08_chapter 3.pdf
TRANSCRIPT
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Chapter 3
Synthesis of Pyrimidinones and Thiopyrimidinones
3.1. Introduction
Pyrimidine is one of the most important classes of biologically active
molecules.1 It is a basic part of DNA and RNA and so widely distributed in
living beings.2 In the last few years pyrimidinone derivatives substituted
either at the C-5 or C-6 position have emerged as potent drugs in the field of
chemotherapy.3 They possess a long range of biological properties such as
antimicrobial,4 antibacterial, 5 antitumour,6,7 antiviral,8 antitubercular,9 and
antifungal10,11 activities. Many marine natural products having pyrimidine
as its core nucleus are used as thyroid drugs.12 The pyrimidine-2-thiol
moiety is present in several compounds of biological and medicinal
interest.13 Pyrimidine-5-carboxamides possess anticarcinogenic activity.14
Antiinflammatory,15 analgesic, and blood platelet aggregation inhibitory
activity16 was found in a number of pyrimidine derivatives. For example,
AZD6140 ticagrelor showed an oral antiplatelet activity,17 6-substituted
uracil derivatives, HEPT,18 emivirine19 (EMV) have been chosen as
candidates for clinical trials and DABOs,20 potent and selective activity
against HIV-1 synthesis and have subjected to biological evaluation as
antitumor and antiviral agents. The dihydropyrimidinones (DHPMs), which
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56
constitute a very important class of organic compounds due to their
attractive pharmacological properties, are also found in many natural
products.21
HN
NO
O
OH
O
S
HN
NO
O
O
HEPT Emivirine (EMV)
N
NNN
N
O OH
OH
SC3H7
NH
F
F
HO
HN
N
O
R
SR2
R1
AZD6140 TicagrelorDABOs
Figure 1
As a part of ongoing research work in our laboratory, 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes were treated with urea and thiourea
resulting the formation of pyrimidinones and thiopyrimidinones respectively
and it is the subject matter of present chapter.
3.2. Pyrimidinones: General methods of synthesis
Pyrimidines are important biological molecule. Biginelli reaction is one
of the most important reactions for the synthesis of pyrimidines. This involves
acid-catalyzed three-component reaction between an aldehyde, a -ketoester
and urea constituting a rapid and facile synthesis of dihydropyrimidines.
For example an efficient synthesis of 3,4-dihydropyrimidinones 4 was
resulted from the reaction of a -ketoester 1, aldehyde 2 and urea 3 in
ethanol, using ferric chloride hexahydrate or nickel chloride hexahydrate as
the catalyst (Scheme 3.1).22
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57
O
OR
O
H2N NH2
O
NH
NH
R1
O
RO
O 0.25 eq. FeCl3.6H2O or NiCl2.6H2o
R1
O
Conc. HCl (cat)EtOH, reflux, 4-5 h
1 2 3 4
H
Scheme 3.1
Uracil and its derivatives can be synthesized by in situ oxidative
decarboxylation of the product obtained from the reaction of malic acid and
urea in modest yields. Another method for the preparation of uracil 6 is the
reaction of -ketoester 5 with urea and subsequent ring closure of the
intermediate on treatment with sodium ethoxide (Scheme 3.2).23
R
O
OR2
O
R1
+H2N NH2
O
NH
NHR1
O
OR
NaOEt
35 6
Scheme 3.2
Substituted uracil derivative 6 can also be prepared by one-pot
condensation reaction of methyl or ethyl -ketoesters 5 and urea in solvent
free condition under microwave irradiation (Scheme 3.3).24
R
O
OR2
O
R1
+H2N NH2
OSolvent-free
MW, 2-6 min NH
NHR1
O
OR
35 6
Scheme 3.3
The reaction of aldehyde 7, -ketoester 8 and urea in the presence of
CAN in methanol under sonication resulted in the formation of 3,4-
dihydropyrimidin-2(1H)-ones 9 in 92% yield (Scheme 3.4) .25
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58
R H
O+ R1
O
OR2
OCAN, urea
MeOH NH
NH
O
R2O
O
R1
R
7 8 9
Scheme 3.4
Substituted 1H-pyrimidin-2-ones 11 have been prepared from
corresponding -ketoacetals 10 on reaction with urea (Scheme 3.5).26
R
O
OMe
OMe
2 h, reflux
Urea, HCl, EtOH N NH
R
O
10 11
Scheme 3.5
In 1996, Hu et al. reported the synthesis of 2-substituted
6-fluoroalkyl-4-(3H)-pyrimidinones, in excellent yields from -fluoroalkyl
acetates or ethyl 3-fluoroalkyl-2-iodoacrylates on treatment with
benzamidine and acetamidine.27 Similarly H.G. Bonacorso et al. have
synthesized 4-phenyl-6-(trifluromethyl)-2(3H)-pyrimidinone 13 from
4-methoxy-1,1,1-trifluro-4-phenyl-3-butene-2-one 12 (Scheme 3.6).28
CF3
O
NH
N
O
CF3
urea, MeOH, Conc. HCl
24-72 h, reflux
H3CO
12 13
Scheme 3.6
4-Trifluoromethyl-5,6,7,8-tetrahydro-2(1H)-quinazolinones 15 can be
obtained by the reaction of -methoxyvinyl trifluoromethyl ketones 14 with
urea in the presence of catalytic amount of BF3-Et2O (Scheme 3.7).29
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H2N NH2
O
ROMe
CF3
O
i-PrOH, BF3.OEt2
reflux, 20 h
NH
NR1
CF3
OR1 R
14 15
Scheme 3.7
Similarly the condensation of 3-(4-methoxyphenyl)-1-(3-pyridyl)-
2-propene-1-one 16 with urea in refluxing ethanolic KOH afforded
4-(4-methoxyphenyl)-6-(3-pyridyl)-3,4-dihydro-2(1H)-pyrimidinone 17
(Scheme 3.8).30
N
O
OMe N
HN
OMe
NH
O
H2N
O
NH2
EtOH/KOH
16 17
Scheme 3.8
El-Gazzar et al. have synthesized thieno[2,3-d]pyrimidin-2-ones 19
from 2-aminothiophene-3-nitriles 18 on reaction with urea (Scheme 3.9).31
SNH2
CNH2N
O
NH2
SNH
NO
H2N
1800 C
18 19
Scheme 3.9
Pyrazolopyrimidinones 21 were synthesized from 5-amino-1-aryl-3-
(methylsulfanyl)-1H-pyrazole-4-carbonitrile 20 by treating with urea
(Scheme 3.10).32
NN
MeS CN
NH2
Ar
H2N NH2
O
NN
MeS
Ar
NH
NH2N
O
1800 C
20 21
Scheme 3.10
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60
The [4+2] cycloaddition reactions of 1,3-diazabuta-1,3-dienes 22
with butadienylketene 23 resulted in the formation of 5-(buta-1,3,-
dienyl)pyrimidinones 25 in excellent yields (Scheme 3.11).33
N
NR1
R3+
H
CO
N
NR1
R2R3
OH
PhPh
N
NR1 OPh
R2R2
22 23 24 25
Scheme 3.11
From the literature survey, it is clear that the reaction of
1,3-bielectrophiles with binucleophile like urea is an effective method for
the synthesis of pyrimidine derivatives.
3.3. Thiopyrimidinones: General methods of synthesis
Biginelli reaction is one of the important reactions for the synthesis of
thio-derivatives of dihydropyrimidinones. This involves acid-catalyzed,
three-component reaction between an aldehyde, a -ketoester and thiourea
constituting a rapid and facile synthesis of thio-derivatives of
dihydropyrimidinones. For example ethyl 6-methyl-4-(4-methylphenyl)-2-
thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate 29 can be synthesized by
the reaction of ethyl acetoacetate 26, 4-methylbenzaldehyde 27 and thiourea
28 using NBS as catalyst (Scheme 3.12).34
O
OEt
O
O
H2N NH2
S
NH
NH
S
EtO
O
0.2 eq. NBS
DMAC, MW (600 W)open vessal, 3-6 min
26 27 28 29
Scheme 3.12
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61
Substituted malonic ester derivatives and Meldrums acid react with
thiourea to yield thiouracil derivatives.35 Substituted thiouracil derivatives
31 can also be prepared by one-pot condensation reaction of -ketoesters 30
and thiourea 28 in solvent free condition under microwave irradiation in
short time (Scheme 3.13).36
R
O
OR2
O
R1
+H2N NH2
SSolvent-free
MW, 2-6 min NH
NHR1
O
SR
30 3128
Scheme 3.13
5,6-Dialkyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinones 34 can be
synthesized by using solid phase approach. In the key step, a polymer-bound
thiouronium salt 32 is condensed with different -ketoesters in presence of
excess Ca(OH)2 in water-ethanol solution (Scheme 3.14).37
SNH.HBr
NH2P
O
EtOR
O R1
Ca(OH)2, H2O/EtOH
HN
N
OR
R1S
5% TFA
CH2Cl2
HN
NH
S
OR
R1
=
O
32 33 34
P
P
Scheme 3.14
Bio et al. synthesized pyrimidinethiol 36 by the condensation of
2-(2,2-diethoxyethyl)malononitrile 35 with thiourea in the presence of
t-BuOK (Scheme 3.15).38
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62
H2N NH2
S
N N
NH2H2N
SH
NC CN
OEt
OEt
OEt
OEt
35 36
t-BuOK
Scheme 3.15
Thiouracil derivative, 6-(1-arylethyl)-5-alkyl-2-thioxo-3,4-dihydro-
4(1H)-pyrimidinone 38 was obtained by the condensation of thiourea in
alkaline medium with ethyl 4-aryl-3-oxopentanoates 37 and ethyl 4-aryl-3-
oxohexanoates (Scheme 3.16).39
Ar
Me
O
OEt
O
NH2CSNH2
EtONa/EtOH
HN
NH
O
SMe
Ar
RR
37 38
Scheme 3.16
Ethyl 2-alkyl-3-oxo-4-(1-naphthyl)butyrates 39 were converted into
5-alkyl-6-(1-naphthylmethyl)-2-thiouracil 40 by reaction with thiourea in the
presence of NaOEt (Scheme 3.17).40
O R1
COOEt H2N NH2
S
NaOEt
NH
NH
O
S
R1
39 40
Scheme 3.17
N-Substituted 5-acetyl-4-alkylthio-6-methyl-2(1H)-pyrimidinethiones 42
can be obtained by the reaction of N,S-acetals 41 with phenylisothiocyanate
and allylisothiocyanate in boiling toluene (Scheme 3.18).41
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63
Me
O
Me
O
R1S NH2
R2NCS
Toulene, reflux N
N S
R2
R1S
Me
O Me
41 42
Scheme 3.18
Britsun et al. reported the synthesis of 3-amino-2-thioxo-2,3-dihydro-
4(1H)-quinazolinone 44 by condensation of methyl 2-(thioxoamino)
benzoate 43 with hydrazine in diethyl ether (Scheme 3.19).42
NCS
COOMe
N2H4, Et2O N
ONH2
NH
S
43 44
Scheme 3.19
Condensation of substituted enaminones 45 with thiourea afforded
corresponding 4,5-bisubstituted pyrimidine-2-thiones 46 (Scheme 3.20).43
R1 O
R2
Thiourea
NaOC2H5/EtOH reflux
NH
N SR1
R2
45 46
N
Scheme 3.20
Condensation of ,-unsaturated ketones 47 with thiourea in
refluxing ethanolic potassium hydroxide afforded 2-thioxopyrimidine
derivatives 48 (Scheme 3.21). 44
NH
Ar
O
H2N
S
NH2NH
HN
Ar
SNH
47 48
Scheme 3.21
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64
Condensation of 3-(4-methoxyphenyl)-1-(3-pyridyl)-2-propene-1-one
49 with thiourea in refluxing ethanolic potassium hydroxide afforded
2-thioxopyrimidine 50 (Scheme 3.22).45
N
O
OMe N
HN
OMe
NH
S
H2N
S
NH2
EtOH/KOH
49 50
Scheme 3.22
Treatment of ethyl 3-substituted-trans-2,3-difluoro-2-acrylate 51
with thiourea resulted in the formation of 6-n-butyl-5-fluoro-2-thiouracil 52
in 68% yield (Scheme 3.23).46
CO2Et
n-Bu F
F
NH2CSNH2/DMF
K2CO3/1000 C N
H
NH
O
S
F
n-Bu
51 52
Scheme 3.23
The -methoxyvinyl trifluoromethyl ketones 53 on reaction with
thiourea in propan-2-ol in the presence of a catalytic amount of BF3-Et2O
afforded 4-trifluoromethyl-5,6,7,8-tetrahydro-2(1H)-thioquinazolinones 54
(Scheme 3.24).47
H2N NH2
S
ROMe
CF3
O
i-PrOH, BF3.OEt2
reflux, 20 h
NH
NR1
CF3
S
R1 R
53 54
Scheme 3.24
Joshi et al. have reported the reaction of thiourea 28 with
malononitrile 55 in the presence of sodium ethoxide and anhydrous ethanol
to afford 4,6-diamino-2-mercaptopyrimidine 56 (Scheme 3.25).48
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65
H2N
S
NH2NC CN
EtONa/EtOH
2.5 h, reflux N
N
NH2
SHH2N
28 55 56
Scheme 3.25
Similarly 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one 58 can
be synthesized by the reaction of ethyl cyanoacetate 57 with thiourea 28 in
the presence of sodium ethoxide (Scheme 3.26).49
H2N NH2
S
CO2Et
CN EtONa
reflux, 3h NH
NH
NH2
SO
28 57 58
Scheme 3.26
The reaction of ethoxymethylenemalononitrile 59 and thiourea
afforded 4-amino-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile 60 with the
elimination of one molecule of ethanol (Scheme 3.27). 50
NC CN
OEt
H2N NH2
S
N NH
NH2
S
CN
59 60
Scheme 3.27
El-Agrody et al. have synthesized 4-amino-6-aryl-1,2-dihydro-2-
thioxopyrimidine-5-carbonitriles 62 from activated nitriles 61 by treating
with thiourea (Scheme 3.28). 51
H
CN
Ar
CN
N NH
S
H2N
S
NH2NH2Ar
CN
N N
SH
NH2ArCN
61 62 63
Scheme 3.28
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66
Eljazi et al. have synthesized pyrazolopyrimidine 65 derivative by the
reaction of 5-amino-1-aryl-3-methylthiopyrazole-4-carbonitrile 64 with
thiourea (Scheme 3.29).52
NN
MeS CN
NH2
Ar
H2N NH2
S
N N
MeS
Ar
NH
NH2N
S
64 65
Scheme 3.29
The reaction of ketene dithioacetal 66 with thiosemicarbazide in
sodium isopropoxide gave 1,4-diamino-2-thioxo-6-methylthio-2-thioxo-1,2-
dihydro-5-pyrimidinecarbthioamide 67 (Scheme 3.30).53
MeS
MeS CN
SH2N
H2NNHC(S)NH2
NaiOPr/iPrOH
heatN
N
NH2
S
NH2
MeS
H2N
S
66 67
Scheme 3.30
Ketene N,S-acetal 68 reacted with thiourea to form the corresponding
2-thioxo-4-pyrimidinone 69 (Scheme 3.31).54
Scheme 3.31
6-Amino-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile derivative 71
was prepared by the reaction of thiosemicarbazone 70 with
arylidenemalononitrile in boiling DMF containing few drops of piperidine
(Scheme 3.32).55
O
EtOCN
HN
PhSCH3
H2N NH2
S
KOH/EtOH NH
NH
SO
NHPh
NC
68 69
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67
Ar
CN
CN
O
O
ClN
HN NH2
S DMF piperidine O
OCl
NN
NS
NH2
CN
Ar
70 71
Scheme 3.32
The reaction of 3-amino-4-carbethoxy-2-phenylpyrazole 72 with
thiourea and phenylisothiocyanate under microwave irradiation gave
pyrazolo[3,4-d]thiopyrimidine derivatives 73 & 74 (Scheme 3.33). 56
NN NH2
COOEtR
PhNH
N
NN
NH
NH
NN
Ph
R NHAr
S
O
S
R
Ph
H2N NH2
S
Ar N C S
MW MW
7273 74
Scheme 3.33
The reaction of 6-amino-4-(4-chlorophenyl)-2-pyridin-2-yl-pyridine-
5-carbonitrile 75 with carbon disulphide in the presence of aqueous KOH
gave pyrido[2,3-d]pyrimidine-2,4-dithione 76 (Scheme 3.34).57
N
CNAr
NH2Py
CS2, KOH
heat N NH
NH
Py
Ar S
S
75 76
Scheme 3.34
When 2-aminothiophene-3-nitrile 77 was fused with thiourea at
180 C, thioxopyrimidine derivative 78 was formed (Scheme 3.35).58
SNH2
CNH2N
S
NH2
SNH
NS
H2N
77 78
Scheme 3.35
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68
The reaction of 5-amino-1-benzyl-2-hydroxy-1H-imidazole-4-
carbonitrile 79 with benzoyl isothiocyanate followed by treatment with
sodium hydroxide afforded 6-amino-9-benzyl-2-sulfanyl-9H-purin-8-ol 80
(Scheme 3.36).59
N
NOH
H2N
NC N
N N
NOH
NH2
HS
(a) BzNCS, THF, rt
(b) 2N NaOH, THF reflux
79 80
Scheme 3.36
Interaction of 2-amino-4,5,6,7-tetrahydrobenzothiophene-3-
carboxamide 81 with carbon disulphide yielded 2-thioxo-2,3,5,6,7,8-
hexahydro[1]benzothieno-[2,3-d]pyrimidin-4(1H)-one 82 (Scheme 3.37).60
SNH2
ONH2
CS2
SNH
ONH
S
SNH
ON
SH
81 82 83
Scheme 3.37
The reaction of 4-chloro-2,3-dihydro-1,3-thiazole-5-carbaldehyde 84
with thiourea in ethanol solution containing triethylamine at reflux
temperature afforded thiopyrimidinone derivatives 85 (Scheme 3.38).61
N
S
Cl
CHO
Ar
Ar
H2N NH2
S
N
HNN
S
Ar
Ar
S
84 85
Scheme 3.38
6-Amino-5-[bis(benzylthio)methylene]pyrimidine-2,4-dione 87 was
prepared by the reaction of 3,3-bis(benzylthio)-2-cyanoacrylate 86 with
thiourea (Scheme 3.39).62
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69
S
S
NC
EtOOC
Ph
pipiridine/EtOH
O
S
S
Ph
Ph
H2N HN
HNS
86 87
NH2NH2
S
Ph
Scheme 3.39
Bioactive pyrimidines like 5-(1H-imidazol-1-yl)-4-phenyl-2(1H)-
pyrimidinethione 90 can be synthesized from imidazolylacetophenone 88 on
reaction with dimethylformamide dimethylacetal (DMFDMA) in xylene
solution followed by treatment with thiourea (Scheme 3.40).63
NN
DMFDMA
Ph
O N NPh
O
NMe2
H2N NH2
SN N
NH
N
Ph
S
88 89 90
Scheme 3.40
Ethyl 2-benzylaminocyclopent-1-enecarboxylate 91 on treatment with
trimethylsilyl isothiocyanate yielded 1-benzyl-2-thioxo-1,2,3,5,6,7-
hexahydro-4H-cyclopenta[d]pyrimidin-4-one 92 in 83% yield (Scheme
3.41).64
NH
OEt
O
Ph
(CH3)3SiNCS
NaHCO3
HN
N
O
S
Ph
91 92
Scheme 3.41
Thiourea was reacted with 2-formyl-L-arabinal 93 in the presence of
sodium hydride in tetrahydrofuran to afford pyrimidine C-nucleoside
analogue 94 in 38% yield as a pale yellow syrup through the sequential
combination of addition-elimination and ring closure reaction (Scheme
3.42).65
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70
OOBn
BnO
CHO
H2N NH2
S
NaH, THF, 0-220C N
NH
S
HOOBn
OBn
93 94
Scheme 3.42
Literature review showed that the reaction of thiourea with
1,3-bielectrophiles is a general method for the synthesis of functionalized
pyrimidinethiones. Our interest was to explore the synthetic potential of
-formylketene dithioacetals for the synthesis of functionalized heterocyclic
compounds and so we decided to treat -formylketene dithioacetals with
thiourea to get versatile intermediates, pyrimidinethiones, which can find
wide applications for the synthesis of natural products.
3.4. Results and Discussion
3.4.1. Synthesis of 5-Aroyl-4-(methylsulfanyl)-2(3H)-pyrimidinone (96)
2-(4-Methoxybenzoyl)-3,3-bis(alkylsulfanyl)acrylaldehyde 95c on
treatment with urea in the presence of Conc. HCl in methanol at reflux
temperature for an hour, afforded 5-(4-methoxybenzoyl)-4-(methylsulfanyl)-
2(3H)-pyrimidinone 96c as a white solid, mp 184-186, in 81% yield. The
NMR spectrum in DMSO-d6 showed that 96c existed as an equilibrium mixture
with 5-(4-methoxybenzoyl)-4-(methylsulfanyl)-2-pyrimidinol 97c in the
ratio 60:40 (Scheme 3.43).
O
SCH3
SCH3
O H
O
NH
SCH3
N O
O
N
SCH3
N OH
H2N NH2
O
Conc. HClMethanolreflux
96c 97c95c
H3CO H3COH3CO
Scheme 3.43
The products were characterized on the basis of spectroscopic
methods and elemental analyses. GCMS (Fig.2) m/z 276 (M+). The IR
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71
spectrum (Fig.3), gave major absorptions at 3062 due to NH group, 1722
and 1672 due to carbonyl groups. In the 1H NMR spectrum (300 MHz,
DMSO-d6, Fig.4), it gave peaks at 2.44 and 2.45 for methylsulfanyl group,
3.83 and 3.85 for methoxy group, multiplets at 6.98-7.07, doublet at
7.465 and 7.69-7.74 for aromatic protons, a singlet at 7.80 and 7.92 for H-
6 protons and 11.32 for OH proton and a broad singlet at 11.78 for NH
proton. The 13C NMR spectrum (Fig.5) of the compound shows resonance
at 12.88 and 13.03 for methylsulfanyl group, 55.28 and 55.46 for
methoxy group, 189.28 and 189.42 for carbonyl carbon and 177.77 for OH
substituted carbon and 164.55 for carbonyl carbon atoms. The peaks at
112.6, 113.19, 113.4, 113.9, 129.84, 130.43, 131.64, 146.48, 150.86, 152.43,
161.2, 161.78, 162.82, and 162.94 for aromatic and heterocyclic carbon
atoms of both the isomers were in accordance with the proposed structures.
As the 1H NMR spectrum shows the presence of NH and OH groups
in the ratio 60:40, it is clear that there is equilibrium between pyrimidinone
and pyrimidinol.
100 125 150 175 200 225 250 2750
25000
50000
75000
100000
125000
20191
119
230215
24513926018789
186172158103 273
Figure 2 GCMS of 5-(4-methoxybenzoyl)-4-(methylsulfanyl)-2(3H)-
pyrimidinone 96c
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72
Figure 3 IR spectrum of 5-(4-methoxybenzoyl)-4-(methylsulfanyl)-2(3H)-pyrimidinone 96c
Figure 4 1HNMR spectrum of 5-(4-methoxybenzoyl)-4-(methylsulfanyl)-
2(3H)-pyrimidinone 96c
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73
Figure 5 13C NMR spectrum of 5-(4-methoxybenzoyl)-4-(methylsulfanyl)-2(3H)-pyrimidinone 96c
The mechanism for the formation of 5-(4-methoxybenzoyl)-4-
(methylsulfanyl)-2(3H)-pyrimidinone from 2-(4-methoxybenzoyl)-3,3-
bis(methylsulfanyl)acrylaldehyde is explained as follows: Initially, the urea
is condensed with the aldehyde to form an imine intermediate. Cyclization
of the imine intermediate by an intramolecular Michael reaction of the
amino group to the ketene dithioacetal, followed by aromatization with the
elimination of methanethiol resulted in the formation of expected
pyrimidinones in good yields (Scheme 3.44). The pyrimidinone 96c is in
equilibrium with the pyrimidinol 97c.
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74
O
SMe
SMe
O H H2N NH2
O
O
SMe
SMe
N
O NH2
O
NH
SMe
N O
SMeO
NH
SMe
N O
O
SMe
SMe
NH
O NH2
HO
O
N
SMe
N OH
95c 98c 99c
100c 96c 97c
H3COH3CO H3CO
H3COH3COH3CO
Scheme 3.44
The reaction was extended to other substituted 2-aroyl-3,3-
bis(methylsulfanyl)acrylaldehydes 95a-e to get 5-aroyl-4-(methylsulfanyl)-
2(3H)-pyrimidinones 96a-e (Scheme 3.45)
Ar
O
SMe
SMe
Ar
O
NH
SMe
N OO H
Urea, Con.HCl(Cat.)
Methanol,reflux
Ar
O
N
SMe
N OH
95 96 97
Scheme 3.45
Table 1 Synthesis of 5-aroyl-4-(methylsulfanyl)-2(3H)-pyrimidinones 96a-e
95 & 96 Ar Yield %
a C6H5 81
b CH3C6H4 80
c 4-CH3OC6H4 81
d 4-BrC6H4 84
e 4-ClC6H4 82
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75
3.4.2 Synthesis of (Aryl)[6-(methylsulfanyl)-2-thioxo-1,2-dihydro-5-pyrimidinyl]methanone (101)
In a pilot experiment 2-(methoxybenzoyl)-3,3-bis(methylsulfanyl)-
acrylaldehyde 95c was treated with thiourea in the presence of Conc.HCl in
methanol at reflux temperature for one hour. The reaction afforded (4-
methoxyphenyl)[6-(methylsulfanyl)-2-thioxo-1,2-dihydro-5-pyrimidinyl]-
methanone 101c as a white solid, mp 200-202 C in 67% yield. The NMR
spectrum in DMSO-d6 showed that 96c existed as an equilibrium mixture with
(4-methoxyphenyl)[6-(methylsulfanyl)-2-mercaptyl-1,2-dihydro-5-
pyrimidinyl]methanone 102c in the ratio 60:40 (Scheme 3.46).
O
SMe
SMe O
NH
SMe
N SO H
O
N
SMe
N SH
Thiourea, Con.HCl(Cat.)
Methanol,refluxH3CO H3CO H3CO
95c 101c 102c
Scheme 3.46
The products were characterized on the basis of spectroscopic
methods and elemental analyses. GCMS (Fig.6) m/z 292 (M+). In the IR
spectrum (Fig.7), it gave major absorption peaks at 3068, 1664 due to NH
and carbonyl groups respectively. In the 1HNMR spectrum(300 MHz,
DMSO-d6, Fig.8), it gave peaks at major peaks at 2.35 and 2.45 for
methylsulfanyl groups, 3.83 and 3.86 for methoxy groups, 6.99-7.10 (m,
2.464H), 7.73-7.79 (m, 5H) for aromatic protons and 7.70 for H-6,
12.75 for SH and 13.60 for NH proton. The 13C NMR spectrum (Fig.9) of
the compound shows peaks at 12.56 and 13.18 for methylsulfanyl group,
55.51 and 55.59 for methoxy group, 189.25 and 188.76 for carbonyl
carbon,178.69 for thiocarbonyl carbon and 176.23 for SH substituted
carbon. The peaks at 116.64, 116.69, 129.30, 129.78, 131.77, 132.19,
144.52, 146.3, 158.8, 163.19 and 173.18 for aromatic and heterocyclic
carbon atoms of both the isomers were in accordance with the proposed
structures. As the 1H NMR spectrum shows the presence of NH and SH
-
76
groups in the ratio 60:40, it is clear that there is equilibrium between
pyrimidinethione and pyrimidinethiol.
80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 2900
25000
50000
75000
100000
125000
135
77 185
92273
121
107291
187207170 258245146 218
Figure 6 GCMS spectrum of (4-methoxyphenyl)[6-(methylsulfanyl)-2-thioxo-1,2-dihydro-5-pyrimidinyl]methanone 101c
Figure 7 IR spectrum of (4-methoxyphenyl)[6-(methylsulfanyl)-2-thioxo-1,2-dihydro-5-pyrimidinyl]methanone 101c
-
77
Figure 8 1HNMR spectrum of (4-methoxyphenyl)[6-(methylsulfanyl)-2-thioxo-1,2-dihydro-5-pyrimidinyl]methanone 101c
Figure 9 13C NMR spectrum of (4-methoxyphenyl)[6-(methylsulfanyl)-2-thioxo-1,2-dihydro-5-pyrimidinyl]methanone 101c
-
78
The mechanism of the reaction is expected to be same as that in
the formation of pyrimidinones (Scheme 3.47).
O
SMe
SMe
O H H2N NH2
S
O
SMe
SMe
N
S NH2
O
NH
SMe
N S
SMeO
NH
SMe
N S
O
SMe
SMe
NH
S NH2
HO
O
N
SMe
N SH
95c 103c 104c
H3CO H3CO H3CO
H3COH3COH3CO
105c101c102c
Scheme 3.47
The reaction was generalized to other substituted 2-aroyl-3,3-
bis(methylsulfanyl)acrylaldehydes 95a-e to get (aryl)[6-(methylsulfanyl)-2-
thioxo-1,2-dihydro-5-pyrimidinyl]methanones 101a-e (Scheme 3.48).
Ar
O
SMe
SMe
Ar
O
NH
SMe
N SO H
Ar
O
N
SMe
N SH
Thiourea, Con.HCl(Cat.)
Methanol,reflux
101 10295
Scheme 3.48
Table 2 Synthesis of (aryl)[6-(methylsulfanyl)-2-thioxo-1,2-dihydro-5-pyrimidinyl]methanones 101a-e
95 & 101 Ar Yield %
a C6H5 70
b 4-CH3C6H4 66
c 4-CH3OC6H4 67
d 4-BrC6H4 73
e 4-ClC6H4 75
-
79
3.5. Conclusion
In conclusion we have developed a facile method for the synthesis of
biologically important 5-aroyl-4-(methylsulfanyl)-2(3H)-pyrimidinones and
aryl-[6-(methylsulfanyl)-2-thioxo-1,2-dihydro-5-pyrimidinyl]methanone from
2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes. The presence of alkylsulfanyl
and thioxo groups on the pyrimidinone moiety makes the molecule more
facile for further elaboration to annulated heterocyclic compounds.
3.6. Experimental
Melting points were determined on a Buchi 530 melting point
apparatus and were uncorrected. The IR spectra were recorded as KBr
pellets on a Schimadzu IR-470 spectrometer and the frequencies are reported
in cm-1. The 1H NMR spectra were recorded on a Brucker WM 300 (300
MHz) spectrometer using TMS as internal standard and DMSO-d6 as
solvent. The 13C NMR spectra were recorded on a Brucker WM 300 (75.47
MHz) spectrometer using DMSO-d6 as solvent. Both 1H NMR and
13C NMR values are expressed as (ppm). The Electron Impact Mass
spectra were obtained on a GCMS-Schimadzu 5050 model instrument. The
CHN analyses were done on an Elementar Vario EL III Carlo Erba 1108
instrument.
All reagents were commercially available and were purified before
use. The previously reported aroylketene dithioacetals66 and -formylketene
dithioacetals67 were prepared by the known procedures. Anhydrous sodium
sulphate was used as drying agent. All purified compounds gave a single
spot upon TLC analyses on silica gel 7GF using ethyl acetate/hexane
mixture as eluent. Iodine vapors or KMnO4 solution in water was used as
developing agent for TLC.
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80
3.6.1. Synthesis of 5-Aroyl-4-(methylsulfanyl)-2(3H)-pyrimidinone (96)
General procedure
To a solution of 2-aroyl-2-[3,3-bis(methylsulfanyl)acrylaldehyde 95
(1.26 g, 5 mmol) in methanol, urea (300 mg, 5 mmol) and Conc.HCl (1 mL)
were added. The reaction mixture was refluxed for one hour. When the TLC
examination showed the complete disappearance of the aldehyde, the
reaction mixture was cooled and poured into ice-cold water, extracted with
ethyl acetate, the combined organic phase was washed with water, dried and
the solvent was evaporated off. The crude product obtained was
recrystallized from ethyl acetate.
O
N
NH
O
SCH3
C12H10N2O2SMol. Wt.: 246.29
5-Benzoyl-4-(methylsulfanyl)-2(3H)-pyrimidinone
96a was obtanied by the reaction of 2-benzoyl-3,3-
bis(methylsulfanyl)acrylaldehyde 95a (1.26 g, 5
mmol) with urea (300 mg, 5 mmol) as white solid;
mp, 268-270 C; yield 997 mg (81%).
1H NMR (300 MHz, DMSO-d6) = 2.39 (s, 3H,
SCH3), 7.51-7.55 (m, 3H, ArH), 7.565-7.71 (m, 2H,
ArH), 7.93 (s, 1H, H-4), 12.3 (s, 1H, NH) ppm.
13C NMR (75.47 MHz, DMSO-d6) = 14.7 (SCH3),
112.75, 128.99, 129.42, 132.74, 137.92, 151.29,
152.54, 178.52 (CO), 191.19 (CO) ppm.
IR (KBr, max) = 3050, 1670, 1630, 1598, 1527,
1423, 1365, 1305, 1245 cm-1.
GCMS m/z (%) = 246 (M+, 18), 231 (28), 213 (73),
199 (9), 185 (17), 155 (54), 105 (65), 77 (100).
Anal. Calcd for C12H10N2O2S: C, 58.52; H, 4.09; N,
11.37; S, 13.02. Found: C, 58.50; H, 4.11; N, 11.39.
-
81
O
N
NH
O
SCH3
O
N
N
OH
SCH3
andH3C
H3C
C13H12N2O2SMol. Wt.: 260.31
5-(4-Methylbenzoyl)-4-(methylsulfanyl)-2(3H)-
pyrimidinone 96b was obtanied by the reaction of 2-
(4-methylbenzoyl)-3,3-bis(methylsulfanyl)-
acrylaldehyde 95b (1.33 g, 5 mmol) with urea (300
mg, 5 mmol) along with 5-(4-methylbenzoyl)-4-
(methylsulfanyl)-2-pyrimidinol 97b as white solid;
mp 230-232 C; yield 1.04 g (80%, 96b:97b =
60:40).
1H NMR (300 MHz, DMSO-d6) = 2.37 (s, 1.92H,
CH3), 2.38 (s, 1.08H, CH3) 2.39 (s, 1.92H, SCH3),
2.43 (s, 1.08H, SCH3), 7.24-7.39 (m, 2.56H, ArH),
7.59 -7.65 (m, 1.44H, ArH),, 7.83 (s, 0.64H, H-6),
7.92(s, 0.46H, H-6), 11.33 (s, 0.46H, OH), 11.88 (s,
0.64H, NH) ppm.
13C NMR (75.47 MHz, DMSO-d6) = 13.03 (SCH3),
13.19 (SCH3), 20.89 (CH3), 21.07 (CH3), 112.35,
112.53, 128.28, 128.61, 129.08, 129.24, 134.72, 135.10,
140.15, 142.94, 147.01, 150.76, 152.22, 161.63, 164.28
(CO), 177.92 (C OH), 190.36 (CO) ppm.
IR (KBr, max) = 3122, 1726, 1677, 1606, 1514,
1338, 1218, 1174 cm-1.
GCMS m/z (%) = 260 (M+, 76), 259 (54), 245 (100),
243 (0.9), 244 (2), 230 (4), 229 (22), 218 (5), 216
(5), 213 (2), 203 (2), 202 (11), 201 (15), 199 (4), 186
(8), 141 (1), 134 (41), 119 (8), 103 (6), 77 (10)
Anal. Calcd for C13H12N2O2S: C, 59.98; H, 4.65; N,
10.76; S, 12.32. Found: C, 60; H, 4.62; N, 10.77; S,
12.30.
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82
O
N
NH
O
SCH3
O
N
N
OH
SCH3
andH3CO
H3CO
C13H12N2O3SMol. Wt.: 276.31
5-(4-Methoxylbenzoyl)-4-(methylsulfanyl)-2(3H)-
pyrimidinone 96c was obtanied by the reaction of 2-
(4-methoxylbenzoyl)-3,3-bis(methylsulfanyl)-
acrylaldehyde 95c (1.41 g, 5 mmol) with urea (300
mg, 5 mmol) along with 5-(4-methoxybenzoyl)-4-
(methylsulfanyl)-2-pyrimidinol 97c as a white solid;
mp 184-186 C; yield 1.11 g (81%, 96c:97c =
60:40).
1H NMR (300 MHz, DMSO-d6) = 2.44 (s, 1.92H,
SCH3), 2.45 (s, 1.08H, SCH3), 3.83 (s, 1.92H, OCH3),
3.85 (s, 1.08H, OCH3), 6.98-7.07 (m, 2.56H, ArH), 7.46
(d, 0.44H, J = 9 Hz, ArH), 7.69-7.74 (m, 1H, ArH),
7.80 (s, 0.46H, H-6), 7.92 (s, 0.64H, H-6), 11.32 (s,
0.64, NH), 11.78 (s, 0.46H, OH) ppm.
13C NMR (75.47 MHz, DMSO-d6) = 12.88 (SCH3),
13.03 (SCH3), 55.28 (OCH3), 55.46 (OCH3), 112.65,
113.19, 113.40, 113.90, 129.84, 130.43, 131.64,
146.48, 150.86, 152.43, 161.20, 161.78, 162.82,
162.94, 164.55 (CO), 177.77 (OH C), 189.28 (CO),
189.42 (CO) ppm.
IR (KBr, max) = 3062, 1722, 1672, 1566, 1512,
1375, 1282, 1261, 1122, 1026, cm-1.
GCMS m/z (%) = 276 (M+, 0.2), 261 (4), 260 (22) 259
(20), 245 (34), 230 (49), 229 (25), 215 (41), 202 (36),
201 (100), 135 (9), 119 (67), 104 (1), 91 (9), 76 (16).
Anal. Calcd for C13H12N2O3S: C, 56.51; H, 4.38; N,
10.14; S, 11.60. Found: C, 56.53; H, 4.40; N, 10.11; S,
12.32.
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83
O
N
NH
O
SCH3
O
N
N
OH
SCH3
andBr
Br
C12H9BrN2O2SMol. Wt.: 325.18
5-(4-Bromobenzoyl)-4-(methylsulfanyl)-2(3H)-
pyrimidinone 96d was obtanied by the reaction of 2-(4-
bromobenzoyl)-3,3-bis(methylsulfanyl)acrylaldehyde
95d (1.66 g, 5 mmol) with urea (300 mg, 5 mmol) along
with 5-(4-bromobenzoyl)-4-(methylsulfanyl)-2-
pyrimidinol 97d as white solid; mp 224-226 C; yield
1.37 g (84%, 96d:97d = 80:20).
1H NMR (300 MHz, DMSO-d6) = 2.38 (s, 2.3H,
SCH3), 2.41 (s, 0.7H, SCH3), 7.42 (d, 1.52H, J = 9
Hz, ArH), 7.62-7.66 (m, 0.96H, ArH), 7.73 (d,
1.52H, J = 9 Hz, ArH), 7.91 (s, 0.76H, H-6), 8.61 (s,
0.24H, H-6), 12.39 (s, 0.76H, NH/OH) ppm.
13C NMR (75.47 MHz, DMSO-d6) = 13.12 (SCH3),
13.13 (SCH3), 106.69, 112.17, 123.72, 126.22,
130.39, 130.70, 131.06, 131.60, 136.64, 151.17,
152.12, 155.12, 163.85 (CO), 178.03 (OH C), 189.85
(CO), 206.45 (CO) ppm.
IR (KBr, max) = 3217, 3068, 1720, 1666, 1585,
1560, 1413, 1359, 1278, 1116, 1089 cm-1.
GCMS m/z (%) = 326 (M++2, 6), 324 (M+ 8), 310
(30), 308 (27), 295 (97), 293 (100), 278 (3), 184
(28), 182 (31), 77 (21).
Anal. Calcd for C12H9BrN2O2S: C, 44.32; H, 2.79; N,
8.61; S, 9.86. Found: C, 44.52; H, 2.57; N, 8.62; S, 9.88.
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84
O
N
NH
O
SCH3
O
N
N
OH
SCH3
andCl
Cl
C12H9ClN2O2SMol. Wt.: 280.73
5-(4-Chlorobenzoyl)-4-(methylsulfanyl)-2(3H)-
pyrimidinone 96e was obtanied by the reaction of 2-(4-
chlorobenzoyl)-3,3-bis(methylsulfanyl)acrylaldehyde
95e (1.43 g, 5 mmol) with urea (300 mg, 5 mmol) along
with 5-(4-chlorobenzoyl)-4-(methylsulfanyl)-2-
pyrimidinol 97e as white solid; mp 244-246 C; yield
1.15 g (82%, 96e:97e = 60:40). 1H NMR (300 MHz, DMSO-d6) = 2.38 (s, 1.71H, SCH3), 3.75 (s, 1.29, SCH3), 7.51-7.61 (m, 2.28H,
ArH), 7.70-7.77 (m, 1.72, ArH), 7.94 (s, 0.57H, H-
6), 8.62 (s, 0.43H, H-6), 11.38 (s, 0.43H, OH), 12 (s,
0.57H, NH) ppm. 13C NMR (75.47 MHz, DMSO-d6) = 13.12 (SCH3), 13.3 (SCH3), 111.82, 127.77, 128.15, 130.19,
130.94, 134.91, 136.29, 136.65, 137.17, 137.32,
148.11, 150.79, 152.18, 161.67, 163.87 (CO), 178.02
(C OH), 189.70 (CO), 189.85 (CO) ppm.
IR (KBr, max) = 3072, 1687, 1645, 1587, 1479, 1427, 1380, 1292, 1230, 1164 cm-1.
GCMS m/z (%) = 282 (M+2, 1), 280 (M+, 0.4), 279
(0.5), 262 (20), 261 (100), 245 (1), 232 (3), 190 (5),
139 (1), 103 (7), 77 (46).
Anal. Calcd for C12H9ClN2O2S: C, 51.34; H, 3.23; N,
9.98; S, 11.42. Found: C, 51.37; H, 3.20; N, 9.99; S,
11.43.
3.6.2 Synthesis of (Aryl)[6-(methylsufanyl)-2-thioxo-1,2-dihydro-5-pyrimidinyl]methanone
General procedure
The 2-aroyl-3,3-bis(methylsulfanyl)acrylaldehyde 95 (1.26 g, 5
mmol) was dissolved in methanol, thiourea (380 mg, 5 mmol) and Conc.
HCl (1 mL) were added. The reaction mixture was refluxed for an hour. The
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85
TLC examination shows the complete disappearance of the aldehyde. Then
the reaction mixture was poured into ice-cold water. Extracted with ethyl
acetate, the combined organic phase was washed with water, dried and the
solvent was evaporated off. The crude product obtained was recrystallized
from ethyl acetate.
O
NH
SMe
N S
C12H10N2OS2Mol. Wt.: 262.35
[6-(Methylsulfanyl)-2-thioxo-1,2-dihydro-5-
pyrimidinyl](phenyl)methanone 101a was obtanied by
the reaction of 2-benzoyl-3,3-bis(methylsulfanyl)-
acrylaldehyde 95a (1.26 g, 5mmol) with thiourea
(380 mg, 5 mmol) as white solid; mp 240-242 C;
yield 918 mg (70%).
1H NMR (300 MHz, DMSO-d6) = 2. 5 (s, 3H, SCH3),
7.31-7.78 (m, 6H, ArH, H-6), 13.23 (s, 1H, NH) ppm.
13C NMR (75.47 MHz, DMSO-d6) = 13 (SCH3),
116.44, 128.62, 129.57, 133.38, 137.64, 145.94,
159.12, 176.78 (C=S), 190.92 (CO) ppm.
IR (KBr, max) = 3066, 1658, 1652, 1589, 1546,
1510, 1348, 1240, 1218, 1186, 1078.
GCMS m/z (%) = 262 (M+, 32), 247 (14), 229 (46),
215 (5), 142 (6), 105 (64), 77 (100).
Anal. Calcd for C12H10N2OS2 C, 54.94; H, 3.84; N, 10.68;
S, 24.44. Found: C, 54.97; H, 3.82; N, 10.65; S, 24.47.
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86
O
N
SMe
N SH
C13H12N2OS2Mol. Wt.: 276.38
O
NH
SMe
N Sand
(4-Methylphenyl)[6-(methylsulfanyl)-2-thioxo-1,2-
dihydro-5-pyrimidinyl]methanone 101b was obtanied
by the reaction of 2-(4-methylbenzoyl)-3,3-
bis(methylsulfanyl)acrylaldehyde 95b (1.33 g, 5
mmol) with thiourea (380 mg, 5 mmol) in equilibrium
with (4-methylphenyl)[6-(methylsulfanyl)-2-
mercaptyl-1,2-dihydro-5-pyrimidinyl]methanone
102b as white solid; mp 234-236 C; yield 912 mg
(66%, 101b: 102b = 50:50).
1H NMR (300 MHz, DMSO-d6) = 2.37 (s, 1.5H,
CH3), 2.39 (s, 1.5H, CH3), 2.45 (s, 1.5H, SCH3),
2.49 (s, 1.5H, SCH3), 7.28 (d, 1H, J = 9Hz), 7.34 (d,
1H, J = 9Hz), 7.71-7.63 (m, 2.5H, ArH, H-6), 7.76
(s, 0.5H, H-6), 12.75 (s, 0.5H, SH), 13.49 (s, 0.5H,
NH) ppm.
13C NMR (75.47 MHz, DMSO-d6) = 13.22 (SCH3),
21.13 (CH3), 21.17 (CH3), 116.34, 116.57, 128.81,
129.26, 129.34, 129.40, 134.26, 134.61, 143.39,
143.49, 145.06, 147.16, 158.73, 173.33, 176.30 (SH
C), 178.69 (C=S), 189.98 (CO), 190.42 (CO) ppm.
IR (KBr, max) = 3195, 1668, 1646, 1583, 1522,
1393, 1298, 1203, 1146 cm-1.
GCMS m/z (%) = 276 (M+, 32), 261 (13), 243 (42),
228 (8), 185 (16), 171 (30), 157 (10), 156 (7), 137 (20),
119 (74), 105 (11), 91 (100), 77 (7).
Anal. Calcd for C13H12N2OS2 C, 56.49; H, 4.38; N,
10.14; S, 23.20. Found: C, 56.45; H, 4.37; N, 10.17; S,
23.22.
-
87
O
NH
SMe
N SMeO
C13H12N2O2S2Mol. Wt.: 292.38
O
N
SMe
N SHMeO
OR
(4-Methoxylphenyl)[6-(methylsufanyl)-2-thioxo-
1,2-dihydro-5-pyrimidinyl]methanone 101c was
obtanied by the reaction of 2-(methoxylbenzoyl)-
3,3-bis(methylsulfanyl)acrylaldehyde 95c ( 1.41 g,
5mmol) with thiourea (380mg, 5 mmol) in
equilibrium with (4-methoxylphenyl)[6-
(methylsufanyl)-2-mercaptyl-1,2-dihydro-5-
pyrimidinyl]methanone 102c as white solid; mp 200-
202 C; yield 979 mg (67%, 101c: 102c = 60: 40).
1H NMR (300 MHz, DMSO-d6) = 2.45 (s, 1.8H,
SCH3), 2.49 (s, 1.2H, SCH3), 3.84 (s, 1.2H, OCH3),
3.86 (s, 1.8H, OCH3), 6.99-7.10 (m, 1.6H, ArH),
7.70(s, 0.4H), 7.73-7.79 (m, 3H, ArH, H-6), 12.75
(s, 0.4H, SH), 13.60 (s, 0.6H, NH) ppm.
13C NMR (75.47 MHz, DMSO-d6) = 12.56
(SCH3), 13.18(SCH3), 55.51(OCH3), 55.59 (OCH3),
113.52, 114.02, 116.64, 116.69, 129.30, 129.78,
131.77, 132.19, 144.52, 146.30, 158.80, 163.19,
173.18 (ArC) 176.23 (SH C), 178.69 (C=S), 188.76
(CO), 189.25 (CO) ppm.
IR (KBr, max) = 3068, 1664, 1637, 1595, 1512,
1392, 1240, 1180, 1080 cm-1.
GCMS m/z (%) = 292 (M+, 4), 291 (17), 277 (2), 259
(4), 245 (5), 218 (3), 185 (58), 135 (100), 121 (29), 107
(22), 92 (44), 77 (59).
Anal. Calcd for C13H12N2O2S2 C, 53.40; H, 4.14; N,
9.58; S, 21.93. Found : C, 53.44; H, 4.16; N, 9.58;
S, 21.93
and
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88
O
N
SMe
N SHBr
C12H9BrN2OS2Mol. Wt.: 341.25
O
NH
SMe
N SBrand
(4-Bromophenyl)[6-(methylsulfanyl)-2-thioxo-1,2-
dihydro-5-pyrimidinyl]methanone 101d was
obtanied by the reaction of 2-(4-bromobenzoyl)-3,3-
bis(methylsulfanyl)acrylaldehyde 95d (1.66 g,
5mmol) with thiourea (380mg, 5 mmol) in
equilibrium with (4-bromophenyl)[6-(methylsulfanyl)- 2-
mercaptyl-1,2-dihydro-5-pyrimidinyl]methanone
102d as white solid; mp 224-226 C.; yield 1.26 g
(73%, 101d: 102d = 60:40).
1H NMR (300 MHz, DMSO-d6) = 2.36 (s, 1.98H,
SCH3), 2.46 (s, 1.02H, SCH3), 7.47 (d, 0.68H, J = 9
Hz, ArH), 7.69-7.65 (m, 2.64H, ArH), 7.74 (s, 0.66H,
H-6), 7.78 (d, 0.68H, J = 9 Hz, ArH), 7.83 (s, 0.44)
12.80 (s, 0.44H, SH), 13.81 (s, 0.66H, NH) ppm.
13C NMR (75.47 MHz, DMSO-d6) = 13.26
(SCH3), 14.12 (SCH3), 115.65, 116.05, 126.76,
130.74, 130.84, 131.12, 131.18, 131.23, 131.72,
136.11, 138.44, 147.90, 158.71, 173.31, 176.44 (SH
C), 178.74 (C=S), 189. 69 (CO), 189.94 (CO) ppm.
IR (KBr, max) = 3150, 1724, 1666, 1598, 1564,
1402, 1350, 1232, 1201 cm-1.
GCMS m/z (%) = 342 (M+2, 33) 340 (M+, 35), 338
(31), 325 (91), 323 (100), 311 (54), 309 (31), 295 (13),
185 (17), 184 (43), 158 (14), 155 (26), 127 (44), 76 (41).
Anal. Calcd for C12H9BrN2OS2: C, 42.24; H, 2.66; N,
8.21; S, 18.79. Found: C, 42.23; H, 2.67; N, 8.21;
18.79.
-
89
O
NH
SMe
N SCl
C12H9ClN2OS2Mol. Wt.: 296.80
(4-Chlorophenyl)[6-(methylsulfanyl)-2-thioxo-1,2-
dihydro-5-pyrimidinyl]methanone 101e was
obtanied by the reaction of 2-(4-chlorobenzoyl)-
3,3-bis(methylsulfanyl)acrylaldehyde 95e ( 1.43 g,
5mmol) with thiourea (380mg, 5 mmol) as white
solid; mp 244-246 C; yield 1.11 g 75%.
1H NMR (300 MHz, DMSO-d6) = 2.46 (s, 3H,
SCH3), 7.71(d, 2H, J = 8 Hz, ArH), 7.76 (d, 2H, J =
8 Hz, ArH), 7.85 (s, 1H) 12.80 (s, 1H, NH) ppm.
13C NMR (75.47 MHz, DMSO-d6) = 13.45 (SCH3),
117.42, 128.52, 131.18, 139.65, 143.94, 155.12,
164.56, 178.68 (C=S), 190.92 (CO) ppm.
IR (KBr, max) = 3095, 1643, 1596, 1587, 1512,
1353, 1253, 1176, 1078 cm-1.
GCMS m/z (%) = 296 (M+, 21), 298 (M+2, 8), 281
(10), 279 (21), 263 (7), 261 (4), 249 (10), 185 (100),
141 (27), 139 (73), 111 (76), 77 (52).
Anal. Calcd for C12H9ClN2OS2: C, 48.56; H, 3.06; N,
9.44; S, 21.61. Found: C, 48.50; H, 3.9; N, 9.44; S,
21.62.
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90
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