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
constitute a very important class of organic compounds due to their
attractive pharmacological properties, are also found in many natural
products.21

F
F
NH
O O O N N
R N
HN HN HN N N SC3H7
O N S R2
O N S N OH
O O
R1 OH
O
OH HO
HEPT Emivirine (EMV) DABOs AZD6140 Ticagrelor

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 β-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 β-ketoester 1, aldehyde 2 and urea 3 in
ethanol, using ferric chloride hexahydrate or nickel chloride hexahydrate as
the catalyst (Scheme 3.1).22

56
 0.25 eq. O R1
O O O O FeCl3.6H2O or NiCl2.6H2o
RO NH
OR R1 H H2N NH2 Conc. HCl (cat)
EtOH, reflux, 4-5 h N O
H
1 2 3 4

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 β-ketoester 5 with urea and subsequent ring closure of the
intermediate on treatment with sodium ethoxide (Scheme 3.2).23
O
O O O R1
NaOEt NH
R OR 2 +
H2N NH2
R N O
R1 H
5 3 6

Scheme 3.2

Substituted uracil derivative 6 can also be prepared by one-pot

condensation reaction of methyl or ethyl β-ketoesters 5 and urea in solvent
free condition under microwave irradiation (Scheme 3.3).24
O
O O O R1
Solvent-free NH
R OR2 + H2N NH2 MW, 2-6 min
R N O
R1 H
5 3 6

Scheme 3.3

The reaction of aldehyde 7, β-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

57
 O R

O O O 2
R O NH
CAN, urea
+ R1 OR 2
R H MeOH R1 N O
H
7 8 9

Scheme 3.4

Substituted 1H-pyrimidin-2-ones 11 have been prepared from

corresponding β-ketoacetals 10 on reaction with urea (Scheme 3.5).26
O
O OMe
Urea, HCl, EtOH N NH
R OMe
2 h, reflux R
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 α-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
H3CO O N

CF3 urea, MeOH, Conc. HCl N O

H
24-72 h, reflux

12 13

Scheme 3.6

4-Trifluoromethyl-5,6,7,8-tetrahydro-2(1H)-quinazolinones 15 can be
obtained by the reaction of β-methoxyvinyl trifluoromethyl ketones 14 with
urea in the presence of catalytic amount of BF3-Et2O (Scheme 3.7).29

58
 OMe O O CF3
R H2N NH2 R1
CF3 N

i-PrOH, BF3.OEt2 N O
H
R1 reflux, 20 h 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
O
O O HN NH
H2N NH2

N OMe EtOH/KOH N OMe

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
O H2N
CN N
H 2N NH2 O
NH2 0 NH
180 C
S S

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

O H2 N
MeS CN N
MeS
H2N NH2 O
N NH2 NH
N N
1800 C N
Ar Ar
20 21
Scheme 3.10

59
 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

Ph
Ph O Ph
R1 N O
R1 N C R1 N O
H
+ N
N R3 H N
R3
R2 R2
R2

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 β-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
O
O O S
0.2 eq. NBS
EtO NH
OEt H2 N NH2 DMAC, MW (600 W)
open vessal, 3-6 min N S
H

26 27 28 29

Scheme 3.12

60
 Substituted malonic ester derivatives and Meldrum’s acid react with
thiourea to yield thiouracil derivatives.35 Substituted thiouracil derivatives
31 can also be prepared by one-pot condensation reaction of β-ketoesters 30
and thiourea 28 in solvent free condition under microwave irradiation in
short time (Scheme 3.13).36
O
O O S R1
Solvent-free NH
+
R OR2 H2 N NH2 MW, 2-6 min
R N S
R1 H

30 28 31

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 β-ketoesters in presence of
excess Ca(OH)2 in water-ethanol solution (Scheme 3.14).37
O
R
EtO O
O
NH.HBr O R1 R R
S HN 5% TFA HN
P
NH2 CH2Cl2 S N R1
P Ca(OH)2, H2O/EtOH S N R1
H

32 33 34

O
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

61
 OEt

OEt S OEt

OEt H2N NH2 H2N NH2

N N
NC CN t-BuOK
SH

35 36
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

Me R O
OEt NH2CSNH2 R
Ar HN
O O EtONa/EtOH S Me
N
H
Ar
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
S NH

COOEt H2N NH2 N S

H
O R1 NaOEt

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

62
 O O
R1S N S
R2NCS
Me Me
Toulene, reflux Me N
R2
R1S NH2
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
O
NCS NH2
N2H4, Et2O N

COOMe N S
H

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 Thiourea R1 N S

N NaOC 2H5/EtOH 2 NH
R2 reflux
R

45 46

Scheme 3.20

Condensation of α,β-unsaturated ketones 47 with thiourea in

refluxing ethanolic potassium hydroxide afforded 2-thioxopyrimidine
derivatives 48 (Scheme 3.21). 44
S
H
N S
Ar H2N NH2 N
H
NH
N
H O
Ar
47 48
Scheme 3.21

63
 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
S
O S HN NH
H2N NH2

N OMe EtOH/KOH N OMe

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
O
F
n-Bu F NH2CSNH2/DMF NH
0
F CO2Et K2CO3/100 C n-Bu N S
H

51 52
Scheme 3.23

The β-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

OMe O S CF3
R H2N NH2 R1
CF3 N

i-PrOH, BF3.OEt2 N S
H
R1 reflux, 20 h 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

64
 NH2
S
EtONa/EtOH N
H2N NH2 NC CN
2.5 h, reflux H N N SH
2

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
NH2
S CN EtONa NH
H2N NH2 reflux, 3h
CO2Et O N S
H
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

S S

NC CN H2N NH2 N NH

NH2
OEt
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
S SH
S
Ar
N NH N N
H H2N NH2
CN
Ar NH2 Ar NH2
CN
CN CN
61 62 63

Scheme 3.28

65
 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

S H2 N
MeS CN N
MeS
H2 N NH2 S
N NH
N NH2 N
N
Ar Ar
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
S NH2
MeS CN
H2NNHC(S)NH2 H2N N
i i
MeS S Na OPr/ PrOH MeS N S
H2N heat NH2
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

S Ph
NH
CN
H H2N NH2 NC
EtO N NH
Ph
KOH/EtOH O N S
O SCH3
H
68 69

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

66
 O Ar CN S N Ar
H O
Cl N NH2
N CN Cl N
N CN
S DMF
O NH2
piperidine O
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

NH S O
R R
R COOEt
Ar H2N NH2
N Ar N C S NH
N N
N NH2
N N S MW N MW N N S
Ph H Ph H
Ph
73 72 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
Ar Ar S
CN CS , KOH
2 NH

Py N NH2 heat Py N N S
H
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
S H2N
CN N
H2N NH2 S
NH2 NH
S S
77 78

Scheme 3.35

67
 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
NH2

NC N N N
OH (a) BzNCS, THF, rt OH
N (b) 2N NaOH, THF HS N N
H2N 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

O O O
NH2 NH N
CS2 S SH
NH2 NH NH
S S S

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
S
Ar Cl Ar H
H2N NH2 N N S
N
Ar
Ar CHO S N
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

68
 Ph S
NH2 Ph
NC S H2N NH2 HN S
S
EtOOC S pipiridine/EtOH HN S
O Ph
Ph
86 87
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

O S Ph
N N N
O DMFDMA N N
N Ph H2N NH2
N
Ph N S
NMe2 H
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
O
Ph
HN
NH O (CH3)3SiNCS
NaHCO3 S N
OEt
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

69
 S OBn
OBn
O H2N NH2 HO NH
BnO
NaH, THF, 0-220C OBn
CHO N S
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
α-formylketene dithioacetals for the synthesis of functionalized heterocyclic
compounds and so we decided to treat α-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
O SCH3 O SCH3 O SCH3
H2N NH2
SCH3 NH N

H3CO O H Conc. HCl H3CO N OH

H3CO N O
Methanol
reflux
95c 96c 97c

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

70
 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 δ 2.44 and 2.45 for methylsulfanyl group,
δ 3.83 and 3.85 for methoxy group, multiplets at δ 6.98-7.07, doublet at
7.465 and 7.69-7.74 for aromatic protons, a singlet at δ 7.80 and 7.92 for H-
6 protons and δ 11.32 for OH proton and a broad singlet at δ 11.78 for NH
13
proton. The C NMR spectrum (Fig.5) of the compound shows resonance
at δ 12.88 and 13.03 for methylsulfanyl group, δ 55.28 and 55.46 for
methoxy group, δ 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 δ
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.

125000

100000 201
91

75000
119

50000 230
215
139 245
25000 187 260
89
158 172 186
103
273
0
100 125 150 175 200 225 250 275

Figure 2 GCMS of 5-(4-methoxybenzoyl)-4-(methylsulfanyl)-2(3H)-

pyrimidinone 96c

71
Figure 3 IR spectrum of 5-(4-methoxybenzoyl)-4-(methylsulfanyl)-2(3H)-
pyrimidinone 96c

1
Figure 4 HNMR spectrum of 5-(4-methoxybenzoyl)-4-(methylsulfanyl)-
2(3H)-pyrimidinone 96c

72
 13
Figure 5 C 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.

73
 O SMe O SMe O SMe

SMe O SMe SMe

H3CO O H H2N NH2 H3CO HO NH H3CO N

O NH2 O NH2
95c 98c 99c

O SMe O SMe O SMe

SMe
NH NH N
H3CO N O H3CO N O H3CO N OH
100c 96c 97c

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)
O SMe O SMe O SMe
Urea, Con.HCl(Cat.) Ar NH
Ar SMe Ar N

O H Methanol,reflux N O 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 C6 H 5 81

b CH3C6H4 80

c 4-CH3OC6H4 81

d 4-BrC6H4 84

e 4-ClC6H4 82

74
 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 O SMe O SMe

Thiourea, Con.HCl(Cat.)
SMe NH N
Methanol,reflux
H3CO O H H3CO N S H3CO N SH

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 δ 2.35 and 2.45 for
methylsulfanyl groups, δ 3.83 and 3.86 for methoxy groups, δ 6.99-7.10 (m,
2.464H), δ 7.73-7.79 (m, 5H) for aromatic protons and δ 7.70 for H-6, δ
12.75 for SH and δ 13.60 for NH proton. The 13C NMR spectrum (Fig.9) of
the compound shows peaks at δ 12.56 and 13.18 for methylsulfanyl group, δ
55.51 and 55.59 for methoxy group, δ 189.25 and 188.76 for carbonyl
carbon,178.69 for thiocarbonyl carbon and 176.23 for SH substituted
carbon. The peaks at δ 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

75
 groups in the ratio 60:40, it is clear that there is equilibrium between
pyrimidinethione and pyrimidinethiol.

135

125000

100000

77 185
75000
92
273
50000
121
107
25000 291
187
170 207 245 258
146 218
0
80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290

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

76
 1
Figure 8 HNMR spectrum of (4-methoxyphenyl)[6-(methylsulfanyl)-2-
thioxo-1,2-dihydro-5-pyrimidinyl]methanone 101c

13
Figure 9 C NMR spectrum of (4-methoxyphenyl)[6-(methylsulfanyl)-2-
thioxo-1,2-dihydro-5-pyrimidinyl]methanone 101c

77
 The mechanism of the reaction is expected to be same as that in
the formation of pyrimidinones (Scheme 3.47).
O SMe O SMe O SMe

SMe S SMe SMe

H3CO O H H2N NH2 H3CO HO NH H3CO N

S NH2 S NH2
95c 103c 104c

O SMe O SMe O SMe

SMe
N NH NH
H3CO N SH H3CO N S H3CO N S
102c 101c 105c
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).
O SMe O SMe O SMe

Ar SMe Thiourea, Con.HCl(Cat.) Ar NH Ar N

O H Methanol,reflux N S N SH
95 101 102
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 C6 H 5 70

b 4-CH3C6H4 66

c 4-CH3OC6H4 67

d 4-BrC6H4 73

e 4-ClC6H4 75

78
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
1
MHz) spectrometer using DMSO-d6 as solvent. Both H NMR and
13
C NMR values are expressed as δ (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 α-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.

79
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 SCH3 5-Benzoyl-4-(methylsulfanyl)-2(3H)-pyrimidinone
NH
96a was obtanied by the reaction of 2-benzoyl-3,3-
N O
C12H10N2O2S bis(methylsulfanyl)acrylaldehyde 95a (1.26 g, 5
Mol. Wt.: 246.29
mmol) with urea (300 mg, 5 mmol) as white solid;
mp, 268-270 °C; yield 997 mg (81%).
1
H NMR (300 MHz, DMSO-d6) δ = 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.
13
C NMR (75.47 MHz, DMSO-d6) δ = 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, νmax) = 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.

80
 O SCH3 5-(4-Methylbenzoyl)-4-(methylsulfanyl)-2(3H)-
NH
pyrimidinone 96b was obtanied by the reaction of 2-
H3C N O
and (4-methylbenzoyl)-3,3-bis(methylsulfanyl)-
O SCH3
acrylaldehyde 95b (1.33 g, 5 mmol) with urea (300
N

H3C N OH
mg, 5 mmol) along with 5-(4-methylbenzoyl)-4-

C13H12N2O2S
(methylsulfanyl)-2-pyrimidinol 97b as white solid;
Mol. Wt.: 260.31
mp 230-232 °C; yield 1.04 g (80%, 96b:97b =
60:40).
1
H NMR (300 MHz, DMSO-d6) δ = 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.
13
C NMR (75.47 MHz, DMSO-d6) δ = 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, νmax) = 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.

81
 O SCH3 5-(4-Methoxylbenzoyl)-4-(methylsulfanyl)-2(3H)-
NH
pyrimidinone 96c was obtanied by the reaction of 2-
H3CO N O
and (4-methoxylbenzoyl)-3,3-bis(methylsulfanyl)-
O SCH3
acrylaldehyde 95c (1.41 g, 5 mmol) with urea (300
N
mg, 5 mmol) along with 5-(4-methoxybenzoyl)-4-
H3CO N OH
(methylsulfanyl)-2-pyrimidinol 97c as a white solid;
C13H12N2O3S
Mol. Wt.: 276.31 mp 184-186 °C; yield 1.11 g (81%, 96c:97c =
60:40).

H NMR (300 MHz, DMSO-d6) δ = 2.44 (s, 1.92H,

1

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.
13
C NMR (75.47 MHz, DMSO-d6) δ = 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, νmax) = 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.

82
 O SCH3
5-(4-Bromobenzoyl)-4-(methylsulfanyl)-2(3H)-
NH
pyrimidinone 96d was obtanied by the reaction of 2-(4-
Br N O
and
bromobenzoyl)-3,3-bis(methylsulfanyl)acrylaldehyde
O SCH3

N
95d (1.66 g, 5 mmol) with urea (300 mg, 5 mmol) along
Br N OH with 5-(4-bromobenzoyl)-4-(methylsulfanyl)-2-
C12H9BrN2O2S
Mol. Wt.: 325.18
pyrimidinol 97d as white solid; mp 224-226 °C; yield
1.37 g (84%, 96d:97d = 80:20).
1
H NMR (300 MHz, DMSO-d6) δ = 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.
13
C NMR (75.47 MHz, DMSO-d6) δ = 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, νmax) = 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.

83
 O SCH3
5-(4-Chlorobenzoyl)-4-(methylsulfanyl)-2(3H)-
NH
pyrimidinone 96e was obtanied by the reaction of 2-(4-
Cl N O
and chlorobenzoyl)-3,3-bis(methylsulfanyl)acrylaldehyde
O SCH3 95e (1.43 g, 5 mmol) with urea (300 mg, 5 mmol) along
N with 5-(4-chlorobenzoyl)-4-(methylsulfanyl)-2-
Cl N OH pyrimidinol 97e as white solid; mp 244-246 °C; yield
C12H9ClN2O2S
1.15 g (82%, 96e:97e = 60:40).
Mol. Wt.: 280.73 1
H NMR (300 MHz, DMSO-d6) δ = 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.
13
C NMR (75.47 MHz, DMSO-d6) δ = 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, νmax) = 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

84
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 SMe [6-(Methylsulfanyl)-2-thioxo-1,2-dihydro-5-
NH
pyrimidinyl](phenyl)methanone 101a was obtanied by
N S
C12H10N2OS2 the reaction of 2-benzoyl-3,3-bis(methylsulfanyl)-
Mol. Wt.: 262.35
acrylaldehyde 95a (1.26 g, 5mmol) with thiourea
(380 mg, 5 mmol) as white solid; mp 240-242 ° C;
yield 918 mg (70%).

H NMR (300 MHz, DMSO-d6) δ = 2. 5 (s, 3H, SCH3),

1

7.31-7.78 (m, 6H, ArH, H-6), 13.23 (s, 1H, NH) ppm.
13
C NMR (75.47 MHz, DMSO-d6) δ = 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, νmax) = 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.

85
 O SMe (4-Methylphenyl)[6-(methylsulfanyl)-2-thioxo-1,2-
NH
dihydro-5-pyrimidinyl]methanone 101b was obtanied
N S
and by the reaction of 2-(4-methylbenzoyl)-3,3-
O SMe
bis(methylsulfanyl)acrylaldehyde 95b (1.33 g, 5
N

N SH
mmol) with thiourea (380 mg, 5 mmol) in equilibrium
C13H12N2OS2 with (4-methylphenyl)[6-(methylsulfanyl)-2-
Mol. Wt.: 276.38
mercaptyl-1,2-dihydro-5-pyrimidinyl]methanone
102b as white solid; mp 234-236° C; yield 912 mg
(66%, 101b: 102b = 50:50).
1
H NMR (300 MHz, DMSO-d6) δ = 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.
13
C NMR (75.47 MHz, DMSO-d6) δ = 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, νmax) = 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.

86
 O SMe (4-Methoxylphenyl)[6-(methylsufanyl)-2-thioxo-
NH
1,2-dihydro-5-pyrimidinyl]methanone 101c was
MeO N S
and
OR obtanied by the reaction of 2-(methoxylbenzoyl)-
O SMe 3,3-bis(methylsulfanyl)acrylaldehyde 95c ( 1.41 g,
N
5mmol) with thiourea (380mg, 5 mmol) in
MeO N SH
C13H12N2O2S2 equilibrium with (4-methoxylphenyl)[6-
Mol. Wt.: 292.38
(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).
1
H NMR (300 MHz, DMSO-d6) δ = 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.
13
C NMR (75.47 MHz, DMSO-d6) δ = 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, νmax) = 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

87
 O SMe (4-Bromophenyl)[6-(methylsulfanyl)-2-thioxo-1,2-
NH
dihydro-5-pyrimidinyl]methanone 101d was
Br N S
and
obtanied by the reaction of 2-(4-bromobenzoyl)-3,3-
O SMe

N
bis(methylsulfanyl)acrylaldehyde 95d (1.66 g,
Br N SH 5mmol) with thiourea (380mg, 5 mmol) in
C12H9BrN2OS2
Mol. Wt.: 341.25 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).

H NMR (300 MHz, DMSO-d6) δ = 2.36 (s, 1.98H,

1

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.
13
C NMR (75.47 MHz, DMSO-d6) δ = 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, νmax) = 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.

88
 O SMe
(4-Chlorophenyl)[6-(methylsulfanyl)-2-thioxo-1,2-
NH
dihydro-5-pyrimidinyl]methanone 101e was
Cl N S
C12H9ClN2OS2 obtanied by the reaction of 2-(4-chlorobenzoyl)-
Mol. Wt.: 296.80
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%.
1
H NMR (300 MHz, DMSO-d6) δ = 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.
13
C NMR (75.47 MHz, DMSO-d6) δ = 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, νmax) = 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.

89
3.7. References

1. a) El-Agrody, M. A; Ali, M. F; Eid, A. F; El-Nassag, A. A. M; El-

Sherbeny, G; Bedair, H. A. Phosphorus Sulfur and Silicon, 2006, 181,
839; b) Katritzky, A. R. Advances in Heterocyclic Chemistry
(Academic Press, New York, 1966), Vol. 6. Thioxopyrimidines and
Related Derivatives 863; c) Criag C. R.; Shidenman, E. F J.
Pharmacal. Exp. Ther., 1971, 35, 179; Chem.Abstr., 74, 62990j (1971).
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