synthesis of pyrimidinones and...

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

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 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

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 β-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 β-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, 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

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 β-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 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

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 β-methoxyvinyl trifluoromethyl ketones 14 with

urea in the presence of catalytic amount of BF3-Et2O (Scheme 3.7).29

59

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

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 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

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

61

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

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 β-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

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

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 α,β-unsaturated ketones 47 with thiourea in

refluxing ethanolic potassium hydroxide afforded 2-thioxopyrimidine

derivatives 48 (Scheme 3.21). 44

NH

Ar

O

H2N

S

NH2

NH

HN

Ar

SNH

47 48

Scheme 3.21

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 NH

NH

O

S

F

n-Bu

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

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

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

NH2

NH2ArCN

N N

SH

NH2ArCN

61 62 63

Scheme 3.28

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

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

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

69

S

S

NC

EtOOC

Ph

pipiridine/EtOH

O

S

S

Ph

Ph

H2N HN

HNS

86 87

NH2

NH2

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

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

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

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

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 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

proton. The 13C 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.

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

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

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.

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

H3CO H3CO 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

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 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

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 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.

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) 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.

13C 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.

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) 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.


13.19 (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)


10.76; S, 12.32. Found: C, 60; H, 4.62; N, 10.77; S,

12.30.

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).


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.


13.03 (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).


10.14; S, 11.60. Found: C, 56.53; H, 4.40; N, 10.11; S,

12.32.

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).


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.


13.13 (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.

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) 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. 13C 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

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) δ = 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) 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.

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).


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.


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.

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).


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) 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

and

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).


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) 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.

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) 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.


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.

90

3.7. References

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