Reactions of α-Formylketene Dithioacetals with Amidines: A …shodhganga.inflibnet.ac.in/bitstream/10603/7091/9/09_chapter 3.pdf · Chapter 3 Reactions of α-Formylketene Dithioacetals

Chapter 3

Reactions of α-Formylketene Dithioacetals with Amidines: A Facile Method for the Synthesis of Pyrimidinecarbaldehydes and their Derivatives

3.1 Introduction

The chemistry of pyrimidine and its derivatives has been studied

extensively since the past century due to their diverse biological activities.1

Though pyrimidine itself does not exist in nature, substituted pyrimidine

moieties are found as a part of more complex systems like Vitamin B1 and

nucleic acids and are widely distributed in nature. Some pyrimidine

derivatives give stable and good quality nanomaterials with many

important electrical and optical properties.2 They are also important as an

interesting structural coordinating substitute ligand in supramolecular

metallo-grid like architectures3 and in novel inorganic/organic hybrid types

of molecular wires.4 In addition pyrimidines are important for many

biochemical processes, including sucrose and cell wall polysaccharide

metabolism5 and also as drugs in medicinal chemistry.6 They possess

antifoliate, antimicrobial, anticancer, anticonvulsant, antirubella, antiHIV-1

and selective hepatitis B virus inhibiting activities.7 Dihydropyrimidinones,

the products of the Biginelli reaction, are widely used in the

pharmaceutical industry as calcium channel blockers.8 Pyrimidine-5-

carbaldehydes are valuable precursors for the synthesis of drugs used for

the treatment of Alzheimer disease.9 Some annulated pyrimidines are used

in the treatment of cardiovascular diseases,10 human cancers produced by

oncogenic activation of RET,11 insomnia12 and asexual blood stages of all

types of malaria.13 The increasing importance of pyrimidine and its

derivatives as intermediates for the synthesis of biologically and

Pyrimidinecarbaldehydes 18

industrially useful compounds prompted us to develop a new method for

their synthesis from α-formylketene dithioacetals. In this Chapter we

describe the reactions of α-formylketene dithioacetals with various

amidines leading to the synthesis of pyrimidinecarbaldehydes and their

derivatives. A study on the fluorescent behaviour of the derivatives of

pyrimidinecarbaldehydes is also described in this chapter.

3.2. Pyrimidines: General Methods of Synthesis

Generally pyrimidines are prepared by the reactions of 1,3-bielectrophilic

substrates like 1,3-dicarbonyl compounds,14 α-oxoketene acetals,15

enaminoketones,16 vinylamidinium salts, β-substituted α,β-unsaturated

ketones and aldehydes17 with suitable N-C-N fragments such as urea, thiourea

or amidines. The cyclization usually involves a double condensation with the

elimination of molecules like water, thiols, hydrogen halides, alcohols etc or

condensation by addition of amino group to CN or to polarized double bonds

without an elimination reaction. In the literature there are many reports

including multicomponent reactions like Biginelli reactions for the synthesis

of functionalized pyrimidines and their derivatives.18 Pinner’s classical

condensation of acetylacetone with benzamidine to give 4,6-dimethyl-2-

phenylpyrimidine is a typical reaction to get pyrimidines from 1,3-dicarbonyl

compounds.19 The reaction is usually done under alkaline conditions but

sometimes neutral or acidic conditions are also advantageous. α, β-

Unsaturated carbonyl compounds are also good source of substituted

pyrimidines.20 Pyrimidines have been obtained from α-oxoketene

dithioacetals also by combining with proper 1,3-dinitrogen nucleophiles. The

general procedure involves the reaction of a 1,3-dinitrogen nucleophile with a

β-alkylthio or β,β-bis(alkylthio)-α,β-unsaturated carbonyl compound in a

sequential conjugated addition-elimination reaction to afford vinylogous

amides or ketene-N,S-acetals respectively. These intermediates could undergo


intramolecular 1,2-nucleophilic addition to the carbonyl group to afford

pyrimidines.21 Originally this strategy was used for the synthesis of annulated

pyrimidines 3 by the reaction of ketene dithioacetal 2 with 2-aminopyridine 1

(Scheme 1). 22

ROCN

H3CS SCH3

N

NH2

N

N

CN

SCH3

O O

n-BuOH, 5h, Reflux+

1 2 3

Scheme 1

Subsequently Junjappa and co-workers extended the generality of this

strategy by using guanidine and thiourea as nucleophilic reagents. Reaction

of α-unsubstituted-β,β-bis(alkylthio)-α,β-enones 4 with guanidinium

nitrate in refluxing methanolic sodium methoxide afforded 2-amino-4-

methoxypyrimidines 5, while utilization of thiourea afforded the

corresponding 2-mercapto-4-alkoxy analogs (Scheme 2). These procedures

have been extended to α-aryl substituted β,β-bis(alkylthio)-α,β-enones and

oxoketene dithioacetals derived from cyclicketones.23

N N

XH

OMeH

R

H2N

H2N

X= NH,S

MeONa,MeOH

R = Alkyl, Aryl.

H

H3CS SCH3

O

RX

4 5 Scheme 2

Similarly 6-styryl and 6-(4-aryl-1,3-butadienyl)pyrimidines 7 had been

prepared from the styryl and butadienyl substituted α-oxoketene

dithioacetals 6 (Scheme 3).24 This procedure had also been used with a


slight modification in the reaction of ketene dithioacetals derived from α-

cyanoketones with guanidine or S-alkylthioureas.

SCH3

SCH3O

N N

X

OMe

H2N

X

NH2

X= NH,S

Ar

ArMeONa,MeOH

6 7

Scheme 3 Rudorf and Augustin also had reported the synthesis of a pyrimidine 9

employing amidines and ketene dithioacetals 8 derived from α-

cyanoketones (Scheme 4).25

Ar

H3CSH2N

X

NHN N

X

CNAr

OCN NaOEt, EtOH

Reflux, 10-12 h+

SCH3 SCH3

X = Me, Ph 8 9

Scheme 4

β,β-Bis(alkylthio)-α,β-enones containing an α−alkyl substituent undergo

base promoted isomerizations prior to reaction with guanidine. Thus 2-

aminopyrimidines 11 had been prepared from vinylogous thiol esters 10B

obtained by base promoted rearrangement of α−oxoketene dithioacetals 10

(Scheme 5).26

Ar

H3CS SCH3H2N

NH

NH2

N N

NH2

Ar

OCH3 MeONa, MeOH

Reflux, 10-12 h

H3CS

Ar

SCH3

OCHBase

+

SCH3

10 10B 11

Scheme 5


Potts et al synthesized a variety of 2,6-disubstituted-4-methylthiopyrimidines

14 containing heteroaryl substituents in the 2,6-positions from ketene

dithioacetal of 2-acetylthiophene 12 by reacting with substituted amidines

13 (Scheme 6).27

SO

MeS SMeH2N

HN SS N

NS

SMe

DMF / C6H6+

12 13 14

Scheme 6

Tominaga used 1,3-dimethyl-6-aminouracil 15 with α-oxoketene

dithioacetals 16 in the presence of K2CO3 to produce pyridopyrimidines

17 (Scheme 7).28

N

N

O

O

Me

NH2Me

SMe

O R1

N

N N

SMe

R1Me

Me

O

O

MeS K2CO3 /DMF

Heat+

15 16 17 Scheme 7

Junjappa and Ila had studied the above reaction with unsubstituted uracil

18 and cyclic ketene dithioacetals 19 to afford pyridopyrimidines 20

(Scheme 8).29

HN

NH

O

O NH2

SMe

OHN

NH

N

SMe

O

OMeS K2CO3 / DMF

Heat+

18 19 20

Scheme 8

Ried and coworkers tried similar reactions with 3-aminopyrazoles 22 30

and aminotriazoles 24 31 (Scheme 9) to synthesize pyrazolopyrimidines 23


and the new heteroannulated 8-azapurines 25 respectively starting from

bis(methylthio)methylenemalononitrile 21.

NC CN

MeS SMe N NH

CN

R NH2N N

N

H2N CN

SMe

CNR

+

NN

N NH2

Et3N

Ar

NH

N NN

N

HNNAr

N

NCCN

+

21 22 23

24 25

Scheme 9 Earlier Tominaga and coworkers had reported similar reactions. Cyano or

α-oxoketene dithioacetals 27 were treated with 3-aminotriazoles 26 as an

amidine functionality under direct thermal conditions in the presence of

potassium carbonate to afford triazolopyrimidines 28 (Scheme 10).32

N N

HN

NH2

MeS

MeS

X

Y

NN

N

N

X

Y

SMe

K2CO3 / heat+

DMF 26 27 28

X=CN, H, SO2Ph, CO2Ph;

Y= CN, COPh, CO2Me

Scheme 10

Zaharan et al utilized the above reaction to synthesize new

pyrazolopyrimidine derivatives 31 starting from ketene dithioacetals 30

and aminopyrazoles 29 (Scheme 11).33


NHN

CNArHN

NH2

NC CN

MeS SMe+ N N

N

MeS CN

NH2

CNArHN

Ar =C6H4OC2H5-o C6H4OC2H5-p

29 30 31 Scheme 11

A convenient and efficient synthesis of highly functionalized

dihydropyrido[2,3-d]pyrimidines 34 and 35 via a double [5 + 1] annulation

strategy starting from easily available α-alkenoyl-α-carbamoylketene-

(S,S)-acetals 32 and the readily available reagents such as NH4OAc, DMF,

and POCl3 had been developed by Liu et al (Scheme 12).34

R2

O

SEtEtS

O

NH

R1

NH

O

R2 NH2

O

NH

R1N N

N

N N

N

DMF / POCl3

R1= H

DMF / POCl3R1=Ar

OHCCl NMe2

CHOR2

Cl OAr

CHOR2

OHC

NH4OAc34

32 33 35

Scheme 12

The ring opening reaction of cyclic α-oxoketene dithioacetal 36 with N,N-

diethylguanidine sulfate 37 was reported by Mellor for the efficient

synthesis of pyrimidine 38 (Scheme 13).35

R1R

S S H2N NEt2

NH.H2SO4 N N

NEt2

S SR1

O

Ra; R=COMe,R1= Me.b; R = H,R1 = CF3

+

H

36 37 38

Scheme 13


Tominaga treated α-cyano-α-carbethoxy dithioacetals 39 with urea and

thioacetamide in the presence of NaH to afford pyrimidines 40 and 41

respectively (Scheme 14).36

SMe

SMe

MeO2C

NC

N

NH

OCN

SMeO

H

NaH / Heat

NH2CONH2

39 40

N

NMe

SMeCO2Me

SH

MeCSNH2 / NaH

41

Scheme 14

Use of KF / Al2O3 to catalyze the synthesis of 2-alkylthio-4-amino-5-cyano-

6-methylthiopyrimidines 44 by the reaction of ketene dithioacetal 42 and

isothiouronium salts 43 was first reported by Yu and Cai (Scheme 15).37

SMe

SMeNC

NC

H2N SR

NHN N

SR

SMeCN

H2N

.HXKF / Alumina

CH3CN+

42 43 44

R = Alkyl

Scheme 15


Cyclization of ketene dithioacetal of ethylcyanoacrylate 45 with substituted

urea gave 3-phenyl-5-cyano-6-methylthiopyrimidine–2,4-diones 46

(Scheme 16).38

NC

EtOOC

SMe

SMe N

NPh

O

CNSMe

H

O

PhNHCONH2

45 46

Scheme 16 Cyclocondensation of ketene dithioacetal 47 with thiobenzamides gave 6-

amino-6H-1,3-thiazines 48. Dimroth rearrangement of the above

compounds in the presence of sodium alkoxide gave thioxopyrimidines 49

(Scheme 17).39

NC

NC

SMe

SMeNC

S

C SMe

NHPh

NC

NH

C SM

S

CN

Ph

CNPhCSNH2 RONa e

47 48 49

Scheme 17

Junjappa et al had found that two molecules of vinylogous thiol esters 50

were utilized in the reaction with guanidine when NaH in DMF were used

instead of sodium alkoxide / alcohol, producing pyrimidines 51 with high

substitutions (Scheme 18).40

Ar

H3CSH2N

NH

NH2N N

HN

Ar

OCH NaH / DMF

80-85ο C, 10-12 h+

H3CS

SMe

O

Ar

SMe

2

50 51

Scheme 18


Pyrimidines 53 had been prepared from ketene N,S-acetals 52 by treating

with an alkaline ethanolic solution of guanidine in a procedure similar to

that described with α-oxoketene dithioacetals (Scheme 19).41

Ar

SMe

NHRH2N

NH

NH2

NaOEt, EtOHN N

NH2

NHRAr

O

52 53

Scheme 19

α-Oxoketene-N,S-acetals 54 reacted with isothiocyanates to afford 4-

thioxopyrimidines 56 (Scheme 20). 42

MeS NHR2

O

MeS NHR2

O S

NHCPhMeS N

O

N

S

PhR2

PhCNS

Et2O or THF

54 55 56

Scheme 20

Junjappa and co-workers treated α-cyano-N,S-acetals 57 with guanidine or

thiourea to give the corresponding 6-anilinopyrimidines 58 in good yields

(Scheme 21).43

NHArMeS

H2NX

H2NN

N

NH2

XHArHN

R1CN

+R1

Guanidine Nitrate or Thiourea

Sodium t-butoxide, t-BuOH.Heat

R1= Ar

X= NH, S

57 58

Scheme 21


It is clearly indicated from the above discussions that ketene dithioacetals

and ketene-N,S-acetals are very good precursors for the synthesis of

substituted pyrimidines. In the light of earlier reported methods we treated

α-formylketene dithioacetals with guanidine and benzamidine to

synthesize novel pyrimidines. The reaction afforded synthetically

important pyrimidine-5-carbaldehydes in good yields.44

3.3 Pyrimidinecarbaldehydes: General Methods of Synthesis

Literature survey indicated that there are only very few methods for the

synthesis of pyrimidinecarbaldehydes. The most direct route to pyrimidine-

4-carbaldehydes was through the general procedure first described by

Bredereck et al.45 In this method the vinylogous amide 61 obtained by the

reaction of pyruvaldehydedimethyl acetal 60 and DMF acetal 59 was

treated with formamidine to give the pyrimidine acetal 62. The treatment of

this acetal with warm dil. sulfuric acid afforded the pyrimidine aldehyde 63

(Scheme 22).

Me2NOMe

OMe Me

O OMe

OMe Me2N

OOMe

OMe

+ 100 o CH HH

59 60 61

NH2HN

R

N

N

RN

N

CHO MeO OMe

Warm H2SO4

R

EtOH / base

R = H, NH2,,Ph

H

63 62

Scheme 22


Sisco et al recently extended the above method to produce

thiomethylpyrimidine-4-carbaldehyde 65 using S-methylisothiourea in

MeOH (Scheme 23).46

NH2HN

SMe

N

N

SMe

MeO OMe

MeOH / NaOMeMe2N

OOMe

OMe N

N

CHO

Warm H2SO4

SMe 61 64 65

Scheme 23 A similar synthesis was reported by Johnson and Cretcher for

4-formylpyrimidines, starting from diethoxyethylacetoacetate 66 and

thiourea in alcohol in the presence of sodium alkoxide.47 The reaction

produced a pyrimidine acetal 67 from which the aldehyde 68 was generated

by hydrolysis with mineral acids as in the above cases (Scheme 24).

OEt

EtOO O

OEt

Thiourea

EtOH / EtONa

HN NHOEt

OEt

S

O

dil. acid HN NH

S

O CHO

66 67 68 Scheme 24

No “one-pot” reactions are known for the synthesis of 5-formylpyrimidines

from open chain substrates. The usual methods for their synthesis involve the

formylation of pyrimidines or by functional group interconversion of

substituents already present in the pyrimidine ring. Formylation of simple

pyrimidine will not generate 5-formyl derivative, so Herberz et al synthesized

5-formyl-4,6-dichloropyrimidines 70 starting from 4,6-dihydroxypyrimidines

69 by the Vilsmeier reaction (Scheme 25).48


N N

OHHO

POCl3 / DMF N N

ClClCHO

69 70 Scheme 25

Vilsmeier reaction was used for the synthesis of 4,6-diarylpyrimidine–5-

carbaldehydes from substituted hydroxypyrimidines via the chloroformyl

derivatives 70. The nucleophilic substitution of the chloroderivatives 70 using

2.2 equivalents of phenolates produced the required 4,6-diarylpyrimidine-5-

carbaldehydes 71 (Scheme 26). These 4,6-diarylpyrimidine–5-carbaldehydes

are used to synthesize double picket fence porphyrins which are used as

models for hemoproteins49 and are also used to prepare annulated heterocyclic

compounds like thienopyrimidines. 50

N N

OHHO

POCl3 / DMF N N

ClClCHO

N N

PhPhCHO

PhOH/K2CO3

THF, Reflux

69 70 71

Scheme 26

Ple and coworkers reported a similar method to synthesize 2,4-dimethoxy-6-

chloro-5-formylpyrimidine 73 from 6-chloro-2,4-dimethoxypyrimidine 72 by

formylation method (Scheme 27).51 McArdle et al had utilized the above

method to synthesize pyrimidine-5-carbaldehyde from which they

prepared imidazolopyrimidines.52

N N

OMeCl

N N

OMeClCHO

OMe OMe

POCl3 / DMF

72 73

Scheme 27


Bredereck et al used the hydroxypyrimidones 74 to synthesize the

5-formylpyrimidines. They treated the starting compound with DMF and

phosgene to give the intermediate iminium ion 75, which on hydrolysis

afforded the aldehyde 76 (Scheme 28).53

N

NH

O

HO

DMF / Phosgene

N

NH

O

HO

Me2N

N

NH

O

HO

OHCHydrolysis

74 75 76

Scheme 28

Nielsen and coworkers reported the synthesis of 6-benzyl-2,4-dioxo-

1,2,3,4-tetrahydropyrimidine-5-carbaldehydes 79 from substituted pyrimidines

77 and 78 by two different methods (Scheme 29).54 They used 79 for the

synthesis of 6-benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-

5-carbaldehydes a very potent inhibitor of HIV-1 reverse transcriptase.

HN

NH

O

OPh

1. CH2O, NaOH, H2O

2. Pot. persulfate, AgNO3 H2O, CH3CN

HN

NH

O

OPh

CHO

HN

NH

O

OPh

CN

RaNiHCOOH

77

78 79

Scheme 29

5-Hydroxymethylpyrimidine-2,4(1H,3H)-diones 80 was converted to

pyrimidine-5-carbaldehydes 81 by oxidation with ceric amonium nitrate

(Scheme 30).55


N

N

O

O

CH2OH N

N

O

O

CHOCeric ammonium nitrate

80 81

Scheme 30

Thus the synthetic routes to pyrimidinecarbaldehydes are very few and any

novel method for their synthesis is highly relevant. Therefore we planned

to devise a new simple method for the synthesis of pyrimidine-5-

carbaldehydes 84 starting from α-formylketene dithioacetals 83 which in

turn were prepared by the Vilsmeier reaction of ketene dithioacetals 82

(Scheme 31).

Ar SCH3

O SCH3Ar SCH3

O SCH3

O H

1. DMF/POCl3

2. aq. K2CO3

NH

NH2HClR

Reflux 20H

N N

SCH3

O H

R

ArDMF or CH3CN / K2CO3

R = a, NH2 b, Ph

82 83 84 Scheme 31

3.4 Pyrimidinecarbaldehydes and Aminopyrimidines: Synthetic Applications

Pyrimidinecarbaldehydes are considered as important substrates for the

synthesis of annulated or complex molecules, which find applications in

catalysis, medicinal chemistry and heterocyclic chemistry. 4,6-Diaryl-

pyrimidinecarbaldehydes 85 are used to prepare double picket fence

porphyrins 86, which are used as models for hemoproteins and as second

generation oxidation catalysts (Scheme 32).56


N

N

O

H

R

R

1, Pyrrole,BF3.OEt2

2, p-Chloranil, Reflux N

HN

N

R

R

N

NN

R

R

N

N

N

R

R NH

NN

R

R

85 86 Scheme 32

Soai et al found that the 5-pyrimidinyl alkanols 88 formed by the action of

the pyrimidine-5-carbaldehydes 87 by diisopropyl zinc are efficient

asymmetric autocatalysts (Scheme 33).57

87 88

Starting from pyrimidinecarbald eph Sisco and Mark Mellinger

N

NR

O

H N

NR

OHPri2Zn, 0 ο C

t-Bu C CR =

Scheme-33

ehyde 89 Jos

synthesized highly substituted imidazole derivatives 93, which are drugs

for rheumatoid arthritis (Scheme 34).46

N NN

SPr

CHO

CO2Et

NH2

N N

SPr

N

NCO2Et

+ EtOAc / NaOH F

TolSO2

NC

Piperazine, 25 0 C

N N

PrS

N

N

F

NCO2Et

92

89 90 91 93 Scheme 34


Susvilo et al had utilized 6-phenylethynylpyrimidine-5-carbaldehyde 94 for

the preparation of pyridopyrimidines 95 (Scheme 35).58

N

N

NH2CHO

PhMeS

1. H2NBu-t

2.AgNO3 / CHCl3

N

N

NH2

MeS

N

Ph

94 95 Scheme 35

Tumkevicius et al prepared fused isoxazolopyrimidine 98 which is of

biological interest starting from 4,6-dichloro-2-methylthiopyrimidine-5-

carbaldehyde 96. First step was the synthesis of an azide 97 from 96, which

in turn produced the final product by refluxing in DMF (Scheme 36).59

N

N

ClCHO

ClMeS

1, R2NH

2,NaN3/DMF.70ο C

N

N

NR2CHO

N3MeS

N

N

NR2

NMeSO

DMF/Refluxing

96 97 98

Scheme 36

Similar to the formyl group present on the pyrimidine nucleus,

appropriately positioned alkylsulfanyl group and amino group are also

useful for further transformations. Novel thienopyrimidines 100 and

pyrrolopyrimidines 101, which are effective anticancer and antiviral

agents, are developed by Tumkevicius et al starting from 4,6-dichloro-2-

methylthiopyrimidine-5-carbonitriles 99 (Scheme 37).60


N

N

ClCN

ClMeS

1,H2NCH2CO2R.ROH,Et3N,r.t.

2, HSCH2CO2Et.EtOH,Et3N,Reflux.

N

N

Cl

NMeS

NH2

CO2Et

Me

1,H2NCH2CO2R.ROH,Et3N, rt.

2,NaH,C6H6, rt.

N

N

HN

SMeS

COOEt

COOEt

NH2

100

99

101

Scheme 37

Lehn et al have reported the synthesis of pyrimidine- pyridine molecular

strands which displayed folded structures similar to α-helices, β-turns of

proteins and double helix of nucleic acid and revealed interesting physical

and mechanical properties giving more conformation on natural

intramolecular self organizations in natural products. 61

Recently Han et al reported the synthesis of pyrimidine core liquid crystals

104 using substituted amidines 102 (Scheme 38).62

R

HN NH2

OH

NMe2NMe2

N

NRHO

Pyridine / 80 o C

8h+

R = (S)-2-methylbutyl

102 103 104 Scheme 38

Radwan et al prepared a number of fused heterocyclic ring systems starting

from 2-aminopyrimidines 105 (Scheme 39).63


N N

Ar Ar'

N N

Ar Ar'

N N

Ar Ar'

N N

Ar Ar'

NH2

NO

N N

S

NO2

N

O

ClCH2COOR

Pyridine.O2N

CONCS

Dry Acetone.Pyridine.

CH2=CH-CN

105

106 107 108

Scheme 39

A novel tricyclic 4-chloropyrimido[1,4]benzodiazepine 110 was reported

by Yang et al from a simple 5-aminopyrimidine 109 (Scheme 40).64

N

N N

N

ClNH2

NMe

MeMe

O OH

ClN

NMe

Me

Me+ Reflux, 5h

POCl3, PPA

109 110

Scheme 40

The above discussion revealed that appropriately substituted pyrimidines

could be effectively transformed to useful fused heterocyclic systems. We

envisioned that the presence of highly reactive formyl group on the

pyrimidine-5-carbaldehydes synthesized might make the compounds 84a

and 84b valuable precursors for the synthesis of highly functionalized and

annulated heterocyclic compounds. So we explored the synthetic potential

of pyrimidinecarbaldehydes 84a for the synthesis of pyridopyrimidines and


isoxolopyrimidines by treating them with malononitriles and

hydroxylamine hydrochloride respectively.

3.5 Results and Discussion 3.5.1. Reactions of α-Formylketene dithioacetals (2-aroyl-3,3-

bis(alkylsulfanyl)acrylaldehydes) with Amidines: A Facile Method for the Synthesis of Pyrimidinecarbaldehydes and their derivatives

The α-formylketene dithioacetals were synthesized according to the

reported method.65 Generally the reaction of ketene dithioacetals and

amidines are carried out in presence of strong bases like sodium alkoxide,

sodium hydride etc. Junjappa and coworkers developed a general method

for the synthesis of 6-alkoxy pyrimidines by reacting guanidine with α-

oxoketene dithioacetal in the presence of corresponding alcohol / alkoxide

medium.23 In the presence of strong bases we have encountered the problem

of deformylation of 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes.66 So bases

like K2CO3 was the best choice for the reaction. In this context we

examined the reactions of guanidine and benzamidine, with 2-aroyl-3,3-

bis(alkylsulfanyl)acrylaldehydes in the presence of K2CO3. The reaction

led to the formation of functionalized pyrimidinecarbaldehydes. However

in this reaction we expected the formation of a mixture of aroyl

pyrimidines and pyrimidinecarbaldehydes. Contrary to our expectations the

formyl group on the acrylaldehyde remains unreactive and the reaction

afforded pyrimidinecarbaldehydes as a single product in the reaction. As

they contain a reactive formyl group at C-5 we have also made attempts to

synthesize annulated pyrimidines by treating them with malononitriles and

hydroxylamine hydrochloride.

There are only very few methods reported for the synthesis of pyrimidine-

5-carbaldehydes and most of them are multistep syntheses. In this aspect

the new method for the synthesis of pyrimidinecarbaldehydes deserves


special attention. Literature survey shows that this is the first simple and

facile one pot synthesis, for pyrimidine-5-carbaldehydes from open chain

substrates.

3.5.2 Synthesis of 2-amino-4-(methylsulfanyl)-6-phenyl-5-pyrimidine carbaldehydes from α-formylketene dithioacetals (2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes)

There are number of reports for the preparation of pyrimidines

from α-oxoketene dithioacetals using amidines. It was earlier proved

that K2CO3 in DMF is an efficient base for the pyrimidine synthesis.67

Thus we treated 3,3-bis(alkylsulfanyl)-2-(4-methylbenzoyl)-acrylaldehyde

83e with guanidine hydrochloride in the presence of K2CO3 in DMF at

100 °C for 20 h. The reaction afforded 2-amino-4-(4-methylphenyl)-6-

(methylsulfanyl)-5-pyrimidinecarbaldehydes 111e in 45% yields. Yu

and Cai had obtained the highest yield of pyrimidines from ketene

dithioacetals in the presence of acetonitrile among different solvents.68 So we

were interested to study the reactivity of formylketene dithioacetals and

guanidine in acetonitrile. Therefore we conducted the reaction in both the

solvents and compared the yields of the reactions. It was found that acetonitrile

was a better solvent for the preparation of pyrimidine-5-carbaldehyde from

3,3-bis(alkylsulfanyl)-2-benzoylacrylaldehyde. The reaction was extended to

other substituted acrylaldehydes also in order to get corresponding 2-amino-

4-aryl-6-(methylsulfanyl)-5-pyrimidinecarbaldehydes (Scheme 41). All the

products were characterized on the basis of 1H NMR, 13C NMR, IR and

FABMS or CHN analyses.


R1 SCH3

SCH3

O H

O

+NH

NH2HClH2N Heating , boiling water bath, 20h

N N

SCH3

O H

NH2

R1

DMF or CH3CN / K2CO3

83 a-i 111 a-i

Yield % 83, 111 R1 (DMF) (CH3CN)

a 4-CH3OC6H4 50 80 b C6H5 40 70 c 4-ClC6H4 43 76 d 4-BrC6H4 45 78 e 4-CH3C6H4 45 75 f 2-Naphthyl 40 - g 2,3-(CH3O)2C6H3 55 70 h 4-NO2C6H4 40 - i 3-CH3OC6H4 54 82

Scheme 41

The FABMS spectrum (Figure 1) of 111a shows the molecular ion peak at

m/z 276 and it corresponds to 2-amino-4-(4-methoxyphenyl)-6-

(methylsulfanyl)-5-pyrimidinecarbaldehyde 111a. The IR spectrum

(Figure 2) of the compound 111a shows peak at 3322, 3205 cm-1

corresponding to NH2, and peak at 1649 cm-1 represents the aldehyde group.

The 1H NMR (500 MHz, CDCl3) spectrum (Figure 3) of the compound

111a shows a singlet of three protons at δ 2.5 and δ 3.8 for SCH3 and OMe

groups respectively, a broad peak at δ 5.79 represents two protons of NH2,

two doublets at δ 7.03 - 7.01 (J = 10 Hz), 7.56 – 7.54 (J = 10 Hz)

represents four aromatic protons. A sharp singlet at δ 9.86 is due to the

aldehyde proton. The 13C NMR (75 MHz, CDCl3) of 111a (Figure 4)

shows a peak at δ 13.4 for methylsulfanyl group, another at δ 55.5 for


methoxy carbon. Peaks at δ 114.0 (3,3’C, ArH), 116.7 (5C pyrimidine),

128.3 (1C, ArH), 131.5 and 132.0 (2, 2’C, ArH), 160.9 (4C ArH), 161.5

(4C pyrimidine), 172.2 (6C pyrimidine), 175.4 (2C pyrimidine), peak at δ

188.8 represents aldehyde carbon of 111a. Analytical values are as follows:

Calculated; C, 60.21; H, 5.05; N, 16.20, S, 12.37: Found. C, 59.87, H, 4.98,

N, 15.89, S,12.37. All the above factors strongly supported the proposed

structure of 111a as 2-amino-4-(4-methoxyphenyl)-6-(methylsulfanyl)-5-

pyrimidinecarbaldehyde.

Fig-1 FABMS of 2-amino-4-(4-methoxyphenyl)-6-(methylsulfanyl)-5-pyrimidinecarbaldehyde 111a.

4 0 0 0 3 5 0 0 3 0 0 0 2 5 0 0 2 0 0 0 1 5 0 0 1 0 0 0 5 0 0

0

2 0

4 0

6 0

8 0

1 0 0

1 / c m

3 4 1 0

1 5 1 81 6 4 93 2 0 53 3 2 2

% T

Fig-2 IR spectrum of 2-amino-4-(4-methoxyphenyl)-6-(methylsulfanyl)-5-

pyrimidinecarbaldehyde 111 a


Fig-3 1H NMR of 2-amino-4-(4-methoxyphenyl)-6-(methylsulfanyl)-5-pyrimidinecarbaldehyde 111 a


Fig-4 13C NMR of 2-amino-4-(4-methoxyphenyl)-6-(methylsulfanyl)-5-pyrimidine(carbaldehyde) 111 a.

3.5.3. Synthesis of 4-(methylsulfanyl)-2,6-diphenyl-5-pyrimidinecarbaldehydes from α-formylketene dithioacetals

Benzamidine can readily form pyrimidines similar to guanidine with

1,3-dicarbonyl systems or with ketene dithioacetals. So 3,3-bis(alkylsulfanyl)-

2-(4-methoxybenzoyl)acrylaldehyde 83a was treated with 1 equivalent of

benzamidine in DMF at 100°C for 20 h. Reaction generated 4-

(methoxyphenyl)-6-(methylsulfanyl)-2-phenyl-5-pyrimidinecarbaldehyde 112a

in 50% yields. The reaction was extended to other substituted

acrylaldehydes to afford corresponding 4-aryl-6-(methylsulfanyl)-2-

phenyl-5-pyrimidinecarbaldehydes in 35-50% yields (Scheme 42). All the

products were characterized on the basis of 1H NMR, 13C NMR, IR and

FABMS or CHN analyses.

R1 SCH3

SCH3

O H

O+

NH

NH2HClC6H5

DMF /K2CO3 N N

SCH3

O H

C6H5

R1Boiling Water bath,20h

83 a-f 112 a-f

83, 112 R1 Yield % a 4-CH3OC6H4 50

b C6H5 41 c 4-ClC6H4 48 d 4-BrC6H4 48 e 4-CH3C6H4 46 f 2-Naphthyl 35

Scheme 42

The FABMS spectrum (Figure 5) of 112d shows the molecular ion

peak at m / z 387 (M + 2) ion and 385 (M+) ion and it is in agreement

with the expected 4-(4-bromophenyl)-6-(methylsulfanyl)-2-phenyl-5-


pyrimidinecarbaldehyde structure. The IR spectrum (Figure 6) of 112d

reveals a peak at 1672 cm-1 due to aldehyde group. The 1H NMR spectrum

(300 MHz, CDCl3) (Figure 7) of the product 112d has a singlet at δ 2.75 of

three methylsulfanyl protons. A multiplet between δ 7.5 – 8.52 represents

seven ArH protons and another multiplet δ 8.6 - 8.7 represents 2 phenylic

protons. A sharp peak at δ 10.09 represents aldehyde proton. The 13C NMR

spectrum (75 MHz, CDCl3) (Figure 8) of 112d shows a peak at δ 13.6 for

methylsulfanyl group and a peak at δ 121.4 for 5C pyrimidine carbon.

Peaks at δ 125.5, 128.5, 129.2, 131.8, 134.9, 136.5 can be assigned to the

phenyl carbons and the rest of the pyrimidine peaks are as follows

δ 163.1 ( 4C pyrimidine), δ 168.7 (6C pyrimidine) and δ 173.5 (2C

pyrimidine). Peak at δ 189.3 represents aldehyde carbon atom. CHN

analysis of 112d gives supporting values corresponding to the proposed

structure. Analytical values: Calculated: C, 56.11, H, 3.4; N, 7.27. Found:

C, 55.78, H, 3.46, N, 6.98. Analysis of the spectra of other systems is in

agreement with the structure proposed.

Fig-5 FABMS Spectrum of 4-(4-bromophenyl)-6-(methylsulfanyl)-2-phenyl-5-pyrimidinecarbaldehyde 112d


3 5 0 0 3 0 0 0 2 5 0 0 2 0 0 0 1 5 0 0 1 0 0 0 5 0 02 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0

1 5 1 9

1 6 7 2

1 / cm

% T

Fig-6 IR Spectrum of 4-(4-bromophenyl)-6-(methylsulfanyl)-2-phenyl-5-pyrimidinecarbaldehyde 112d

Fig-7 1H NMR of 4-(4-bromophenyl)-6-(methylsulfanyl)-2-phenyl-5-pyrimidinecarbaldehyde 112d


Fig-8 13C NMR Spectrum of 4-(4-bromophenyl)-6-(methylsulfanyl)-2-phenyl-5-pyrimidinecarbaldehydes 112 d

The reaction was extended to 1-aryl-2-(1,3-dithiolan-2-yliden)-3-butene-1-

ones 113. As the cyclic ketene dithioacetals are less reactive, in this case

we expected the formation of some intermediates, which have to be further

treated to obtain functionalized pyrimidines. Our experiments showed that

these substrates are unreactive towards amidines in the presence of weak

bases like K2CO3. The possibility of using strong bases like NaOH, NaH,

t-BuOK etc was ruled out due to the facile deformylation of 113 in their

presence. Thus the synthesis of pyrimidines 114 from 1-aryl-2-(1,3-

dithiolan-2-yliden)-3-butene-1-ones is very remote (Scheme 43).


O S

SCHO

Guanidine or benzamidine XDMF or CH3CN -Reflux

NN

S S

R

R = NH2 or Ph

H

113 114

Scheme 43

3.5.4 Proposed mechanism for the formation of pyrimidinecarbaldehydes from 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes

The formation of substituted pyrimidine-5-carbaldehydes 84 from 2-

aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes 83 using amidines can be

rationalized according to the mechanism proposed by Topfl et al.22

Initially a sequential conjugated addition elimination of amidine on

2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes afford an acyclic N,S-acetal

intermediate 115. The intermediate undergoes intramolecular 1,2-nucleophilic

amination reaction on the carbonyl group followed by elimination of water

molecule to produce the required pyrimidinecarbaldehydes 84. Among the

carbonyl groups, the one near the aromatic ring system is more susceptible to

the 1,2 intramolecular addition reaction (Scheme 44). Therefore the aldehyde

remains unreacted. The nonreactivity of 1-aryl-2-(1,3-dithiolan-2-yliden)-

3-butene-1-ones 113 are justified by the known low reactivity of those

compounds towards amidines.69


R1 SCH3

SCH3

O H

O

NH

H2N

R

N N

SCH3

O H

R

R1

HN

SCH3

O H

R

R1

O

NH

N N

SCH3

O H

R

R1

HHO

83 115 116

84 Scheme 44

3.5.5 Reactions of 6-aryl-2-amino-4-(methylsulfanyl)-5-pyrimidinecarbaldehydes with malononitrile: Synthesis of 3-[2-amino-4-aryl-6-(methylsulfanyl)-5-pyrimidinyl]-2-cyano-2-propenamides

Generally the reactions of aldehydes or ketones with active methylene

compounds like malononitrile, ethyl cyanoacetate are carried out in the

presence of weak bases like an amine or a buffer of ammonium acetate /

acetic acid.29 In many cases such reactions afford corresponding

condensation adducts, which can be in situ cyclized to form heterocyclic

compounds especially functionalized pyridine derivatives.70 So the

2-amino-6-aryl-4-(methylsulfanyl)-5-pyrimidinecarbaldehyde 111 was

subjected to Knoevenagel condensation reaction with malononitrile using

ammonium acetate / acetic acid as the buffer. The reaction on aqueous

work up afforded a mixture of products containing 2-{[2-amino-6-aryl-4-

(methylsulfanyl)-5-pyrimidinyl]methylene}malononitriles 117 and 3-[2-

amino-4-aryl-6-(methylsulfanyl)-5-pyrimidinyl]-2-cyano-2-propenamides

118 (Scheme 45). It was noticed that heating the reaction mixture with

water for 1-2 h increases the yield of the amide. The resulted products were

characterized on the basis of IR and 1H NMR spectral data.


NN

NH2

SMeCHO

NC CN

NN

SMe

NH2

CN

1.NH4COOCH3 / CH3COOH.

Reflux 2h+

H2N O

2. Aqueous work up

NN

SMe

NH2

CN

CN

+

111 a-c

R

R R

117 a-c 118 a-c

Yield 111, 117, 118 R

117 118

a Br 50 30

b Cl 55 25

c H 52 30

Scheme 45

The IR spectrum of the compound 118a (Figure 9) shows two additional

peaks at 3425 cm-1 and 3348 cm-1 due to the amide NH2 in addition to the

free NH2 group in the pyrimidine ring. The cyanide group gives peak at

2220 cm-1 and the amide carbonyl group is visible at 1697 cm-1as a sharp

peak. In the 1H NMR spectrum (300 MHz, CDCl3) three SMe protons

appear as a singlet at δ 2.57, two free NH2 protons on the pyrimidine ring

appear at δ 5.32 and the two amide NH2 protons appear at δ 5.61 and

δ 6.00. The difference in chemical shift value for the amide protons is

attributed to the different chemical atmosphere of these two protons. The

four phenyl protons resonate at δ 7.39 (J = 9 Hz), δ 7.57 (J = 9 Hz) as

doublets. A sharp singlet at δ 8.42 represents the vinylic proton (Figure 10).

Analysis of the spectra of other systems is in agreement with the proposed

structure.


4 0 0 0 3 5 0 0 3 0 0 0 2 5 0 0 2 0 0 0 1 5 0 0 1 0 0 0 5 0 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

3 4 2 5

1 5 9 3

1 6 2 0

1 6 9 7

2 2 2 0

3 1 8 63 3 5 8

3 4 8 5

3 3 4 8

% T

W a v e l e n g t h ( n m )

Fig 9 IR Spectrum of 3-[2-amino-4-(4-bromophenyl)-6-(methylsulfanyl)-

5-pyrimidinyl]-2-cyano-2-propenamides 118a

Fig 10 1H NMR Spectrum of 3-[2-amino-4-(4-bromophenyl)-6-

(methylsulfanyl)-5-pyrimidinyl]-2-cyano-2-propenamides 118a 3.5.6 Reactions of 6-aryl-2-amino-4-(methylsulfanyl)-5-

pyrimidinecarbaldehydes with malononitrile: Synthesis of 2-{[6-aryl-2-amino-4-(methylsulfanyl)-5-pyrimidinyl] methylene}malononitriles

In the above reaction yield of propenamide derivative 118 was increased

when the aqueous solution was heated for 1h after work up. It showed the

product was formed by the hydrolysis of one of the cyanide groups of 117.


So if we avoid the aqueous work up the yield of 2-{[6-aryl-2-amino-4-

(methylsulfanyl)-5-pyrimidinyl]methylene}malononitriles 117 in the above

reaction could be increased. So we tried to improve the yield of 117 from

pyrimidinecarbaldehydes by avoiding the aqueous work up. The 2-amino-

6-(4-methylphenyl)-4-(methylsulfanyl)-5-pyrimidinecarbaldehyde was

subjected to Knoevenagel reaction with malononitrile using ammonium

acetate / acetic acid as the buffer. The reaction mixture was heated at 70 ο C

for 2 h. Cooled the mixture and then it was diluted with ethyl acetate and

further washed with ice-cold water. The organic layer was dried over sodium

sulfate and the solvent was evaporated off. The crude product was purified by

column chromatography and the product was characterized on the basis of IR, 1H NMR and 13C NMR spectral data as 2-{[2-amino-4-(methylsulfanyl)-6-(4-

methylphenyl)-5-pyrimidinyl]methylene}malononitrile. The reaction was

extended to other substituted pyrimidinecarbaldehydes also (Scheme 46). The

yield of 117 was increased drastically and the presence of 118 was negligible

by the slight modification we had carried out in the former procedure.

NN

NH2

SMeCHO

NC CNNN

SMe

NH2

CN

CN

NH4COOCH3 / CH3COOH.

Reflux 2h+

RR

84 a-g 117 a-g

117 R Yield %

a 4-Br 70 b 4-Cl 60 c H 65 d 4-CH3 65 e 4-OCH3 77 f 3-OCH3 75 g 3,4-(OCH3)2 70

Scheme-46


The IR spectrum of the condensation product 117d (Figure 11) shows

peaks at 3414, 3322, 3205 due to free NH2 group. A sharp peak at 2230 cm-1

clearly indicates the presence of cyanide group in the product, showing

condensation of malononitrile moiety with the pyrimidine. The 1H NMR

spectrum of 117d (Figure 12) reveals two singlet peaks at δ 2.42 and δ 2.58

representing methyl and SMe protons respectively. A broad peak at δ 5.63

represents two NH2 protons; a multiplet at δ 7.25 - 7.36 represents four

phenyl protons and a sharp singlet at δ 7.92 represents vinylic proton. 13C NMR spectrum of 117d (Figure 13) reaffirms the predicted structure.

Peaks at δ 13.0, δ 21.3 are of SMe and methyl carbons respectively.

Peak at δ 88.2 is assigned to the carbon atom connected to the nitrile

groups [C(CN)2], δ 111.2 and δ 111.7 are representing the two nitrile

carbon atoms. The peak at δ 113.1 represents the C-5 carbon atom of

pyrimidine ring. The six phenylic carbons are at δ 129.2, 129.4, 133.7

and 141.0. The vinylic carbon is visible at δ 156.0. The three other

pyrimidine carbons show resonance at δ 161.4, 166.2 and 171.7. The

presence of two cyanide groups and the SMe group show that it is only

the condensation product and there is no annulation taken place.

Analysis of the spectra of other systems is in agreement with the

proposed structure.


4 0 0 0 3 5 0 0 3 0 0 0 2 5 0 0 2 0 0 0 1 5 0 0 1 0 0 0 5 0 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0

1 5 1 8

1 6 3 4

2 2 3 0

3 2 0 53 3 2 2

3 4 1 4

% T

w a v e le n g th ( 1 /c m )

Fig 11 IR Spectrum of 2-{[2-amino-4-(methylsulfanyl)-6-(4-methylphenyl)-5-pyrimidinyl]methylene}malononitrile 117d

Fig 12 1H NMR Spectrum of 2-{[2-amino-4-(methylsulfanyl)-6-(4-methylphenyl)-5-pyrimidinyl]methylene}malononitrile 117d


Fig -13 13C NMR Spectrum of 2-{[2-amino-4-(methylsulfanyl)-6-(4-methylphenyl)-5-pyrimidinyl]methylene}malononitrile 117d

Earlier reports from our laboratory have proved that such condensation

products 117 and 118 can be cyclized to 2-pyridones or pyridines under

basic or acidic conditions.71 So we tried to cyclize both the products by

treating them with sodium alkoxide and conc.HCl. Due to the extensive

conjugation with the pyrimidine rings, the condensation adducts are

unreactive under these conditions.

Similar condensation products were obtained by the reaction of

pyrimidinecarbaldehydes and cyanoacetamide also (Scheme 47). The

simple condensation product should be the same propenamide 118

obtained in the reaction with malononitrile. But the IR spectrum of the

product (Fig 14) obtained by the reaction of cyanoacetamide and 2-amino-

4-(4-bromophenyl)-6-(methylsulfanyl)-5-pyrimidinecarbaldehyde reveals

that only one free NH2 group is present in the product (compare with the

Fig 9) and the melting point is 180 – 182 οC which is also different from

118a (3-[2-amino-4-(4-bromophenyl)-6-(methylsulfanyl)-5-pyrimidinyl]-2-


cyano-2-propenamide, mp 218 – 220 °C) indicating the probability of annulated

pyrimidines. Further work on these systems is in progress in our laboratory.

NN

NH2

SMeCHO

NC CONH2

NN

SMe

NH2

CN

1.NH4COOCH3 / CH3COOH.

Reflux 2h+

RR

H2N O

X

111 118

Scheme 47

4000 3500 3000 2500 2000 1500 1000

0

5

10

15

20

25

30

35

40

45

1/ cm

1526

1619

2220

169531913344

% T

Fig 14 IR spectrum of the product of reaction between cyanoacetamide

and 2-amino-4-(4-bromophenyl)-6-(methylsulfanyl)-5-pyrimidinecarbaldehyde.

3.5.7 Reactions of 6-aryl-2-amino-4-(methylsulfanyl)-5-

pyrimidinecarbaldehydes with hydroxylamine hydrochloride

We have also examined the reactions of 6-aryl-2-amino-4-(methylsulfanyl)-5-

pyrimidinecarbaldehydes 111 with hydroxylamine hydrochloride in a view

to synthesize isoxozolopyrimidines 120. The reaction was conducted at reflux

temperature in the presence of K2CO3 in acetonitrile for 10 h. The reaction

afforded only the corresponding oximes 119 in good yields (Scheme 48).


We consider these oximes as stable as in the earlier case because of their

conjugation with the pyrimidine ring. However further studies to be

conducted for the synthesis of annulated pyrimidines from the oxime.

N

CHOR

N

NH2

SMe

N N

NH2

SMe

N N

NH2

O

R

R

+ NH2OH.HClK2CO3 / CH3CN

Reflux 10h

N

NOH111 a-c

119 a-c

120

111, 119 R Yield % a 4-CH3 60 b 4-NO2 50 c 3-OCH3 70

Scheme 48

The conversion of aldehyde to oxime was monitored by IR and 1H NMR

spectroscopy. The NH2 peaks are present in the IR spectrum (Figure 15) of

the oxime 119a at 3328 and 3145 cm-1. In addition to them the oxime OH

peak is visible at 3506 cm-1. In the IR spectrum a new sharp peak appears at

979 cm-1 due to N-O stretching vibrations in the aldoxime. The peak due to

the resonance of the aldehyde proton is absent in the 1H NMR spectrum

(DMSO-d6) (Figure 16). Peaks at δ 2.35 and 2.47 correspond to CH3 and

SCH3 respectively. Aromatic protons appear as a multiplet at δ 7.2 - 7.4.

Singlets at δ 7.77 and δ 11.1 are due to the aldoxime proton and OH proton

respectively. On the basis of these spectral data we propose the structure of

the compound 119a as 2-amino-6-(4-methylphenyl)-4-(methylsulfanyl)-5-

pyrimidinecarbaldehyde oxime


4 0 0 0 3 5 0 0 3 0 0 0 2 5 0 0 2 0 0 0 1 5 0 0 1 0 0 0 5 0 0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

1 / c m

9 7 9

1 5 0 41 5 9 8

1 6 5 53 1 4 5

3 3 2 8

3 5 0 6

% T

Fig 15 IR Spectrum of 2-amino-6-(4-methylphenyl)-4-(methylsulfanyl)-

5-pyrimidinecarbaldehyde oxime 119a

Fig 16 1H NMR Spectrum of 2-amino-6-(4-methylphenyl)-4-(methylsulfanyl)-5-pyrimidinecarbaldehyde oxime 119a


3.5.8 Fluorescent study of 2-{[2-amino-4-(4-chlorophenyl)-6-(methylsulfanyl)-5-pyrimidinyl]methylene}malononitrile (117b)

N N

NH2

SMe

ClN

N (117b)

Number of successful discoveries has been reported for pyrimidine ring

system with extended conjugation as fluorescent materials.72 Extended

π-systems based on heteroatomic units like pyrimidines have been utilized

as electron transport materials in organic electro luminescent devices.73

The extensive conjugation of the malononitrile derivatives of

pyrimidinecarbaldehyde 117 having a highly shining appearance prompted

us to study the fluorescent nature of those derivatives. For that their UV-

visible absorption and fluorescence spectra were recorded. Absorption

spectra were obtained by the use of a Shimadzu UV-2400PC scanning

spectrophotometer and emission spectra were recorded with a Shimadzu

RF-5301PC spectrofluorophotometer, which was corrected for the

instrumental response. We noticed that 117b in CHCl3 showed three

absorption maxima at 379.60, 300.60 and 249.00 nm. Thus we excited at

those wavelengths to study its fluorescent behaviour (Fig 17). The

emission maximum was found to be at 429 nm when the excitation was

carried out at 379 nm. Similarly fluorescent spectra of 117b excited at

other two frequencies were visible in fig 17 which were also near 429 nm.

It revealed that the emission maximum was a constant value in all the three

excitation experiments. It clearly indicated that when pyrimidine derivative

was excited, it could emit radiation in the visible region, thus showing the

fluorescent nature of 2-{[2-amino-4-(4-chlorophenyl)-6-(methylsulfanyl)-5-

pyrimidinyl]methylene}malononitrile 117b. Fluorescent study on other

malononitrile derivatives of pyrimidines also gave the emission maxima in


the higher wave length region confirming the above observation. Further

detailed studies on the quantum yield of the fluorescence and variation in

emission maxima with respect to different solvents has to be done in future.

200 250 300 350 400 450 500 550 600 650 700-5

0

5

10

15

20

25

30

35

40A = UV spectrumE = Fluorescent spectra

nm

426

429

429

E

A

379.60300.60249.00

Inte

nsity

(a.u

)

Fig 17 Absorption spectrum and emission spectrum (excited at 379, 300

and 249 nm) of 2-{[2-amino-4-(4-chlorophenyl)-6-(methylsulfanyl)- 5-pyrimidinyl]methylene}malononitrile

3.6 Conclusion In this chapter we have reported a facile method for the synthesis of

structurally diverse hitherto unreported pyrimidinecarbaldehydes from

α-formylketene dithioacetals. We noted that till now no open chain

one-pot reactions have been reported for the synthesis of

5-pyrimidinecarbaldehydes. We have also made attempts to explore the

synthetic potential of newly synthesized 5-pyrimidinecarbaldehydes for

further elaboration to annulated or highly functionalized pyrimidines.

However these compounds demand further studies due to the increased

stability of the resulting products. The fluorescent study on the derivatives

of malononitrile with pyrimidine-5-carbaldehydes reveals the possibility of

a new class of fluorescent materials. More over the above derivatives of


malononitrile open the path for new annulated pyrimidines and scope for

new extended pyrimidine π-core systems as well.

3.7 Experimental General Melting points were determined on Buchi 530 melting point apparatus

and are uncorrected. The IR spectra were recorded on a Schimadzu IR-

470 spectrometer as KBr pellets and the frequencies are reported in cm-1.

The 1H NMR spectra were recorded on a Brucker WM (300 or 500 MHz)

spectrometer using TMS as the internal standard and CDCl3 or d6-acetone

as solvents. The 13C NMR spectra were recorded on a Brucker WM 300

(75.47 MHz) spectrometer using CDCl3 or acetone-d6 as solvent. Both 1H

NMR and 13C NMR values are expressed as δ (ppm). The CHN analyses

were recorded on an Elementar VarioEL III Serial Number 11042022

instrument. The FAB mass spectra were recorded on a JOEL SX 102/DA-

6000 Mass Spectrometer / Data System using Argon as the FAB gas. The

EIMS spectra were recorded on a MICROMASS QUATTRO 11 triple

quadrupole mass spectrometer. UV / visible spectra were recorded on a

Shimadzu UV-2400PC scanning spectrophotometer and fluorescent spectra

were recorded using Shimadzu RF-5301PC spectrofluorophotometer. TLC

analyses were carried out on silica gel 7GF using an ethyl acetate/hexane

mixture as eluent. Iodine vapors or KMnO4 solution in water was used for

detection of TLC spots. Anhydrous sodium sulfate was used as the

drying agent.

All commercially available reagents were purified before use. The

aroylketene dithioacetals and α-formylketene dithioacetals were prepared

by the known procedure.74,65


Synthesis of Pyrimidinecarbaldehydes and their derivatives from 2-aroyl-3,3-bis(alkylsulfanyl) acrylaldehydes

3.7.1. Synthesis of 2-amino-6-(methylsulfanyl)-4-phenyl-5-pyrimidinecarbaldehydes (111)

General Procedure

The appropriate α-formylketene dithioacetal (2 mmol) was dissolved in DMF

or in CH3CN (20 mL) at room temperature and guanidinehydrochloride

(0.192 g, 2 mmol) and K2CO3 (0.55 g, 4 mmol) were added and the mixture

then heated on a boiling water bath for 15 - 20 h. It was cooled, poured into

ice cold water (50 mL) and the semisolid obtained was extracted with CH2Cl2

(3 x 25 mL). The organic layer was separated, dried and purified by column

chromatography on silica gel (60 x 120) using ethyl acetate-hexane (3:7)

mixture as the eluent. The product was recrystalized from ethyl acetate / hexane

mixture. The yield of the reaction was generally low in DMF than in CH3CN.

N

SCH3

N

O H

NH2

C13H13N3O2SMol. Wt.275.33

H3CO

111 a

2-Amino-4-(4-methoxyphenyl)-6-(methylsulfanyl)-5-

pyrimidinecarbaldehyde was obtained from 3,3-

bis(methylsulfanyl)-2-(4-methoxybenzoyl)acrylaldehyde and

guanidinehydrochloride; yield 80% (0.40 g). in CH3CN; cream

coloured solid; mp 196 - 198 ○C; IR (KBr νmax) = 3455, 3210,

1630, 1525. cm–1; 1H NMR (500 MHz, CDCl3 ) δ = 2.56 (s,

3H, SCH3), 3.84 (s, 3H, OCH3), 5.7 2(s,2H, NH2), 7.03 - 7.01

(d, J = 10 Hz, 2H, ArH), 7.56 – 7.54 (d, J = 10 Hz, 2H, ArH),

9.84 (s, 1H, CHO); 13C NMR (75.47 MHz, CDCl3 ) δ = 13.4

(SCH3), 55.5 (OCH3), 114.0 (3,3’ ArH), 116.7 (5C

pyrimidine), 128.3. 129.4, 132.0, 160.9, 161.5 (4C

pyrimidine), 172.2 (6C pyrimidine), 175.4 (2C pyrimidine),

188.8 (CHO) ppm; FABMS m/z (%) = 276 (M+1,100), 275

(M+, 50), 260 (50), 247 (50), 246 (45), 233 (10), 200 (5), 170

(4), 158 (20), 107 (2), 89 (1); Anal: Calcd. C, 56.71; H, 4.76;

N, 15.26. Found C, 56.85; H, 4.79; N, 15.18.


N

SCH3

N

O H

NH2

C12H11N3OSMol. Wt.245.30

111 b

2-Amino-4-(methylsulfanyl)-6-phenyl-5-

pyrimidinecarbaldehyde was obtained from 2-benzoyl-3,3-

bis(methylsulfanyl)acrylaldehyde and guanidinehydrochloride;

yield 70% (0.35 g) in CH3CN; cream coloured solid; mp 198

- 200 ○C; IR (KBr νmax) = 3480, 3276, 3125, 1636, 1524

cm–1; 1H NMR (500 MHz, CDCl3) δ = 2.56 (s, 3H, SCH3),

7.22 - 7.54 (m, 5H, ArH), 9.83 (s, 1H, CHO); 13C NMR (75.47

MHz, CDCl3) δ = 13.4 (SCH3), 117.8 (5C pyrimidine), 128.5 -

130.3 (ArH), 140.7 (6C pyrimidine), 160.9 (4C pyrimidine),

170.8 (2C pyrimidine), 188.7 (CHO) ppm; FABMS m/z (%)

= 246 (M + 1, 100), 245 (M +, 60), 217 (40), 170 (20), 120

(15), 107 (18), 105 (8); Anal: Calcd. C, 58.76; H, 4.52; N,

17.13. Found C, 58.58; H, 4.53; N, 17.08.

N

SCH3

N

O H

NH2

C12H10ClN3OSMol. Wt.279.75

Cl

111 c

2-Amino-4-(4-chlorophenyl)-6-(methylsulfanyl)-5-


bis(methylsulfanyl)-2-(4-chlorobenzoyl)acrylaldehyde and

guanidinehydrochloride; yield 76% (0.37 g); cream coloured

solid; mp 174 - 176 ○C; IR (KBr νmax) = 3460, 3200, 1630,

1520 cm-1; 1H NMR (500 MHz, CDCl3) δ = 2.55 (s, 3H,

SCH3), 5.74 (b, 2H, NH2), 7.25 - 7.54 (m, 4H, ArH), 9.66

(s, 1H, CHO); 13C NMR (75.47 MHz, CDCl3) δ = 13.4

(SCH3), 116.7 (5C pyrimidine), 127.4 - 136.6 (ArH), 160.8

(4C pyrimidine), 171.5 (6C pyrimidine), 175.7 (2C

pyrimidine), 188 (CHO) ppm; Anal: Calcd. C, 51.52; H, 3.6;

N, 15.02. Found C, 51.57; H, 3.6; N, 14.99.


N

SCH3

N

O H

NH2

C12H10BrN3OSMol. Wt.324.20

Br

111 d

2-Amino-4-(4-bromophenyl)-6-(methylsulfanyl)-5-


bis(methylsulfanyl)-2-(4-bromobenzoyl)acrylaldehyde and

guanidinehydrochloride; yield 78% (0.39 g) in CH3CN;

cream coloured solid; mp 210 – 212 ○C; IR (KBr νmax) =

3440, 3260, 3155, 1624, 1520 cm–1; 1H NMR (500 MHz,

CDCl3 ) δ = 2.49 (s, 3H, SCH3), 5.94 (b, 2H, NH2), 7.22 - 7.65

(m, 4H, ArH), 9.86 (s, 1H, CHO); 13C NMR (75. 47 MHz

CDCl3) δ = 13.4 (SCH3), 115.4 (5C pyrimidine), 125.0 - 135.0

(ArH), 160.8 (4C pyrimidine), 171.6 (6C pyrimidine), 175.8 (2C

pyrimidine), 188.0 (CHO) ppm; FABMS m/z (%) = 326 (M+2,

98), 324. (M+, 100), 287 (4), 273 (2), 242 (2), 235 (2), 220 (1),

209 (1), 120 (4), 107 (1), 89 (4); Anal: Calcd. C, 44.46; H, 3.11;

N, 12.96 Found C, 44.64; H, 3.12; N, 12.93.

N

SCH3

N

O H

NH2

C13H13N3OS

Mol. Wt.259.33

H3C

111 e

2-Amino-4-(4-methylphenyl)-6-(methylsulfanyl)-5-


bis(methylsulfanyl)-2-(4-methylbenzoyl)acrylaldehyde and

guanidinehydrochloride; yield 75% (0.35 g) in CH3CN.; cream

coloured solid; mp 190 – 192 ○C; IR (KBr νmax) = 3390, 3276,

3130, 1636,1522 cm-1; 1H NMR (500 MHz, CDCl3 ) δ = 2.45 (s,

3H, SCH3), 2.57 (s, 3H, CH3 ), 5.95 (m, 2H, NH2 ), 7.27 - 7.34

(m, 2H, ArH), 7.47 - 7.50 (m, 2H, ArH), 9.84 (s, 1H, CHO); 13C NMR (75.47 MHz, CDCl3) δ = 13.3 (SCH3), 21.4 (CH3),

116.8 (5C pyrimidine), 129.2 - 129.7 (ArH), 133.2 (4C

pyrimidine), 140.7 (4C ArH), 150.2 (1C ArH) 160.9 (6C

pyrimidine), 172.8 (2C pyrimidine), 188.8 (CHO) ppm; FABMS

m/z (%) = 260.(M +1, 100), 259 (M+, 40), 244 (15), 231 (15),

212 (5), 184 (4), 165 (4), 120 (3), 107 (5), 105 (2); Anal: Calcd.

C, 60.21; H, 5.05; N, 16.20; Found. C, 60.36; H, 5.04; N, 16.21.


N

SCH3

N

O H

NH2

C16H13N3OS

Mol. Wt.295.36

111 f

2-Amino-4-(methylsulfanyl)-6-naphthyl-5-

pyrimidinecarbaldehyde was obtained from 2-(2-

naphthoyl)-3,3-bis(methylsulfanyl)acrylaldehyde and

guanidinehydrochloride; yield 40% (0.2 g) in DMF; cream

coloured solid; mp 188 – 190 ○C; IR (KBr νmax) = 3480,

3440, 3160, 1634, 1522 cm-1 ; 1H NMR (300 MHz, CDCl3)

δ = 2.51 (s, 3H, SCH3), 5.65 (s, 2H, NH2), 7.24 – 8.02 (m,

7H, Naphthyl), 9.95 (s, 1H, CHO); 13C NMR (75.47 MHz,

CDCl3) δ = 13.4 (SCH3), 111.0 (5C pyrimidine, 126.2 –

140.9 (naphthyl), 147.45 (6C pyrimidine), 155.5 (4C

pyrimidine), 165 (2C pyrimidine), 188.8 (CHO) ppm;

FABMS m/z (%) 296.(M + 1, 98), 260 (100), 258 (5), 244

(5), 226 (3), 215 (4), 202 (1), 178 (5), 165 (6), 120 (6), 107

(2). Anal: Calcd. C, 65.06; H, 4.44; N, 14.23; Found C,

64.98; H, 4.4 5; N, 14.22.

N

SCH3

N

O H

NH2

C14H15N3O3SMol. Wt. 305.35

H3CO

H3CO

111 g

2-Amino-4-(3,4-dimethoxyphenyl)-6-(methylsulfanyl)-5-


bis(methylsulfanyl)-2-(3,4-dimethoxybenzoyl)acrylaldehyde

and guanidinehydrochloride; yield 70% (0.40 g) in

CH3CN; cream coloured solid; mp 156 – 158 ºC.; IR

(KBr νmax) = 3436, 3317, 3186, 2927, 1639 cm-1 ; 1H NMR

(300 MHz, acetone) δ = 2.71 (s, 3H, SCH3), 3.74 (s, 3H.

OCH3), 3.76 (s, 3H, OCH3), 6.92 - 7.12 (m, 5H, NH2 and

ArH), 9.66 (s, 1H, CHO); 13C NMR (75.47 MHz, acetone-d6) δ

= 13.2 (SCH3), 56.2 and 56.3 (two OCH3), 111.9 - 175.2

(ArH), 188.3 (CHO) ppm; Anal: Calcd. C, 55.07; H, 4.95; N,

13.76. Found: C, 54.81; H, 4.94; N, 13.73.


N

SCH3

N

O H

NH2

C12H10N4O3S

Mol. Wt.290.30

O2N

111 h

2-amino-4(methylsulfanyl)-6-(4-nitrophenyl)-5-


bis(methylsulfanyl)-2-(4-nitrobenzoyl)acrylaldehyde and

guanidinehydrochloride; yield 40% (0.23 g) in DMF; yellow

coloured solid; mp 196–198 ºC; IR (KBr νmax) = 3436,

3313, 3193, 2916,1 639, 1569 cm-1 ; 1H NMR (300 MHz,

CDCl3) δ = 2.54 (s, 3H, SCH3), 5.29 (s, 2H, NH2), 7.70 -

7.72 (m, 2H ArH), 8.23 (d, J = 8.7 Hz, 2H, ArH), 8.93 (s,

1H, CHO); 13C NMR (75.47 MHz, CDCl3) δ = 14.3 (SCH3),

99.9 - 170.7 (ArH and pyrimidine), 176.1 (CHO) ppm;

FABMS m/z (%) 291 (M+1, 30%), 275 (10), 259 (5), 227

(3), 213 (2), 209 (1), 182 (1), 165 (4), 120 (4), 107 (3);

Anal: Calcd. C, 49.65; H, 3.47; N, 19.3; Found C, 49.47; H,

3.50; N, 19.32.

N

SCH3

N

O H

NH2

C13H13N3O2SMol. Wt.275.33

H3CO

111 i

2-amino-4-(3-methoxyphenyl)-6-(methylsulfanyl)-5-



guanidinehydrochloride; yield 82% (0.45 g). in CH3CN;

cream coloured solid; mp 144 – 146 ºC; IR (KBr νmax) =

3483, 3286, 3163, 2916, 1662, 1627 cm-1; 1HNMR (300

MHz, CDCl3 ) δ = 2.49 (s, 3H, SCH3), 3.82 (s, 3H, OCH3),

5.66 (s, 2H, NH2 ), 6.78 - 8.32 (m, ArH), 9.85 (s, 1H, CHO); 13C NMR (75.47 MHz, CDCl3) δ = 13.3 (SCH3), 55.4

(OCH3), 114.5 and 114.6 (2C and 4C ArH), 116.7 (5C

pyrimidine), 121.1 – 129.6. (1C, 5C, 6C ArH), 160.7 (3C

ArH), 161.3 (4C pyrimidine), 172.8 (6C pyrimidine), 174.4

(2C pyrimidine). 188.7 (CHO) ppm; FABMS m/z (%) = 276

(M+1, 100), 275 (M+, 45), 247 (50), 246 (40), 233 (14), 200

(4), 170 (4), 158 (15), 107 (2); Anal: Calcd. C, 56.71; H,

4.76; N, 15.26; Found C, 56.67; H, 4.74; N, 15.24.


3.7.2 Synthesis of 4-(methylsulfanyl)-2,6-diphenyl-5-

pyrimidinecarbaldehydes

General Procedure

The appropriate α- formylketene dithioacetal (2 mmol) was dissolved in DMF

(20 mL) at room temperature. To the above solution benzamidinehydrochloride

(0.313 g, 2 mmol) and K2CO3 (0.55 g, 4 mmol) were added and the reaction

mixture was heated on a boiling water bath for 15 - 20 h. It was cooled, poured

into ice cold-water 50 mL and the semisolid obtained was extracted with

CH2Cl2 (3 x 25 mL). The organic layer was separated, dried and purified

by column chromatography on silica gel (60 x 120) using ethyl acetate-

hexane (1:9) mixture as the eluent. The product was recrystallized from

ethyl acetate / hexane mixture

N N

C6H5

SCH3CHO

H3CO

C19H16N2O2SMol.Wt. 336.41

112 a

4-(4-Methoxyphenyl)-6-(methylsulfanyl)-2-phenyl-5-



benzamidinehydrochloride; yield 50% (0.27 g); white solid;

mp: 164 - 166 oC; IR (KBr νmax) = 1674, 1504, 1361,

1114, 833, 694 cm–1; 1H NMR (300 MHz, CDCl3)

δ = 2.74 (s, 3H , SMe), 3.9 (s, 3H, OMe), 7.08 (d, J = 8.7 Hz,

2H, ArH ), 7.33 - 7.7 (m, 3H, ArH), 7.73 (m, 2H, ArH), 8.66

(m, 2H, ArH), 10.11 (s, 1H, CHO).; 13C NMR (75.47 MHz,

CDCl3): δ = 13.6 (SCH3), 55.4 (OCH3 ), 113.7 (5C

pyrimidine), 114.1 - 132.4 (ArH and 4C pyrimidine), 162.0

(6C pyrimidine), 175.6 (2C pyrimidine); FABMS m/z (%) =

337 (M+, 100), 336 (M+, 5), 274 (4), 242 (2), 229 (1), 179 (2),

165 (2), 120 (2), 107 (5), 89 (5) ; Anal: Calcd. C, 67.84; H,

4.79; N, 8.33; Found C, 67.56; H, 4.82; N, 8.14.


N N

C6H5

SMeCHO

C18H14N2OSMol.Wt. 306.38

112 b

4-(Methylsulfanyl)-2,6-diphenyl-5-pyrimidinecarbaldehyde

was obtained from 2-benzoyl-3,3-bis(methylsulfanyl)

acrylaldehyde and benzamidinehydrochloride; yield 41%

(0.24 g); white solid; mp 152- 154 oC; IR (KBr νmax) =

1674, 1515, 1404, 833,694 cm–1; H NMR (300 MHz,

CDCl3) δ = 2.75 (s, 3H, SCH3), 7.51 - 7.74 (m, 8H, ArH),

8.62 - 8.65 (m, 2H, ArH), 10.1 (s, 1H, CHO proton); 13C

NMR (300 MHz, CDCl3) δ = 13.8 (SCH3), 117.0 (5C

pyrimidine), 128.6 – 137.0 (ArH and 6C pyrimidine),

150.2 (4C pyrimidine, 170.0 (2C pyrimidine), 190.2

(CHO) ppm; FABMS m/z (%) = 307 (M+, 100), 278 (2),

261 (2), 243 (2), 229 (1), 215 (2), 128 (2), 105 (5), 91 (2);

Anal: Calcd. C, 70.56; H, 4.61; N, 9.14. Found C, 70.3; H,

4.42; N, 8.91.

N N

C6H5

SCH3CHO

Cl

C18H13ClN2OS

Mol.Wt. 340.83 112 c

4-(4-Chlorophenyl)-6-(methylsulfanyl)-2-phenyl-5-


bismethylsulfanyl)-2-(4-chlorobenzoyl)acrylaldehyde and

benzamidinehydrochloride; yield: 48% (0.26 g); white solid;

mp 194 - 196 oC; IR (KBr νmax) = 1670, 1512, 1404, 1110,

879, 690 cm–1; 1H NMR (300 MHz, CDCl3 ) δ = 2.73 (s,

3H, SCH3), 7.54 – 8.66 (m, 9H, ArH), 10.1 (s, 1H, CHO); 13C NMR (75.47 MHz, CDCl3 ) δ = 13.6 (SCH3 ), 122.0

(5C pyrimidine), 127.2 - 163.3 (ArH and 4C pyrimidine),

170.2 (6C pyrimidine), 173.6 (2C pyrimidine), 188.2

(CHO); FABMS m/z (%) = 341 (M +1, 5), 316 (100), 284

(1), 256 (1), 242 (1), 230 (10), 210 (5), 177 (1), 120 (2),

107 (1), 89(1); Anal: Calcd. C, 63.43; H, 3.84; N, 8.22

Found: C, 63.76; H, 4.01; N, 8.62.


N N

C6H5

SCH3CHO

Br

C18H13BrN2OS

Mol.Wt. 385.28 112d

4-(4-Bromophenyl)-6-(methylsulfanyl)-2-phenyl-5-


bismethylsulfanyl)-2-(4-bromobenzoyl)acrylaldehyde and

benzamidinehydrochloride; yield: 48% (0.27 g); white solid;

mp 198 - 200 oC; IR (KBr νmax) = 1670, 1512, 1404, 879,

690 cm–1; 1H NMR (300 MHz CDCl3 ) δ = 2.73 (s, 3H,

SCH3 ), 7.52 – 8.6 7 (m, 9H, ArH), 10.09 (s, 1H, CHO); 13C NMR (75.47 MHz, CDCl3 ) δ = 13.6 (SCH3 ), 121.4

(5C pyrimidine), 125.5 - 163.1 (ArH and 4C pyrimidine),

168.7 (6C pyrimidine), 173.5 (2C pyrimidine), 189.3

(CHO) ppm; FABMS m/z ( %) 387 [(M+2), (38)], 385

[M+, (40)], 352 (2), 273 (4), 246 (60), 120 (20), 107 (20);

Anal: Calcd. C, 56.11; H, 3.4; N, 7.27 Found C, 55.98; H,

3.38; N, 6.98.

N N

C6H5

SCH3CHO

H3C


112 e

4-(4-Methylphenyl)-6-(methylsulfanyl)-2-phenyl-5-


bis(methylsulfanyl)-2-(4-methylbenzoyl)acrylaldehyde and

benzamidinehydrochloride; yield: 46 % (0.25 g); white solid;

mp 160 - 162 oC; IR (KBr νmax) = 1674, 1504, 1361, 833,

694 cm–1; 1H NMR (300 MHz, CDCl3) δ = 2.68 (s, 3H,

SCH3), 2.85 (s, 3H, CH3 ), 7.66 – 8.84 (m, 9H, ArH), 10.52

(s, 1H, CHO); 13C NMR (75.47 MHz, CDCl3): δ = 13.6

(SCH3), 21.4 (CH3), 121.5 (5C pyrimidine), 128.5 – 163.0

(ArH and 4C pyrimidine), 169.8 (6C pyrimidine), 173.1 (2C

pyrimidine), 190.1 (CHO) ppm; EIMS m/z (%) = 321 (M+,

100), 304 (1), 202 (1), 149 (2), 102 (10); Anal: Calcd. C,

71.22; H, 5.03; N, 8.74; Found: C, 70.98; H, 4.92; N, 8.82.


N N

C6H5

SCH3CHO


112 f

4-(Methylsulfanyl)-6-(2-naphthyl)-2-phenyl-5-


bis(methylsulfanyl)-2-(2-naphthoyl)acrylaldehyde by reacting

with benzamidinehydrochloride; yield 35% (0.21 g); white

solid; mp 162 - 164 oC; IR (KBr νmax) = 1677, 1504, 1404,

833, 694 cm-1; 1H NMR (300 MHz, CDCl3) δ = 2.79 (s, 3H,

SMe), 7.56 – 7.62 ( m, 4H, ArH and 2H Naphthyl), 7.89 -

8.05 (m, 4H, Naphthyl). 8.13 (s, 1H, Naphthyl), 8.69 (s, 1H,

ArH), 10.1 (s, 1H, CHO); 13C NMR (75.47 MHz, CDCl3) δ =

14.0 (SCH3), 122.0 (5C pyrimidine), 127.2 - 163.3 (naphthyl

and 4C pyrimidine), 170.2 (6C pyrimidine), 173.6 (2C

pyrimidine), 190.4 (CHO) ppm; EIMS m/z (%) 357 (M+,

100), 340 (10), 301 (1), 216 (1), 135 (4), 119 (7), 102 (20),

85 (2); Anal: Calcd. C, 74.13; H, 4.52; N, 7.86 Found C,

73.87; H, 4.72; N, 7.68.

3.7.3 Reactions of 2-amino-6-aryl-4-(methylsulfanyl)-5-pyrimidinecarbaldehydes with malononitrile: Synthesis of 3-[2-amino-4-aryl-6-(methylsulfanyl)-5-pyrimidinyl]-2-cyano-2-propenamides

General Procedure A mixture of malononitrile (230 mg, 3.5 mmol), ammonium acetate (0.75

g, 10 mmol) and acetic acid (5 mL) were heated to 70 °C. To this the

appropriate pyrimidinecarbaldehyde (2 mmol) was added, stirred for 2h at

the same temperature and the cooled reaction mixture and was added into

ice cold water, kept for 1h, and then extracted with ethyl acetate. The

organic layer was separated, dried over anhydrous sodium sulfate and the

solvent was evaporated off. The crude product obtained was purified by

column chromatography on silica gel (60 x 120) using ethyl acetate-hexane


(5:5) mixture as the eluent. The product was recrystallized from ethyl

acetate / hexane mixture

NN

SMe

NH2

CN

H2N O

Br

C15H12BrN5OS

Mol. Wt., 390.26

1118 a

3-[2-Amino-4-(4-bromophenyl)-6-(methylsulfanyl)-5-

pyrimidinyl]-2-cyano-2-propenamide was obtained from the

condensation reaction of 2-amino-4-(4-bromophenyl)-6-

(methylsulfanyl)-5-pyrimidinecarbaldehyde (0.62 g, 2 mmol)

and malononitrile (230 mg, 3.5 mmol) as a yellow solid;

mp 218 - 220 °C; yield 0.24 g (30%); IR (KBr νmax) = 3485,

3425, 3358, 3348, 3186, 2220, 1697, 1620, 1593 cm–1; 1H

NMR (300 MHz, CDCl3) δ = 2.57 (s, 3H, SCH3), 5.32 (s,

2H, NH2), 5.61 and 6.00 (b , 2H, CONH2), 7.39 - 7.36 (d, J =

9 Hz, 2H, ArH), 7.57 - 7.54 (d, J = 9 Hz, 2H, ArH), 8.42 (s,

1H, vinylic) ppm; Anal: Calcd. C, 46.17; H, 3.10; N, 17.95;

Found C, 46.05; H, 3.16; N, 17.79.

NN

SMe

NH2

CN

H2N O

Cl

C15H12ClN5OS

Mol. Wt., 345.81

118 b

3-[2-Amino-4-(4-chlorophenyl)-6-(methylsulfanyl)-5-

pyrimidinyl]-2-cyano-2-propenamide was obtained from

the condensation reaction of 2-amino-4-(4-chlorophenyl)-6-

(methylsulfanyl)-5-pyrimidinecarbaldehyde (0.56 g, 2

mmol) and malononitrile (230 mg, 3.5 mmol) as a yellow

colored product; yield 0.17 g (25%); mp 206 - 208 °C; IR

(KBr νmax) = 3444, 3317, 3190 , 2927, 2221, 1693, 1631,

1593, 1527 cm–1; 1H NMR (300 MHz, CDCl3) δ = 2.61 (s,

3H, SCH3), 5.38 (s, 2H, NH2), 5.76 and 6.00 (b, 2H, CONH2),

7.55 - 7.38 (m, 4H, ArH), 8.42 (s, 1H, vinylic) ppm; Anal:

Calcd. C, 52.10; H, 3.50; N, 20.25; Found: C, 52.10; H,

3.46; N, 20.02.


NN

SMe

NH2

CN

H2N O

C15H13N5OS

Mol. Wt., 311.26 118 c

3-[2-Amino-4-phenyl-6-(methylsulfanyl)-5-pyrimidinyl]-

2-cyano-2-propenamide Yellow solid; mp 208 - 210 °C;

yield 0.18 g (30%); IR (KBr νmax) = 3480, 3418, 3356,

3350, 3182, 2223, 1687, 1630, 1583 cm–1; 1H NMR (300

MHz, CDCl3) δ = 2.56 (s, 3H, SCH3), 5.33 (s, 2H, NH2), 5.61

and 5.90 (b, 2H, CONH2), 7.22 (s, 1H, ArH), 7.29 - 7.26 (d, J

= 9 Hz, 2H, ArH), 7.57 - 7.54 (d, J = 9 Hz, 2H, ArH), 8.42 (s,

1H, vinylic) ppm; Anal: Calcd. C, 57.86; H, 4.21; N, 22.49;

Found C, 57.78; H, 4.23; N, 22.53.

3.7.4 Reactions of 2-amino-6-aryl-4-(methylsulfanyl)-5-pyrimidinecarbaldehydes with malononitrile: Synthesis of 2-{[6-aryl-2-amono-4-(methylsulfanyl)-5-pyrimidinyl]methylene} malononitrile

General Procedure

A mixture of malononitrile (230 mg, 3.5 mmol), ammonium acetate

(0.75g, 10 mmol) and acetic acid (5 mL) was heated to 70°C. To this the

appropriate pyrimidinecarbaldehyde (2 mmol) was added, stirred for 2h at

the same temperature and the cooled reaction mixture was diluted with

ethyl acetate (100 mL) and then washed with ice cold water (3 x 25 mL).

The organic layer was separated, dried over anhydrous sodium sulfate and

the solvent was evaporated off. The crude product obtained was purified

by column chromatography using ethyl acetate-hexane (3:7) mixture as

the eluent.


N N

NH2

SCH3

C15H10BrlN5SMol.Wt. 372.24

CN

CNBr

117 a

2-{[2-Amino-4-(4-bromophenyl)-6-(methylsulfanyl)-5-

pyrimidinyl]methylene}]malononitrile was obtained by

the Knoevenagel condensation reaction of 2-amino-4-

(4-bromophenyl)-6-(methylsulfanyl)-5-pyrimidine

carbaldehyde (645 mg, 2 mmol) with malononitrile (230

mg, 3.5 mmol) as deep yellow colored crystals; mp 182 -

184 °C; yield 0.52 g (70%); IR (KBr νmax) = 3467, 3363,

3244, 2221, 1631, 1585, 1519 cm–1; 1H NMR (300 MHz,

CDCl3) δ = 2.65 (s, 3H, SCH3), 5.44 (b, 2H, NH2), 7.36

(d, J = 8.4 Hz, 2H, ArH), 7.62 (d, J = 8.4 Hz. 2H, ArH ),

7.95 (s, 1H, vinylic) ppm; Anal: Calcd. C, 48.40; H, 2.71;

N, 18.81. Found: C, 48.10; H, 3.01; N, 18.5.

N N

NH2

SCH3

C15H10ClN5SMol.Wt. 327.79

CN

CNCl

117 b

2-{[2-Amino-4-(4-chlorophenyl)-6-(methylsulfanyl)-

5-pyrimidinyl]methylene}] malononitrile was obtained

by the Knoevenagel reaction of 2-amino-4-(4-

chlorophenyl)-6-(methylsulfanyl)-5-pyrimidine

carbaldehyde (0.56 g, 2 mmol) with malononitrile (230

mg, 3.5 mmol); yield 0.45 g (70%); deep yellow colored

crystals; mp 182 - 184 °C; IR (KBr νmax) = 3452, 3325,

3201, 2229, 1639, 1573, 1523 cm–1; 1H NMR (300

MHz, CDCl3) δ = 2.62 (s, 3H, SCH3), 5.34 (s, 2H,

NH2), 7.37 - 7.56 (m, 4H, ArH), 7.95 (s, 1H, vinylic)

ppm; Anal: Calcd. C, 54.96; H, 3.07; N, 21.37. Found:

C, 55.32; H, 3.32; N, 21.15.


N N

NH2

SCH3

C15H11N5SMol.Wt. 293.35

CN

CN

117 c

2-{[2-Amino-4-(methylsulfanyl)-6-phenyl-5-

pyrimidinyl]methylene}]malononitrile was obtained

by the Knoevenagel condensation reaction of 2-

amino-4-(methylsulfanyl)-6-phenyl-5-pyrimidine

carbaldehyde (0.5 g, 2 mmol) with malononitrile (230

mg, 3.5 mmol); yield 0.38 g (65%); deep yellow colored

crystals; mp 184 - 186 °C; IR (KBr νmax) = 3456, 3294,

3178, 2229, 1627,1573, 1535 cm-1. 1H NMR (300 MHz,

CDCl3) δ = 2.66 (s, 3H, SCH3), 5.53 (b, 2H, NH2), 7.48

- 7.56 (m, 5H, ArH), 7..93 (s, 1H, vinylic) ppm; Anal:

Calcd. C, 61.42; H, 3.78; N, 23.87. Found: C, 61.48; H,

3.46; N, 24.05.

N N

NH2

SCH3

C16H13N5S

Mol.Wt. 307.37

CN

CNH3C

117 d

2-{[2-Amino-4-(4-methylphenyl)-6-

(methylsulfanyl)-5-pyrimidinyl]methylene}]

malononitrile was obtained by the Knoevenagel

condensation reaction of 2-amino-4-(4-methylphenyl)-

6-(methylsulfanyl)-5-pyrimidinecarbaldehyde (520 mg,

2 mmol) with malononitrile (230 mg, 3.5 mmol) as deep

yellow colored crystals; mp 188 - 190 °C; yield 0.40g

(65%); IR (KBr νmax): 3414, 3322, 3205, 2230, 1634,

1573, 1518. cm–1; 1H NMR (300 MHz, CDCl3) δ = 2.49

(s, 3H, Me), 2.58 (s, 3H, SMe), 5.63 (s, 2H, NH2), 7.25 -

7.34 (m, 4H, ArH), 7.94 (s, 1H, vinylic) ppm.; 13C NMR

(75.47 MHz, CDCl3) δ = 13.0 (SMe), 21.3 (Me), 88.2

(C(CN)2), 111.2 (5C pyrimidine), 111.7 (CN), 113.1

(CN), 129.2, 129.4, 133.7, 141.0, (ArH ), 156.0 (vinylic),

161.4 (6C pyrimidine), 166.1 (4C pyrimidine), 171.7 (2C

pyrimidine) ppm; Anal: Calcd. C, 62.52; H, 4.26; N,

22.78. Found: C, 62.12; H, 4.46; N, 22.55.


N N

NH2

SCH3

C16H13N5OS

Mol.Wt. 323.37

CN

CNH3CO

117 e

2-{[2-Amino-4-(4-methoxyphenyl)-6-


malononitrile was obtained by the Knoevenagel reaction

of 2-amino-4-(4-methoxyphenyl)-6-(methylsulfanyl)-5-

pyrimidinecarbaldehyde (550 mg, 2 mmol) with

malononitrile (230 mg, 3.5 mmol); yield 0.50 g (77%);

deep yellow colored crystals; mp 192 - 194 °C; IR

(KBr νmax) = 3410, 3308, 3182, 2934, 2225, 1648, 1582,

cm–1; 1H NMR (300 MHz, CDCl3) δ = 2.59 (s, 3H,

SMe), 3.87 (s, 3H, OMe), 5.48 (s, 2H, NH2), 6.99 - 6.96

(d, J = 9 Hz, 2H, ArH), 7.45 - 7.42 ( d, J = 9 Hz, 2H,

ArH), 7.93 (s, 1H, Vinylic) ppm ; 13C NMR (75.47

MHz, CDCl3) δ = 13.1 (SMe), 55.4 (OMe), 88.0 (

C(CN)2), 111.7 (5C pyrimidine), 113.1 (CN), 114.3

(CN), 128.9 - 156.1 (ArH), 161.4 (vinylic), 161.6 (4C

pyrimidine), 165.8 (6C pyrimidine), 171.8 (2C

pyrimidine); Anal: Calcd. C, 59.43; H, 4.05; N, 21.66.

Found: C, 58.98; H, 3.96; N, 21.43.

N N

NH2

SCH3

C16H13N5OS

Mol.Wt. 323.37

CN

CN

H3CO

117 f

2-{[2-Amino-4-(3-methoxyphenyl)-6-(methylsulfanyl)-

5-pyrimidinyl]methylene}]malononitrile was obtained

by the Knoevenagel condensation of 2-amino-4-(3-

methoxyphenyl)-6-(methylsulfanyl)-5-pyrimidine

carbaldehyde (550 mg, 2 mmol) with malononitrile (230

mg, 3.5 mmol) as deep yellow colored crystals; mp 132

- 134 °C; yield 0.48 g (75%); IR (KBr νmax) = 3375,

3305, 3182, 2225, 1643, 1581, 1527 cm-1 ; 1H NMR

(300 MHz, CDCl3) = 2.63 (s, 3H, SCH3), 3.82 (s, 3H,

OMe), 5.45 (b, 2H, NH2), 6.98 - 6.95 (d, J = 9 Hz, 1H,

ArH), 7.04 (m, 2H, ArH), 7.39 (m, 1H, ArH ), 7.91 (s,

1H, vinylic) ppm; Anal: Calcd. C, 59.43; H, 4.05; N,

21.66. Found: C, 59.78; H, 4.16; N, 21.53.


N N

NH2

SCH3

C17H15N5O2S

Mol.Wt. 353.40

CN

CN

H3CO

H3CO

117g

2-{[2-amino-4-(3,4-dimethoxyphenyl)-6-


malononitrile was obtained by the Knoevenagel

condensation reaction 2-amino-4-(3,4-dimethoxyphenyl)-

6-(methylsulfanyl)-5-pyrimidinecarbaldehyde (610 mg, 2

mmol) with malononitrile (230 mg, 3.5 mmol) as deep

yellow colored crystals; mp 178 - 180 °C; yield 0.49 g

(70%); IR (KBr νmax) = 3412, 3305, 3182, 2221, 1631,

1577, 1531 cm–1; 1H NMR (300 MHz, CDCl3 ) δ = 2.6 (s,

3H, SCH3), 3.93 (s, 3H, OMe ) and 3.95 (s, 3H, OMe), 5.48

(s, 2H, NH2), 6.90 - 7.11 (m, 3H, ArH), 7.93 (s, 1H, vinylic)

ppm; 13C NMR (75.47 MHz, CDCl3 ) δ = 13.1 (SMe), 56.1

(OMe) and 56.0 (OMe), 88.1 (C(CN)2), 110.8 (5C

pyrimidine), 111.3 (CN), 111.8 (CN), 112.2, 113.2, 123.0,

129.0, 149.3, 151.3, 156.2 (Vinylic), 161.4 (6C

pyrimidine), 165.8 (4C pyrimidine), 171.8 (2C pyrimidine).

Anal: Calcd. C, 57.78; H, 4.28; N, 19.82. Found: C, 57.98;

H, 3.96; N, 19.56.

3.7.5 Reactions of 6-aryl-2-amino-4-(methylsulfanyl)-5-

pyrimidinecarbaldehydes with hydroxylamine hydrochloride

General Procedure

A mixture of hydroxylamine hydrochloride (70 mg, 1 mmol), potassium

carbonate (138 mg, 1 mmol) and acetonitrile (10 mL) was heated to

80 °C. To this solution, the appropriate pyrimidinecarbaldehyde (0.5 mmol)

was added, stirred for 10h at the same temperature and cooled to attain room

temperature. The reaction mixture was extracted with dichloromethane (100

mL) and washed with ice-cold water. The organic layer was separated, dried

over anhydrous sodium sulfate and the solvent was evaporated off. The


crude product was purified by recrystallization using CH2Cl2 / hexane as

the solvent mixture.

N N

NH2

SMe

NOH

C13H14N4OSMol. Wt.,274.34

H3C

119a

2-Amino-4-(3-methylphenyl)-6-(methylsulfanyl)-5-

pyrimidinecarbaldehyde oxime was obtained from 2-

amino-4-(4-methylphenyl)-6-(methylsulfanyl)-5-pyrimidine

carbaldehyde (129 mg, 0.5 mmol.) by the reaction of

hydroxylamine hydrochloride (70 mg,1 mmol) as pale white

solid; mp 230 - 232 °C; yield 0.08 g (60%); IR (KBr νmax) =

3506, 3328, 3244, 3193, 1612, 1535 cm–1; 1H NMR (300 MHz,

DMSO d6) δ = 2.35 (s, 3H, CH3), 2.47 (s, 3H, SMe), 7.24 - 7.46

(m, 4H, ArH), 7.77 (s, 1H, -CH=N-), 11. 1(b, 1H, =N-OH) ppm.

N N

NH2

SMe

NOH

O2N

C12H11N5O3SMol. Wt.,305.31

119b

2-Amino-4(methylsulfanyl)-6-(4-nitrophenyl)-5-

pyrimidinecarbaldehyde oxime was obtained from 2-amino-

4(methylsulfanyl)-6-(4-nitrophenyl)-5-pyrimidine carbaldehyde

(144 mg, 0.5 mmol) by the reaction of hydroxylamine

hydrochloride (70 mg, 1 mmol) as yellow solid. mp 130-132 °C;

yield 0.076 g (50%); IR (KBr νmax) = 3487, 4326, 3371, 3317,

2923, 1654, 1566, 1014 cm–1; 1H NMR (300 MHz, CDCl3) δ =

2.60 (s, 3H, SMe), 4.53 (b, 3H, NH2, OH), 7.80 (d, J = 8.7 Hz,

2H, ArH), 8.25 (s,1H, -CH=N), 8.31 - 8.34 (m, 2H, ArH)

N N

NH2

SMe

NOH

C13H14N4O2SMol. Wt.,290.34

H3CO

119c

2-Amino-4-(3-methoxyphenyl)-6-(methylsulfanyl)-5-

pyrimidinecarbaldehyde oxime was obtained from 2-

amino-4-(3-methoxyphenyl)-6-(methylsulfanyl)-5-

pyrimidinecarbaldehyde (137 mg, 0.5 mmol) by the reaction of

hydroxylamine hydrochloride (70 mg, 1 mmol) as pale white

solid; mp 190 - 192 °C; yield 0.1 g (70%); IR (KBr νmax)=

3350, 3317, 3193, 2997, 1643, 1581 cm–1; 1H NMR (300 MHz,

CDCl3) δ = 2.62 (s, 3H, SMe), 3.85 (s, 3H, OCH3), 5.14 (b, 3H,

NH2, OH), 6.91 - 7.63 (m, 4H, ArH), 8.27 (s, 1H,-CH=N-).


3.8 References

1 (a) Jacobson, K. A.; Jarvis, M. F.; Williams, M., J. Med. Chem., 2002, 45,

4057; (b) Heidelberger, C., Annu. Rev. Pharma., 1967, 7, 101; (c) Jones,

M. E., Annu. Rev. Biochem., 1980, 49, 253.

2 Sołoducho, J.; Doskocz, J.; Cabaj, J.; Roszak, S., Tetrahedron, 2003, 59, 4761.

3 Lehn, J.-M., Supramolecular Chemistry-Concepts and Perspectives,

VCH: Weinheim, 1995; Chapter 9.

4 (a) Harriman, A.; Ziessel, R., Coord. Chem. Rev., 1998, 171, 331; b)

Harriman, A.; Ziessel, R., Chem. Commun., 1996, 1707.

5 Rita, Z.; Mark, S.; Uwe, S.; Ralf, B., Annual Rev. Plant Bio., 2006, 57, 805

6 (a) Edstrom, E.; Wei, Y., J. Org. Chem., 1993, 58, 403; (b) Urban, S.;

Capon, R. J.; Hooper, J. N. A., Aus. J. Chem., 1994, 47 (12), 2279 ; (c)

Looper, R, E.; Maria, T. C. R.; Williams, R. M., Tetrahedron, 2006, 62,

18, 4549 .

7 (a) Xie, W.; Jin, Y.; Wang, P.G., Chemtech., 1999, 223; (b) Varma, R. S.,

Green Chem., 1999, 1, 43;. (c) Monika, J.; Tracey, M.; Dennis, Y. K.;

Rakesh, K., Bioorg. Med. Chem., 2005, 13, 6663; (d) Zlatko, J.; Jan, B.;

Graciela, A.; Robert, E. D.C.; Morris, J. R., J. Med. Chem., 2005, 48,

4690; (e) Yili, D.; Haoyun, A.; Zhi, H.; Jean-Luc, G., Bioorg. Med. Chem.

Lett., 2005, 15, 725; (f) Chris, A. J.; Chris, M.; Charles, M. H., Pharm

Res., 2004, 21, 914 ; (g) Agrofoglio, L. A., Curr. Org. Chem., 2006, 10,

333; (h) Dwivedi, C.M.; Junjappa, H.; Krishnamurthi, C.R., Toxicology,

1981, 21, 253.

8 Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.;

Gougoutas, J. Z.; O'Reilly, B. C.; Schwartz, J.; Malley, M. F., J. Med.

Chem., 1992, 35, 3254 .

9 Jung, M. H.; Park, J. G.; Yang, K. J.; Lee, M. J., Arch Pharm., 2001, 334, 79.


10 George, R. B.; David, M. H.; Elaine, S. E. S.; David, W.; David, S. C.;

Allan, J. F.; Steven, C. G.; McTaggart, F.; Donald, J. M.; Graham, J. S.;

Robin, W., J. Med. Chem., 2000, 43 ,4964.

11 Francesca, C.; Donata, V.; Teresa, G.; Fulvio, B.; Maria, D. C.; Rosa,

M. M.; Alfredo, F.; Massimo, S., J. Clin. Endocrinol. Metab., 2003, 88,

4, 1897 .

12 George, C. F., Lancet., 2001, 358, 1623

13 Chauhan, P. M. S.; Sanjay K. S., Curr. Med. Chem., 2001, 8, 1535.

14 Adrienn, H.; Zoltán, H.; Ilona,V., Synth. Commun., 2006, 36, 129.

15 Metwally, M. A.; Abdel-Latif, E., J. Sul. Chem., 2004, 25, 359.

16 Branko, S.; Jurij, S., Chem. Rev., 2004, 104, 2433.

17 Sergey, A. P.; Tatyana, V. R.; Yury, V. G.; Alexy, V. T., Mendeleev

Commun., 2002, 6.

18 Biginelli, P., Gazz. Chim. Ital., 1893, 23, 360.

19 Pinner, A., Chem. Ber., 1893, 20, 2122.

20 Cernuch ova, P.; Vo-Thanh, G.; Milata, V.; Loupy, A.; Jantova, S.;

Theiszova, M., Tetrahedron, 2005, 61, 22, 5379 .

21 Dieter, R. K., Tetrahedron, 1986, 42, 3029.

22 Gompper, R.; Tofli, W., Chem. Ber., 1962, 95, 2871.

23 (a) Chauhan, S. M. S.; Junjappa, H., Tetrahedron, 1976, 32, 1779; (b)

Chauhan, S.M.S.; Junjappa, H., Synthesis, 1974, 880.

24 (a) Singh, L. W.; Gupta, A. K.; Ila, H.; Junjappa, H., Synthesis, 1984, 516;

(b) Kumar, A.; Ila, H.; Junjappa, H.; J. Chem. Res.(s), 1979, 268.

25 Rudorf, W. D.; Augustian, M., J. Prakt. Chem. ,1978, 320, 576.

26 Chauhan, S. M. S.; Junjappa, H., Tetrahedron, 1976, 32, 1911.


27 Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G.; J. Org. Chem.,

1983, 48, 4841.

28 Tominaga, Y.; Kohra, S.; Okuda, H.; Ushirogochi, A.; Matsuda, Y.;

Kobayashi, G., Chem. Pharm. Bull., 1984, 32, 122.

29 Chakrasali, R. T.; Ila, H.; Junjappa, H., Synthesis, 1988, 87.

30 Ried, W.; Aboul-Fetouh, S., Tetrahedron, 1988, 44, 7155.

31 Ried, W.; Laoutidis, J., Liebigs Ann. Chem., 1990, 2, 207.

32 Tominaga, Y.; Sakai, S.; Kohra, S.; Tsuka, J.; Matsuda, Y.; Kobayashi,

G., Chem. Pharm. Bull., 1985, 33, 962.

33 Zaharan, M. A.; El-Sharief, A. M.; El-Gaby, M. S. A.; Ammar, Y. A.; El-

Sad, U. H., Il Farmaco, 2001, 56, 277.

34 Lei, Z.; Fushun, L.; Xihe, B.; Shaoguang, S.; Liu, Q., J. Org. Chem.,

2006, 71 (3), 1094 .

35 Mellor, J. M.; Schofield, S. R.; Korn, S. R., Tetrahedron, 1997, 53,

17163.

36 (a) Kohra, S.; Tominaga, Y.; Hosomi, A., J. Heterocycl. Chem., 1988, 25,

959; (b) Kohra, S.; Tominaga, Y.; Matsuda,Y.; Kobayashi, G.,

Heterocycles, 1983, 20, 1745.

37 Yu, S. Y.; Cai, Y. X., Synth. Commun., 2003, 33, 3989.

38 Liu, H.; Yang, G.; Chen, K.; Yang, H., Synth. Commun., 1999, 29, 3143.

39 Briel, D.; Sieler, J.; Wagner, G.; Schade, W., Phosphorus, Sulfur Relat.

Elem., 1988, 35, 55.

40 Apparao, S.; Rahman, A.; Ila, H.; Junjappa, H., Synthesis, 1982, 792.

41 Kumar, A.; Aggarwal, V.; Ila, H.; Junjappa, H., Synthesis, 1980, 748.

42 Aggarwal, V.; Ila, H.; Junjappa, H., Synthesis, 1982, 65.


43 Vishwakarma, J. N.; Apparao, S.; Ila, H.; Junjappa, H., Indian J. Chem.,

1985, 24B, 466.

44 Mathews, A.; Asokan, C. V., Tetrahedron, 2007, 33, 7845.

45 Bredereck, H.; Sell, R.; Effenberger, F., Chem. Ber., 1964, 97, 3407 .

46 Sisco, J.; Mellinger, M., Pure Appl. Chem., 2002, 74, 8, 1349 .

47 Johnson, T. B.; Cretcher, L. H., J. Am. Chem. Soc., 1915, 2144

48 (a) Klotzer, W.; Herberz, M., Monatsh. Chem., 1965, 96, 1567 ; (b) Santilli,

A. A.; Kim, D. H.; Wanser, S. V., J. Heterocycl. Chem., 1974, 8, 445.

49 (a) Wouter, M.; Jeroen, V.; Dehaen, W., Chem. Commun., 2005, 2612; (b)

Asokan, C. V.; Smeets, S.; Dehaen, W., Tetrahedron Lett., 2001, 42, 27,

4483; (c) Maes, W.; Vanderhaeghen, J.; Smeets, S.; Asokan, C. V.; Van

Renterghem, L. M.; Du Prez, F. E.; Smet, M.; Dehaen, W., J. Org. Chem.,

2006, 71, 8, 2987 .

50 Ryabova, O. B.; Evstratova, M. I.; Makarov, V. A.; Tafeenko, V. A.;

Granik, V. G., Chem. Heterocycl. Compd., 2004, 40. 1352.

51 Ple, N.; Fiquet, T. E.; Queguiner, G., J. Heterocycl. Chem., 1991, 28, 283.

52 Heaney, F.; Bourke, S.; Burke, C.; Cunningham, D.; McArdle, P., J.

Chem. Soc., Perkin Trans. 1, 1998, 2255.

53 Bredereck, H.; Simchen, G.; Wagner, H.; Santos, A. A., Liebigs Ann.

Chem., 1972, 73, 766

54 Petersen, L.; Pedersen, E. B.; Nielsen, C., Synthesis, 2001, 559 .

55 Brossmer, R.; Ziegler, D., Tetrahedron Lett., 1966, 5253.

56 Smeets, S.; Asokan, C.V.; Motmans, F.; Dehaen, W., J. Org. Chem.,

2000, 65, 5882 .

57 (a) Sato, I.; Shimizu, M.; Kawasaki, T.; Soai, K., Bull. Chem. Soc. Jpn.,

2004, 77, 1587; (b) Sato, I.; Urabe, H.; Ishii, S.; Tanji, S.; Soai, K., Org.


Lett., 2001, 24, 3851; (c) Sato, I.; Ohno, A.; Aoyama, Y.; Kasahara, T.;

Soai, K., Org. Biomol. Chem., 2003, 1(2), 244.

58 Susvilo, I.; Palskyte, R.; Tumkevicius, S.; Brukstus, A.; Chem. Heterocycl .

Compd., 2005, 41, 2, 268.

59 Tumkevicius, S.; Kaminskas, A.; Dailide, M., Pol. J. Chem., 2002, 76, 725.

60 Tumkevicius, S.; Zivile, S.; Viktoras, M., Synthesis, 2003, 1377.

61 Gardinier, K. M.; Khoury, R. G.; Jean-Marie Lehn, Chem. Eur . J., 2000,

6, 22, 4124.

62 Seung-Un, P.; Chan-Jae, L.; Han, J. H., Bull. Korean Chem . Soc., 2005,

26, 7, 1033.

63 Mahmoud, M. R.; Abd-El-Halim, M. S.; Ebrahim, A. E. F.; Radwan, A.

M.; Indian J. Chem., 1996, 35B, 915.

64 Yang , J.; Che, X.; Dang, Q.; Wei, Z.; Gao, S.; Bai, X., Org. Lett., 2005, 7, 8,

1581.

65 Anabha, E. R.; Asokan, C. V., Synthesis, 2006, 151.

66 Anabha, E. R., PhD Thesis, 2004, M. G. University, Kerala, India.

67 Fedorynski, M.; Wojciechowski, K.; Matacz, Z.; Makosza, M., J. Org.

Chem., 1978, 43, 24, 4682.

68 Yu, S. Y.; Cai Y. X., Synth. Commun., 2003, 33, 3989.

69 Rivera, D. G.; Peseke, K.: Jomarron, I.; Montero, A.; Molina, R.; Coll, F.,

Molecules, 2003, 8, 444 .

70 Trost, B. M.; Fleming, I. in Comprehensive Organic Synthesis, Vol 2; Tietze,

L. F.; Beifuss, U., The Knoevenagel Reaction; (ed) Pergamon Press: Oxford,

1993, 341.

71 Anabha, E. R., Nirmala, K. N.; Abraham, T.; Asokan, C. V., Synthesis,

2007, 428 .

72 Itami, K.; Yamazaki, D.; Yoshida, J., J. Am. Chem. Soc., 2004, 126, 15396.


73 Shinar, J., Ed. Organic Light Emitting Devices, Springer, 2004.

74 (a) Junjappa, H; Ila, H; Asokan, C.V. Tetrahedron, 1990, 46, 5423; (b)

Kolb, M., Synthesis, 1990, 171.

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