatization Reactions and Applications of Anthracene Adducts
Introduction
The Addition Reaction of Anthracene
Results and Discussion
Conclusion
Experimental Section
References
NMR Spectrum (1H NMR and 13C NMR)
5
List of Tables
Part І
Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various
Conditions
Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under
NaHCO3-Methanol Conditions
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various
Nucleophiles
Part ІІ
Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
Table-2 AdEAr Rate of Anthracene of the Various Conditions
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditions
6
Abstract
Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction
The electrophilic aromatic addition reaction (AdEAr) at H substituent position has been
extensive studied The bromomethoxylation of 1-methoxynaphthalene in various conditions
showed AdEAr at room temperature using bromine and other brominating agents The
addition reaction could be occurred in either 12-addition or 14-addition manner depend on
structure of starting material Treatments of the addition product 57-dibromo-88-
dimethoxy-2-methyl-78-dihydroquinoline with nucleophiles gave nucleophilic
substitution-rearomatization products which were considered as a new potential route for
synthesis of 7-substituted-8-methoxyquinaldine
Part II Rearomatization Reactions and Applications of Anthracene Adducts
Since the discovery of anticancer drugs such as daunomycin adriamycin and
mitoxantrone a variety of anthracene derivatives have been investigated for significant
activity in the relation to their biological activity and pharmacological properties especially
910-disubstituted anthracene derivatives possesses the DNA accessibility with antitumor
activity Bromination of anthracene with bromine in the basic methanolic gave the adduct
910-dimethoxy-910-dihydroanthracene 2 which is the cis and trans isomers by 14-addition
Formation of adduct on anthracene using 30 equiv bromine and 10 equiv pyridine at room
temperature for 15 min under basic methanolic condition gave 910-dimethoxy-910-
dihydroanthracene adduct 2 Interestingly during do the reaction in the some conditions we
obtained that oxidative demethylation compound such as anthraquinone instead of 910-
7
dimethoxy-910-dihydroanthracene adduct 2 Moreover we can control either methoxylation
or addition reaction or both reaction Also we can obtain both selective 9-methoxy
anthracene in the basic condition and 910-dimethoxyanthracene in the rearomatization
reaction from the 910-dihydro-910-dimethoxyanthracene adduct 2
8
요약문
Part I Non-Ipso 친전자성 방향족 첨가반응
H 치환기 위치에서 친전자성 방향족 첨가 반응(AdEAr)이 폭 넓게 연구되었다
1-메톡시나프탈렌의 브로모메톡시화반응이 다양한 조건에서 친전자성방향족
첨가반응(AdEAr)이 일어날 수 있는 것과 다른 브로민 물질로도 첨가반응이
일어난다는 것을 보여준다 첨가반응은 출발 물질에 따라서 12-첨가 또는 14-
첨가반응이 일어난다 첨가반응의 생성물 57-dibromo-88-dimethoxy-2-
methyl-78-dihydroquinoline을 다양한 친핵체들과 반응을 시키면 7번 위치에
다양한 치환기를 도입시킬 수 친핵성 치환반응을 통한 재방향족화 생성물인 7-
substituted-8-methoxyquinaldine을 합성하는 새로운 길이 될 것이다
Part II AdEAr 반응을 통한 Anthracene 첨가물의 재방향족 반응과 응
용
Daunomycin adriamycin 그리고 mitoxantrone의 anticancer drug을 발견된
이후로 다양한 안트라센 유도체들이 생물학적 활성과 약리학적 성질이 있다는
것을 알게 되었다 특히 910번 위치에 치환된 안트라센 유도체들은 antitumor
활성에 대해서 DNA에 결합하는 능력을 가지고 있다 메탄올 염기조건에서
안트라센의 브롬화반응은 14-첨가반응을 통해 시스 그리고 트랜스 형태로 된
아이소머 첨가물질인 910-dihydro-910-dimethoxyanthracene (2) 를 주
9
생성물로 얻게된다 특히 910 유도체들은 antitumor 활성에 대해서 DNA에
결합하는 능력을 가지고 있다 메탄올 염기조건에서 브로민 30 당량과 피리틴
10 당량을 사용해서 실온에서 15분 동안 반응을 시키면 910-dihydro-910-
dimethoxyanthracene의 첨가 생성물을 얻을 수가 있다 흥미로운 것은 어떤
다른 조건에서는 첨가 반응의 생성물이 아닌 산화탈 메틸반응으로 안트라퀴논
이 얻어지게 된다 더구나 이 반응을 통해서 치환반응의 메톡시반응과 첨가
반응을 조절할 수가 있다 또한 이 조건에서 얻은 첨가물을 가지고 선택적으로
치환되는 메톡시 위치를 조절할 수가 있게 된다 재방향성 반응을 통해서 910-
dimethoxyanthracene와 염기로 처리해서 9-methoxy anthracene 을 얻을
수가 있게 되었다
1
Part I Non-Ipso Attack Electrophilic Aromatic Addition
Reaction
2
Introduction
Unlike aliphatic compounds aromatic systems usually react with electrophiles resulting
substitution which occur via arenium ion mechanism by replacement at hydrogen
substituent In this mechanism the electrophile attacks in the first step giving rise to a
positively charged intermediate and the leaving group departs in the second step1 However
the nucleophilic capture is sometimes faster in the latter step leading to the formation of an
addition tetrahedral intermediate2 which was whether isolated or guessed from products
Electrophilic addition reaction of hetereocyclic compounds such as furan derivatives were
reported3 In bezenoid systems ipso attack addition reactions on aromatic ring by nitronium
ion at the position bearing the substiutents have been extensively studied4 With haloamine
amination of toluene which firstly addition take place and then followed by elimination of
HCl yielding m-methylaniline could be an example of addition reaction on aromatic
systems even though addition adduct was unable to isolated5
In our previous work we reported an unusual electrophilic aromatic addition reaction at H
substituent position and its mechanism of methoxyquinaldine derivatives and 1-
methoxynaphthalene by bromomethoxylation at rt6 The reaction proceeded via a stable
cation intermediate and gave 12-addition products in high yield Herein we investigated
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
3
이 論文을 張根三의 碩士學位論文으로 認定함
2005 년 2 월
主審 (인)
副審 (인)
副審 (인)
4
Contents
Abstract (English)
Abstract (Korean)
Part І Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
Introduction
The AdEAr in various conditions
Results and Discussion
Conclusion
Experimental Section
References
NMR Spectrum (1H NMR and 13C NMR)
Part II Rearomatization Reactions and Applications of Anthracene Adducts
Introduction
The Addition Reaction of Anthracene
Results and Discussion
Conclusion
Experimental Section
References
NMR Spectrum (1H NMR and 13C NMR)
5
List of Tables
Part І
Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various
Conditions
Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under
NaHCO3-Methanol Conditions
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various
Nucleophiles
Part ІІ
Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
Table-2 AdEAr Rate of Anthracene of the Various Conditions
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditions
6
Abstract
Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction
The electrophilic aromatic addition reaction (AdEAr) at H substituent position has been
extensive studied The bromomethoxylation of 1-methoxynaphthalene in various conditions
showed AdEAr at room temperature using bromine and other brominating agents The
addition reaction could be occurred in either 12-addition or 14-addition manner depend on
structure of starting material Treatments of the addition product 57-dibromo-88-
dimethoxy-2-methyl-78-dihydroquinoline with nucleophiles gave nucleophilic
substitution-rearomatization products which were considered as a new potential route for
synthesis of 7-substituted-8-methoxyquinaldine
Part II Rearomatization Reactions and Applications of Anthracene Adducts
Since the discovery of anticancer drugs such as daunomycin adriamycin and
mitoxantrone a variety of anthracene derivatives have been investigated for significant
activity in the relation to their biological activity and pharmacological properties especially
910-disubstituted anthracene derivatives possesses the DNA accessibility with antitumor
activity Bromination of anthracene with bromine in the basic methanolic gave the adduct
910-dimethoxy-910-dihydroanthracene 2 which is the cis and trans isomers by 14-addition
Formation of adduct on anthracene using 30 equiv bromine and 10 equiv pyridine at room
temperature for 15 min under basic methanolic condition gave 910-dimethoxy-910-
dihydroanthracene adduct 2 Interestingly during do the reaction in the some conditions we
obtained that oxidative demethylation compound such as anthraquinone instead of 910-
7
dimethoxy-910-dihydroanthracene adduct 2 Moreover we can control either methoxylation
or addition reaction or both reaction Also we can obtain both selective 9-methoxy
anthracene in the basic condition and 910-dimethoxyanthracene in the rearomatization
reaction from the 910-dihydro-910-dimethoxyanthracene adduct 2
8
요약문
Part I Non-Ipso 친전자성 방향족 첨가반응
H 치환기 위치에서 친전자성 방향족 첨가 반응(AdEAr)이 폭 넓게 연구되었다
1-메톡시나프탈렌의 브로모메톡시화반응이 다양한 조건에서 친전자성방향족
첨가반응(AdEAr)이 일어날 수 있는 것과 다른 브로민 물질로도 첨가반응이
일어난다는 것을 보여준다 첨가반응은 출발 물질에 따라서 12-첨가 또는 14-
첨가반응이 일어난다 첨가반응의 생성물 57-dibromo-88-dimethoxy-2-
methyl-78-dihydroquinoline을 다양한 친핵체들과 반응을 시키면 7번 위치에
다양한 치환기를 도입시킬 수 친핵성 치환반응을 통한 재방향족화 생성물인 7-
substituted-8-methoxyquinaldine을 합성하는 새로운 길이 될 것이다
Part II AdEAr 반응을 통한 Anthracene 첨가물의 재방향족 반응과 응
용
Daunomycin adriamycin 그리고 mitoxantrone의 anticancer drug을 발견된
이후로 다양한 안트라센 유도체들이 생물학적 활성과 약리학적 성질이 있다는
것을 알게 되었다 특히 910번 위치에 치환된 안트라센 유도체들은 antitumor
활성에 대해서 DNA에 결합하는 능력을 가지고 있다 메탄올 염기조건에서
안트라센의 브롬화반응은 14-첨가반응을 통해 시스 그리고 트랜스 형태로 된
아이소머 첨가물질인 910-dihydro-910-dimethoxyanthracene (2) 를 주
9
생성물로 얻게된다 특히 910 유도체들은 antitumor 활성에 대해서 DNA에
결합하는 능력을 가지고 있다 메탄올 염기조건에서 브로민 30 당량과 피리틴
10 당량을 사용해서 실온에서 15분 동안 반응을 시키면 910-dihydro-910-
dimethoxyanthracene의 첨가 생성물을 얻을 수가 있다 흥미로운 것은 어떤
다른 조건에서는 첨가 반응의 생성물이 아닌 산화탈 메틸반응으로 안트라퀴논
이 얻어지게 된다 더구나 이 반응을 통해서 치환반응의 메톡시반응과 첨가
반응을 조절할 수가 있다 또한 이 조건에서 얻은 첨가물을 가지고 선택적으로
치환되는 메톡시 위치를 조절할 수가 있게 된다 재방향성 반응을 통해서 910-
dimethoxyanthracene와 염기로 처리해서 9-methoxy anthracene 을 얻을
수가 있게 되었다
1
Part I Non-Ipso Attack Electrophilic Aromatic Addition
Reaction
2
Introduction
Unlike aliphatic compounds aromatic systems usually react with electrophiles resulting
substitution which occur via arenium ion mechanism by replacement at hydrogen
substituent In this mechanism the electrophile attacks in the first step giving rise to a
positively charged intermediate and the leaving group departs in the second step1 However
the nucleophilic capture is sometimes faster in the latter step leading to the formation of an
addition tetrahedral intermediate2 which was whether isolated or guessed from products
Electrophilic addition reaction of hetereocyclic compounds such as furan derivatives were
reported3 In bezenoid systems ipso attack addition reactions on aromatic ring by nitronium
ion at the position bearing the substiutents have been extensively studied4 With haloamine
amination of toluene which firstly addition take place and then followed by elimination of
HCl yielding m-methylaniline could be an example of addition reaction on aromatic
systems even though addition adduct was unable to isolated5
In our previous work we reported an unusual electrophilic aromatic addition reaction at H
substituent position and its mechanism of methoxyquinaldine derivatives and 1-
methoxynaphthalene by bromomethoxylation at rt6 The reaction proceeded via a stable
cation intermediate and gave 12-addition products in high yield Herein we investigated
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
4
Contents
Abstract (English)
Abstract (Korean)
Part І Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
Introduction
The AdEAr in various conditions
Results and Discussion
Conclusion
Experimental Section
References
NMR Spectrum (1H NMR and 13C NMR)
Part II Rearomatization Reactions and Applications of Anthracene Adducts
Introduction
The Addition Reaction of Anthracene
Results and Discussion
Conclusion
Experimental Section
References
NMR Spectrum (1H NMR and 13C NMR)
5
List of Tables
Part І
Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various
Conditions
Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under
NaHCO3-Methanol Conditions
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various
Nucleophiles
Part ІІ
Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
Table-2 AdEAr Rate of Anthracene of the Various Conditions
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditions
6
Abstract
Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction
The electrophilic aromatic addition reaction (AdEAr) at H substituent position has been
extensive studied The bromomethoxylation of 1-methoxynaphthalene in various conditions
showed AdEAr at room temperature using bromine and other brominating agents The
addition reaction could be occurred in either 12-addition or 14-addition manner depend on
structure of starting material Treatments of the addition product 57-dibromo-88-
dimethoxy-2-methyl-78-dihydroquinoline with nucleophiles gave nucleophilic
substitution-rearomatization products which were considered as a new potential route for
synthesis of 7-substituted-8-methoxyquinaldine
Part II Rearomatization Reactions and Applications of Anthracene Adducts
Since the discovery of anticancer drugs such as daunomycin adriamycin and
mitoxantrone a variety of anthracene derivatives have been investigated for significant
activity in the relation to their biological activity and pharmacological properties especially
910-disubstituted anthracene derivatives possesses the DNA accessibility with antitumor
activity Bromination of anthracene with bromine in the basic methanolic gave the adduct
910-dimethoxy-910-dihydroanthracene 2 which is the cis and trans isomers by 14-addition
Formation of adduct on anthracene using 30 equiv bromine and 10 equiv pyridine at room
temperature for 15 min under basic methanolic condition gave 910-dimethoxy-910-
dihydroanthracene adduct 2 Interestingly during do the reaction in the some conditions we
obtained that oxidative demethylation compound such as anthraquinone instead of 910-
7
dimethoxy-910-dihydroanthracene adduct 2 Moreover we can control either methoxylation
or addition reaction or both reaction Also we can obtain both selective 9-methoxy
anthracene in the basic condition and 910-dimethoxyanthracene in the rearomatization
reaction from the 910-dihydro-910-dimethoxyanthracene adduct 2
8
요약문
Part I Non-Ipso 친전자성 방향족 첨가반응
H 치환기 위치에서 친전자성 방향족 첨가 반응(AdEAr)이 폭 넓게 연구되었다
1-메톡시나프탈렌의 브로모메톡시화반응이 다양한 조건에서 친전자성방향족
첨가반응(AdEAr)이 일어날 수 있는 것과 다른 브로민 물질로도 첨가반응이
일어난다는 것을 보여준다 첨가반응은 출발 물질에 따라서 12-첨가 또는 14-
첨가반응이 일어난다 첨가반응의 생성물 57-dibromo-88-dimethoxy-2-
methyl-78-dihydroquinoline을 다양한 친핵체들과 반응을 시키면 7번 위치에
다양한 치환기를 도입시킬 수 친핵성 치환반응을 통한 재방향족화 생성물인 7-
substituted-8-methoxyquinaldine을 합성하는 새로운 길이 될 것이다
Part II AdEAr 반응을 통한 Anthracene 첨가물의 재방향족 반응과 응
용
Daunomycin adriamycin 그리고 mitoxantrone의 anticancer drug을 발견된
이후로 다양한 안트라센 유도체들이 생물학적 활성과 약리학적 성질이 있다는
것을 알게 되었다 특히 910번 위치에 치환된 안트라센 유도체들은 antitumor
활성에 대해서 DNA에 결합하는 능력을 가지고 있다 메탄올 염기조건에서
안트라센의 브롬화반응은 14-첨가반응을 통해 시스 그리고 트랜스 형태로 된
아이소머 첨가물질인 910-dihydro-910-dimethoxyanthracene (2) 를 주
9
생성물로 얻게된다 특히 910 유도체들은 antitumor 활성에 대해서 DNA에
결합하는 능력을 가지고 있다 메탄올 염기조건에서 브로민 30 당량과 피리틴
10 당량을 사용해서 실온에서 15분 동안 반응을 시키면 910-dihydro-910-
dimethoxyanthracene의 첨가 생성물을 얻을 수가 있다 흥미로운 것은 어떤
다른 조건에서는 첨가 반응의 생성물이 아닌 산화탈 메틸반응으로 안트라퀴논
이 얻어지게 된다 더구나 이 반응을 통해서 치환반응의 메톡시반응과 첨가
반응을 조절할 수가 있다 또한 이 조건에서 얻은 첨가물을 가지고 선택적으로
치환되는 메톡시 위치를 조절할 수가 있게 된다 재방향성 반응을 통해서 910-
dimethoxyanthracene와 염기로 처리해서 9-methoxy anthracene 을 얻을
수가 있게 되었다
1
Part I Non-Ipso Attack Electrophilic Aromatic Addition
Reaction
2
Introduction
Unlike aliphatic compounds aromatic systems usually react with electrophiles resulting
substitution which occur via arenium ion mechanism by replacement at hydrogen
substituent In this mechanism the electrophile attacks in the first step giving rise to a
positively charged intermediate and the leaving group departs in the second step1 However
the nucleophilic capture is sometimes faster in the latter step leading to the formation of an
addition tetrahedral intermediate2 which was whether isolated or guessed from products
Electrophilic addition reaction of hetereocyclic compounds such as furan derivatives were
reported3 In bezenoid systems ipso attack addition reactions on aromatic ring by nitronium
ion at the position bearing the substiutents have been extensively studied4 With haloamine
amination of toluene which firstly addition take place and then followed by elimination of
HCl yielding m-methylaniline could be an example of addition reaction on aromatic
systems even though addition adduct was unable to isolated5
In our previous work we reported an unusual electrophilic aromatic addition reaction at H
substituent position and its mechanism of methoxyquinaldine derivatives and 1-
methoxynaphthalene by bromomethoxylation at rt6 The reaction proceeded via a stable
cation intermediate and gave 12-addition products in high yield Herein we investigated
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
5
List of Tables
Part І
Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various
Conditions
Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under
NaHCO3-Methanol Conditions
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various
Nucleophiles
Part ІІ
Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
Table-2 AdEAr Rate of Anthracene of the Various Conditions
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditions
6
Abstract
Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction
The electrophilic aromatic addition reaction (AdEAr) at H substituent position has been
extensive studied The bromomethoxylation of 1-methoxynaphthalene in various conditions
showed AdEAr at room temperature using bromine and other brominating agents The
addition reaction could be occurred in either 12-addition or 14-addition manner depend on
structure of starting material Treatments of the addition product 57-dibromo-88-
dimethoxy-2-methyl-78-dihydroquinoline with nucleophiles gave nucleophilic
substitution-rearomatization products which were considered as a new potential route for
synthesis of 7-substituted-8-methoxyquinaldine
Part II Rearomatization Reactions and Applications of Anthracene Adducts
Since the discovery of anticancer drugs such as daunomycin adriamycin and
mitoxantrone a variety of anthracene derivatives have been investigated for significant
activity in the relation to their biological activity and pharmacological properties especially
910-disubstituted anthracene derivatives possesses the DNA accessibility with antitumor
activity Bromination of anthracene with bromine in the basic methanolic gave the adduct
910-dimethoxy-910-dihydroanthracene 2 which is the cis and trans isomers by 14-addition
Formation of adduct on anthracene using 30 equiv bromine and 10 equiv pyridine at room
temperature for 15 min under basic methanolic condition gave 910-dimethoxy-910-
dihydroanthracene adduct 2 Interestingly during do the reaction in the some conditions we
obtained that oxidative demethylation compound such as anthraquinone instead of 910-
7
dimethoxy-910-dihydroanthracene adduct 2 Moreover we can control either methoxylation
or addition reaction or both reaction Also we can obtain both selective 9-methoxy
anthracene in the basic condition and 910-dimethoxyanthracene in the rearomatization
reaction from the 910-dihydro-910-dimethoxyanthracene adduct 2
8
요약문
Part I Non-Ipso 친전자성 방향족 첨가반응
H 치환기 위치에서 친전자성 방향족 첨가 반응(AdEAr)이 폭 넓게 연구되었다
1-메톡시나프탈렌의 브로모메톡시화반응이 다양한 조건에서 친전자성방향족
첨가반응(AdEAr)이 일어날 수 있는 것과 다른 브로민 물질로도 첨가반응이
일어난다는 것을 보여준다 첨가반응은 출발 물질에 따라서 12-첨가 또는 14-
첨가반응이 일어난다 첨가반응의 생성물 57-dibromo-88-dimethoxy-2-
methyl-78-dihydroquinoline을 다양한 친핵체들과 반응을 시키면 7번 위치에
다양한 치환기를 도입시킬 수 친핵성 치환반응을 통한 재방향족화 생성물인 7-
substituted-8-methoxyquinaldine을 합성하는 새로운 길이 될 것이다
Part II AdEAr 반응을 통한 Anthracene 첨가물의 재방향족 반응과 응
용
Daunomycin adriamycin 그리고 mitoxantrone의 anticancer drug을 발견된
이후로 다양한 안트라센 유도체들이 생물학적 활성과 약리학적 성질이 있다는
것을 알게 되었다 특히 910번 위치에 치환된 안트라센 유도체들은 antitumor
활성에 대해서 DNA에 결합하는 능력을 가지고 있다 메탄올 염기조건에서
안트라센의 브롬화반응은 14-첨가반응을 통해 시스 그리고 트랜스 형태로 된
아이소머 첨가물질인 910-dihydro-910-dimethoxyanthracene (2) 를 주
9
생성물로 얻게된다 특히 910 유도체들은 antitumor 활성에 대해서 DNA에
결합하는 능력을 가지고 있다 메탄올 염기조건에서 브로민 30 당량과 피리틴
10 당량을 사용해서 실온에서 15분 동안 반응을 시키면 910-dihydro-910-
dimethoxyanthracene의 첨가 생성물을 얻을 수가 있다 흥미로운 것은 어떤
다른 조건에서는 첨가 반응의 생성물이 아닌 산화탈 메틸반응으로 안트라퀴논
이 얻어지게 된다 더구나 이 반응을 통해서 치환반응의 메톡시반응과 첨가
반응을 조절할 수가 있다 또한 이 조건에서 얻은 첨가물을 가지고 선택적으로
치환되는 메톡시 위치를 조절할 수가 있게 된다 재방향성 반응을 통해서 910-
dimethoxyanthracene와 염기로 처리해서 9-methoxy anthracene 을 얻을
수가 있게 되었다
1
Part I Non-Ipso Attack Electrophilic Aromatic Addition
Reaction
2
Introduction
Unlike aliphatic compounds aromatic systems usually react with electrophiles resulting
substitution which occur via arenium ion mechanism by replacement at hydrogen
substituent In this mechanism the electrophile attacks in the first step giving rise to a
positively charged intermediate and the leaving group departs in the second step1 However
the nucleophilic capture is sometimes faster in the latter step leading to the formation of an
addition tetrahedral intermediate2 which was whether isolated or guessed from products
Electrophilic addition reaction of hetereocyclic compounds such as furan derivatives were
reported3 In bezenoid systems ipso attack addition reactions on aromatic ring by nitronium
ion at the position bearing the substiutents have been extensively studied4 With haloamine
amination of toluene which firstly addition take place and then followed by elimination of
HCl yielding m-methylaniline could be an example of addition reaction on aromatic
systems even though addition adduct was unable to isolated5
In our previous work we reported an unusual electrophilic aromatic addition reaction at H
substituent position and its mechanism of methoxyquinaldine derivatives and 1-
methoxynaphthalene by bromomethoxylation at rt6 The reaction proceeded via a stable
cation intermediate and gave 12-addition products in high yield Herein we investigated
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
6
Abstract
Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction
The electrophilic aromatic addition reaction (AdEAr) at H substituent position has been
extensive studied The bromomethoxylation of 1-methoxynaphthalene in various conditions
showed AdEAr at room temperature using bromine and other brominating agents The
addition reaction could be occurred in either 12-addition or 14-addition manner depend on
structure of starting material Treatments of the addition product 57-dibromo-88-
dimethoxy-2-methyl-78-dihydroquinoline with nucleophiles gave nucleophilic
substitution-rearomatization products which were considered as a new potential route for
synthesis of 7-substituted-8-methoxyquinaldine
Part II Rearomatization Reactions and Applications of Anthracene Adducts
Since the discovery of anticancer drugs such as daunomycin adriamycin and
mitoxantrone a variety of anthracene derivatives have been investigated for significant
activity in the relation to their biological activity and pharmacological properties especially
910-disubstituted anthracene derivatives possesses the DNA accessibility with antitumor
activity Bromination of anthracene with bromine in the basic methanolic gave the adduct
910-dimethoxy-910-dihydroanthracene 2 which is the cis and trans isomers by 14-addition
Formation of adduct on anthracene using 30 equiv bromine and 10 equiv pyridine at room
temperature for 15 min under basic methanolic condition gave 910-dimethoxy-910-
dihydroanthracene adduct 2 Interestingly during do the reaction in the some conditions we
obtained that oxidative demethylation compound such as anthraquinone instead of 910-
7
dimethoxy-910-dihydroanthracene adduct 2 Moreover we can control either methoxylation
or addition reaction or both reaction Also we can obtain both selective 9-methoxy
anthracene in the basic condition and 910-dimethoxyanthracene in the rearomatization
reaction from the 910-dihydro-910-dimethoxyanthracene adduct 2
8
요약문
Part I Non-Ipso 친전자성 방향족 첨가반응
H 치환기 위치에서 친전자성 방향족 첨가 반응(AdEAr)이 폭 넓게 연구되었다
1-메톡시나프탈렌의 브로모메톡시화반응이 다양한 조건에서 친전자성방향족
첨가반응(AdEAr)이 일어날 수 있는 것과 다른 브로민 물질로도 첨가반응이
일어난다는 것을 보여준다 첨가반응은 출발 물질에 따라서 12-첨가 또는 14-
첨가반응이 일어난다 첨가반응의 생성물 57-dibromo-88-dimethoxy-2-
methyl-78-dihydroquinoline을 다양한 친핵체들과 반응을 시키면 7번 위치에
다양한 치환기를 도입시킬 수 친핵성 치환반응을 통한 재방향족화 생성물인 7-
substituted-8-methoxyquinaldine을 합성하는 새로운 길이 될 것이다
Part II AdEAr 반응을 통한 Anthracene 첨가물의 재방향족 반응과 응
용
Daunomycin adriamycin 그리고 mitoxantrone의 anticancer drug을 발견된
이후로 다양한 안트라센 유도체들이 생물학적 활성과 약리학적 성질이 있다는
것을 알게 되었다 특히 910번 위치에 치환된 안트라센 유도체들은 antitumor
활성에 대해서 DNA에 결합하는 능력을 가지고 있다 메탄올 염기조건에서
안트라센의 브롬화반응은 14-첨가반응을 통해 시스 그리고 트랜스 형태로 된
아이소머 첨가물질인 910-dihydro-910-dimethoxyanthracene (2) 를 주
9
생성물로 얻게된다 특히 910 유도체들은 antitumor 활성에 대해서 DNA에
결합하는 능력을 가지고 있다 메탄올 염기조건에서 브로민 30 당량과 피리틴
10 당량을 사용해서 실온에서 15분 동안 반응을 시키면 910-dihydro-910-
dimethoxyanthracene의 첨가 생성물을 얻을 수가 있다 흥미로운 것은 어떤
다른 조건에서는 첨가 반응의 생성물이 아닌 산화탈 메틸반응으로 안트라퀴논
이 얻어지게 된다 더구나 이 반응을 통해서 치환반응의 메톡시반응과 첨가
반응을 조절할 수가 있다 또한 이 조건에서 얻은 첨가물을 가지고 선택적으로
치환되는 메톡시 위치를 조절할 수가 있게 된다 재방향성 반응을 통해서 910-
dimethoxyanthracene와 염기로 처리해서 9-methoxy anthracene 을 얻을
수가 있게 되었다
1
Part I Non-Ipso Attack Electrophilic Aromatic Addition
Reaction
2
Introduction
Unlike aliphatic compounds aromatic systems usually react with electrophiles resulting
substitution which occur via arenium ion mechanism by replacement at hydrogen
substituent In this mechanism the electrophile attacks in the first step giving rise to a
positively charged intermediate and the leaving group departs in the second step1 However
the nucleophilic capture is sometimes faster in the latter step leading to the formation of an
addition tetrahedral intermediate2 which was whether isolated or guessed from products
Electrophilic addition reaction of hetereocyclic compounds such as furan derivatives were
reported3 In bezenoid systems ipso attack addition reactions on aromatic ring by nitronium
ion at the position bearing the substiutents have been extensively studied4 With haloamine
amination of toluene which firstly addition take place and then followed by elimination of
HCl yielding m-methylaniline could be an example of addition reaction on aromatic
systems even though addition adduct was unable to isolated5
In our previous work we reported an unusual electrophilic aromatic addition reaction at H
substituent position and its mechanism of methoxyquinaldine derivatives and 1-
methoxynaphthalene by bromomethoxylation at rt6 The reaction proceeded via a stable
cation intermediate and gave 12-addition products in high yield Herein we investigated
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
7
dimethoxy-910-dihydroanthracene adduct 2 Moreover we can control either methoxylation
or addition reaction or both reaction Also we can obtain both selective 9-methoxy
anthracene in the basic condition and 910-dimethoxyanthracene in the rearomatization
reaction from the 910-dihydro-910-dimethoxyanthracene adduct 2
8
요약문
Part I Non-Ipso 친전자성 방향족 첨가반응
H 치환기 위치에서 친전자성 방향족 첨가 반응(AdEAr)이 폭 넓게 연구되었다
1-메톡시나프탈렌의 브로모메톡시화반응이 다양한 조건에서 친전자성방향족
첨가반응(AdEAr)이 일어날 수 있는 것과 다른 브로민 물질로도 첨가반응이
일어난다는 것을 보여준다 첨가반응은 출발 물질에 따라서 12-첨가 또는 14-
첨가반응이 일어난다 첨가반응의 생성물 57-dibromo-88-dimethoxy-2-
methyl-78-dihydroquinoline을 다양한 친핵체들과 반응을 시키면 7번 위치에
다양한 치환기를 도입시킬 수 친핵성 치환반응을 통한 재방향족화 생성물인 7-
substituted-8-methoxyquinaldine을 합성하는 새로운 길이 될 것이다
Part II AdEAr 반응을 통한 Anthracene 첨가물의 재방향족 반응과 응
용
Daunomycin adriamycin 그리고 mitoxantrone의 anticancer drug을 발견된
이후로 다양한 안트라센 유도체들이 생물학적 활성과 약리학적 성질이 있다는
것을 알게 되었다 특히 910번 위치에 치환된 안트라센 유도체들은 antitumor
활성에 대해서 DNA에 결합하는 능력을 가지고 있다 메탄올 염기조건에서
안트라센의 브롬화반응은 14-첨가반응을 통해 시스 그리고 트랜스 형태로 된
아이소머 첨가물질인 910-dihydro-910-dimethoxyanthracene (2) 를 주
9
생성물로 얻게된다 특히 910 유도체들은 antitumor 활성에 대해서 DNA에
결합하는 능력을 가지고 있다 메탄올 염기조건에서 브로민 30 당량과 피리틴
10 당량을 사용해서 실온에서 15분 동안 반응을 시키면 910-dihydro-910-
dimethoxyanthracene의 첨가 생성물을 얻을 수가 있다 흥미로운 것은 어떤
다른 조건에서는 첨가 반응의 생성물이 아닌 산화탈 메틸반응으로 안트라퀴논
이 얻어지게 된다 더구나 이 반응을 통해서 치환반응의 메톡시반응과 첨가
반응을 조절할 수가 있다 또한 이 조건에서 얻은 첨가물을 가지고 선택적으로
치환되는 메톡시 위치를 조절할 수가 있게 된다 재방향성 반응을 통해서 910-
dimethoxyanthracene와 염기로 처리해서 9-methoxy anthracene 을 얻을
수가 있게 되었다
1
Part I Non-Ipso Attack Electrophilic Aromatic Addition
Reaction
2
Introduction
Unlike aliphatic compounds aromatic systems usually react with electrophiles resulting
substitution which occur via arenium ion mechanism by replacement at hydrogen
substituent In this mechanism the electrophile attacks in the first step giving rise to a
positively charged intermediate and the leaving group departs in the second step1 However
the nucleophilic capture is sometimes faster in the latter step leading to the formation of an
addition tetrahedral intermediate2 which was whether isolated or guessed from products
Electrophilic addition reaction of hetereocyclic compounds such as furan derivatives were
reported3 In bezenoid systems ipso attack addition reactions on aromatic ring by nitronium
ion at the position bearing the substiutents have been extensively studied4 With haloamine
amination of toluene which firstly addition take place and then followed by elimination of
HCl yielding m-methylaniline could be an example of addition reaction on aromatic
systems even though addition adduct was unable to isolated5
In our previous work we reported an unusual electrophilic aromatic addition reaction at H
substituent position and its mechanism of methoxyquinaldine derivatives and 1-
methoxynaphthalene by bromomethoxylation at rt6 The reaction proceeded via a stable
cation intermediate and gave 12-addition products in high yield Herein we investigated
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
8
요약문
Part I Non-Ipso 친전자성 방향족 첨가반응
H 치환기 위치에서 친전자성 방향족 첨가 반응(AdEAr)이 폭 넓게 연구되었다
1-메톡시나프탈렌의 브로모메톡시화반응이 다양한 조건에서 친전자성방향족
첨가반응(AdEAr)이 일어날 수 있는 것과 다른 브로민 물질로도 첨가반응이
일어난다는 것을 보여준다 첨가반응은 출발 물질에 따라서 12-첨가 또는 14-
첨가반응이 일어난다 첨가반응의 생성물 57-dibromo-88-dimethoxy-2-
methyl-78-dihydroquinoline을 다양한 친핵체들과 반응을 시키면 7번 위치에
다양한 치환기를 도입시킬 수 친핵성 치환반응을 통한 재방향족화 생성물인 7-
substituted-8-methoxyquinaldine을 합성하는 새로운 길이 될 것이다
Part II AdEAr 반응을 통한 Anthracene 첨가물의 재방향족 반응과 응
용
Daunomycin adriamycin 그리고 mitoxantrone의 anticancer drug을 발견된
이후로 다양한 안트라센 유도체들이 생물학적 활성과 약리학적 성질이 있다는
것을 알게 되었다 특히 910번 위치에 치환된 안트라센 유도체들은 antitumor
활성에 대해서 DNA에 결합하는 능력을 가지고 있다 메탄올 염기조건에서
안트라센의 브롬화반응은 14-첨가반응을 통해 시스 그리고 트랜스 형태로 된
아이소머 첨가물질인 910-dihydro-910-dimethoxyanthracene (2) 를 주
9
생성물로 얻게된다 특히 910 유도체들은 antitumor 활성에 대해서 DNA에
결합하는 능력을 가지고 있다 메탄올 염기조건에서 브로민 30 당량과 피리틴
10 당량을 사용해서 실온에서 15분 동안 반응을 시키면 910-dihydro-910-
dimethoxyanthracene의 첨가 생성물을 얻을 수가 있다 흥미로운 것은 어떤
다른 조건에서는 첨가 반응의 생성물이 아닌 산화탈 메틸반응으로 안트라퀴논
이 얻어지게 된다 더구나 이 반응을 통해서 치환반응의 메톡시반응과 첨가
반응을 조절할 수가 있다 또한 이 조건에서 얻은 첨가물을 가지고 선택적으로
치환되는 메톡시 위치를 조절할 수가 있게 된다 재방향성 반응을 통해서 910-
dimethoxyanthracene와 염기로 처리해서 9-methoxy anthracene 을 얻을
수가 있게 되었다
1
Part I Non-Ipso Attack Electrophilic Aromatic Addition
Reaction
2
Introduction
Unlike aliphatic compounds aromatic systems usually react with electrophiles resulting
substitution which occur via arenium ion mechanism by replacement at hydrogen
substituent In this mechanism the electrophile attacks in the first step giving rise to a
positively charged intermediate and the leaving group departs in the second step1 However
the nucleophilic capture is sometimes faster in the latter step leading to the formation of an
addition tetrahedral intermediate2 which was whether isolated or guessed from products
Electrophilic addition reaction of hetereocyclic compounds such as furan derivatives were
reported3 In bezenoid systems ipso attack addition reactions on aromatic ring by nitronium
ion at the position bearing the substiutents have been extensively studied4 With haloamine
amination of toluene which firstly addition take place and then followed by elimination of
HCl yielding m-methylaniline could be an example of addition reaction on aromatic
systems even though addition adduct was unable to isolated5
In our previous work we reported an unusual electrophilic aromatic addition reaction at H
substituent position and its mechanism of methoxyquinaldine derivatives and 1-
methoxynaphthalene by bromomethoxylation at rt6 The reaction proceeded via a stable
cation intermediate and gave 12-addition products in high yield Herein we investigated
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
9
생성물로 얻게된다 특히 910 유도체들은 antitumor 활성에 대해서 DNA에
결합하는 능력을 가지고 있다 메탄올 염기조건에서 브로민 30 당량과 피리틴
10 당량을 사용해서 실온에서 15분 동안 반응을 시키면 910-dihydro-910-
dimethoxyanthracene의 첨가 생성물을 얻을 수가 있다 흥미로운 것은 어떤
다른 조건에서는 첨가 반응의 생성물이 아닌 산화탈 메틸반응으로 안트라퀴논
이 얻어지게 된다 더구나 이 반응을 통해서 치환반응의 메톡시반응과 첨가
반응을 조절할 수가 있다 또한 이 조건에서 얻은 첨가물을 가지고 선택적으로
치환되는 메톡시 위치를 조절할 수가 있게 된다 재방향성 반응을 통해서 910-
dimethoxyanthracene와 염기로 처리해서 9-methoxy anthracene 을 얻을
수가 있게 되었다
1
Part I Non-Ipso Attack Electrophilic Aromatic Addition
Reaction
2
Introduction
Unlike aliphatic compounds aromatic systems usually react with electrophiles resulting
substitution which occur via arenium ion mechanism by replacement at hydrogen
substituent In this mechanism the electrophile attacks in the first step giving rise to a
positively charged intermediate and the leaving group departs in the second step1 However
the nucleophilic capture is sometimes faster in the latter step leading to the formation of an
addition tetrahedral intermediate2 which was whether isolated or guessed from products
Electrophilic addition reaction of hetereocyclic compounds such as furan derivatives were
reported3 In bezenoid systems ipso attack addition reactions on aromatic ring by nitronium
ion at the position bearing the substiutents have been extensively studied4 With haloamine
amination of toluene which firstly addition take place and then followed by elimination of
HCl yielding m-methylaniline could be an example of addition reaction on aromatic
systems even though addition adduct was unable to isolated5
In our previous work we reported an unusual electrophilic aromatic addition reaction at H
substituent position and its mechanism of methoxyquinaldine derivatives and 1-
methoxynaphthalene by bromomethoxylation at rt6 The reaction proceeded via a stable
cation intermediate and gave 12-addition products in high yield Herein we investigated
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
1
Part I Non-Ipso Attack Electrophilic Aromatic Addition
Reaction
2
Introduction
Unlike aliphatic compounds aromatic systems usually react with electrophiles resulting
substitution which occur via arenium ion mechanism by replacement at hydrogen
substituent In this mechanism the electrophile attacks in the first step giving rise to a
positively charged intermediate and the leaving group departs in the second step1 However
the nucleophilic capture is sometimes faster in the latter step leading to the formation of an
addition tetrahedral intermediate2 which was whether isolated or guessed from products
Electrophilic addition reaction of hetereocyclic compounds such as furan derivatives were
reported3 In bezenoid systems ipso attack addition reactions on aromatic ring by nitronium
ion at the position bearing the substiutents have been extensively studied4 With haloamine
amination of toluene which firstly addition take place and then followed by elimination of
HCl yielding m-methylaniline could be an example of addition reaction on aromatic
systems even though addition adduct was unable to isolated5
In our previous work we reported an unusual electrophilic aromatic addition reaction at H
substituent position and its mechanism of methoxyquinaldine derivatives and 1-
methoxynaphthalene by bromomethoxylation at rt6 The reaction proceeded via a stable
cation intermediate and gave 12-addition products in high yield Herein we investigated
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
2
Introduction
Unlike aliphatic compounds aromatic systems usually react with electrophiles resulting
substitution which occur via arenium ion mechanism by replacement at hydrogen
substituent In this mechanism the electrophile attacks in the first step giving rise to a
positively charged intermediate and the leaving group departs in the second step1 However
the nucleophilic capture is sometimes faster in the latter step leading to the formation of an
addition tetrahedral intermediate2 which was whether isolated or guessed from products
Electrophilic addition reaction of hetereocyclic compounds such as furan derivatives were
reported3 In bezenoid systems ipso attack addition reactions on aromatic ring by nitronium
ion at the position bearing the substiutents have been extensively studied4 With haloamine
amination of toluene which firstly addition take place and then followed by elimination of
HCl yielding m-methylaniline could be an example of addition reaction on aromatic
systems even though addition adduct was unable to isolated5
In our previous work we reported an unusual electrophilic aromatic addition reaction at H
substituent position and its mechanism of methoxyquinaldine derivatives and 1-
methoxynaphthalene by bromomethoxylation at rt6 The reaction proceeded via a stable
cation intermediate and gave 12-addition products in high yield Herein we investigated
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
3
extensively in addition condition and in various aromatic systems Moreover reactivity of
addition product with nucleophile was also presented and discussed
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
4
Results and Discussion
In Table 1 we investigated in a role of pyridine in AdEAr reaction and mechanism of the
reaction We found that we were able to obtain only addition adduct 2a when pyridine was
added (entry 2) whereas in entry 1 without pyridine at rt only substitution products 4a and
5a were obtained Moreover we exchanged the 1-methoxy naphthalene 1a to 1-ethoxy
naphthalene 1b as starting material we also obtained only addition adduct 3a Therefore we
suggested that pyridine may play some roles in producing addition adduct However the
reaction without pyridine could also produce addition adduct 2a when we controlled
reaction temperature as well as work-up temperature at nearly zero degree (entry 4) By our
observation we found that the addition adduct 2a containing pyridine (before purification of
entry 2) was not or very slowly decomposed at rt but the purified adduct 2a was much faster
decomposed to dibromo product 4a at rt From this result pyridine did not play a role in
AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine are decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to catalyze the decomposition Perhaps pyridine would neutralize acidity of glassware and
then prevent the adduct from decomposition The reactions were then carried out with other
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
5
two brominating agents pyridinium hydrobromide perbromide (PyHBr3) and NBS (entry 5-
8) NBS could not produce addition product even though pyridine was also added Reaction
with PyHBr3 gave addition adduct in a very high yield (93) PyHBr3 would be suitable to
be used as brominating agent in future work due to easy handling This showed that
reactivity of brominating agent is important for addition reaction In entry 9 and 10 the 1-
methoxynaphthalene was treated in ethanol as a solvent The reaction in the presence of
pyridine gave addition product 2b as well as mono-brominated intermediate 5a However
we could not obtain the addition product without pyridine
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
6
Table 1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy naphthalene (1b) in
Various Conditionsa
OR
[Br]Br
BrR2O OR1 OR2
Br
R1OBr
OR
Br
BrOR
Br
NaHCO3 R2OH+ +
1a R1 = Me1b R2 = Et
2a R1=R2=Me2b R1=Me R2=Et
4a R1=Me4b R2=Et
5aR1=Me5bR2=Et
3a R1=Me3b R2=Et
+
yield of products ()b
entry R condition solventwork-up
temp (degC) 2 or 3 4 5
1 1a Br2 MeOH rt - 4a (33) 5a (17)
2 1a Br2py MeOH rt 2a (91) - -
3 1b Br2py MeOH rt 3a (90) - -
4 1a Br2 MeOH 0-5 2a (90) - -
5 1a PyHBr3 MeOH rt 2a (93) - -
6 1b PyHBr3 MeOH rt 3a (91) - -
7 1a NBS MeOH 0-5 - 4a (6) c 5a (91) c
8 1a NBSpy MeOH rt - - 5a (80) c
9 1a Br2py EtOH rt 2b (37) - 5a (39)
10 1a Br2 EtOH rt - 4a (15) 5a (82)
a unless otherwise noted all reactions were carried out on 20 mmol reaction scale of 1-methoxy naphthalene (1a) and 1-ethoxy naphthalene (1b) using 3 equiv of bromine for 15 min at rt b Isolated yield c NMR ratio yield
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
7
To check the generality of the reaction we attempted the bromoalkoxylation of various
bicyclic aromatic compounds under the same reaction conditions as Table 1 entry 1 (Table
2) Most of the starting compounds were obtained from commercially available reagents or
synthesized by previously reported methods The AdEAr reaction of 58-dimethoxy-2-
methylquinoline (6) (entry 1) gave two new addition products (6a and 6b) 5588-
Tetramethoxy-58-dihydroquinaldine (6a) would be produced via 12-addition of
bromomethoxide and then bromo was rapidly replaced by excess methoxide anion whereas
the double 14-addition reaction yielded 6b In entry 2 58-dimethoxy-4-methylquinoline (7)
also gave two new addition products (7a and 7b) but ratio is different Due to steric
hindrance of methyl group at 4-position 7a was obtained as a major product The treatment
of 5-bromo-8-methoxy-2-methylquinoline (7) gave 12-addition product 8a in a very high
yield Our previous work6 reported 8a could be obtained from 8-methoxy-2-methylquinoline
in moderate yield This result showed that bromide ion might reduce reactivity of bromine
To proof 14-addition 7-bromo-8-methoxy-2-methylquinoline (9) was designed and
synthesized As expected the 14-addition product 9a of two methoxy groups was obtained
as a major product (entry 4) Like entry 1 and 2 the unstable 57-dibromo-88-dimethoxy-
58-dihydro-2-methylquinoline was prior to be produced as an intermediate Other aromatic
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
8
compound were also treated under bromomethoxylation (entry 5) No addition product was
observed
Table 2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic
Compounds under NaHCO3-Methanol Conditionsa
Entry substrate major products yield ()b
1
NOCH3
OCH3
6
NH3CO
H3CO OCH3
OCH3
NH3CO OCH3
Br OCH3H3CO
Br
6a 6b
6a(14) 6b(36)
2
NOCH3
OCH3
7
NH3CO
H3COOCH3
OCH3 N
H3CO
Br OCH3
OCH3
H3CO
Br
7a 7b
7a(51)7b(10)
3
NOCH3
Br
8
NH3CO
Br
OCH3
Br
8a
8a(90)
4
NOCH3
Br
9
NOCH3
BrH3CO
H3CO H
N
OCH3
Br
Br
9a 9b
9a(67) 9b(15)
5
NMe2 10
NMe2
Br
Br
10a
10a(42)
a Unless otherwise noted all reactions were carried out under the same conditions as Table 1 entry 1 b Isolated yield
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
9
The synthetic utilities of the addition products 8a were demonstrated by transformations
of the representative product 8a (Table 3) The nucleophilic substitution-rearomatization of
compound 8a with five equivalents of benzylamine or piperidine gave (5-bromo-8-
methoxyquinaldin-7-yl)-amine 11 and 12 respectively in moderate yield (entry 1 and 2) On
the other hand treatment of 8a with NaOH in methanol gave only 57-dibromo-8-
methoxyquinaldine (14) in almost quantitative yield
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
10
Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine
(8a) with Various Nucleophilesa
entry condition product yield ()f
1b benzylamineTHFreflux6hN
Br
NH OCH3 11
42
2c piperidineTHFreflux 8h N
Br
NOCH3 12
30
3d KCNTHFreflux5~6 h N
Br
NCOCH3 13
22
4e NaOHMeOH N
Br
BrOCH3 14
99
a Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) b one equiv of benzylamine was used for 6 h in dryTHF (10 mL) c
one equiv of piperidine was used for 8 h in dry THF (10 mL) d five equiv of potassium cyanide was used for 5 h in dry THF (10 mL) e Reaction were carried out on 10 mmol reaction scale of 57-dibromo-88-dimethoxy-78-dihydroquinaldine (8a) was stirring at NaOH in MeOH solution f Isolated yield
The addition adduct 8a possess considerably synthetic potential because of it could be
transformed into 7-substituted-8-methoxyquinaldine by one step of SN2-aromatization
(Scheme 1) It was illustrated that the AdEAr reaction allowed a new facile synthetic route
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
11
for the substitution of 8-alkoxyquinoline at 7-position which is synthetically difficult by
other methods
Scheme 1 A new facile synthetic route for 7-substituted-8-methoxyquinaldine
NOCH3
N
Br
NuOCH3
NNuOCH3
NOCH3
Br
BrH3CO
AdEAr Nu-
Mechanistic Study
We propose a mechanism for this addition reaction for 58-dimethoxy-2-methylquinoline
(5) in which first step the bromination at 5 or 8-position quinoline and then the intermediate
state was stabilized by 12-nucleophilic methoxide addition or 14- nucleophilic methoxide
addition We already have proposed a mechanism for 8-methoxyquinaldine addition reaction
in which the brominated reactant forms a cationic intermediate (σ complex) leading to
either deprotonation-aromatization or nucleophilic addition But in this case it was happened
nucleophilic addition reaction Now we propose the two route for the stabilization of
intermediate by 14-addition or 12-addition in 58-dimethoxy-2-methylquinoline (6) First
the intermediate stabilize by 14-nucleophilic addition and then again bromination at 7-
position Last we think that we obtain the 57-dibromo-5688-tetramethoxy-2-methyl-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
12
5678-tetrahydro-quinoline (6b) addition compound Another route that we get the 5588-
tetramethoxy-58-dihydroquinaldine (6a) through 12-nucleophilic addition More
bromination at the 67-position we think that it was a 67-dibromo-5588-tetramethoxy-2-
methyl-5678-tetrahydro-quinoline In case attack at 5-position bromine another route
attack at 8-position bromine as same mechanism We will confirm the structure by X-ray
crystallography
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
13
N
OCH3
OCH3
-OCH3N
+OCH3
Br OCH3
-OCH3
NH3CO OCH3
Br OCH3
NH3CO OCH3
H3CO OCH3
N
Br OCH3
OCH3
H3CO
N
Br OCH3H3CO
+OCH3
Br
NH3CO OCH3
H3CO OCH3
Br
BrN
Br OCH3H3CO
BrH3CO OCH3
14-addition 12-addition
(6b)
(6a)
(6)
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
14
Conclusion
We reported an unusual electrophilic aromatic addition reaction at H substituent position
and its mechanism of methoxyquinaldine derivatives and 1-methoxynaphthalene by
bromomethoxylation at room temperature By our observation pyridine did not play a role
in AdEAr reaction but in stabilization of adduct after reaction (or during reaction) How did
pyridine work We know that some addition adducts of quinaldine can decomposed rapidly
in either acid or basic condition and glassware made form SiO2 is acidic which may be able
to be catalyzed the decomposition Perhaps pyridine would neutralize acidity of glassware
and then prevent decomposition of adduct And another bromine agent such as pyridinium
hydrobromide perbromide (PyHBr3) suitable to be used as brominating agent in future work
due to easy handling
Herein we investigated extensively in addition condition and in various aromatic systems
Moreover reactivity of addition product with nucleophile possess considerably synthetic
potential because of it could be transformed into 7-substituted-8-methoxyquinaldine by one
step of SN2-aromatization It was illustrated that the AdEAr reaction allowed a new facile
synthetic route for the substitution of 8-alkoxyquinoline at 7-position which is synthetically
difficult by other methods
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
15
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the suspension
of methoxy compound (20 mmol) and NaHCO3 (35 equiv or 175 equiv) in MeOH (6 mL)
was added the solution of Br2 (30 equiv or 15 equiv) in MeOH (15 mL) with stirring at rt
After 5 min water (3 mL) was added and the reaction was stirred for another 5 min Then
water (30 mL) and Na2SO3 (032 g) were added The mixture was extracted with CH2Cl2 (20
mL x 2) and the combined organic layers were washed by brine and dried (Na2SO4) The
residue was purified by flash column chromatography
OEt
1-Ethoxynaphthalene (1b) To the mixture of 1-Naphthol (301 g 2088
mmol) potassium carbonate (432 g 3132 mmol) in acetone (15 ml) stirring for 1 h at 60degC
Iodo ethane (423 g 2714 mmol) was added dropwise to the mixture and then refluxed for
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
16
7 h After cooling to room temperature the mixture was extracted with CH2Cl2 (20 mL x 2)
and the combined organic layers were washed by brine and dried (Na2SO4) The residue
was purified by flash column chromatography (10 EtOAcHx) to obtain 287g of 1-ethoxy
naphthalene as greenlish blue color liquid 1H NMR (400 MHz CDCl3) δ 158-165 (m 3H)
425 (m 2H) 684 (d J =80 Hz 1H) 740-757 (m 4H) 785-788 (m 1H) 838-840 (m
1H) 13C NMR (50 MHz CDCl3) δ 148 636 1045 1199 1221 1250 1257 1259
1263 1274 1344 1547 MS(EI) mz(relative intensity) 173 172 145 144(M+) 127 115
114 89 77 63 62 51 HRMS (EI) calcd for C12H12O (M+) 1720888 found 1720888 CAS
No5328-01-8
H3CO
Br
BrOCH3
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a) Colorless
liquid 1H NMR (200 MHz CDCl3) δ 288 (s 3H) 344 (s 3H) 482 (d J = 70 Hz 1H)
665 (d J = 70 Hz 1H) 740-766 (m 2H) 767-779 (m 2H) 13C NMR (50 MHz CDCl3)
δ 474 485 513 986 1253 1273 1282 1290 1293 1296 1310 1325 MS (CI) 350
(M+) 348 (M+) 346 (M+) 332 330 328 318 316 314 303 301 299 275 273 271 238
236 223 221 195 193 Anal Calcd C 4141 H 348 Found C 4146 H 385
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
17
EtO
Br
BrOCH3
trans-24-Dibromo-1-methoxy-1-ethoxy-12-dihydronaphthalene (2b)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 72 Hz 3H) 289 (s 3H) 367-
375 (m 2H) 483 (d J = 68 Hz 1H) 665 (d J = 68 Hz 1H) 742-746 (m 2H) 767-
770 (m 1H) 781-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1271 1279 1288 1290 1292 1307 1323
Br
BrMeO OEt
trans-24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Colorless liquid 1H NMR (400 MHz CDCl3) δ 138 (t J = 160 Hz 3H) 290 (s 3H) 369-
375 (m 2H) 483 (d J = 80 Hz 1H) 665 (d J = 80 Hz 1H) 743-746 (m 2H) 768-
770 (m 1H) 782-784 (m 1H) 13C NMR (50 MHz CDCl3) δ 149 477 510 560 981
1249 1270 1279 1288 1290 1292 1307 1323
OCH3
Br
Br
24-Dibromo-1-methoxynaphthalene (4a) Off-white solid mp 472-
483degC 1H NMR (200 MHz CDCl3) δ 400 (s 3H) 752-758 (m 2H) 787 (s 3H) 808-
814 (m 2H) 13C NMR (50 MHz CDCl3) δ 619 1123 1183 12280 1278 1279 1281
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
18
1300 1320 1333 1534 MS (CI) 319 (M+1+) 318 (M+) 317 (M+1+) 316 (M+) 315
(M+1+) 266 264 238 236 CAS No28768-94-7
OCH3
Br 1-Bromo-4-methoxynaphthalene (5a) Colorless liquid 1H NMR (200 MHz
CDCl3) δ 393 (s 3H) 661 (d J = 84 Hz 1H) 745-764 (m 3H) 812-828 (m 2H) 13C
NMR (50 MHz CDCl3) δ 560 1048 1135 1227 1262 1271 1271 1281 1298 1327
1555 MS (CI) 239 (M++1 36) 238 (M+ 74) 237 (M++1 42) 236 (M+ 71) 186 158
CAS No 5467-58-3
NOCH3
OCH3
58-Dimethoxy-quinaldine (6) To 25-dimethoxyaniline (100 g 654
mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at 20degC was
added crotonaldehyde (060 mL 654 mmol) The mixture was heated from 20 degC to 70 degC
for 15 min and then stirred at 70 degC for 15 min H2O (50 mL) was added with stirring and
then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc
The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was purified
by flash column chromatography (40 EtOAcHx) giving 6 (756 mg 371 mmol 60 ) as
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
19
a brownish-yellow solid mp 734-740 degC 1H NMR (400 MHz CDCl3) δ 278 (s 3H) 393
(s 3H) 402 (s 3H) 668 (d J = 84 Hz 1H) 69 (d J = 84 Hz 1H) 73 (d J = 88 Hz
1H) 842 (d J = 84 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 256 556 559 1027 1067
1197 1216 1309 1399 1486 1488 1584 MS (EI) mz(relative intensity) 203 (M+ 44)
188 (100) 173 160 145 130 77 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found
2030946 CAS No 58868-31-8
N
H3CO OCH3
OCH3H3CO 5588-Tetramethoxy-58-dihydroquinaldine (6a) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 260 (s 3H) 310 (s 6H) 327 (s 6H) 622 (d J = 108 Hz 1H)
641 (d J = 108 Hz 1H) 719 (d J = 80 Hz 1H) 780 (d J = 84 Hz 1H) 13C NMR (100
MHz CDCl3) δ 247 510 (2C) 512 (2C) 935 962 1238 1287 1306 1329 1348
1528 1596 MS (EI) 265 234 204 (M+ 100) 188 174 160 130 117 102 89 75 65
HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
NH3CO
H3CO Br
OCH3
H3CO
Br57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine
(6b) White solid mp 1241-1242 degC 1H NMR (400 MHz CDCl3) δ 267 (s 3H) 317 (s
3H) 325 (s 3H) 330 (s 3H) 333 (s 3H) 500 (d J = 100 Hz 1H) 509 (d J = 100 Hz
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
20
1H) 726 (d J = 84 Hz 1H) 781 (d J = 80 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1+) 426 (M+1+) 424 (M+1+) 394 314 266 234 (100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1+) 4239759 found 4259739
NOCH3
OCH3
58-Dimethoxy-4-methylquinoline (7) To 25-dimethoxyaniline (100 g
654 mmol) in conc HBr (48 10 mL) and glacial acetic acid (10 mL) with stirring at
20degC was added methacrolein (060 mL 654 mmol) The mixture was heated from 20 degC to
70 degC for 15 min and then stirred at 75 degC for 15 min H2O (40 mL) was added with stirring
and then the reaction mixture was neutralized with aqueous Na2CO3 and extracted with
EtOAc The organic layer was dried (Na2SO4) and concentrated in vacuo The residue was
purified by flash column chromatography (35 EtOAcHx) giving 7 (756 mg 371 mmol
45 ) as a brownish-yellow solid mp 806-807 degC 1H NMR (400 MHz CDCl3) δ 283 (s
3H) 384 (s 3H) 399 (s 3H) 670 (d J = 80 Hz 1H) 687 (d J = 80 Hz 1H) 711 (d J
= 40 Hz 1H) 869 (d J = 40 Hz 1H ) 13C NMR (100 MHz CDCl3) δ 244 555 559
1045 1065 1217 1238 1413 1456 1489 1496 1511 MS (EI) 203(M+) 188(100)
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
21
174 160 130 117 89 HRMS (EI) calcd for C12H13O2N (M+) 2030946 found 2030946
CAS No 58868-33-0
NH3CO
H3COOCH3
OCH3 5588-Tetramethoxy-58-dihydro-4-methylquinoline (7a) Off white
solid mp 495-496 degC 1H NMR (400 MHz CDCl3) δ 257 (s 3H) 310 (s 6H) 330 (s
6H) 612 (d J = 120 Hz 1H) 646 (d J = 80 Hz 1H) 710 (m 1H) 856 (d J = 80 Hz
1H) 13C NMR (100 MHz CDCl3) δ 201 509 511 937 984 1271 1293 1315 1319
1484 1498 1545 MS (EI) 265 (M+) 250 234 218 204 (100) 188 174 160 145 130
117 102 HRMS (EI) calcd for C14H19O4N (M+) 2651314 found 2651314
N
Br OCH3H3CO
BrH3CO OCH3 57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-
methylquinoline (7b) Colorless liquid 1H NMR (200 MHz CDCl3) δ 259 (s 3H) 320 (s
3H) 328 (s 3H) 330 (s 3H) 339 (s 3H) 494 (d J = 120 Hz 1H) 519 (d J = 120 Hz
1H) 721 (d J = 40 Hz 1H) 859 (d J = 40 Hz 1H) 13C NMR (100 MHz CDCl3) δ 247
498 507 516 559 562 984 985 1228 1255 1362 1511 1590 MS (FAB) 428
(M+1)+ 426 (M+1)+ 424 (M+1)+ 394 314 266 234(100) 204 188 174 106 HRMS
(FAB) calcd for C14H20O4NBr2 (M+1)+ 4259759 found 4259739
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
22
NOCH3
Br
5-Bromo-8-methoxyquinaldine (8) 1H NMR (200 MHz CDCl3) δ 279 (s
3H) 402 (s 3H) 682 (d J = 84 Hz 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 1H)
827 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 254 561 1081 1118 1235
1263 1289 1354 1402 1545 1586 MS (CI) 254 (M+1+) 252 (M+1+ 100) 174 Anal
Calcd C11H10BrNO C 5241 H 400 N 556 Found C 5238 H 385 N 511 CAS No
103862-55-1
NOCH3
Br
Br
H3CO 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) Yellowish
crystalline solid mp 142-143 degC 1H NMR (200 MHz CDCl3) δ 269 (s 3H) 300 (s 3H)
354 (s 3H) 487 (d J = 70 Hz 1H) 668 (d J = 70 Hz 1H) 724 (d J = 80 Hz 1H)
785 (d J = 82 Hz 1H) 13C NMR (50 MHz CDCl3) δ 251 471 489 520 984 1232
1240 1251 1292 1359 1504 1588 MS (EI) 365 (M+) 363 (M+) 361 (M+) 330 254
252 (100) 250 237 222 203 188 174 157 142 128 115 102 86 71 51 31 Anal
Calcd C 3970 H 361 N 386 Found C 3974 H 366 N 361
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
23
NOCH3
Br
7-Bromo-8-methoxyquinaldine (9) 1H NMR (400 MHz CDCl3) δ 277
(s 3H) 417 (s 3H) 728 (d J = 84 Hz 1H) 736 (d J = 88 Hz 1H) 757 (d J = 88 Hz
1H) 798 (d J = 84 Hz 1H) 13C NMR (100 MHz CDCl3) δ 256 619 1165 1223 1237
1271 1296 1361 1428 1529 1591 MS (EI) 254 252 (M+) 250 222 221 208 172
171 142 (100) 128 115 102 HRMS (EI) calcd for C11H10ONBr (M+) 2509946 found
2509946
NOCH3
BrH3CO
H3CO H
7-Bromo-588-trimethoxy-58-dihydro-quinaldine (9a) 1H NMR (200
MHz CDCl3) δ 267 (s 3H) 312 (s 3H) 314 (s 3H) 362 (s 3H) 503 (d J = 36 Hz
1H) 693 (d J = 36 Hz 1H) 727 (d J = 80 Hz 1H) 778 (d J = 82 Hz 1H) 13C NMR
(50 MHz CDCl3) δ 244 513 516 532 722 963 1236 1285 1288 1352 1358
1496 1594 MS (EI) 314 (M+) 300 282 255 254 (100) 237 224 202 188 174 172
142 130 115 102 HRMS (FAB) calcd for C13H17O3NBr (M+1+) 3140392 found 3140392
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
24
NOCH3
Br
Br
57-Dibromo-8-methoxyquinaldine (9b) White solid mp 1319-
1320 degC 1H NMR (200 MHz CDCl3) δ 280 (s 3H) 416 (s 3H) 738 (d J = 88 Hz 1H)
756 (s 1H) 831 (d J = 88 Hz 1H) 13C NMR (50 MHz CDCl3) δ 258 625 1165 1237
1266 1327 1362 1435 1532 1603 MS (CI) 334 (M+1+) 332 (M+1+ 100) 330
(M+1+) 252 Anal Calcd C 3991 H 274 N 423 Found C 3958 H 277 N 394
CAS No 91063-10-4
NMe2
Br
Br
24-Dibromo-1-(dimethylamino)naphthalene (10a) 1H NMR (400
MHz CDCl3) δ 303 (s 6H) 751-763 (m 2H) 817-820 (m 1H) 833-835 (m 1H) 13C
NMR (100 MHz CDCl3) δ 425 1191 1197 1250 1273 1274 (C2) 1319 1341 1351
1470 MS (EI) 331 (M+) 329 (M+ 100) 327 (M+) 312 273 247 246 232 168 154 126
125 HRMS (EI) calcd for C12H11NBr2 (M+) 32903 found 3289238 CAS No 539857-01-7
NOCH3
NH
Br
Ph
7-(N-Benzyl)amino-5-bromo-8-methoxyquinaldine (11) A
solution of 2a (0363 g 10 mmol) benzylamine (054 g 50 mmol) in dry THF (10 mL)
was refluxed under nitrogen atmosphere for 6 h After cooling water was added to the
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
25
reaction mixture The mixture was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic layer was washed with water and brine and evaporated The residue was purified by
flash column chromatography (15 EtOAc-Hx) yielding 11 (015 g 42 ) as an off-white
solid 1H NMR (400 MHz CDCl3) δ 274 (s 3H) 404 (s 3H) 438 (s 2H) 671 (s 1H)
720 (d J = 84 Hz 1H) 732-749 (m 5H) 799 (d J = 88 Hz 1H) 13C NMR (100 MHz
CDCl3) δ 254 487 617 1079 1172 1177 1205 1277 1279 (2C) 1288 (2C) 1293
1381 1401 1432 1447 1590 MS (EI) 359 357 (M+) 355 327 325 265 (100) 238
236 186 185 155 117 Anal Calcd C 6052 H 480 N 784 Found C 6028 H 519
N 780
NOCH3
N
Br
5-Bromo-8-methoxy-7-piperidin-1-yl-quinaldine (12) White solid
mp 1018-1020 degC 1H NMR (400 MHz CDCl3) δ 156 (brs 2H) 170-176 (m 4H) 269
(s 3H) 288 (brs 4H) 402 (s 3H) 704 (s 1H) 718 (d J = 84 Hz 1H) 824 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 243 255 264 548 618 1164 1184 1213
1229 1329 1435 1475 1486 1589 MS (EI) 337 335(M+) 333 319 (100) 305 303
277 265 251 237 225 210 195 169 155 142 128 115 101 HRMS (EI) calcd for
C16H19BrN2O (M+) 33524 found 3360662
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
26
NOCH3
NC
Br
5-Bromo-7-cyano-8-methoxy-quinaldine (13) 1H NMR (400 MHz
CDCl3) δ 274 (s 3H) 425 (s 3H) 743 (d J = 88 Hz 1H) 797 (s 1H) 829 (d J = 84
Hz 1H) 13C NMR (100 MHz CDCl3) δ 257 630 1055 1150 1158 1244 1273 1337
1359 1420 1576 1606 MS (EI) 277 (M+) 275 (M+) 249 247 167 153 140 113 83
57 40 Anal Calcd C 5201 H 327 N 1011 Found C 5232 H 322 N 1043
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
27
References
(1) a) Smith M B March J Advanced Organic Chemistry 5th ed John Wiley amp Sons
Inc New York 2001
(2) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Kovacic P Levisky
J A J Am Chem Soc 1966 88 1000-1005 c) DeRosa M Brillembourg I J
Chem Soc Chem Commun 1986 1585-1586 d) DeRosa M Nieto G C
Tetrahedron Lett 1988 29 2405-2408
(3) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
(4) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(5) Strand J W Kovacic P J Am Chem Soc 1973 95 2977-2982
(6) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
28
NMR Spectra (1H and 13C NMR)
1-Ethoxynaphthalene (1b)
OEt
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
29
24-Dibromo-11-dimethoxy-12-dihydronaphthalene (2a)
H3CO
Br
BrOCH3
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
30
24-Dibromo-1-ethoxy-1-methoxy-12-dihydronaphthalene (3a)
Br
BrOCH2CH3H3CO
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
31
24-Dibromo-1-methoxynaphthalene (4a)
OCH3
Br
Br
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
32
1-Bromo-4-methoxynaphthalene (5a)
OCH3
Br
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
33
58-Dimethoxyquinaldine (6)
NOCH3
OCH3
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
34
5588-Tetramethoxy-58-dihydroquinaldine (6a)
NH3CO
H3CO OCH3
OCH3
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
35
57-Dibromo-5688-tetramethoxy-5678-tetrahydroquinaldine (6b)
NH3CO
H3CO Br
OCH3
H3CO
Br
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
36
58-Dimethoxy-4-methyl-quinoline (7)
NOCH3
OCH3
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
37
5588-Tetramethoxy-58-dihydro-4-methyl-quinoline (7a)
NH3CO
H3COOCH3
OCH3
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
38
57-Dibromo-5688-tetramethoxy-5678-tetrahydro-4-methyl-quinoline (7b)
NH3CO
Br OCH3
OCH3
H3CO
Br
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
39
5-Bromo-8-methoxyquinaldine (8)
NOCH3
Br
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
40
57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a)
NOCH3
Br
Br
H3CO
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
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(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
41
7-Bromo-8-methoxyquinaldine (9)
NOCH3
Br
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
42
7-Bromo-588-trimethoxy-58-dihydroquinaldine (9a)
NOCH3
BrH3CO
H3CO H
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
43
57-Dibromo-8-methoxyquinaldine (9b)
NOCH3
Br
Br
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
44
24-Dibromo-1-(dimethylamino)naphthalene (10a)
NMe2
Br
Br
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
45
7-(N-benzyl)amino-5-bromo-8-methoxyquinaldine (11)
NOCH3
NH
Br
Ph
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
46
5-Bromo-8-methoxy-7-(piperidin-1-yl)quinaldine (12)
NOCH3
N
Br
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
47
5-Bromo-7-cynano-8-methoxyquinaldine (13)
NOCH3
NC
Br
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
48
Part II Rearomatization Reactions and Applications of
Anthracene Adducts
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
49
Introduction
Electrophilic addition to carbon-carbon multiple bonds are well-studied reactions
Especially electrophilic additions to asymmetric alkenes have been contributed significantly
to understand the stereoselectivity1 According to the electrophilic addition a positive
electrophile approaches the double or triple bond and at the first step makes a bond by
converting the π pair of electrons into a σ pair2 During the process the intermediate
suggestes two mechanistic pathways with the competition for aromatization and nucleophile
addition3 However inability of the intermediate isolation due to the rapid rearomatization
or further reactions to multi-addition products was observed The series of adducts isolated
in the nitration of furan and nitronium acetate of furan derivatives are an exceptional case4
Further when rearomatization by deprotonation is blocked the known ipso attack of nitro
group at a substituted position also showed possibility of electrophilic addition on benzenoid
systems5 Also benzenoid compounds supported the values for the relative reactivities and
proportion of addition by chlorination of some aromatic hydrocarbons6
Recently we reported the first isolation of an addition adduct as a key intermediate
compound7 The identification of this unusual adduct by X-ray crystallography means that
electrophilic aromatic addition reactions (AdEAr) may be a useful reaction to develop To
extension to this we have applied this AdEAr reaction to the tricyclic aromatic compounds
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
50
A variety of anthracene derivatives show significant activities in the relation to their
biological and pharmacological properties After the discovery of anticancer drugs such as
daunomycin adriamycin and mitoxantrone8 a variety of anthracene derivatives have been
investigated for their biological activities especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity9 In the condition of
bromination of the anthracene in the basic methanolic condition 910-dimethoxy-910-
dihydroanthracene 2 which does not have no bromine could be isolated in high yield In this
reaction the products are obtained as a mixture of the cis and trans isomers by 14-addition
Furthermore the controls of the selective rearomatizations as well as the mechanism of this
adduct would be studied
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
51
Results and Discussion
Reaction of anthracene (1) with the treatment of bromine (30 equiv) in the presence of
NaHCO3 (20 equiv) at room temperature (Scheme 1) gave a consistant formation of an
intermediate 910-dimethoxy-910-dihydroanthracene (2) which was indentified by TLC
monitoring First we thought that this spot is anthraquinone because 910-dimethoxy
anthracene could be oxidized to anthraquinone by either direct oxidation or demethylation-
oxidation using NBS in acid condition10 But after isolation we found this spot was an
addition adduct A small amount of the substituted compound identified as 9-
methoxyanthracene (4) was also obtained The prime observation was that the amounts of
base and bromine regulate either addition reaction or substitution reaction
Scheme 1 The Addition Reaction of Anthracene (1)
OCH3
OCH3
Br2 NaHCO3 pyridine
MeOH H2O rt 15 min
2 (82)1
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
52
Having established the optimal conditions first we investigated the effect of amine base
on the reaction (Table 1) We proceed to on the AdEAr rate of the anthracene with various
amine base We varied the amine base pKa value standard According to using some amine
mixtures color changed when bromine added by dropwise condition mixturersquos color
changed by red when bromine put as soon as although in DMAP condition color be seen
yellow when bromine addition Notably pyridine (pKa=53) was the judicious base of
choice delivering addition adduct 2 in the high yield and purity (entry 2) On the other hand
amines of high basicity and low steric hindrance around the nucleophilic nitrogen atom such
as 4-Dimethylaminopyridine (DMAP) and 18-Diazabicyclo[540]undec-7-ene (DBU)
(entries 4 and 6) offered no conversion of 2 under the same condition DBU with bromine in
acetic acid improved the preparation of 910-dibromoanthracene 411 Next the moderately
hindered weakly basic 14-Diazabicyclo[222]octane (DABCO) which provided 2
Interestingly after addition of water during do the reaction in the same conditions (entries
34 and 6) we obtained oxidative demethylation compound such as anthraquinone 610
instead of 910-dimethoxy-910-dihydroanthracene adduct 2 Lastly when we experimented
without any amine base we also obtained anthraquinone 6 and another compound such 10-
methoxy-10H-anthracen-9-one (7) as by- product
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
53
Table 1 Effect of Amine Base on the AdEAr Rate of the Anthracenea
Br2 NaHCO base
MeOH H2O
OCH3
OCH3
OCH3
OCH3
OCH3 Br
Br
O
O
1 2 3 4
15 min rt
5
+ + + +
6
yield of product()b Entry Amine base
1 2 3 4 5 6
1 urea 1 64 - 3 trace -
2 pyridine - 82 - 1 trace -
3 imidazole 24 - 4 10 trace 5
4 DMAP 8 8 6 trace 4
5 DABCO 5 54 2 10 trace -
6 DBU 10 - 7 11 trace 7
7c None 5 - 9 7 trace 43
a All reaction were carried out on 20 mmol reaction scale of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 7 was obtained in 20 isolated yield
When we experimented the addition reactions (entries 3-6) we were able to obtain to
forming the substitution products like 910-dimethoxy anthracene (3) and 9-methoxy
anthracene (4) as the minor product Both 3 and 4 were very expensive like this (4-ALD
S304093 25mg 108000) But using 910-dimethoxy-910-dihydroanthracene adduct (2)
compound which get through AdEAr we can also control both 910-dimethoxyanthracene
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
54
(3) in the rearomatization reaction by DDQ (23-dichloro-56-dicyano-14-benzoquinone)
and selective 9-methoxy anthracene 4 in the basic condition
Scheme 2 The Addition Reaction of anthracene (1) in the absence of pyridine
OCH3
Br2 NaHCO3
MeOH H2O rt 15 min
71
O
Next our attention was examined the effect of inorganic base on the reaction (Table 2) To
demonstrate the efficiency of base we briefly screened several bases Treatment of
anthracene (1) under several conditions with divided by from 4 to 3 and 2 equiv of NaHCO3
allowed get the 2 as 59 56 and 82 yield (entries 8 and 9entry 2 in Table 1) But as
using a amount of 4 equiv gave about 3 impurity mixture Impurity mixture compound
was anthraquinone Alternatively reaction of anthracene (1) with strong bases such as
sodium hydroxide or sodium methoxide (entries 5 and 6) resulted in little to no formation of
the addition product 2 Compared the reactive orientation 2 to 6 was likely that compound 6
could be obtained as a product by increasing the amount of strong base used In addition
KOtBu (entry 1) gave rise to similar results In contrary the reaction using alkali metal
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
55
carbonate including cesium potassium carbonate under the same procedure offered the
addition adduct (entry 2-3) Next the reaction was carried out in utilizing other brominating
agent pyridinium hydrobromide perbromide (PyHBr3)12 and N-bromosuccinimide (NBS)
(entries 10-11) PyHBr3 would be suitable to be used as brominating agent in the AdEAr
reaction in the methoxy-naphthalene due to easy handling But in this case pyridinium
hydrobromide perbromide (PyHBr3) is not matched (entry 9) Using the NBS for the
reaction 9-methoxy anthracene 4 only methoxy compound was observed Itrsquos possibly due
to the lower electrophilic reactivity of NBS toward aromatic systems These results
indicated that the reactivity of the base as well as that of the bromine reagent are very
important in forming the addition adduct Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitution product Finally regulation of
bromine amount and reaction when we put bromine 2eq reaction was going clear but yield
is 59 When we put bromine 1eq starting material remain suitable amount (19) although
addition adduct comes out (27) Therefore we knew that we must put bromine amount
was 3eq
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
56
Table-2 AdEAr Rate of Anthracene of the Various Conditionsa
MeOH
OCH3
OCH3
O
O
[Br] base+
1 2 6
yield of products ()b
entry condition solvent Base 1 2 6 others
1 Br2py MeOH t-BuOK 23 - 5 3(5) 4(38)
2 Br2py MeOH Cs2CO3 22 49 - -
3 Br2py MeOH K2CO3 - 25 - -
4 Br2py MeOH NaOH 27 - 14 3(20) 4(16)
5 Br2py MeOH NaOMe c 23 - 3(4)
6 Br2py MeOH NaHCO3d - 59 - -
7 Br2 e py MeOH NaHCO3 - 52 - -
8 Br2f py MeOH NaHCO3 19 27 - 4(6)
9 PyHBr3 MeOH NaHCO3 5 - 27 3(11) 4(6)
10 NBSpy MeOH NaHCO3 - - - 4(48)g
a All reactions were carried out on 20 mmol of anthracene 1 using 3 equiv of bromine for 15 min at rt b Isolated yield c 05 M solution in methanol d Three equiv of NaHCO3 used e
Two equiv of bromine used and acetone was used as solvent for work up f One equiv of bromine used and acetone was used as solvent for work up g NMR yield
We can also control both 910-dimethoxyanthracene (3) in the rearomatization reaction by
DDQ and selective 9-methoxy anthracene (4) in the basic condition During do the AdEAr
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
57
reaction the two compound separate is very difficult due to the polarity is almost similar
The two compound is commercial available but itrsquos expensive Follow this method we can
get selective mono- di- methoxy anthracene
Scheme 3 Application of Adduct by DDQ and Basic Condition
OCH3
OCH3
OCH3
OCH3
DDQ
NaOH
MeOH
OCH3
OCH3
OCH3
2 4 (72)
2 3 (16)
THFreflux (65oC)
In Table 3 we have carried out the various functional group like EDG amp EWG (entry 1
and 2 in Table 3) with corresponding AdEAr reaction under the same conditions as for Table
1 Entry 1 show the AdEAr reaction using 9-methoxy anthracene (4) providing another
addition adduct 9910-trimethoxy-10-hydroanthracene (8) in high yield (92) Itrsquos result
explain about the mechanism of 910-dimethoxy anthracene Itrsquos not go through 9-methoxy
anthracene In case of dimethoxy such as 910-dimethoxy anthracene (9) we also could get
the another addition adduct 991010-tetramethoxy anthracene (10) In other case EWG
functional group like 9-cyanide anthracene (13) could know that AdEAr reaction does not
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
58
occur AdEAr reaction applied to another tricyclic aromatic compound such as phenathrene
(entry 3) It was also working the AdEAr reaction but it was different reactivity from the
anthracene Because of the fused ring was buckled itrsquos impossible of 2-methoxy attack 910-
position due to steric hindrance Therefore in that case we obtained addition adduct 9-
bromo-10-methoxy-910-dihydro-phenathrene (12)
Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
entry compound product yield()b
1
OCH3
4
H3CO OCH3
H OCH3
8
92
2
OCH3
OCH3
9
OCH3H3CO
OCH3H3CO
10
25
3
11 12
16
4
CN
13
No Reaction -
a All reactions were carried out on 20 mmol of each material under same condition as Table 1 b
Isolated yield
BrOCH3
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
59
Mechanistic study
We propose a mechanism for this addition reaction for anthracene 1 in which first step the
bromination at 9-position anthracene and then the intermediate state was stabilized by
methoxide addition Bromination of anthracene with bromine in the basic methanolic 910-
dibromo anthracene comes out trace amount Itrsquos mean that methoxide attack more quickly
than bromide re-attack at 10-position Therefore we know that intermediate that methoxide
attacks is important step Bromine occupy at benzylic position in the intermediate state then
methoxide attack SN2 type Itrsquos come out 910-dimethoxy-910-dihydroanthracene 2 Another
route that we get the 9-methoxy anthracene 4 through debromination in the basic condition
We think that 910-dimethoxy anthracene 3 comes out that 910-dimethoxy-910-
dihydroanthracene 2 become oxidation
We do the AdEAr reaction using 9-methoxy anthracene 4 which get the basic condition
under same condition According to our expectation we get the new adduct 9910-
trimethoxy-10-hydroanthracene 8 We think that anthracene derivatives apply to the AdEAr
in the same reaction condition Through the adduct which come from anthracene derivatives
it seems to follow the below mechanism In case of 910-dimethoxy anthracene derivatives
itrsquos the same
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
60
A plausible Mechanism of the Anthracene on the AdEAr
Br
Br
OCH3
OCH3
Br
[O]
H OCH3
H3CO OCH3
H OCH3
H OCH3
Br
-OMe
-OMe
Br
Br
H3CO OCH3
Br
H OCH3
Br2
-HBr
-OMe-OMe
OCH3
Br HBr2
OCH3
base
1
5
2 3
4 8
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
61
Conclusion
In summary a variety of anthracene derivatives show significant activity in the relation to
their biological and pharmacological properties especially 910-disubstituted anthracene
derivatives possesses the DNA accessibility with antitumor activity The bromination of the
anthracene in the basic methanolic condition to give 910-dimethoxy-910-
dihydroanthracene 2 In this reaction the product is a mixture of the cis and trans isomers
by 14-addition We can also control both 910-dimethoxyanthracene 3 in the
rearomatization reaction by DDQ and selective 9-methoxy anthracene 4 in the basic
condition During do the AdEAr reaction the two compound separate is very difficult due to
the polarity is almost similar The two compound is commercial available but itrsquos expensive
Follow this method we can get selective mono- di- methoxy anthracene
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
62
Experimental Section
Materials 1H and 13C NMR spectra were recorded on a 200 or 400 MHz spectrometer and
chemical shifts were reported in δ units (ppm) relative to tetramethylsilane TLC analysis
was performed using glass plate with silica gel 60 F254 Flash chromatography was
performed with 230-400 mesh silica gel
Typical Procedure for the Electrophilic Aromatic Addition Reaction To the
anthracene (2 mmol) and NaHCO3 (10 equiv ) in MeOH (60 mL) was stirring at rt After
3min pyridine was added After 2min solution of Br2 (30 equiv) in MeOH (15 mL)
addition by dropwise stirring at rt H2O (3 mL) was added and the reaction was stirred for
another 15 min Then H2O (30 mL) and Na2SO3 (032 g) were added The mixture was
extracted with CH2Cl2 (20 mL x 2) and the combined organic layers were washed by brine
and dried (Na2SO4) and concentrated in vacuo The residue was purified by flash column
chromatography (2 EtOAcHexane)
OCH3
OCH3 910-Dimethoxy-910-dihydroanthracene (2) Colorless liquid 1H
NMR (400 MHz CDCl3) δ 342 (s 3H) 540 (s 2H) 724-740 (m 4H) 755-762 (m 4H)
13C NMR (100 MHz CDCl3) δ 566 779 1268 1275 1372 MS (EI) 240(M+) 225
208(100) 193 178 165 152 151 139 104 HRMS(EI) calcd for C16H16O2(M+) 2401150
found 2401150
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
63
OCH3
OCH3 910-Dimethoxy-anthracene (3) Yellow solid mp 1965-1966 degC 1H
NMR (200 MHz CDCl3) δ 413 (s 6H) 748-753 (m 4H) 828-833 (m 4H) 13C NMR
(100 MHz CDCl3) δ 632 1225 1248 1253 1484 MS (EI) 238(M+) 223(100) 208 207
180 152 149 125 111 HRMS(EI) calcd for C16H14O2(M+) 2380994 found 2380994 CAS
No 2395-97-3
OCH3
9-Methoxy-anthracene (4) Pale yellow solid mp 932-933 degC 1H NMR
(400 MHz CDCl3) δ 416 (s 3H) 746-751 (m 4H) 799 (dd 2H J=16 20Hz) 823
(s1H) 831 (dd2H J=68 16Hz) 13C NMR (100 MHz CDCl3) δ 632 1222 1223 1244
1252 1255 1284 1324 1522 MS (EI) 208(M+) 193(100) 176 165 163 139 115
104 HRMS(EI) calcd for C15H16O (M+) 2080888 found 2080888 CAS No 2395-96-2
Br
Br 910-Dibromo-anthracene (5) Yellow solid mp 2118-2136 degC 1H
NMR (400 MHz CDCl3) δ 762-765 (m 4H) 858-861 (m 4H) 13C NMR (100 MHz
CDCl3) δ 1235 1275 1283 1311 MS (EI) 338(M+) 336(M+) 334(M+) 295 279 240
208(100) 178 165 152 139 HRMS(EI) calcd for C14H8Br2(M+) 3338993 found 3358973
CAS No 523-27-3
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
64
O
O Anthraquinone (6) 1H NMR (400 MHz CDCl3) δ 779-781 (m 4H)
830-833 (m 4H) 13C NMR (100 MHz CDCl3) δ 1272 1335 1341 1832 MS (EI) 223
208(M+100) 180 179 152 151 126 HRMS(EI) calcd for C14H8O2 (M+) 2080524 found
2080524 CAS No 84-65-1
O
OCH3 10-Methoxy-10H-anthracen-9-one (7) Yellow solid mp 996-998 degC 1H
NMR (400 MHz CDCl3) δ 293 (s 3H) 581 (s1H) 752-756 (m 2H) 768-772 (m 2H)
779-781 (m 2H) 833 (dd 2H J=12 12Hz) 13C NMR (100 MHz CDCl3) δ 515 723
1276 1287 1289 1327 1337 1404 1836 MS (EI) 224(M+) 209 193(100) 180 165
152 149 139 115 105 HRMS(EI) calcd for C15H12O2 (M+) 2240837 found 2240837
CAS No 14629-83-5
H3CO OCH3
H OCH3 9910-Trimethoxy-10-hydroanthracene (8) Pale yellow solid mp 451-
452 degC 1H NMR (400 MHz CDCl3) δ 292 (s3H) 311 (s3H) 317 (s3H) 550 (s 1H)
13C NMR (100 MHz CDCl3) δ 477 569 814 1243 1245 1279 1284 1298 1299
1310 1312 1323 1324 1334 MS (EI) 270(M+) 255 239 238 208 193(100) 180 165
152 151 139 104 HRMS(EI) calcd for C17H18O3 (M+) 2701256 found 2701256
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
65
BrOCH3
9-Bromo-10-methoxy-910-dihydro-phenathrene (12) Greenlish solid
mp 886-888 degC 1H NMR (400 MHz CDCl3) δ 330 455 (d 1H J=24Hz) 545 (d 1H
J=28Hz) 732-752 (m 6H) 787-791 (m 2H) 13C NMR (100 MHz CDCl3) δ 477 569
814 1243 1245 1279 1284 1298 1299 1310 1312 1323 1324 1334 MS (EI)
290 (M+) 288 (M+) 286 (M+) 272 243 223 208 194 178 (100) 165 163 151 139 104
HRMS(EI) calcd for C15H13BrO (M+) 2880150 found 2880150
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
66
Referenes
(1) a) Chamberlin A R Mulholland Jr R L Scott D K Hehre W J J Am
Chem Soc 1987 109 672 and references therein (b) Kahn SD Rau C F
Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650 (c) Kahn S D
Hehre W J J Am Chem Soc 1987 109 666 (d) Chemberlin A R Dezube M
Dussault P McMills M C J Am Chem Soc 1983 105 5819 (e) Chamberlin A
R Dezube M Dessault P Tetrahedron Lett 1981 22 4611
(2) See Smith M D March J Advanced Organic Chemistry 5nd ed Wiley-
Interscience New York 2001 pp 970-1171
(3) a) Hebel D Rozen S J Org Chem 1991 56 6298-6301 b) Strand J W
Kovacic P J Am Chem Soc 1973 95 2977-2982 c) Kovacic P Levisky J A J
Am Chem Soc 1966 88 1000-1005 d) DeRosa M Brillembourg I J Chem
Soc Chem Commun 1986 1585-1586 e) DeRosa M Nieto G C Tetrahedron
Lett 1988 29 2405-2408
(4) a) Michels J G Hayes K J J Am Chem Soc 1958 80 1114-1116 b) Kolb V
M Darling S D Koster D F Meyers C Y J Org Chem 1984 49 1636-1639
c) Gisela B Patricia K Janet P Dung P Arnulf V J Org Chem 1986 51 3811-
3818
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
67
(5) a) Fischer A Ramsay J N Can J Chem 1974 52 3960-3970 b) Fisher A
Greig C C Roderer R Can J Chem 1975 53 1570-1578 c) Hahn R C Strack
D L J Am Chem Soc 1974 96 4335-4337
(6) a) G H Beaven P B D de la Mare M Hassan E A Johnson and N V Klassen
J Chem Soc 2749 (1961) b) G H Beaven P B D de la Mare M Hassan E A
Johnson and N V Klassen J Chem Soc 988 (1962) c) G W Burton P B D de
la Mare L Main and B N Hannan J Chem Soc Perkin Trans 2 265 (1972)
(7) Choi H Y Srisook E Jang K S Chi D Y J Org Chem 2005 in press
(8) Daunomycin (a) Di Marco A Gaetani M Orezzi P Scarpinato B M
Silvestrini R Soldati M Dasdia T Valentini L Nature 1964 201 706-707
Mitoxantrone (b) White R J Durr F E Invest New Drugs 1985 3 85-93
(9) Timothy P W Mary T C Michael D K Craig H William A R J Med
Chem 1990 33 1549-1553
(10) Kim D W Choi H Y Lee K-J Chi D Y Org Lett (Communication)
2001 3(3) 445-447
(11) Simon Jones J C Christian Atherton Synth Commun 2001 13 1799 ndash 1802
WP Reeves and R M King Synth Commun 1993 23 855 J Berthelot C Guette
P-L Desbene and J-J Basselier Can J Chem 1989 67 2061
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
68
NMR Spectrum (1H and 13C NMR) 910-dimethoxy-910-dihydroanthracene (2)
OCH3
OCH3
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
69
910-Dimethoxy-anthracene (3)
OCH3
OCH3
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
70
9-Methoxy-anthracene (4)
OCH3
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
71
910-Dibromo-anthracene (5)
Br
Br
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
72
Anthraquinone (6)
O
O
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
73
10-Methoxy-10H-anthracen-9-one (7)
O
OCH3
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
74
9910-Trimethoxy-10-hydro-anthracene (8)
H3CO OCH3
H OCH3
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
75
9-Bromo-10-methoxy-910-dihydro-phenathrene (12)
BrOCH3
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
76
감사의 글
2년 동안 석사 생활을 하면서 날 도와준 많은 사람들의 얼굴이 떠 오릅니다 먼
저 하늘이라는 경계선을 두고 우리 식구랑 먼저 헤어지신 아버지께 다른 누구보
다 감사하다는 말씀을 드리고 싶습니다 위에서 바라봐 주고 계시고 있다는 거 믿
고 앞으로 더 열심히 하는 막둥이 근삼이가 되겠습니다 혼자 남으셔서 뒷바라지
하시느냐 고생하신 어머니께도 감사하다는 말씀 올리겠습니다 큰형 작은형 그
리고 형수님에게도 감사드립니다
부족한 저를 지도해 주시고 나아갈 바를 지적하여 주시고 현재의 제가 있도록 이
끌어주신 지대윤 교수님께 진심으로 고개 숙여 감사하다는 말씀을 올립니다 항상
스마일로 대해주신 김유항 교수님 많은 충고와 조언을 해 주신 이해황 교수님
생화학분야에 많은 도움을 주신 조형진 교수님께도 감사드립니다 본 논문의 심사
위원으로 많은 충고와 조언을 해 주신 이본수 교수님 이건형 교수님께도 깊은 감
사를 드립니다
지난 2년 동안 의약화학 연구실에서 함께 고생하고 즐거움을 나눴던 여러 선배
님과 동기들 그리고 후배들에게 고개 숙여 감사드립니다 처음 실험을 할 때 많
은 지식과 노하우를 가르쳐 준 동욱이형 많은 사회적 얘기와 앞으로 나아갈 길을
제시해 준 병철이형 첫 SCI 논문을 낼 수 있게 도와주시고 지금도 많은 도움을
주시는 한영이형 저 형 만큼 해야 되겠구나 하구 생각하게 만드는 재웅이형 후
배들을 잘 이끌어주시고 항상 스마일로 대해주시는 재학이형 지금은 한국에 없지
만 화학에 대해서 많은 얘기를 나눈 EK 형 2달만 있으면 애기 아빠가 되는 희섭
이형 따뜻함이 느껴지는 상돈이형 에게 감사의 마음을 전합니다 같은 실험실에
서 대학원 생활을 보내지는 못했지만 교철이형 비롯해 여러 선배님들에게도 감사
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-
77
의 마음을 전합니다
2년 동안 같이 힘든 역경을 동고동락한 동진이 학부 때부터 같이 다니면서 대학
원까지 같은 곳에 오게 되서 많은 도움이 되어준 용현이에게 너무나 고마운 마음
을 전합니다
1년 같이 보내구 앞으로 1년 더 보내야 하면서 여러 추억을 함께 했던 후배 지
선이 유정이 그리고 내 밑에서 가르침을 받는 희영이에게 감사의 마음을 전합니
다
2달 있으면 아줌마가 되는 미자 누나 옆에서 우리 실험실의 업무를 보는 세영이
같이는 없지만 여진이 에게도 감사의 마음을 전합니다
또 석사 생활 때 많은 도움을 주신 관훈이형 구일이형 강래형 흥진이형 정호
형에게도 감사드리며 호석이 두원이 대호 병철이DCT 멤버들에게도 감사의 마
음을 전합니다 이외에도 고마운 마음을 전해야 할 선배님들 동기들 그리고 후
배들이 너무나 많습니다 그 분들 모두에게 감사의 마음을 전하고 싶습니다
앞으로 박사 과정을 밟으면서 지금 가지고 있는 마음 변함없이 더 열심히 하는
근삼이 더 생각하는 근삼이가 될 수 있도록 노력하겠다는 말을 남기며 날 지켜주
시며 따뜻함을 주시는 아버님과 어머님 두 분에게 부끄럽지 않은 아들이 되겠다
구 약속 드리며 다시 한번 고개 숙여 깊은 감사의 마음을 전합니다
장근삼 올림
- 목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr)
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part II Rearomatization Reactions and Applications of Anthracene Adducts
-
- Introduction
- Results and Discussion
- Mechanistic Study
- Conclusion
- Experimental Section
- References
- NMR Spectrum (1H NMR and 13C NMR)
-
- Part I
- Table-1 The AdEAr of 1-Methoxy (1a) and 1-Ethoxy Naphthalene (1b) in Various Conditions
- Table-2 Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol Conditions
- Table-3 Treatment of 57-Dibromo-88-dimethoxy-78-dihydroquinaldine (8a) with Various Nucleophiles
- Part II
- Table-1 Effect of Amine Base on the AdeAr Rate of the Anthracene
- Table-2 AdEAr Rate of Anthracene of the Various Conditions
- Table-3 AdEAr of Various Tricyclic Aromatic Compounds under NaHCO3-Methanol Conditions
-
- 그림목차
-
- Part I Non-Ipso Attack Electrophilic Aromatic Addition Reaction (AdEAr) NMR Spectrum (1H NMR and 13C NMR)
- Part II Rearomatization Reactions and Applications of Anthracene Adducts NMR Spectrum (1H NMR and 13C NMR)
-