Chapter four Miscellaneous synthetic transformations

4.1 Synthesis of olivacene, a constituent of Archilefeuna olivacea

Amongst the several hydrocarbons isolated and identified in the Diets-

Alder reaction of isoprene with myrcene l , the hydrocarbon 5-isopropeny1-1-(4-

methyl-3-penteny1)-1-cyclohexene 1, when heated with 85% formic acid cyclized

to give 1,1-dimethy1-6-isopropyl-1,2,3,4-tetrahydronaphthalin 2 1 . This appears to

be a fortuitous synthesis of olivacene 2, recently isolated as a naturally occurring

bicyclic sesquiterpenoid hydrocarbon from Archilejeunea olivacea2 .

The structure 2 was well established by mass and elaborate NMR spectral

data including DEPT, HMQC and HMBC experiments. Particularly, the long-

range 1 H- 13C correlation studies supported the position of the isopropyl group in

the aromatic ring. This clearly indicated that olivacene 2 is a modified or irregular

sesquiterpenoid and has carbon framework exactly the same as a bis-nor-sesqui-

terpenoid called C 13-diosphenol 3 a constituent of Ipomea pes caprea3 .

1 2 0 3

The key step in the synthesis of 3 4 involved the conversion of13-ionone 4 to

ionene 5 by simple distillation of 4 in the presence of catalytic amount of iodine5.

249

CHO Aniline ether, r.i

H2SO4

Schiffs base

6

Scheme-1

2 7

12 (cat. ant. heat

4 R= CH3 6 R = cH(cH3)2

It was therefore anticipated, that similar distillation of the ketone 6 should

give olivacene 2. Retro synthetic analysis indicated that the a,(3-unsaturated

ketone 6 can be easily obtained by aldol condensation of synthons p-cyclocitral 7

and 3-methyl-2-butanone 8, which in turn can be prepared from citral and ethyl

acetoacetate respectively.

Thus in this section, we describe a simple synthesis of olivacene 2 from

citral as depicted in scheme-1.

Citral was converted into fl-cyclocitral 7 by using the method of Colombi et

al.6 wherein, the Schiffs base of citral with aniline was first prepared by adding

aniline to a solution of citral in ether at room temperature followed by drop-wise

addition of the Schiffs base to an ice-cold solution of cone H2504. The dark

250

9

brown, viscous oil obtained gave upon steam distillation, a mixture of a- and

13-cyclocitral in 47% yield. This mixture when refluxed with 8.5% methanolic

KOH afforded 13-cyclocitral 7 in almost quantitative yield. Its UV, IR and 1H

NMR spectral data was found to be identical with the reported one ' .

Aldol condensation of 13-cyclocitral 7 with 3-methyl-2-butanone 8 in the

presence of NaOEt gave the required a,13-unsaturated ketone

6 in 82% yield. Compound 6 has been prepared previously s

in about 40% yield by the reaction of diisopropyl cadmium

with acid chloride 9, but except UV A, (ethanol) 283 nm, no other spectral data

was available. Therefore, we recorded UV, IR, and 1H NMR spectra, which were

in perfect agreement with the structure 6. The UV A, (ethanol) 224 and 294 nm

(calcd. 299nm) and IR band at 1680 cm -1 clearly indicated the presence of an

a,13-unsaturated ketone system. The 1H NMR spectrum showed a six-proton

singlet at 5 1.06 indicating the presence of two tertiary methyl groups. A six-

proton doublet at 5 1.14 and a septet at 5 2.83 (J = 6.9 Hz) confirmed the presence

of an isopropyl group. A three-proton singlet at 5 1.76 indicated the presence of an

olefinic methyl. Two multiplets at 5 6.19 and 7.35 (J = 16 Hz) integrating for one

proton each established the presence of two trans olefin protons of an

a,13-unsaturated ketone system. A two proton triplet at 5 2.06 and a four proton

multiplet between 5 1.45-1.66 indicated the presence of three methylene groups at

C3., C4' and C5. respectively.

251

3-Methyl-2-butanone 8 was prepared 9 by acid catalyzed decarboxylation of

ethyl-2,2-dimethyl-3-oxo-butanoate, which in turn was prepared 1° by base

catalyzed methylation of ethyl-3-oxobutanoate using iodomethane as follows.

0 0 absolute Et0H 00 0 1) 5%NaOH

0% H2SM4

heat

Slow distillation of the ketone 6, with catalytic quantity of iodine, gave

after the usual work-up and silica gel column chromatography, a pale yellow oil of

olivacene 2, C151122 ([Ml at m/z 202). The IR spectrum of 2 showed bands at

1610, 1500 and 830 cm4 due to aromatic ring. Its 1H NMR spectrum contained

two tertiary methyl [5 1.26 (s, 6H)], an isopropyl group [5 1.236 (d, 6H, J = 6.9

Hz) and 2.81 (1 H, sept, J = 6.9 Hz)], three multiplets centered at 5 1.61-1.65

(m, 2H, C2-Hs), 1.76-1.78 (in, 2H, C3-Hs) and 2.73 (t, 2H, J= 6.3 Hz, C4-Hs) due

to the three methylenes and three protons on a 1,2,4-trisubstituted benzene ring at

5 6.87 (s, 1H), 6.99 (d, 1H,J= 8.1 Hz) and 7.24 (d, 1H,J= 1.5, 8.1 Hz).

The 13C NMR and DEPT spectra showed three sp 3 methylenes (19.91,

30.89, 39.52), one sp3 methine (33.5), three-sp 2 methine (124.02, 126.51, 126.85),

two singlets due to four methyls (24.01, 31.93) and four quaternary (33.5, 135.77,

143.10, 145.48) carbons, thereby accounting for all the 15 carbons. Comparison of

the 1 H and 13C NMR spectral data (see Table-1) established the identity of the

synthetic sample with the natural one reported by Asakawa and co-workers i .

A)L0Et CH3I (2 moles) OEt 2) 5 Na 30.

252

m/z 187 m/z 159 m/z 145 miz 202

Table-1: 13C NMR assignments of 2

Carbons Chemical shift (5 ppm) of natural 2

Chemical shift (5 ppm) of synthetic 2

C1 33.5 33.5

2C1-CH3 - 31.93

C2 39.4 39.52

C3 19.8 19.91

C4 30.8 30.89

C4a 135.8 135.77

Cs 126.8 126.85

C6 145.5 145.48

C7 124.0 124.02

C8 126.5 126.51

C8a 143.0 143.10

-CH(CH3)2 24.0 24.01

-CH(CH3)2 33.5 33.5

The EIMS mass spectral fragmentation pattern also supports structure 2. In

addition to the base peak at m/z 202 (M) its mass spectrum showed significant

peaks at m/z 187 (100%), 159 and 145. The possible mode of major fragmentation

and the likely structures for these fragment ions are shown in chart-1.

Chart-1: Mass spectral fragmentation of olivacene 2

253

The number of ways in which the enzyme bound isomeric farnesyl

pyrophosphate (FPP) precursors gets folded and produce incredibly large number

of novel sesquiterpene skeletons has attracted the attention of organic chemists all

over the world. The regular or normal sesquiterpenoids may undergo further

transformations through rearrangements leading to modified or irregular

sesquiterpenoids. Asakawa and co-workers' have proposed a biogenetic pathway

(Scheme-2) for olivacene 2, which explains its formation from farnesylpyro-

phosphate. A modified version of this biogenetic proposal based on the labeling

Scheme-2

studies of Coates" for the transformation of labdane diterpenoids into abiatane

series is presented below in scheme-3.

Scheme-3

254

4.2 Unusual KMnO4 oxidation product of 13-ionone: Confirmation

of the assigned structure

The compound hydroxyionolactone obtained by Tiemarm 12 from 0-ionone

10 was formulated" as a 0-lactone 11. Due to doubts in the assigned structure,

Brooks and co-workers' 4 reinvestigated the permanganate oxidation of 10 and

obtained a product resembling the lactone 11 described by Tiemann 12 and assigned

structure 12 on the basis of its elemental analysis, UV and IR spectral data.

10 11

12

Since, no 'H, ' 3C NMR and mass spectra were recorded, it seemed

desirable to repeat the reaction and isolate the desired hydroxyionolactone 12 and

collect additional proof for the assigned structure 12. Moreover, formation of 12

by KMnO4 oxidation seemed interesting from the mechanistic point of view. We,

therefore, carried out KMn04 oxidation of 0-ionone 10 and obtained

hydroxyionolactone as a crystalline solid (8.9%), m.p. 122°C. The results

presented in this section confirm the structure 12 assigned by Brooks and co-

workers. A plausible mechanism for its formation is also presented.

All the structural features of 12 including the conjugated enol lactone

butenolide part are consistent with the UV absorption at 238 nm (EtOH), the IR

absorption bands at 3340, 1735, 1680 cm' as well as the 'H and ' 3C NMR data.

255

Its 111 NMR showed three singlets (8 1.19, 1.46, 1.53), each integrating for

three protons corresponding to two tertiary methyl groups (gem dimethyl) at C4

and a tertiary methyl at C7 a respectively. The three methylene Hs appeared as

multiplets in the region 8 1.5-2.27 and did not allow assignment for individual

protons due to overlapping signals. The 13C NMR signals for all the ten carbons

shown below (Figure-1) fully support the structure 12

Figure-1: 13C NMR assignments of 12

The DEPT and H decoupled 13C NMR spectra exhibited three sp 3 methyls

(8 25.24, 25.66, 29.67), three sp 3 methylenes (8 19.94, 39.03, 41.6) and five

quaternary (8 35.81, 85.13, 133.39, 141.27, 170.07) carbons.

The high resolution CIMS* showed a M + peak at m/z 219 (100% M+Na)

corresponding to the molecular formula CI IH1603 and significant peaks at m/z 196

(M+), 151, 139, 123, 121, 109, 95 and 69. The genesis of the observed fragment

ions (relative abundance >20% w.r.t. the base peak) is presented in chart-2.

* We are thankful to Shri. Manoj Samant, IICT, Hydrebad for the CIMS spectrum of 12

256

m/z 123 m/z 109 m/z 109 1 -CH3 -H

-211

-CO II--

m/z 93 m/z 95

-CO

m/z 123

+

c f . o 41E-111.

m/z 139

Chart-2: Mass spectral fragmentation of 12

Brooks and co-workers 14, suggested the formation of 12 through a diol

intermediate 13 to give a-keto acid 14 which then cyclizes to the lactone 12 as

shown below. (Scheme-4)

257

14 12

Scheme-4

We believe that, the initially formed manganate ester 15 (without arrows)

undergoes a cleavage * as shown in 15 (with arrows) to give Mn(III) complex 16.

This complex 16 then cleaves to give 17, which in turn oxidizes further to the a-

keto acid 14 and then cyclises to give 12. (Scheme-5)

In order to confirm that our KMnO4 oxidation product is identical with the

one reported by Tiemann 12 and Brooks & co-workers 14, the preparation of bromo

derivative looked desirable.

* A similar cleavage without participation of the carbonyl group has been reported earlier 15 .

258

Hydroxyionolactone 12 is reported to form a bromo lactone 18 on

treatment with hydrobromic acid (under unstated conditions) 12 and by the addition

of bromine to the aqueous solution of the lactone 12 14. However, by these

methods, the authors obtained 18 as a mixture of stereoisomers melting over a

range of 166-173 °C. We could prepare the same bromolactone 18 in 89% yield by

generating bromine in-situ using KBr03/HBr/Ac0H 16 .

12

18

Compound 18, a pale yellow crystalline solid that melted at 214 °C with

decomposition was analyzed for C1 1 I-11503Br (mass spectrum). Although, the

spectral data of 18 (discussed below) is in agreement with the structure, the

melting point (214°C) obtained by our method does not tally with that reported by

earlier workers (166-173 °C) 12,14 and may be attributed to the presence of a single

isomer.

The IR spectrum showed the presence of carbonyl bands at 1790, 1770

(shoulder) cm-1 and the absence of the hydroxyl functionality. The 1 H NMR

spectrum of 18 could nicely account for all the 15 Hs present as 3 methyls (9 Hs)

and 3 methylenes (6 Hs) as follows: 8 1.29 (s, 3H, C4-CH 3), 1.46 (s, 3H, C4-CH3),

1.53-1.75 (m, 4H, C5, and C6 Hs), 1.79 (s, 3H, Cg-Hs), 2.48 (m, 1H, C 7-H), 2.52

(m, 1H, C7-H).

259

The H decoupled ' 3C NMR. spectrum of 18 showed distinct 11 signals

whose assignments are shown below (Figure-2).

Figure-2: 13C NMR assignments of 18

Further support to the structure was found in the mass spectral data*. The

characteristic feature of EIMS is the fragment ions m/z 202, 204 and 187, 189

obviously indicating the presence of bromine atom in these fragment ions. The

genesis of these and other significant fragment ions is shown in chart-3.

* Thanks are due to Shri Ratnakar Asolkar, University of Gottingen, Germany for the MS spectrum of 18

260

m/z 123 m/z 202, 204

-CH3

9ca m/z 187, 189

m/z 123

m/z 81

-H

-CH3

m/z 107 m/z 123

-CO

m/z 151

-C2114

RDA

-CO2 o —

0 1' -CO

Br o

m/z 274, 276

(

.

)13r

0

0

H3 0 +

m/z 43

Chart-3: Mass spectral fragmentation of 18

Vinyl bromide 19 was required as a starting material for a synthetic

sequence. We envisaged its preparation by treatment of 18 with KHCO3 17 as per

the mechanism shown below.

0

C- OH IC14°33

18

19

261

When the aqueous suspension of 18 was stirred with KHCO3 at a

temperature less then 10 °C, most of the solid dissolved with effervescence

resulting in a clear solution, which was extracted with ether and dried over

anhydrous Na2SO4. Evaporation of ether did not leave any organic material worth

characterization. We feel that the isolation of 19 depends on some undetermined

factors, which are not understood at present.

262

4.3 Synthesis of 4-amino-6,7-dimethoxy carbostyril

Coumarins both naturally occurring as well as synthetic derivatives, have

found widespread applications as photo sensitizers, laser dyes or pH indicators in

biochemistry and medicines". However, less attention was paid to carbostyrils, an

important class of heterocyclic compounds called [2(1H)-quinolones], which can

be considered as aza-analogues of cournarins 18. In contrast to coumarins,

carbostyrils offer the advantage of greater chemical and thermal stability. This

makes them possible candidates as wave-shifting fluors in high-energy particle

detection for which coumarins are found to be unsuitable as they offer insufficient

resistance against radiation damage.

Carbostyril ring system is present in several natural compounds and has

been used as intermediates in the synthesis of various alkaloids and biologically

active compounds. They have been used as sensitizing chromophors for lanthanide

chellates 192021 . For example, such a lanthanide complex of 7-amino-4-methy1-

2(1H)-quinolone (carbostyril-124) is used as a probe in biological system for the

detection of lipoprotein, a risk factor of coronary heart diseases 22. They are also

used as an alternative for UV detection and in other luminescence techniques for

the chromatographic separation of drugs and xenobiotics 23 .

Due to the increasing importance of carbostyrils in analytical, medicinal

and biochemical applications we found it worthwhile to synthesize these

compounds using readily available starting materials and reagents.

263

0 0 )koc2H5

110°C

N1-12

I Diphenylether, N2 Iv

RCH(COOE02

I-1 21

A brief literature survey indicated that the commonly employed methods

for the synthesis of carbostyrils make use of aniline or its derivatives as starting

material24. For example, in the Conrad-Limpach and Knorr synthesis, aromatic

amines react with j3-keto esters such as ethylacetoacetate in the presence of

catalytic quantity of an acid to give 2-quinolone 20 as the major product when the

reaction is carried out at refluxing temperatures. In the Combes synthesis

2-substituted malonyl ester is used in place of ethylacetoacetate to give

3-substituted-4-hydroxy-2-quinolone 21.

Cycli7ation of 2-amino derivatives of cinnamic acid in the presence of

Ac20 or H2SO4 and that of cinnamanilides of the type 22 using PPA or A1C13 to

give 2-quinolones 23 and 4-aryl-3,4-dihydro-2-quinolones 24 respectively are the

well known and commonly used methods for the preparation of these carbostyrils.

3,4-Dihydro-2-quinolones are also prepared by the Beckmann rearrangement of the

oxime of indan-l-one24.

264

Ac20 or

^ 2SO4 heat

AlC13 (3rnal) 1000C, lhr

PPA 100-1900C

24 H H

22

Sometime back in our laboratory 4-(4'-methoxypheny1)-6,7-dimethoxy-3,4-

dihydrocarbostyril 25 was prepared by the condensation of veratryl amine 26 with

4-methoxycinnamic acid in the presence of P205 in AcOH 25 .

H3C0

H3 • II NE12

26 25

Recently Ganguli and co-workers26 have prepared substituted pyrido-

quinoxalin derivative 27 in three steps from 6-aminoquinoxalin 28.

1 ) CICH20 OC1, pyr toluene, reflux

2) KCN/EtOH NH2 3)PPA or H2SO4 0

H 28

27

We thought of using this method to synthesize the title compound 4-amino-

6,7-dimethoxycarbostyri1 33 as shown in scheme-6.

265

1:1 HNO3 H3C0 H3C0

li •NO2 H3 lie Nell NI-12

11,, Pd/c. < 50C Et0H

30

i

C1CH2COCI pyridine, toluene, reflux

32

Scheme-6

Nitration of veratrole using 1:1 HNO 3 below 5 °C gave yellow crystals of

4-nitroveratrole27 29 in almost quantitative yield. Catalytic hydrogenation of 29

using 10% Pd/C in ethanol afforded veratrylamine 30 as a colorless solid turning

pink on exposure to air28'29. Reaction of 30 with chloroacetyl chloride * at refluxing

temperatures of toluene gave a complex mixture of products along with black tarry

material. However, when toluene was replaced by benzene the desired product 31

was obtained as needles (m.p.125 °C) in 62% yield.

Its 'H NMR spectrum (Figure-3) showed two singlets at ö 3.845 and 3.862

due to the two OCH3 groups, two proton singlet at ö 4.15 due to the methylene

group flanked between CO and Cl, the three aromatic protons at ö 6.80 (1H, d,

J = 8.7 Hz, C5-H), ö 6.93 (dd, 1H, J = 8.7, 2.4 Hz, C6-H), ö 7.248 (d, 1H, J = 2.1

* We thank Dr. P. R. Pednekar of CIBA GEIGY, Goa for a generous gift of chloroacetyl chloride

29

33

266

H H 7.248 (d) 8.15

.1= 2.1 Hz

8.7, 2.4 Hz 6.93 (dd) 55.93

H3CO 4.15 146.4

149.0

NO H3CO 56.04

3.845

H3CO

J= 8.7 Hz 6.80 (d) H

H3CO 3.862

Hz, C2-H), and the NH proton at 8 8.15. The ' 3C NMR assignments for the

individual carbons agreed well with structure 31 and are shown below in figure-3.

Figure-3: 111 and 13C NMR assignment of 31

Refluxing the ethanolic solution of 31 with KCN afforded the cyano-

compound 32 in 82% yield. Recrystallisation from aqueous ethanol gave needles

melting at 168°C. The IR spectrum of 32 clearly indicated the presence of CN

group at 2260 cm-1 in addition to NH and CO at 3275 & 1660 cm-1 respectively.

The 1 11 NMR spectrum was consistent with structure 32 and established the

identity of the cyano-compound beyond doubt. The assignments for the various

protons are shown below in figure-4.

267

H ,CN ,, ,/ 4 3.545

H3CO

H3CO 3.887

H 7.201 (d)

J= 2.4 Hz

1 1

N 0

H 7.639

J= 8.6 1-1z 6.832 (d)

H J= 8.6, 2.4 Hz 3.876 6.93 (dd)

Figure-4: 1H NMR assignments of 32

Cyclisation of 32 using different reagents such as PPA, H2SO4 and

anhydrous AIC13 under varying experimental conditions was tried with no success.

It appears that the expected product 4-amino- or 4-hydroxy-6,7-dimethoxy

carbostyril 33 is formed (TLC), however, we are unable to isolate it, may be due to

the formation of a salt under the work-up conditions used and is getting lost in the

aqueous phase.

268

6 7

, , .y; • r .11 0 0 a, 0 '0 .-4 rfl ‘0•("V (0 en , 'I' ,1('(N , r, Os ■ 11 in as a, .1-7 Nt 0 47, ,0 tv1 vvr

rik rs ■ kr. r-- , I1 r • 7• I c)cpacr co . • • • . . . . . . . . . . . . . • . . . . • . • . . . . . • • • • •

.N (si L‘l 0,1 t‘i 0.1 1,3 , , r ■ I'ry rrrrIrl , • •—• , , r-r■ r-rrl CD CD

r- t •

• • • •

111 CD ■ 0

,D CD 0•3 •

5 4

Fig. 4.01: NM R spectrum of 6

rn r- 0 10

r A 0, 0 0. (N v1 11 vA

(V (V CV (V

' I '

7 . 4 7 . 2 7 . 0 6 . 8 6 . 6 6 . 4 ppm

3 2 • 1

(r) CO Cr) CO CU CD (D CU Cr) CU Cr) CO Cr) Cr)

CO "cr CU 0 CO

0 CO 0 Cr) (C CO (r) 'V N. (r) CU CO CU (r) ••,0 CU Cr) Cr) 'V CU Cr) CO CD (C (r) CD 'V 0 (r) (r) Cr) CU 'V (1 ) (C (r) 0 W CU .4-0 N. CO V' cn co CD CD (C (r) CU ti CU CD (C 'V (r) CU 0 0 .-I N- CD CD CD CD CD Cr) CU CU CU CU CU CU CU

CU

O O cn

c:1313, cn c, cn cu cn cu

cp O O c,

cn co cn

O CT)

LD Cr)CD CO •.4-0 (r) CU LC) LD Q(r) CO 'V 0 Cr) CD CO 'V cn co co co cn in c) CD 0 (r) 0 (r) CD CU

0 C Cr) CD r CU •,)

'V

N. CU 'cr Cr) V' N. CO r) •-0 LD V' 0 E •cr co cn h. CU (r) 0 Cu O Cr) N- CD Cr) CU Q CU CU CU 0 0 Co Cr) Cr) CO CD '4" '4' cn cn co co co tr) cr.)

• • • • • • • • • • • h. h. N. h. CD CD CD CD CD CD LD

III rr

CU CU CU CU CU

\11 pt) (r)

c•4

In CA

E "z ; • 13

I I I

7 . 2 7 . 0 6 . 8

9 2 . 8 2 . 7 ppm

PPM 7 6 5 4 3 2

Fig. 4.02: 11-I NMR spectrum of 2

111111 III I

200 175 150 1 I

125 100 I

75 50 25 ppm

cr) co in o o in co o) No 0 "7 N m'7 )11 (D N N (D

"7 "7 -roo ol m LL7 "7 r, O CD

(D )11 N No (D (D )11 '7 '7 Cr) '7 '7 '7 '7 Cr) cr)

N )11 CV 0 a)

N N CD

No No No

V

(D a) in in co N. c=i vq-

'7 01 CD Co D -rot CD

.ti If co In C

Cr) Cr) CD co in in in cu

E Lr3 0

128 127 126 125 ppm

40 30 20

Fig. 4.03: 13C NMR spectrum of 2 with inset APT

187.3 100 -

80 -

60 -

40 -

202.

199.2

143.2 20

91.

I S .1,1.1 1 ,11111. 1 .111111).. 11. (

Fig. 4.04: Mass spectrum of 2

,TD

v.) ,0 o o cn r NeNCO•-• cn O, NrO. err.Onar 0 0 Qra co r .+W en 0 r o r Or Iv r r 0 0 0 0 0 vi• rt C.7

. . . . . . . . . . . . . . . . ............... •• 0 0

‘'''4%.1( \

,II ,O.—, CD CD N N 0,1 c0 ■—■ 0, 0, NN N •a• rn N 0 OD N rn ,rrn000N N N N N N ,O V) r+11n1,101,) CV

O

W

(11111Tif I

'11

10 9 8 7 6 5 4 3 2 1 0 ppm

Fig. 4.05: 'H NMR spectrum of 12

40 20

1 1 1 1 1 I I 1

50 25

0 1 1 1 I 1 F I '

175 150 125

I //

O

OH

in I"- '1:1' 11-1 Cu CD NCI' Cu 11-I 'V 0 CD

in N. I"- CD CO t•••• f•■ 1•••••.

13) rn in CD CD CT) CT) cr) co CD CD 01 a)

• • • • • • • 11-1 01 W 01 tL 111 01 `tr CT) CT) Cu Cu Cu ••-1

1 1 1 1 1 1

PPM 200 1 1 1

100 75

Fig. 4.06: BC NMR spectrum of 12 with inset APT

219

O

H

0

O

197 •

Fig. 4.07: Mass spectrum of 12

100-

Fig. 4.08: 'H NMR spectrum of 18

0

..5 3 . 0 0.0 ppm

00 0, C I-. NJ C4 01 00 r- ,r c ,r

• • • . • cq N N CV 0,1 CV

A\V

CO c.r. NJ 0.1 C) 00 0 CO (NI 0 NJ (fl C T (0

0 0.- ,0 CN . . . . . . . . . . . . . . . .

'7/ I 01 0'1 !-- • • • • • • • • • 0 r0 .--■ a' 0 r.- <7 01 r-. 0 ■0

(2,i lii, .0 re. c.C. ,T, z -.. C

,Z c: il

00 NJ .-, ,-, 0 C .31 01 01 00 , , , , , nrr , , , r' '' 0 r, *-40 00 0

0 :7 (O 01

I \C'\ ' csi ,r)

(0 •-■ CO 01

00 r`•

r r r

1.7 ppm

r 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30

Fig. 4.09: "C NMR spectrum of 18

ppm

100 — 12'). _ 05

4.22

187.1

107.2 80

60 — O

O 1.3

43.1 81.1

40 —

20 —

93.1

ti

25 (1

.()4.

Fig. 4.10: Mass spectrum of 18

I I I I { 1 1 7 6 5 4 . 3 2 1 0 ppm

Fig. 4.11: 111 N1VIR spectrum of 31 8

,o co N c (7, N OD co Ntf) rs)

N N CV N cs,Nncoco

N N N N

co 00

rn

7 . 5 7 . 0 6 . 5 6 . 0 5 . 0 4 . 5 4 . 0 ppm .5

CI

II 141 0)

0 01 N V 01 IA

I's 14 1/40 n. I TN

■eilbe ALA la...1116.101 ObolL.10 luta a i......10,1 ■611, markt; u41.

LISS PPR 1 ? I)

Fig. 4.12: "C NMR spectrum of 31

280

8 .0 7. 5 1. 0 5.5

1 I Lid 4 . 0 3 . 5 3 . 0 2.5 2 . 0 1 . 5 1 . 0 0 . 5 4- 5

Fig. 4.13: NMR spectrum of 32

• • • • • • •

tO rn 0 N

CD

11

1, tOt el, r- r- 1,

to ¶ • TN-

,r (0 to N- tON-

tO N ro co co • • • •

N

1, ,0 C tO r- N QD ro 0 1, 4,

41/ tO N N ,+ 1• •7, 1. en 4) 0 N( . . . . . . . .

N - r-- r-- ,S,/

NY HI

Experimental:

Citralydeneaniline (Schiff's base) 6

To a solution of aniline (18.6 g, 0.2 mole) in ether (20 mL) was added drop-wise,

without stirring a solution of freshly distilled citral (30.0 g, 0.2 mole) in ether (30

mL). Towards the end of addition, cloudiness developed in the reaction mixture,

which was then kept at room temperature for half an hour. The water that

separated out was decanted off from the etherial solution of the Schiffs base and

dried over anhydrous Na2SO4. Evaporation of the solvent gave pale yellow oil of

citralydeneaniline (43 g, 96.2%). IR v (film): 2980, 2920, 1640 (C=C, C=N),

1580, 1490, 1450, 1375, 1220, 760, 695cm-1 .

Above citralydeneaniline, was dissolved in ether (20 mL) and gradually

added while stirring, to an ice-cold solution of 87% H2SO4 (215 mL). The

reaction mixture was then stirred for 3 hours in an ice bath. The dark brown

viscous oil formed was poured over crushed ice and extracted with ether (3 x 50

mL). The combined organic extracts were washed with water, saturated NaC1

solution and dried over anhydrous Na2SO4. Evaporation of the solvent afforded

brown oil, which was purified by steam distillation. The steam volatile fractions

were extracted with ether (3 x 50 mL) and dried over anhydrous Na2SO4.

Evaporation of the solvent gave a mixture of a- and 0-cyclocitra1 (14.23 g,

47.5%) as pale yellow oil.

282

0 0

P-cyclocitral 76

To a cooled (0°C) and well-stirred solution of a- and 13-cyclo- c o

citral (14.0 g) was added drop-wise, 8.5% methanolic KOH (70M 7

mL). The mixture was stirred for 2 hours, at room temperature and then kept

overnight in a refrigerator. The reaction mixture was neutralized with 1N HC1

(105 mL) and then extracted with ether (3 x 20 mL). The combined organic

extracts were washed with 5% NaHCO3 (3 x 10 mL), water (3 x 10 mL) and dried

over anhydrous Na2SO4. Evaporation of the solvent gave a pale yellow oil of

13-cyclocitral 7 (13.9 g, 99.3%).

UV X. (ethanol): 250 nm (calcd. 249 nm)

IR v. (film) - 2920, 2880(-CO-H), 1670(C=C-CHO), 1610, 1460, 1380, 1355,

1305, 1270, 1205, 1120, 1050, 830 cm4

111 NMR (5 ppm, CDC13, 300 MHz): 1.16 (s, 6H, two tert. -CH3), 1.42-1.48 (m,

2H, Cy-Hs), 1.62-1.71 (m, 2H, C4-Hs), 1.78 (s, 3H, olefinic -C113), 2.02 (t, 2H, J

= 6.3, C3.-Hs).

Ethy1-2-methy1 -3-oxobutanoate 1°

A two-neck round-bottomed flask containing absolute

ethanol (mL), fitted with a reflux condenser, a calcium chloride guard tube and a

separating funnel was placed in an ice-bath. On addition of sodium metal (4.6 g,

283

0.2 mole), a violent reaction took place and ethanol started refluxing gently.

Cooling was maintained to moderate the reaction and stirring was continued until

sodium dissolved completely. Ethyl-3-oxobutanoate (26.0 g, 25.3 mL, 0.18

mole) was added to the stirred solution in one portion when the sodium salt of

ethyl-3-oxobutanoate separated out as a white solid. To this was added methyl

iodide (28.4 g, 12.46 mL, 0.2 mole) slowly, and then refluxed for 3 hours.

Ethanol was removed by distillation and the product filtered off, from the salt.

The filtrate extracted with ether (3 x 20 InL), washed with water (3 x 20 mL) and

finally dried over anhydrous Na2SO4. Evaporation of the solvent afforded crude

orange-red liquid, which was distilled under reduced pressure to give colorless

liquid of ethyl-2-methyl-3-oxobutanoate (22.28 g, 77.4%).

UV A. (ethanol): 255 nm

IR v. (film): 2995, 2950, 1740(ester CO), 1715(ketone CO), 1450, 1355, 1260,

1245, 1200, 1150, 1100, 1100, 1050, 1020, 955, 855, 810 cm -1

111 NMR ppm, CDCb, 300 MHz): 1.319 (t, 3H, J = 7.2, 6.6 Hz, -CH2-CH),

1.38 (d, 3H, J = 7.5 Hz, -CH-CH), 2.286 (s, 3H, -CO-CH), 3.54 (q, 1H, J = 7.2,

6.6 Hz, -CH-CH3), 4.24 (q, 2H, J = 7.2 Hz, -CH-CH3).

Ethyl-2, 2-dimethy1-3-oxobutanoate 1°

0 0

The sodium salt of ethyl-2-methyl-3-oxobutanoate was

prepared as above, using sodium (3.3 g, 0.143 mole), ethyl-2-methyl-3-oxo-

butanoate (20 g, 0.138 mole) and absolute ethanol (48 mL). After adding methyl

284

iodide (20.52 g, 9.0 mL, 0.14 mole), the mixture was refluxed for 4 hours and

then worked up as described above, to give reddish brown oil which on

distillation under reduced pressure afforded ethyl-2,2-dimethyl-3-oxobutanoate as

colorless liquid (13.57 g, 61.8%).

UV Xina„ (ethanol): 215 nm

IR vmax (film)• 2990, 2930, 1740(ester CO), 1715(ketone CO), 1455, 1270, 1155,

1120, 1030, 860 cm-1 .

3-Methyl-2-butanone 8 9

8 dimethyl-3-oxobutanoate (6.5 g, 50 mmole) and stirred vigorously at room

temperature until a clear pale yellow solution was obtained (about 2.5 hours). To

this was added drop-wise while stirring 50% H2SO4 (6.5 mL), which resulted in

vigorous evolution of CO2. The mixture was heated to boiling for 1 hour. On

cooling, the ketone that separated out as a pale yellow volatile liquid was

extracted with ether (3 x 10 mL), washed with water (3 x 10 mL) and dried over

anhydrous Na2SO4. Evaporation of the solvent at 40°C gave 3-methy1-2-

butanone 8 (2.72 g, 77%). NOTE: The ketone being volatile is lost to some

extent during removal of the solvent.

IR v. (film)• 2980, 2930, 2880, 1715(C0), 1465, 1385, 1150, 1100, 955 cm-1.

An aqueous solution of 5% NaOH (65 mL), was added to ethyl-2,2-

285

To a thoroughly cooled (-5°C) mixture of 13.-cyclocitral 7

(2.5 g, 16 mmole) and 3-methyl-2-butanone 8 (2.5 g, 29

(E)-4-Methyl-1-(2',6',6 1-trimethykyclohex-l'-en-1 1-y1)-pent-1-en-3-one 6

mmole), was added slowly, a cooled solution of sodium 6

(1.15 g) in absolute ethanol (2.5 mL). The mixture was agitated vigorously for a

period of 15 minutes while maintaining the temperature at -5°C and then treated

with 15% aqueous tartaric acid (5 mL) to remove the excess of alkali. The

residue was extracted with ether (3 x 10 mL), washed with water (3 x 10 mL),

dried over anhydrous Na 2SO4 and concentrated to give 6 as pale yellow, pleasant

smelling oil (3.0 g, 82%).

UV A,„,.(ethanol) 224 and 294 tun, (calcd. 299 nm), Lie (ethanol) 283 nm.

IR v (film) 2975, 2930, 2880, 1670(C=C-CO-), 1620, 1460, 1380, 1360,

1300, 1205, 1120, 1050, 1030, 980 cm-1 .

'H NMR (8 ppm, CDC13, 300 MHz, Fig. 4.01): 1.06 (s, 6H, two tert. -CH), 1.14

[d, 6H, J = 6.9 Hz, -CH(CH3)2], 1.45-1.49 (m, 2H, C5'-Hs), 1.56-1.66 (m, 2H,

C4-Hs), 1.76 (s, 3H, olefinic -CH), 2.06 (t, 2H, J = 6.0, 5.9, C3—Hs), 2.83 [sept,

1H, J = 6.9 Hz, CH(CH3)2], 6.19 (d, 1H, J= 16 Hz, -CH=CHCO-), 7.35 (d, 1H,

J= 16 Hz, CH=CHCO-).

286

Olivacene (1,1-dimethy1-6-isopropyl-1,2,3,4-tetrahydronaphthalin) 2

(E)-4-Methy1-1-(2',6',6'-trimethylcyclohex-1'-en- 1 '-y1)-pent-

1 -en-3-one 6 (1.0 g, 4 4 mmol) was refluxed for 1 hour and

then slowly distilled in presence of catalytic quantity of

iodine (7 mg). The fraction that distilled around 240 °C 2

contained mainly the unreacted ketone 6. The residue was then treated with a

pinch of powdered sodium thiosulphate and filtered through a small silica gel

column using pentane as the eluent. Evaporation of the solvent gave olivacene

(0.643 g, 70%), as pale yellow oil.

IR v. (neat film)• 2970, 2920, 2880, 1610, 1500, 1460, 1390, 1360, 1290, 1205,

1195, 1180, 1155, 920, 890, 825, 705 cm-1 ;

1H NMR (8 ppm, CDC13 , 300 MHz, Fig. 4.02): 1.26 (s, 611, C9, C10 Hs), 1.236 (d,

6H, J= 6.9 Hz, C12, C13 Hs), 1.61-1.65 (m, 2H, C2-Hs), 1.76-1.78 (m, 2H, C3-Hs),

2.73 (t, 2H, J= 6.3 Hz, C4-Hs), 2.81 (1H, sept, J= 6.9 Hz, C11-H), 6.87 (s, IH, H-

5), 6.99 (d, 1H, J= 8.1 Hz, H-8), 7.24 (dd, 1H, J= 8.1, 1.5 Hz, H-7).

13C NMR (8 ppm, CDC13, 300 MHz, Fig. 4.03): 19.91 (C-3), 24.01 (C-12, C-13),

30.89 (C-4), 31.93 (C-9, C-10), 33.55 (C-1, C-11), 39.52 (C-2), 124.02 (C-7),

126.51 (C-8), 126.85 (C-5), 135.77 (C-4a), 143.10 (C-8a), 145.48 (C-6).

EIMS (Fig. 4.04): m/z 202.3 (M+, 24%), 187.3 (MtCH3, 100%), 159.2, 145.2

(32%), 143.2 (16%), 128.2, 117.2.

287

Oxidation of f3-ionone, formation of hydroxyionolactone 12 14

A solution of KMnO4 (10.0 g, 63.3 mmole) in water (150 mL)

was added drop-wise, to a stirred solution of p - ionone (5.0 g,

26 mmole) in a mixture of acetone (55 mL) and water (15 mL)

8

12

for a period of 4.5 hours. The temperature of the reaction mixture was

maintained between 0-5°C, and was not allowed to exceed 6°C during the

addition. The mixture was kept overnight at room temperature. To this was

added sodium acetate (1.25 g) and SO 2 gas (prepared by the action of dil HC1 on

Na2SO3) was bubbled until a clear pale yellow solution was obtained. It was then

saturated with NaC1 and extracted with ether (4 x 25 mL). The combined ether

extracts were treated with saturated NaHCO3 (4 x 25 mL). Acidification of the

alkaline phase followed by ether extraction afforded yellow oil (1.87 g), which

was subjected to steam distillation. The steam volatile fraction was discarded and

the residue remaining in the flask on cooling gave a waxy solid (0.453 g, 8.9%).

Recrystallization from hot water, afforded colorless cubic plates of 12 having m.p

121°C (Lit14. 122°C), which was further purified by sublimation under reduced

pressure, however the m.p of the product remained unchanged.

UV Xmax (EtOH) 238 nm as reported 14

FR v (KBr): 3340 (OH), 2925, 1735, 1455, 1465, 1400, 1390, 1330, 1310,

1270, 1240, 1210, 1110, 1035, 900, 780, 650 cm - 1 .

288

111 NMR (5 ppm, CDC13, 300 MHz, Fig. 4.05): 1.197 (s, 3H, C4-CH3), 1.45 (s,

3H, C4-CH3), 1.53 (s, 3H, C8-Hs), 1.5-2.21 (m, 6H, C5, C6 and C7 Hs).

13C NMR (5 ppm, CDCb, 300 MHz, Fig. 4.06): 19.94 (C-6), 25.24 (C-8), 25.66

(C4-CH3), 29.67 (C4-CH3), 35.81(C-4), 39.03 (C-5), 41.60 (C-7), 85.13 (C-7a),

133.93 (C-3), 141.27 (C-3a), 170.07 (C-2).

CIMS (Fig. 4.07): m/z 219 (M+Na, 100%), 197(M+1, 55%), 179 (29%), 151

(36%), 139 (17%), 123 (37%), 121 (29%), 109 (23%), 95 (26%), 93 (13%), 69

(17%).

Bromination of hydroxyionolactone 12, formation of bromolactone 1814

Potassium bromate (0.085 g, 0.5 mmole) was added to a

solution of 12 (0.07 g, 0.36 mmole) in acetic acid (2 mL). To 0 3

this mixture was added with stirring 48% HBr (0.3 mL) and Br o

18 then stirred at room temperature for 10 minutes. Water (10 mL)

was added to the reaction mixture, when a pale yellow solid separated out, which

was filtered, washed with dilute NaHSO3 (3 x 2 mL), water (3 x 2 mL) and dried

to give 18 (0.088 g, 89.8%). Recrystallisation from petroleum ether containing

traces of benzene, gave pale yellow crystalline solid, which melted with

decomposition at 214°C (Lit 14 . 166-173°C, from ether and petroleum ether).

IR vmax (KBr): 2940, 1790, 1775, 1455, 1385, 1310, 1270, 1245, 1160, 1145,

1060, 1035, 900, 875, 805, 705, 690 cm-1.

289

1II NMR (8 ppm, CDC13, 300 MHz, Fig. 4.08): 1.29 (s, 3H, C4-CH3), 1.46 (s,

3H, C4-CH3), 1.53-1.75 (m, 4H, C5 and C6 Hs), 1.79 (s, 3H, Cg-Hs), 2.476 (m,

1H, H-7b), 2.523 (m, 1H, H-7a),

13C NMR (8 ppm, CDC13, 300 MHz, Fig 4.09): 18.65 (C-6), 23.77 (C-8), 26.25

(C4-CH3), 27.05 (C4-CH3), 36.80 (C-7), 38.92 (C-4), 42.09 (C-5), 79.99 (C-7a),

85.43 (C-3a), 159.76 (C-2), 183.0 (C-3).

EIMS (Fig.4.10): m/z 274.2, 276.2(M), 204.2, 202.2(36%), 187.1, 189.1 (87%),

167.2, 152.2, 151.2(72%), 123.2 (100%), 107.2 (79%), 93.1 (27%), 81.1 (54%),

79.1 (27%), 55.1 (23%), 53.1 (26%), 43.1(55%)

2-Bromo-1,2,2, trimethyl cyclohexene 19 17

To a suspension of bromolactone 18 (0.312 g, 1.13 mmole) in H2O (0.9 mL),

cooled to10°C, was added potassium bicarbonate (0.320 g, 3.2 mmole), and the

mixture stirred vigorously for 45 minutes by maintaining the temperature of the

reaction mixture at 10°C. The bromo compound dissolves completely with

effervescence to give a clear solution. The contents of the flask were extracted

with ether (3 x 2 mL) and the combined ether extracts were washed several times

with water and dried over anhydrous Na2SO4 at 5°C. However, evaporation of

the solvent left behind no organic residue.

290

4-Nitroveratrole 2927

To a stirred solution (<5°C) of 1:1 HNO 3 (3 mL) taken in a

round-bottomed flask was added veratrole (2.71 g, 2.5 mL)

drop-wise. The temperature of the reaction mixture was maintained below 5°C

throughout the addition and then gradually allowed to attain room temperature.

The reaction mixture was poured over crushed ice, the solid that separated was

filtered washed with water and recrystallized from aqueous ethanol to give bright

yellow needle shape crystals of 4-nitroveratrole 29 (3.5 g, 97.4%) having

m.p.95°C as reported 27.

Veratrylamine (3, 4 -dimethoxyaniline) 30 28'29

4-Nitroveratrole 29 (2.0 g, 10.9 mmole) was dissolved in

absolute ethanol (50 mL) and hydrogenated over 10% Pd/C NH2

30

(0.2 g) at room temperature, until absorption of H2 ceased (2 hours). Filtration

followed by evaporation of the solvent under suction gave veratrylamine 30 (1.25

g, 93%) as a white solid in quantitative yield, having imp. 86-87 °C as

. reportea 28'29. NOTE: Veratrylamine being sensitive to light turns pink and then

brown-black when exposed to air and/or light. Hence it is stored away from light

and used immediately after its preparation.

291

2T-Chloro-N-(3,4-dimethoxyphenyl) acetamide 31 11300

To a warm (50°C) mixture of veratrylamine 30 (2.0 g, H

13 mmole) in benzene (20 mL), containing few drops of 31

H

pyridine, was added chloroacetylchloride (1.0 mL) drop-wise while stirring

continuously and then refluxed for 3 hours. The cooled reaction mixture was

poured in ice-cold water, neutralized with aqueous NaHCO3 and extracted with

ethylacetate (3 x 5 mL). The combined organic extracts were washed with water

(2 x 5 mL), dried over anhydrous MgSO4 and concentrated to give long, colorless

needles of 31 (1.86 g, 62%) having m.p. 125 °C.

IR v (KBr): 3261(NH), 1664 (amide CO), 1606, 1515, 1406, 1319, 1174,

1134, 1024, 952, 842, 804, 682, 547 cm -1 .

III NMR (8 ppm, CDC13, 300 MHz, Fig. 4.11): 3.862 (s, 3H, -OCH3), 3.845

(s, 3H, OCH3), 4.15 (s, 2H, CO-CH-C1), 6.80 (1H, d, J = 8.7 Hz, H-5), 6.93

(dd, 1H, J = 8.7, 2.4 Hz, H-6), 7.248 (d, 1H, J= 2.1 Hz, H-2), 8.15 (s, 1H, N-H).

13C NMR (8 ppm, CDC13, 300 MHz, Fig. 4.12): 56.04 (C3-OCH3), 55.93

(C4-0CH3), 42.84 (CH2-Cl), 111.15 and 112.32 (C-2, C-5, C-6), 138.06 (C-1),

146A7 (C-4), 149.05 (C-3), 163.65 (CO).

2 1-Cyano-N-(3,4-dimethoxyphenyl) acetamide 32

To a solution of 31 (0.5 g, 2.1 mmole) in ethanol (25

mL) taken in a two-necked round-bottomed flask was 32

added drop-wise, while stirring, an aqueous solution of KCN (0.156 g, 2.4

292

mmole, dissolved in 10 mL of water), NOTE: Gloves are used throughout the

reaction. The reaction mixture was refluxed for 3 hours, acidified with 2N HCl

(20 mL) and extracted with CH2C12. The aqueous layer discarded and the

combined organic extracts washed with water (2 x 10 mL), dried over anhydrous

MgSO4 and concentrated to give 32 (0.4g, 82%). Recrystalli7ation from aqueous

ethanol afforded white needles (m.p. 168 °C).

IR v (KBr): 3275(NH), 2920, 2260(CN), 1660(C0), 1605, 1560, 1515, 1410,

1260, 1240, 1140, 1020, 960, 840, 690 cm-1 .

1 H NMR (5 ppm, CDC13, 300 MHz, Fig. 4.13): 3.55 (s, 2H, CO-CH-CN), 3.88

(s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.83 (d, 1H, J= 8.6 Hz, H-5), 6.93 (dd, 1H,

J= 8.6, 2.4 Hz, H-6), 7.2 (d, 1H, J= 2.4 Hz, H-2), 7.64 (s, 1H, NH-)

293

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295