STUDIES ON NITROGEN
HETEROCYCLIC SYSTEMS
A thesis submitted in partial fulfillment of the requirements for the degree of
1

STUDIES ON NITROGEN
HETEROCYCLIC SYSTEMS
B.Sc. IN CHMISTRY 1986
M. Sc. IN ORGANIC CHEMISTRY 1992
Under the supervision of:
Prof.Dr. Said El-Bahaie Prof. Of Organic Chemistry,
Faculty of Science, Zagazig
University,
Prof. Dr. Mohammed Gomh Assy Prof. Of Organic Chemistry,
Dr. Gamal A. Abd El-Attif
Faculty of Science, Zagazig
University
Assoc. Prof. Of Organic
Chemistry Faculty of Science,
Dr. Amani M. El-Mosulmi
Zagazig University
Assoc. Prof. Of Organic
Chemistry Faculty of Science,
Zagazig University
2

STUDIES ON NITROGEN
HETEROCYCLIC SYSTEMS
B.Sc. IN CHMISTRY 1986
M. Sc. IN ORGANIC CHEMISTRY 1992
Approved by:
Prof. Dr. Maher A. El-Hashash
Prof. Of Organic Chemistry, Ain-Shams University
Prof. Dr. Ahmed M. Farg
Prof. Of Organic Chemistry, Cairo University
Prof. Dr. Said El-Bahaie
Prof. Of Organic Chemistry, Zagzig University
Date of examination: / / 2003
3

In the name of Allah the beneficent, the Merciful first and above all praise be to Allah the Almighty, the glorious who has bestowed upon us the faculties of thanking, searching and learning.
I would like to express my sincere gratitude and great appreciation to Prof. Dr. Said El-Bahaie, Professor of Organic
Chemistry, Chemistry Department, Faculty of Science, Zagazig
University, for his continuous interest, valuable criticism, encouragement and moral support during this work.
I wish to record my deep gratefulness to Prof. Dr.
Mohammed Gomh Assy, Professor of Organic Chemistry,
Chemistry Department, Faculty of Science, Zagazig University, for continuous guidance, invaluable advice and also for his simulating discussions.
I am immeasurably thankful to Dr. Gamal Ahmed Abd
El-Attif, Associate Professor of Organic Chemistry, Chemistry
Department, Faculty of Science, Zagazig University, for his continuous help, guidance and encouragement during the progress of this work.
I wish to express my thanks to Dr. Amani M. El-
Mosulmi, Associate Professor of Organic Chemistry, Chemistry
Department, Faculty of Science, Zagazig University, for guidance and continuos help.
Finally, I express my sincere thanks to all staff members, colleagues and technicians in the same Department, for their help and facilities kindly provided.
4

INTRODUCTION
SYNTHESIS OF PYRIMIDINE
Page
1
3
(I): Synthesis from N-C-C-C-N and C- fragment
(II): Synthesis of Pyrimidine from N-C-N-C and C-C
Fragment:
(III): Synthesis of Pyrimidine from C-C-C and N-C-N
Fragment:
(IV): Synthesis from C-C-C-N and C-N Fragment.
(V): Synthesis of Pyrimidine from N-C-C and C-N-C
Fragment:
(VI): Synthesis from N-C-C-C-N-C Fragment:
Synthesis of Pyrimidine from Ring Transformation
I- Ring transformation of pyran into pyrimidine
II-Ring transformation of azetes into pyrimidines
74
76
III- Ring transformation of 1,3-oxazine and oxazole into pyrimidine 77
IV- Ring transformation of 1,3-thiazine into pyrimidine 80
V- Ring transformation of isoxazole into pyrimidine 81
57
66
71
74
4
9
12
Reaction of Pyrimidine derivatives
Electrophilic Substitution Reaction
Nucleophilic Substitution Reaction
SYNTHESIS OF PYRIDONE
PYRIDINETHIOE DERIVATIVES
1- From α, β-unsaturated Ketones
82
82
86
AND
100
100
5

2- From malonic acid derivative 110
3- From heterocyclic compounds 113
Reactions of Pyridone and Pyridinethione Derivatives 118
1- Alkylation
2-Displacement by halogen
118
121
3- Nitration 124
Biological Importance
EXPERIMENTAL
Table 1. Analytical and Physical Data for Pyrimidine
Derivatives
Table 2. Analytical and Physical Data for Pyridinethione
Derivatives
DISCUSSION
PYRIMIDINETHIONE
125
127
139
146
149
149
PYRIDINETHIONE
Figures of IR spectra
Figures of 1 HNMR spectra
SUMMARY
References
ARABIC SUMMARY
163
175
192
202
211
6

Pyrimidine (1) is the trivial name for 1,3-diazine: two meta oriental CH units in benzene have been replaced by nitrogen atom.
1
N
2 6
3 N 5
4
1
Pyrimidine has one axis of symmetry about the 2-5 axis, it has three different pairs of bond lengths and four different bond angels. Accordingly in 1 H and 13 CNMR spectra the 1 H and 13 C nuclei are found at three different chemical shifts. Symmetry is lost by unequal substitution at the 4 or/and 6 position (Brown et al., 1994) .
Hydroxy, thiol and amino groups in pyrimidine exist in tautomeric equilibria with oxo, thioxo and imino forms
(Woodgate et al., 1987) .
7

I) Hydroxy-oxo-tautomerism
Physiochemical technique show that 2- and 4-hydroxy pyrimidine are predominantly in the oxo forms. The former as
(2 a
) and the latter in ortho-quinonoid structure (3 a
Z = O) in preference it’s para-quinonoid isomer
(Pozharski and
Dalnikovskaya 1981) .
H
Z N N Z
H N N
2a, Z = O
2b, Z = S
3a, Z = O
3b, Z = S
In dihydroxy derivatives, such as uracil, the dioxo form
2,4(1H, 3H)-pyrimidindione is the predominant form and in the trihydroxy pyrimidine, barbituric acid, the 2,4,6-(1H, 3H, 5H)pyrimidinetrione formis predominant (Woodgate et al., 1987) .
II) Thiol-thioxo-tautomerism
Pyrimidines with a thiol group in an electrophilic position exist predominantly in thione form as shown in structure (2b) and (3b Z = S), in the pyrimidines series 2-thiolpyrimidines exist almost exclusively in the thione form (Pozharski and
Dalnikovskaya 1981) .
8

III) Amino-imino-tautomerism
All spectroscopic and pK a
of amino pyrimidines show the amino form an over whelming extent (Brown et al., 1994) .
Pyrimidine does not normally serve as a starting point for preparation of substituted pyrimidine. These compounds are generally prepared by five types of ring synthesis (I, II, III, IV and V) according to the nature of the fragments which combing together to form the pyrimidine nucleus (Elderfield 1966) .
C C C C C
C N C C C N C N C N
C
N
I
C
C
N
II
C C
N
III
C C
N
IV
C C
N
V
C
9

Heating of acetyl acetone and benzaldehyde in presence of two equivalent of ammonium acetate yielded the pyrimidine derivatives 5 (Lweis and Rosenbach 1981) via the intermediate
4.
O CH
3 O
CH
3
CH
3
MeCO
2
NH
4
CH
3
DMSO/AcOH
NH
2
H C
6
H
5
N
O
H
3
C
4
NH H
5
C
6
N
5
The reaction of 1,3-diaminopropane with formaldehyde yielded perhydropyrimidine 6a, and with diethylcarbonate yielded the 2-oxo derivative 6b and with carboxylic acid and give tetrahydropyrimidine 6c (Bischoff et al., 1901; Fischer and
Koch 1986 and Grath 1988) .
CH
3
10

NH
HCHO
N
H
6a
NH
2
NH
O=C.(CO
2
C
2
H
5
)
2
NH
2
N
H
6b
O
RCOOH o-xylene
N
N R
H
6c
Cyclocondensation of enaminonitrile 7 with CS
2
in the presence of sodium methoxide gave pyrimidinethione derivative
8 (Briel et al., 1992) .
S
NH
2 CN
RCH
2
S-C=
CN
+ CS
2
MeOH/MeONa
5M
H
N
CN
S N SCH
2
R
7
H
8
Cyanocrotonamide derivatives 9 condensed with diethoxyalkyl-amine 10 to yield the pyrimidine derivative 11
(Gronik and Kaimanakava 1983) .
11

O
R
1
HN CH
3
NH
2
H
3
C
CH
3
NC
+ R
OC
2
H
5
N
CH
3
CH
3
OC
2
H
5
R
1
N
N
N
CH
3
9 10
11
The reaction of malonodiamide 12 with an ester such as malonic ester 13 yielded the 4,6-dihydroxypyrimidine derivative
14 (Remfry 1911) .
CN
O
OH
O O
NH
2
CH
3
OMe N
H
3
C + H
3
C
NH
2
OMe
H
3
C
N OH
O
12
O
13
O OMe
14
The reaction of

-aminocrotonamide 15 (Hiromichi and
Kato 1983) with succinic anhydride yielded

-succinamidocrotonamide, which inturn undergoes cyclization in basic medium to give 3,4-dihydro-6-methyl-4-oxo-2-pyrimidinylpropanoic acid 16.
12

O
O
O O
Me NH
2
15
NH
2
+ (CH
2
)n O
Me N
O n = 2
R = (CH
2
)
2
COOH
H
NH
2
COR
R
HN
Treatment of 3-amino-2-(methylamino)propionaldehyde-
O-methyl-oxime 2HCl with trimethyl orthoformate gave Z and
E-1,2,5,6-tetrahydro-5-pyrimidine carboxaldehyde-O-methyloxime 17 (Plate 1994) .
CH=N-OR
HCl.H
2
N
H
C=N OMe + HC(OMe)
2
HCl.H
2
N HN N
N
16
17
N-Methyl-2-thiocarbamoylacetamide reacts with ethyl formate to form the 6-thioxo-4-(3H)-pyrimidinone 18 (Sasse
1976) .
S O
NH
2
N
Me
O NHMe
HCO
2
Et
39% S N
18
Me
13

Malondiamide derivative 19 condensed with ethyl chloroformate to produce methylthio-2,4-(1H, 3H)-pyrimidindione 20 (Sasse 1976) , cyclization of

-aminothiocrotamide 21 with dimethyl formamide dimethylacetal yielded 4-(3H)-pyrimidinethione 22 (Stropnik et al., 1984) .
O O
NHEt
+
O
Cl-C-OC
2
H
5
OH
N
Et
MeS NH
19
MeS N
H
20
O
S S
N
H
Me NH
2
21
NH
2
+ HC(OMe)
2
NMe
2 ref
68%
Me N
22
14

The four atom component is an N-formyl, N-cyano or Nmethylene amidine, an N-carbonyl or N-cyanocarboximidate or
N-cyano or N-methylene urea or thiourea the two atom component is an oxo derivative or a nitrile with an

-hydrogen.
A number of substituted pyrimidine-5-carbonitriles 24a,b and ethyl pyrimidine-5-carboxylate 25 were prepared by the reaction of methyl-N-aminocarbonyl 23a or Naminothiocarbonyl 23b imidates with malononitriles, methyl, cyanoacetate or diethyl malonate by refluxing in alkoxide
(Krech et al., 1988) .
R'
NH
N
R' + R-N= C = X
OMe
HN X
R
23a,b a) X= O b) X= S
15

R'
CN
NC
MeONa
N
CN
H
2
N N
R
24a
R'
X
CN
CO
2
CH
3
CH
3
ONa
NC
23a,b
N H
O
OEt
O N
R
24b
R'
X
OEt
EtONa
H
5
C
2
O
2
C
N H
O
23a, X= O 23b, X = S
O N X
R
25
Reaction of 1,3-dicarbonyl compound 26 with N-Cyanoguanidine in the presence of Ni(OAc)
2
gave the pyrimidine derivatives 27a,b (Dorokhov et al., 1991) .
16

O
R
R H
2
N
COR'
Ni(OAc)
2
N
+
N-C N
R' H
2
N
H
2
N N NH
2
O
26 27a,b a, R=R'=Me b, R=Me, Ph, R'= Me, OEt
Reaction of 1,3-diaza derivative 28 with keten derivative
29 afforded pyrimidine derivatives 30 (Mazumdar and
Mahajan 1991) .
Ph'
R' N O
Ph'-N=C-N=CHR'
R''
+
H
C
R'''
C O
N
R'''
28 29
R''
30
R'=Ph, MeS-, R''= Me
2
N-, R'''= Cl, Ph, Ph'= Ph, p-MePh, p-BrPh, p-ClPh, p-MeOPH
Cycloaddition between diazadiene 31 and alkynes derivatives afforded pyrimidine derivative32 (Guzman et al.,
1992) .
17

NMe
2
R'
R'
HN
N
31
CCl
3
+ R'' C C COR'''
38-98%
Cl
3
C
N
N
COR'''
R''
32
Reversed polarization as in the 2-trimethylsilyloxy and 2trimethylsilylthio-1,3-diene 33 allow percyclic reaction with acyclic enamines from pyrrolidines or morpholine pyrimidinones and pyrimidinethione 34 (Sain et al., 1991) are formed in high yields in dichloromethane.
Ar
1 Ar
1
Ar
1
R
2
N
+
-25 o
C HN
R
2
PtSOH
HN
Ar
2
N XSiMe
3
NR
1
2
80-93%
X N
Ar
2
NR
1
2
X
33
X = O, S
N
Ar
2
34
The ring atoms in the C3 component are from a 1,3dicarbonyl derivatives, the oxo group may be that an aldehyde, ketone, ester or equivalents such as an amide or nitrile in any combination, the N-C-N component is most frequently an
R
2
18

amidine, a guanidine, urea or thiourea or their equivalents, the first synthesis of pyrimidine nucleus is achieved from the condensation of urea with malonic acid in the presence of phosphoryl chloride, it was named barbituric acid 35 (Grimoux
1879) .
O
O
OH
NH
2
OH
+
N
NH
2
OH
HO N OH
O
35
Condensation of benzamidine with ethylacetoacetate in alkaline solution yielded 4-hydroxy-6-methyl-2-phenylpyrimidine36 (Pinner 1884) .
O OH
H
5
C
6
NH
2
NH
+
H
5
C
2
O
NaO
H
CH
3
H
5
H
6
N
N
36
The enamino ester 37 condensed with amidine derivatives
38 to yield ethyl pyrimidine-5-carboxylate derivative 39
(Breaux and Zwikelmaier 1981) .
CH
3
19

R
O
N
CH
3
CH
3
CO
2
C
2
H
5
+
R'
NH
NH
2
R'
N
N
CO
2
C
2
H
5
R
37
38
39
4-Carbethoxy-2,6-dihydroxypyrimidine 42 was obtained by the reaction of urea with diethyloxaloacetate 40 presumably via intermediacy of 5-carb-ethoxymethylenehydention 41
(Atkinson et al., 1957 and Ivin et al., 1970) that rearranged to give 42 (Lemieur and Puskas 1964) .
OH
NH
2
+
O CH
2
CO
2
C
2
H
5
CHCO
2
C
2
H
5
O
HN
N
NH
2 O
40
OC
2
H
5
O N
H
41
O
HO N
42
CO
2
C
2
H
5
The reaction of ethylcyanoacetate derivatives 43a,b with
S-alkyl isothiourea derivatives 38 yielded pyrimidine derivatives
44 (Melik-Ogandznyan et al., 1975) .
20

OH
R'S
NH
NH
2
HCl +
H
5
C
2
O
2
C
NC
43
R
R'S
N
R
N
44a,b
NH
2
44a, R=NHCOCH
3
44b, R=NHCH
2
C
6
H
5
The reaction of bromopyruvate esters 45 with urea yielded the 71-89% of the corresponding uracil derivatives 46
(Andreichikov and Plakhina 1987) .
O
O
Br
CO
2
C
2
H
5
H
2
N
+
HN
OH
H
2
N
O
O N
H
R
R
45 46
The reaction of diethylmalonate derivative 47 with urea gave the pyrimidine derivative 48 (Macquarrie and
Imwinkelried 1995) .
21

O
O CH
2
R
RH
2
C OC
2
H
5
H
2
N HN
C
2
H
5
+ O
H
5
C
2
OC
2
H
5
H
2
N
O N O
O H
47
48
S-(p-methoxybenzyl)thioureahydrochloride reacts with

acetyl-cinnamic esters 49 in presence of sodium hydroxide to yield 1,3-dihydro-6-methyl-5-pyrimidine carboxylic acid esters
50 (Atwal et al., 1987) .
Ar
COCH
3
HN
Ar CH + R
HN
CO
2
C
2
H
5
CO
2
C
2
H
5
H
2
N
R N CH
3
49 R=
MeO CH
2
S
50
The ketoester 51 reacted with guanidine derivative 38 to yield 2-ureido-6-triflouromethyl-3,4-dihydropyrimidine-4-one
52 (Alferd and Fenning 1981) .
22

O O
NH O
OR
CF
3
+
H
2
N N NH
2
O HN
O
H
H
2
N N N CF
3
51
38
H
52
The guanidine derivatives 38 reacted with the ketoesters
53 to yield the corresponding pyrimidine derivatives 54
(Kramer et al., 1971 and Aroyan, A.A., and Kramer 1971) .
R
NH
NH
2
+
O
OC
2
H
5
HN
O
CH
2
OCH
3 R N CH
2
O
53
54
The reaction of diaminoguanidine with

-ketoester 55
OCH
3 yielded 3-amino-2-hydrazino-6-phenyl-3,4-dihydro-4-pyrimidinone 56 (Hlavka et al., 1984) .
O NH
O
OC
2
H
5
+
H
2
N
N N
NH
2
H
2
N
N
C
6
H
5
H H H
2
N
N N C
6
H
5
O
55 H H
56
23

The condensation of diethylmalonate with formamidine acetate in basic medium led to formation of 4,6-dihydroxy-5ethylpyrimidine 57 (Feit, B.A., and Teuerstein 1973) .
O
OH
H
5
C
2
OC
2
H
5
OC
2
H
5
+
H
2
N
NH
H
.CH
3
COO
N
C
2
H
5
N OH
O
57
When the isothiocyanate derivative 58 reacted with diethylmalonate the pyrimidine derivative 59 (Feit and
Teuerstein 1974) was obtained.
S
N
C
6
H
5
O
OC
2
H
5
N
CO
2
C
2
H
5
+
H
5
C
6
N C S OC
2
H
5 H
5
C
6
N O
58
O
C
6
H
5
59
Ethyl cyanoacetate and urea or thiourea undergo cyclization in alkaline medium via the intermediacy of the open form to yield the corresponding 4-aminopyrimidine derivatives
60 (Rupe et al., 1925; Bergman and Johnson 1933 and
Traube 1904) .
24

X NH
2
O
CN
OC
2
H
5
+
H
2
N
H
2
N
X
O
HN NH
2
CN
HX
N
N
60a,b a, X= O b, X=S
Heating a mixture of ethyl cyanoacetate with aldehydes and S-methylisothiourea gave the corresponding 4-aryl-5-cyano-
OH
2-methylthhio-6-oxopyrimidine derivative 61 (Hussain et al.,
1985) .
O
O
O
OC
2
H
5 HN
Ar H
NC
NH
+ SCH
3
CN
H
2
N Ar N
61
SCH
3
Condensation of ethyl-

-bromoacetoacetate with S-methyl or S-benzyl isothiourea yielded the corresponding pyrimidine derivatives 62a,b (Dodson et al., 1950) .
O
CH
2
Br
CH
2
Br
HN
HCO
-
3
N
+ SR
O
OC
2
H
5 H
2
N HO N
62a,b
SR a, R= CH
3
b, R= C
6
H
5
CH
2
-
25

The reaction of cyanoolefine 63a with guandine, urea, thiourea or S-methyl-thiourea yielded the corresponding 4aminopyrimidine derivatives 64a,b (Lorente et al., 1985; El-
Shahat et al., 1984 and Daboun et al., 1983) .
R
H CN H
2
N
R'
NH
+ X
R R'
H
2
N H
2
N N X
63 a
X= NH, O, S or MeS a, R=Ph R
'
=CONH
2 b, R= p-ClC
6
H
4
R
'
=PhCO
H
64a,b
Cyclocondensation of acetamidinehyrochloride with cyanoolefine 63b yielded 4-amino-5-aminomethyl-2-methylpyrimidine 65 (Ernst and Paust 1986) .
NH
2
H OMe
NH.HCl
H
2
NH
2
C
NC
O
CH
2
NH-CH
+
H
2
N CH
3
NH
N CH
3
63b
65
The reaction of formylacetic acid with urea yielded uracil
66 (Von Meyer 1919) .
26

O
O
H O
NH
+
OH
H
2
N NH
2
N O
O
H
66
Heating a mixture of 2,3-diphenylcyclopropanone with amidoxime yielded the corresponding 2,5,6-triphenylpyrimidine-
4-one 67 (Takahashi et al., 1984) .
O
O
OH
H
5
C
6
N NH
H
5
C
6
+
C
6
H
5
H
5
C
6
NH
2
H
5
C
6
N C
6
H
5
67
The reaction of acetophenonesemicarbazone with ethylacetoacetate gave N-alkylidineaminouracil 68 (Kato and
Katagiri 1970) .
N
O
NH-C-NH
2
O
+
CH
3
H
3
C
H
5
C
6
N
N
O
NH
H
5
C
6
CH
3
OC
2
H
5 H
3
C O
O
68
27

Condensation of phenylacetylene with benzaldehyde and urea in butanol containing dry hydrochloric acid forming 2hydroxy-4,6-diphenylpyrimidine 69 (Mamaev and Yakovleva
1970) .
C
6
H
5
H
5
C
6
+
H
2
N
O
NH
2
H
5
C
6
CHO
BuOH/HCl
HO
N
N C
6
H
5
69
Acetyl acetone condensed with acetamidine, p-methylphenylguanidine, urea, thiourea or nitroguanidine to give the corresponding pyrimidine derivatives 70a-e (Browman 1937;
Berger and Jutla 1984; Cambers and Cambes 1983;
Erlenmeyer and Heitz 1942 and Hubele 1991) .
O
CH
3
CH
3
NH
N
+
CH
3
H
2
N R
R N
O
70 a-e
CH
3 a, R= CH
3
b, R= HNC
6
H
4
CH
3
(p) c, R= OH d, R= SH e, R= NHNO
2
The reaction of thiobenzamide with 3-alkoxy-3-aryl(or alkyl)-2-cyanoacrylo-nitriles 71 and sodium isopropoxide in 2-
28

propanol afforded 4-thioxo-3,4-dihydro-pyrimidine derivatives
73 (Leach and Nobbs 1991) through formation of the 3-aryl(or alkyl)-2-cyano-3-thiobenzamide acrylonitriles 72.
R R
CN CN
H
2
N
S
R'O
Ph
+
NC
R
CN
PrONa
HCl
S
HN
C
6
CN
H
5
Ph
N
72
S NH
71
R
CN
N
Ph N S
H
73
Treatment of thioazolyl thiourea derivative 74 with malonic acid in the presence of acetyl chloride gave pyrimidine derivative 75 (Soto 1985) .
EtO
2
C
EtO
2
C
N S
N
S
74
S
NH-C-NH-Me
+
HOOC
HOOC
AcCl S
O
N
75
N
Me
O
29

Reaction of 1,1-cycloalkanedicarboxylic acid diethyl esters with thiourea gave barbituric acid derivative 76 (El-
Subbagh 1990) .
O H
COOEt H
2
N
(CH
2
)n n= 1-3
COOEt
+
H
2
N
S (CH
2
)n
N
N
O
76
Condensation of the O-ethylthiourea with diethylmalonate gave the pyrimidine derivative 77 (Youssef et al., 1994) .
OH
HN CO
2
Et
CO
2
Et
+
H
2
N
OEt
EtONa N
HO N OEt
H
S
77
Heatrocyclization of thiourea derivative 78 with the enolate of 1,3-dicarbonyl derivative 79 afforded hydroxyhexahydropyrimidinthiones 80, which upon dehydration afforded tetrahydropyrimidinthiones 81 (Hintermaier et al.,
1994) .
30

R
The reaction of diketone carboxylic acid with
(R
4
O)
2
P(O)X
1
in the presence of a base yielded enol phosphate ester which was cyclocondensed with amidine derivative in
R
1 presence of a base to give 5-alkoxycarbonyl pyrimidine derivative 82 (Shutalev and Kuksa 1993) .
OH
CO
2
R
3
R
2
+
(R
4
O)
2
P(O)X
O base
R
1
O
CO
2
R
3
R
2
OP=O
HN
H
2
N
Ar
R
1
N
CO
2
R
3
R
2
N
Ar
82
Reaction of 1,3-dicarbonyl compound 83 with
(azidomethyl) thiourea or [(P.tolylsulphonyl)methyl]-thiourea gave pyrimidine derivative 84 (Koike et al., 1993) .
31

R
''
R
'
ONa
R
''
HN
+
SCH
2
N
3 HN NH
H
2
N
83
O S
84
Treatment of 2-methylpyrimidine derivatives 85 with
R
'
POCl
3
/ DMF afforded diformyl derivative 86 that treated with formamidine derivative to give 2,5-bipyrimidine derivative 87
(Shutalev and Kuksa 1995) .
N
N CHO
R Me
POCl/DMF
R
N
85
86
N CHO
R
N N
R
'
R
'
NH
2
.HCl
NH
2
N N
87
R= substituted phenyl R '
= substituted phenyl, C
7
H
5
Cyclocondensation of 1,3-dicarbonyl derivatives 88 with urea gave pyrimidines 89 (Mikaleva et al., 1990 and
Ankhiwala 1990) .
32

R
4
R
5
R
3
R
3
R
2
R
R
1
+
H
2
N
H
2
N
O
R
4
R
2
R
R
6
O O
R
5
R
6
N
88
89
OH
Treatment of guanidine nitrate with acetylacetone in the
N presence of potassium carbonate gave 2-amino-4,6dimethylpyrimidine 90 (Olugbade et al., 1990) .
R
1
H
3
C
H
3
C
O
+
H
2
N
NO
3
NH
2
H
2
N
K
2
CO
3
/H
2
O
24h/room temp
H
3
C
N N
O NH
2
90
Cyclocondensation of benzaldehyde derivatives 91 with
CH
3 urea or thiourea and acetoacetate derivative 92 in the presence of
HCl according to Biginelli reaction gave pyrimidine derivatives
93 (Xue et al., 1993; Jani et al., 1990 and Ertan et al., 1991) .
33

R
1
R
4
R
3
R
2
R
4
CHO
O
NH
+
H
3
C HX
NH
2
R
1
CO
2
R
R
2
RO
2
C HN
R
3
91
92
X N CH
3
X= O or S
H
93
Reaction of aldehyde 94 with ketomethylene derivatives
95 and urea or N-alkylurea in presence of HCl afforded 2oxopyrimidine derivatives 96a,b (Jain et al., 1991 and
Remennikov 1993) .
R-CHO
94
+
H
3
C
R
R
95
1
O
O
R
2
NH-C-CH
3
R
2
=H, alkyl a, R= alkyl R
1
= NO
2
HN
O N
R
2
96a,b b, R= Ph R
1
= acetyl
R
1
CH
3
Cyclization of N-arylbiguanidines 97 with ethyl acetoacetate derivative 98a,b yielded pyrimidine derivatives
99a,b (Isobe et al., 1991 and Eisa et al.,1990) .
34

R
' R
'
OH
R
N
H
NH
N
NH
NH
2
+
H
3
C
EtO
2
C
O
H
97
X
R
2
98a,b a, X= H b,X=
N:N-
R
N
NH
N
N
N
H
99a,b
H a, R= 4-EtO, 2-Br R
'
= H b, R= 2,3-F, R
'
= H
Reaction of 3-pyridinecarboxyaldehyde, thiourea and ethyl cyanoacetate gave 5-cyano-2-mercapto-6-(3-pyridyl-2thiouracil) derivative 100 (Tantawy et al., 1989) .
O
S
CHO
CN HN
H
2
N NH
2
+
N
CO
2
Et HS N N
100
Condensation of ethyl guanidium nitrate and ethyl acetoacetate ester in presence of sodium hydroxide in alcohol give the two isomers pyrimidines 101a,b (Ram 1991) .
X
35

Me Me
H
3
C
BuO
2
C
O
H
2
N
+
H
2
N
NO
2
NEt reflux alc.
EtHN
N
N a
Bu
OH
+
H
2
N
N
N b
Et
101
Cyclocondensation of methyl methoxyacetate, Smethylthiourea sulphate and ethyl formate gave 2-methylthio-5-
Bu
O methoxy-3,4-dihydropyrimidin-4-one 102 (Mager et al., 1991) .
O
H
2
N
HSO
4
NH
+
OMe
HCOOEt
MeO
NH
MeS
CO
2
Me
N
102
SMe
Cyclocondensation of 1,3-dicarbonyl derivative 103 with formamidine derivatives 104a,b afforded pyrimidine derivatives
105 (Binet and Deffosse 1992 and Hoornaert et al., 1992) .
36

OH
R
''
103
CH
2
CO
2
R R
'
Bu
+
H
2
N
O
NH
104a,b a, R
'
=Et b, R
'
=Me
R
'
N
N
Bu
CH
2
105
R
''
Condensation of benzamide with propargylamine and the product cyclocondensed with 1,3-dicarbonyl compound to give pyrimidine derivative 106 (Herold and Buehlmayer 1991) .
O
CF
3
F
3
C
Et Et
NH
NH
EtO N
O
+
O N
OMe NH
2
NH Ph
106
Reaction of ethyl 4-(acetyloxy)-2-[2-(methylthio)-3nitrophenyl] methylene-3-oxobutanoate and 2-methyl-2-thiopseudourea sulphate in the presence of sodium acetate afforded ethyl (hydroxymethyl)pyrimidine carboxylate derivative 107 which cyclized in NaOH to give compound 108 (Tice 1994 and
Rovnyak, G.C., and Kimball 1992) .
37

MeS
NH
HSO
4 +
O
2
N
NH
2
O
HO
R
SMe
CO
2
Et
AcONa
DMF
MeS
N
CH
2
OH
N
H
107
CO
2
Et
CH
2
OH
MeOH/DMSO
NaOH
R O
N O
MeS N
H
108
Treatment of acrylonitrile derivatives 109a,b with Nacetylurea led to the formation of ureido acrylonitrile derivatives
110a,b which undergo intramolecular cyclization upon treatment with alkali to give pyrimidine derivatives 111a,b (Deshmakh et al., 1995) .
38

O X O
R CN
O
+
Me
Me
2
N H
109a,b a, R= CHO b, R= CO
2
Et
N
H
2
N
H
O
NC R
HN
N
H
110a,b
O
Me
NC
N
N O
111a,b a, X = H b, X = OH
1,3-Dicarbonyl compound 112a,b were condensed with formamidineacetate to give pyrimidine derivatives 113a,b
Me
(Satow et al., 1995 and Satow et al., 1995 ) .
O
ClF
2
C
H
2
N
.
OOCCH
3
EtONa
N CF
2
Cl
CHEt +
H
2
N
EtOH
N O
R
O
112a,b a, R = CHO b, R = p-C
6
H
4
-Cl
Et
113a,b
R
Cyclocondensation of anilinoformamidine derivative with

-ketone compound 114 gave pyrimidine derivative 115
(Zimmermann 1995) .
39

NH Cl N
H
O
N NH
2
R
+
N
Me
2
N
Cl
N N
114
R=2-Cl-4-pyridyl
115
H
Cyclocondensation of p-methoxybenzamidine HCl with
2-methoxycarbonyl-3-dimethylaminoacrolin in presence of
EtONa in refluxing EtOH afforded the 2-p-anisyl pyrimidine 116
(Morita et al., 1992) .
Cl
MeO
NH (CH
3
)
2
N
NH
2
.HCl
+
H
O
OEt
H
EtO
2
C
EtONa
EtOH
N
N
O
116
Ethyl 3-oxo-2-(4-flourobenzylidine)-4-methylpentanoate was refluxed with benzamidine hydrochloride and potassium acetate to give 4-(4-flurophenyl)-6-isopro-pyl-2-phenyl-5-ethoxy carbonyl-1,2-dihydro-pyrimidine 117 (Robl 1993) .
OMe
40

O CO
2
Et
Me
2
CH-C-C
Me CO
2
Et
Ph
NH
NH
2
.HCl
+
AcOK toluene
Me
HN N
F
Ph
117
A mixture of O-methyl isourea hydrogensulphate, chalcone 118 and NaHCO
3
in DMF was heated to give dihydropyrimidine 119
(Cooper 1990) .
F
MeO
NH
2
.HSO
4
NH
2
+
O
Cl
CO
2
Et
70 o
C
NaHCO
3
DMF
MeO
N
N
H
N N
Cl
CO
2
Et
N N
119
N
118
N
41

Treatment of S-[3-(3-methoxyphenoxy)propyl]-isothiourea hydrobromide with ethoxy methylidine malonate in
H
2
O/EtOH and K
2
CO
3
was heated to give pyrimidine derivatives
120 (Kosegi et al., 1990) .
NH
HBr
O
(H
2
C)
2
-CH
2
-S
O
NH
2
+
EtO
EtO
2
C
CO
2
Et
K
2
CO
3
CO
2
Et
H
70
2 o
O/EtO
C, 2h
N
NH
S (CH
2
)
3
-O
OMe
120
Ethyl (3-triflouromethylbenzoyl) acetate was refluxed with N,N-dimethylformamid acetal in tetrhydrofuran to give the
OMe
1-(3-triflouro-methylbenzoyl)-1-ethoxy-carbonyl-2-(N,N-dimeth-ylamino) ethene which was refluxed with benzamidine HCl in the presence of potassium ethoxide and gave 2-phenyl-4-(3triflouromethylphenyl)-5-ethoxy-carbonylpyrimidine 121 (Sato et al., 1991) .
42

O
C-CH
2
CO
2
Et
Me
N
Me
THF
+
MeO OMe
CF
3
O
N
CH
3
CO
2
Et CH
3
CF
3
CO
2
Et
N N
CF
3
NH
HCl
NH
2
C
2
H
5
OK reflux,
5 h
Ph
121
Condensation of 2-chloro-3-nitrobenzaldehyde with acetoacetate derivative 122 and MeSC(=NH)NH
2
yielded 3,4dihydropyrimidine carboxylate 123 (Kappe et al., 1992) .
NO
2
CHO NH
Cl
O MeS
+ Me-C-CH
2
-CO
2
(CH
2
)
2
SiMe
3
NH
2
Cl
CO
2
(CH
2
)
2
SiMe
HN
NO
2
122
MeS N
123
Me
Condensation of benzylacetoacetate with N-methylurea and 2-naphthaldehyde gave Biginelli compound 124 (Rovnyak and Kimball 1992) .
43

O
O
NHCH
3
+
NH
2
O O
H
3
C- C-CH
2
-C-OCH
2
C
6
H
5
RO
2
C
NH
Me N O
Me
124
R=CH
2
.C
6
H
5
Refluxing of benzoylethylene derivative 125 and benzamidine derivative 126 gave pyrimidine derivative 127
(Kawamura et al., 1990) .
CF
3
O
SMe
HN
C-CH=C +
SMe H 2
N
K
2
CO
3
CF
3
Me
2
CHOH reflux
Cl
N
N
125
126
127
SMe
Treatment of pyridylamidine salt 128 with enamines and sodium methoxide in presence of methanol gave the pryidylpyrimidine derivative 129 (Heinemann et al., 1991) .
44

O
N Cl
H
2
C-C(Me)
2
-C-CH=CH-N(Me)
2 N(Me)
2
MeOH
N N
NH
2 +
NH
MeONa
129
N
QAr
Me
128
Q= CMe
2
-CH
3
Ar = 4-MeC
6
H
4
The dihydropyrimidine 131 (El-Hashash et al., 1991) was obtained by the reaction of thiourea with benzoylethylene derivative 130.
Cl
Ar
'
O
H
2
N
N
+ S
Me
H
2
N
Ar N S
130 131
Cyclocondensation of amidino-oxoimidazolidine derivative 132 with acrylamide derivative 133 gave 4-aminopyrimidine derivative 134 (Kampe et al., 1993) .
45

Me
Me
Me
HN
CN O
O
N NH
HC = C - C-NMe
OEt
+
NH
2
Me
CF
3
HN
O
N
N
N NH
2
O
N
CH
3
CF
3
132 133 134
Reaction of acrylonitrile derivative 135 with nitroguanidine gave (3,4,5-trimethoxy benzyl) pyrimidine 136
(Novacek et al., 1991) .
NHNO
2
H CN
N N
HN
+
HN
N
CN
NO
2
MeONa
H
2
N
EtOH
NHPh
OMe
MeO
OMe H
2
N
OMe
135
OMe
136
Cyclocondensation of acrylate derivative 137 with guanidine gave pyrimidine derivative 138 (Rittinger and
OMe
Rieber 1993) .
46

R
1
N
R
2
R
1
O
R
2
N-CH= CH-C
OMe
+
HN
NH
2
N
H
2
N
O N
137
H
138
Reaction of acrylate derivative 139 with formamidine derivative 140 yielded the cyanopyrimidine derivative 141 (Ram et al., 1992) .
R
NH
2
MeS CO
2
Et HN
HN N
+ R
MeS CN H
2
N
O SMe
2
139
140
CN
141
Treatment of benzamidine derivative 142 with acrolein derivative 143 under basic condition in methanol gave pyrimidine derivative 144 (Yamada et al., 1992) .
47

F
O
F
NH
2
Cl
NH
2
+
H
5
C
2
O
Bu
MeONa
MeOH
N N
F
142
143 144
Bu
Reaction of acrylonitrile derivative 145 with guanidine and thiourea led to 2-amino-5-cyanopyrimidine 146 and 2formyl-2-thiopyrimidine 147 (Jachak et al., 1993) .
HN
NC
NH
2
H
2
N
H CHO
N
146
N
NH
2
F
Me
2
N
145
CN
H
2
N
H
2
N
S
H
O NH
2
N
N
147
SH
Condensation of acrylate 148 with O-methylisourea gave methoxypyrimidine 149 and subsequent amonolysis give aminopyrimidine 150 (Snider and Shi 1992) .
48

OMe
Me O
Me
3
C-Si-O-(CH
2
)
3
-C-C= CH-(CH
2
)
11
-Me
+
Me COMe
H
2
N
148
NH
OMe
HO.(CH
2
)
3
HN N
COCH
3
149
(CH
2
)
11
.Me
NH
2
HN N amonolysis
HO.(CH
2
)
3
150
COCH
3
(CH
2
)
11
.Me
Cyclization of piperazinylamidine salt 151 with dimethylamino acraldehyde in presence of base afforded pyrimidine derivative 152 (Kuo 1992) .
H R
'
HN N
NH
2
X n
+
NH
2 Me
2
N
O N
N
N NH
151 152
R
'
= H, C-4 alkyl, X = salt anion, n = charge of X
Treatment of guanidine derivative 153 with dimethyl acetylene dicarboxylate in toluene under heating overnight gave pyrimidine derivative 154 (Kosegi et al., 1991) .
49

R
2
R
1
N
H
NH
+
CO
2
Me
CO
2
Me
CO
2
Me/
Ph.Me
R
1
R
2 N
HN
O
N CO
2
Me
H
2
N
153
R
1
=2-OBu R
2
=H
154
H
Cyclocondensation of benzamidines 155 with amino allylidene dimethyl ammonium perchlorates 156 gave pyrimidine derivative 157 (Mikhaleva et al., 1992) .
Bu
HO
NH
+
NH
2
H
2
N NMe
2
ClO
4
H
2
N
N N
Bu
OH
155
156
157
Cyclocondensation of R 1 CH
2
CH(CN)CH(OR)
2
with guanidine gave 2,4-diaminopyrimidine derivative 158 (Ege and
Pross 1995) .
50

R
'
RO OR
H
2
N
N
+
NH
CN
R
' N
H
2
N
R
'
= (unsubstituted p-naphthyl..)
NH
2
158
A mixture of 1-(3-triflouromethylphenyl)2-(N,N-dimethylaminomethylene)-1-butanone benzamidine hydrochloride and sodium carbonate were refluxed in ethanol to give pyrimidine derivatives 159 (Prisbylla 1991) .
O
C
2
H
5
C
2
H
5
CH
3
N
CH
3
+
NH
2
Cl
NH
2
Na
2
CO
3
EtOH reflux 6h
Ph
N
N
NH
2
CF
3
CF
3 159
Condensation of malonic acid with thiourea in acetic acid/acetic anhydride mixture gave 5-acetylthiobarbituric acid
160a and condensed with 5-N,N-diphenyl- thiourea in phosphoryl chloride give 1,3-diphenyl-2-thiobarbituric acid
160b, 1-[1-

-naphthylethyl-2-thiobarbituric acid 160c was obtained from condensation of malonic acid with N-aryl-2[1-

naphlhyl]ethylthiourea (Zigeler and Steiner 1965; Isherwood
1910 and Singh et al., 1985) .
51

H
2
N
S
H
2
N
AcOH/Ac
2
O
O
Ac
H
N
NH
S
PhHN
S
O
O
160a
Ph
N S
CO
2
H
PhHN
CO
2
H
ArHN
HN
S
O
O
160b
Ar
N
N
Ph
S
CH
3
H
7
C
10
N CH
3
O
160c
C
10
H
7
Condensation of 4-ethoxy-3-formyl-3-butene-2-one with methyl-thiourea gave mixture of acetyl-2-methylthiopyrimidine and isomeric 5-formyl-4-methyl-2-methyl-thiopyrimidine 161a,b
(Hunt et al., 1959 and Tore and Kjell 1982) , respectively, the yield and the isomer ratio depends on the reaction condition.
52

O
Me
OEt
O
HN
+
CHO H
2
N
SCH
3
H
3
C
N a
N
+
OHC
SCH
3 H
3
C N b
N
SCH
3
161
Thiourea condensed with 2-amino-1-cyanopropene 162a or

-imi-nopropionitrile 162b to give 4-amino-2-mercapto-6methylpyrimidine 163, also diethoxy-methylenemalononitrile
164 reacted with S-methyl thiourea and gave 4-amino-5-cyano-
6-ethoxy-2-methylthio-pyrimidine 165 (Stanek 1958 and
CTBA Ltd 1963) .
NH
2
CN CN
+
H
2
N
S
N
H
3
C
162a
NH
2
H
3
C
162b
NH H
2
N
H
3
C N
163
SH
NH
2
NC CN
HN
NC
+ SCH
3
N
EtO OEt H
2
N
164
EtO N
165
SCH
3
53

Variety of heterocyclic chalcones were used in the synthesis of pyrimidine with heterocyclic moiety to 4 or 6 position, thus the use of benzal-

-acetothienone 166a, 2cinnamoylbenzimidazole 166b and 4-cinnamoyl-3-methyl-1,5diphenylpyrazol 166c afforded pyrimidine-2-thione 167a, 167b,
167c (Sammour et al., 1976 and Ali et al., 1976, 1974) .
Ph
COCH=CHPh
S
NH
166a S
N
167a
N
S
Ar
H
2
N
S
N
H
166b
COCH=CHAr
N
N
NH
H
2
N
167b
N
H
Ar
N
H
H
3
C COCH=CHPh
S
S
Ph
H
3
C N
N
N
Ph
166c
N
N
167c Ph
Ph
54

Fusion of arylmethylene 2,3,4,5-tetrahydrobenzo(b)oxepin-5-one 168 with thiourea at about 185 o C lead to the formation of aryl 6,7,8,4,10,11-hexahydro-5H-benzo(b)oxepino-
[5,4-d]pyrimidine 169 (Ali and Hammam 1976) .
H
2
N
O
O
H
2
N
S
O
H
N
S
CHAr
N
H
168
Ar
169 a, Ar = C
6
H
5
b, Ar = C
6
H
4
OCH
3
(p) c, Ar = C
6
H
3
O
2
CH
2
(p)
Bis-arylmethylenecycloalkanone 170a, bis-arylmethylene cyclo-heptanone170b, were refluxed with thiourea in ethanolic potassium hydroxide to give the corresponding condensed pyrimidine derivative 171a,b (Ali et al., 1979), respectively.
O
H
2
N
O H
ArHC CHAr S
ArHC N S
H
2
N
N
(CH
2
)n
(CH
2
)n
170a n = 1
170b n = 2
171a n = 1
Ar
171b n = 2
Ar=C
6
H
5
, C
6
H
4
OCH
3
(p), C
6
H
4
Cl(p), C
6
H
4
CH=CH
2
, C
6
H
4
.NHe
2
(p)
55

Thiourea react with malonitriles to give 4,6-diamino-2mercaptopyrimidine 172a, ethylmalononitrile and diethyl malononitrile give 5-ethyl and 5,5-diethyl, derivatives 172a-c
(Bayer 1904 and Daboun, H.A., and El-Ready 1983) .
NC NH
2
NC
N
NC
H
2
N N
172a
NH
2
SH
Et
NH
2
Et
NC N
S
NH
2 H
2
N N
172b
NH
2
SH
NC
Et
Et
NC
Et
Et
N
H
2
N N
172c
SH
S-Benzylisothiourea hydrochloride reacted with p-chloro benzoyl-phenyl-acetylene to give 2-benzylthio-4-p-chlorophenyl pyrimidine 173 (Sammour et al., 1970) .
56

Ph
C
6
H
4
Cl(p)
+
HN
SCH
2
Ph
-H
2
O N
COC
6
H
4
Cl(p) H
2
N
Ph N
173
SCH
2
Ph
When S-ethylisothiourea sulphate was allowed to react with methylphenylpropiolate in ethanol and sodium acetate it gave 1,4 or (3,4)-dihydro-2-methylthio-6-phenylpyrimidine-4one174 (Hammam and Ali 1981 ) .
Ph
.
H
2
SO
4
HN
CO
2
CH
3
+
H
2
N
SC
2
H
5
O
NH
Ph N
174
SC
2
H
5
2-Thiopyrimidine of type 176 (Sammour et al., 1970) was synthesized by the base catalyzed reaction of ethylinic ketone 175 with thiourea.
R R
O
H
2
N
N
+ S
H
2
N
Ar SH
Ar
175
N
176
57

The reaction may proceed via Michael addition of thiourea followed by cyclization, also mesityl oxide 177 react with thiourea for 8 hour to give 3,4-dihydro-4,4,6-trimethyl-2-
(1H)pyrimidine 178 (Takeshima et al., 1968) .
Me Me
O
H
2
N
NH
+ S Me
Me
H
2
N N S
Me
177
Me
H
178
Ketone derivative 179 is reported to condense with thiourea to give 2-mercapto-4-methylpyrimidine 181 (Hant et al., 1959) . This compound also obtained from the reaction of 4- methoxybutenyne 180 and thiourea.
CH
H
2
N
MeOHC
CH
+
H
2
N
180
S
CH
3
N
181
N
SH
H
3
C
O
+
H
2
N
CH
2
(OMe)
2
H
2
N
179
Acetylacetone reacts with thiourea to give 2-mercapto-
4,6-dimethyl-pyrimidine and with N-methyl thiourea to give 1,2dihydro-1,4,6-trimethyl-2-thiopyr-imidine also, it condensed with S-alkyliso-thiourea to give 4,6-dimethyl-2-alkylthiopy-
S
58

rimidine 182a-c (Evana 1893; Halle and Williams 1951 and
Brokke 1960) , respectively.
H
2
N CH
3
S
H
2
N
NH
H
3
C
O
HN
CH
3
S
H
2
N
H
3
C N
182a
CH
3
S
N
CH
3
H
3
C
O
HN
H
3
C N
182b
CH
3
S
SR
H
2
N
N
H
3
C N
182c
SR
Ethyl

-ethoxyethylidinecyanoacetate which is virtually react with N-butyl-thiourea to give 3-butyl-5-cyano-4-hydroxy-
6-methyl-2-thiopyrimidine 183 (Ballard and Johnson 1942) .
NC Bu
OH
H
3
C
OEt
CO
2
Et
+
HN
H
2
N
NC
NaOEt/EtOH
S
20 o
C, 5 days
H
3
C N
183
N
Bu
S
59

The condensation of thiourea and 2-arylmethylene-1,3indanedione 184 resulted in pyrimidine ring affording indenopyrimidine 185 (Faheim 1989) .
H
O N
H
2
N
NH
O
+
H
2
N
S
CH
3
COOH solvent O
X
184
185
Thiourea reacts with 3-methyl-1-phenyl-4-arylidine-2pyrazoline-5-ones 186 to give pyrazolopyrimidine 188
X
(Hammam and Ali 1981) presumably via the formation of isololble intermediate 187.
Ar
CH
3 H
Ar
H
3
C
N
N
CHAr
H
2
N
+
O H
2
N
S
KOH/EtOH
H
3
C
N
N
H
C
O
NH
2
S N
N
N
NH
S
Ph
186
Ph
187
Ph
188
H
Ar = C
6
H
5
, C
6
H
4
Cl(p), C
6
H
4
NO
2
(p), C
6
H
4
OCH
3
(p), C
6
H
4
CH
3
(p)
60

The synthesis of isobutyl-5-vinylpyrimidine 190 (Kvita
1986) was achieved by the reaction of piperidino-2-vinylacrolein
189 and isovaleramidine in methanolic acetonitrile.
N
CHO
HN
+ Bu i
MeOH/MeCN r.r. 77%
N
H
2
N N Bu i
189
190
Thiourea react readily with

-diketones to give pyrimidine of higher yields than urea, as a typical example, reaction of thiourea with benzoylacetone in acidic ethanol gives
6-methyl-4-phenyl-2(1H)-pyrimidinethione 191 (Brown 1984) .
Ph PH
O
H
2
N
N
+ S
O
H
2
N
80%
H
3
C N S
H
3
C
H
191
The reaction of

-diketoester with urea may be a two step process in which case acid catalysis can be used in the formation of a cyclic intermediate with ring closure effected by strong alkali in the synthesis of 2-methoxy-6-methyl-4(3H)-
61

pyrimidinone 192 (Botta et al., 1984) ethyl acetoacetate was reacted with O-methylisourea in an aqueous mixture.
O
CO
2
Et
HN
+ OMe
H
2
O NH
H
3
C
O
H
2
N
H
3
C N OMe
192
Barbiturates are often made from substituted malonates by this route, thus, the reaction between diethyl fluoromalonate and N-methyl-urea gave 5-fluoro-1-methyl-2,4,6-(1H, 3H, 5H)pyrimidinetrione 193 (Fuchikami et al., 1984) .
O
F CO
2
Et
CO
2
Et
H
2
N
NaOEt
F
+
MeHN
O
EtOH
73%
O N
NH
O
Me
193
The reaction of nitrile 194 with guanidine yielding 2,4pyrimidindiamine 195 (Smal et al., 1986) .
62

NH
2
PhHN
194
CN
+
H
2
N
H
2
N
NH
NaOMe
MeOH
N
195
N
NH
2
The synthesis of 4-amino-2,6(1H, 3H)-pyrimidindione
196 (Lespangol et al., 1970) was achieved by the reaction of cyanoacetic acid and urea using acetic anhydride that yield a cyclic intermediate N-(cyanoacetyl)urea which is subsequently ring closed under strongly alkalic conditions
NH
2
CN
H
2
N
CO
2
H
+
H
2
N
O
Ac
2
O heat
O
CN
NH
2
N
O
OH
90%
O N
NH
O
H
196
The four-atom unit is unsaturated

-aminoester,

aminonitrile,

-aminoamide or equivalent structure, the two atom units is an isocyanate or an isothiocyanate, a carboximide ester or caboximidoyl chloride, a thioamide or amidine cyanamide, carbodimide and a nitrile.
63

Condensation of malononitrile and formamidine yielded
4-amino-5-cyanopyrimidine 198 (Baddiley et al., 1943) via elimination of ammonia, in the same year Kenneretl found that an aminomethylene compound 197 in this reaction.
NH
2
NH
2
NC CN NH
2
NC CN
CN
+ NH
N
HN NH
2
NH
H
2
N H
N
198
197
Benzoylacetonitrile reacted with two moles of trichloroacetonitrile to give 2,4-bis-trichloromethyl-5-cyano-6phenylpyrimidine 199 (El-Nagdi et al., 1979) .
Ph
O CCl
3
CN NC
Ph
Cl
3
C-CN
N
CN
O
+ Cl
3
C-CN
H
2
N CCl
3
Cl
3
C N
199
The reaction of enaminoester 200 and phenylisocyanate in
Ph refluxing DMF yielded the corresponding pyrimidine 201 (Choji et al., 1983) .
64

O O
Ph
OC
2
H
5
N
+ Ph-N=C=O
H
2
N Me O N Me
200
H
201
The condensation of diethyl aminofumarate with isocyanate yielded 3-alkyloratic acid ester derivatives 202
(Stephen et al., 1975) .
O O
R
OC
2
H
5
N
+ R-N=C=O
H
2
N CO
2
Et O N CO
2
Et
H
202
The amide ester 203 reacts with methyl isocyanate to give the pyrimidine derivative 204 (Capuano et al., 1973) .
O O
Ph
N
O N
OC
2
H
5
+
Ph
2CH
3
-N = C= O
H
203
O N
CH
3
204
O
65

Cyclization of enaminonitrile ester 205 and trichloroacetonitrile yielded the corresponding pyrimidine derivatives 206a-b (El-Nagdi et al., 1982) .
O CH
2
R
NC
H
2
N
OC
2
H
5
+ Cl
3
C-CN
205
CH
2
R a, R = CN b, R = CO
2
C
2
H
5
Cl
3
C
N
N
206a,b
CO
2
C
2
H
5
NH
2 isothiocyanate to give the corresponding pyrimidinethione derivatives 208a,b (Mohamed et al., 1987) .
Ethyl enaminonitrile 207 reacted with phenyl or benzyl
NC CN
EtO
2
C NH
2
HN
NC
207
CN
+ R-N=C=S
S N
R
208a,b
OH a, R=Ph b, R=PhCH
2
-
Ethyl 2-chloro-3,3-dicyanoacrylate 209 reacted with N,Ndialkycyanamide to give the chloropyrimidine 211 (Ried and
Beller 1988) via the intermediate 210.
66

Cl
NC
Cl
CO
2
C
2
H
5
+
R
2
N-CN
NC CO
2
C
2
H
5
N
CN
NC N=C-R
CN
R N CO
2
C
2
H
5
Cl
209
211
210
The ketene S,N-acetals 212 reacted with isocyanate to yield 5-cyanopyrimidine derivatives 213 (Gelbin et al., 1987) .
X
X CN R CN
N
+
R-N=C=O
MeS NHMe O N SMe
212
Me
213
Reaction of aroyl isothiocyanate 214 with cyanothioacetamide yielded the pyrimidinethione derivatives 215a-c (Assy and Moustafa 1995) .
S
H
N
CN
O
CN
R-C-N= C =S +
H
2
N
S
214 a, R=C
6
H
4
Cl(p) b, R=C
6
H
5
S N c, R=C
6
H
4
OMe (p)
H
215a-c
R
67

Cyclocondensation of isothiocyanate derivative 216 with methyl aminoacrylate derivative 217 gave the pyrimidine derivative 218 (Andree et al., 1994) .
F
NC
F O
CO
2
Et
N= C =S +
N
F
F
3
C
NHMe F
3
C N S
F
216 217
Me
218
Treatment of aryl iosyanate derivative 219 with 1,3-
CN dicarbonyl compound derivative 220 in the presence of amonia gave N-arylpyrimidine derivative 221 (Brouwer et al., 1990) .
R
3
OCN
R
4
R
1
219
R
4
O
R
5
R
3 O
+ F
3
C-C-CH
2
CO
2
Et
CO
2
R
2
NH
3
70 o
C
N
F
3
C N O
220
H
R
1
=R
3
=R
4
=R
5
=H R
2
= Me
2
CH
221
R
1
R
3
CO
2
R
2
68

Treatment of methyl-2-cyano-3,3-bis[methylthio]prope-nate with
NaOH/DMF and thioacetamide gave bis[5-(methoxy-carbonyl)-
2-methyl-6-methylthio-4-pyrimidine] disulfide 222a and 5-
(methoxycarbonyl)-2-methyl-4-(methylthio)-1(H)-pyrimidinethione 222b (Lorente et al., 1992) .
SMe
CO
2
Me
N
Me
S
NH
2
+
MeO
2
C
MeS
CN
SMe
NaOH
DMF
Me
N
N
222a
SMe
S
2
CO
2
Me
O
Me N S
H
222b
Cyclocondensation of aminoethylene derivative with isocyanat derivative gave pyrimidine derivative 223 (Gordeev et al., 1990) .
Me
H
3
C NH
2
+
RN=C=O toluene
12h reflux
MeOC
N
R
H
3
C
O
SMe
MeS N
223
O
69

When 2-alkyl-

-aminocrotonic esters react with imidoyl chlorides can yield 3-alkyl-4-oxo-dihydro pyrimidine 224
(Staskun and Stephen 1956) .
O
R
'' CO
2
Et
N
R
'
R
'
R
''
+ N
Me NH
2
Cl R
R= aryl, R
'
= aryl, ethyl R
''
= alkyl
R N
224
Me
Phenyl isocyanate reacts with the ethyl-3-phenylaminoacrylate 225 and triethylamine as a base to form 4-methylthio-2,6-dioxo-1,3,4,5-tetrahydropyrimidine-5-carbonitrile 226
(Ried and Stock 1966) .
O
NC
CO
2
Et Ph CN
PhN=C=O
NEt
3
, PhMe
N
MeS NHPh
O N SMe
2225
Ph
226
Cinnamonitrile 227 reacted with benzamide in the presence of phosphorous oxychloride to give 6-chloro-2,4diphenylpyrimidine 228 (Harris et al., 1979) .
70

Ph
Ph CN
NH
2
POCl
3
N
+
O Ph heat
227
Cl N
228
Ph
Cyanamide reacts with 4-aminopent-3-en-2-one and substituted derivatives in aqueous solution to form the 2aminopyrimidine 229 (Alherola et al., 1987) in high yield.
Me Me
NH
2
H
2
N-CN
H
2
O, reflux
N
Me O H
2
N N
229
Me
Ethyl 3-amino-2,4-dicyanocrotonate as its sodium salt is reacted with 2,2,2-trichloroacetonitrile, while the amino nitrogen initiates the reaction by addition to the cyano group of the acetonitrile eventually forming 230 (El-Nagdi et al., 1987) .
NH
2
EtO
2
C CN
CO
2
Et
Na
N
CN
NH
2
+ Cl
3
C-CN
PhMe, Et
2
O
Cl
3
C N
230 CN
71

Heating ethyl 2-amino-4-methyl-5-phenylthiophene-3carboxylate 231 with potassium thiocyanate in dioxane in presence of conc. HCl flowed by cyclization with acetic acid yield compound 232 (Abdel-Raouf 1994) .
O
H
3
C CO
2
Et
KSCN
Ph
H
3
C
N
H
Ph
S
NH
2 S
N
S
231
H
232
Addition of nucleophilic carbon of enaminoketone enaminoester 233 to the electrophilic carbon of aroyl isothiocyanate or alkoxy carbonyl isothiocyanate yielded the intermediates 234, which in turn cycles in basic medium to give the corresponding pyrimidinethione derivative 235 (Goerdeler and Pohland 1961; Goerdeler and Wieland 1967 and Assy
1990) .
72

O O S O R O
O
X R
'
-C-N= C =S X N R
'
N
R
233
NH
2
R
H
NH
2
234
R=CH
3
R
'
=Ph X=CH
3
or OC
2
H
5
R
'
N
235
Regioselective heterocyclization of the isocyanate derivatives 236 with aminocrotonate 237 afforded tetrhydropyrimidine-4-ones 238 (Vouk and Pirozhenko 1994) .
O
SH
Cl
F
3
C-C-N= C =O
Ph
+
Me
CO
2
Et
NHMe
F
3
C
HN
Ph
N
CO
2
Et
Me
236
237
Me
238
The reaction of N-acetylacetamidrazones 239 with N-[bis
(methylthio)methylene] cyanamide 240 at room temp. in the presence of potassium carbonate in dimethyl sulphoxide afforded ethyl-4-acylhydr-azino-2-amino-6-methylthio-5-pyrimidine carboxylate 241 (Cocco et al., 1992) .
X
73

CO
2
R
NH
2
O
EtO
2
C-HC=C-NH-HN-C-R
+
H
N
MeS
CN
MeS
SMe
DMSO/K
2
CO
3 room temp.
N N
NHHNCOR
239 240
R =Me, Ph, C
6
H
4
NO
2
(p), pyridyl
NH
2
241
Aminocrotonates 242 reacted with two moles of aldehyde derivative in the presence of ammonium acetate to give benzoate salts of pyrimidine derivative 243
(O’Callaghan and McMurry
1990) .
CHO
R
1
CO
2
R
2 +
Me NH
2
AcONH
4
EtOH
RO
2
C
R
1
242
R= Me, Et R
1
= H, 3-Cl, 4-Cl, 3-Me, 3-OMe
Me
243
N
H
N
H
Base-induced reaction between 3-amino-3-(dialkylamino) propenenitriles and N-[bis(methylthio)methylene] cyanoamide afforded pyrimidine amine derivative 244 (Cocco et al., 1991) .
R
1
74

CN
CN
MeS
Me SMe base
+ N-CN
N N
H
2
N NH
2
MeS
NH
2
244
R=OEt, pyrrolidine, piperidine, morpholino, 4-methylpiprazine
Treatment of pyridine derivative 245 with methylamine and formaldehyde afforded pyrimidine derivative 246
(Kishimoto et al., 1991) .
Me
Me
N
Cl
N
CH
2
CHNO
2
N-C-NMe
+
MeNH
2
HCHO
Me
MeOH/H
2
O
245
Cl
N
N
O
2
N
246
N
Me
Cyclocondensation of nitroethylene derivative 247 with methylamine and formaldehyde and heating the product with methylamine gave pyrimidine derivative 248 (Shiokawa et al.,
1991) .
75

Cl
Me
N
N
NO
2
CH
2
NH-C=CH
+
MeNH
2
HCHO
S
H
3
C
247
MeOH/H
2
O
MeNH
2 Cl
N
N
248
Me
NH
NO
2
Cyanothioacetamide react with 249 in ethanol containing ethoxide followed by aqueous HCl to give pyrimidinethione derivatives 250 (Plitvinov et al., 1987) .
SMe
MeS
CN
N
CN
EtOH/EtONa
MeS
N-CN +
H
2
N S aq. HCl
H
2
N N S
249
H
250
Benzensulphonylacetamide reacts with methyl N-cyanoformimidate to yield 2-amion-5-benzenesulphonyl-4(3H)-pyimidinone 251 (Pére et al., 1985) .
PhSO
2
MeO
MeONa
PhSO
2
N
+
N
MeOH
O N
O
NH
2
NC
NH
2
H
251
76

Hofman type degradation of appropriate diamides 252 afforded pyrimidine 254 presumably via the initial formation of an isocyanate intermediate 253 (Barluenga et al., 1984) .
O O O
NH
2
NH
2
NaOCl
NH
2
H
+
NH
NCO N O
O
252 253
H
254
Addition of HCl to N-cyano group whereby the nitrogen becomes nucleophilic and add to the appropriately positioned Ccyano group with formation of the 2,6-diamino-2-chloropyrimidine 255 (Barluenga et al., 1984) .
NH
2
NH
2
Et
Et
CN
N
CN
HCl
Et
2
O
N
H
2
N N
255
Cl
In the formation 4,6-diphenyl-1-propyl-2(1H)pyrimidinone 257 (Nishio and Omote 1984) , the uriedo nitrogen in the
77

propylurido substrate 256 is made nucleophilic by running the cyclization under alkaline conditions.
Ph Ph
Et
PhN
NH
Ph
CONHPr alkali
75%
Ph N
N
O
256
Pr
257
Intramolecular cycloaddition of amino group to the activated double bond in the thiourea derivative 258 yielded perhydropyrimidine 259 (Elghandour et al., 1988) .
O O
NH NaOEt, EtOH
DMF
NH
R HN S R N S
Ph
258
Ph
259
Cyclization of 1,3-diacetamidopropane 260 using hydrogen chloride as cyclizating agent yielded 3-acetyl-2methyl-4,5,6-tetrahydro-pyrimidine 261 (Hofmann 1992) .
78

H
Me
N
N
HCl
O
O N Me
N
H
260
Me Me
261
O
An oxidative cyclization of methylene and benzoyl asporagine derivatives 262 using potassium permanganate followed by dehydrogenation in phosphorus pentachloride and chloroform yielded 4-carboxy-6-hydroxyprimidine 263
(Cherbuliez and Starvritch 1992 and Miyamichi 1927) .
COOR COOR
O
N
NH
2
CHR
'
262
KMnO
4 or NaOBr
PCl
5
/CHCl
3 HO N
263
N
R
'
79

The reaction of pyran 264 with benzamidine in the presence of acetic acid and ammonium acetate gave the pyrazolpyrimidine ketone 265 (Fritz and Guenther 1979) .
R
O
Me
O Me O
O
COR
NH
AcOH/AcONH
4
N
O
264
+ Ph
Me NH
2
Ph N
265
Me
Me
N
R=CH
3
Treatment of 4(1H)-pyran derivative 266 with
NH acetamidine and thiourea and 5-methylisothiourea yielded the corresponding pyrimidine derivative 267 (Hussain et al., 1988) .
Ph NH
2
NC CN
NH
NC
N
+ Ph
Ph O
266
Ph NH
2
Ph N
267
R
80

Treatment of 4-hydroxyimino-2,3,5-triphenylpyrrole 268 with PCl
5
two intermediate product 269a,b are isolated the former on heating give 4-hydroxy-2,5,6-triphenylpyrimidine
270a and the latter on reduction with zinc and acetic acid gives
4-amino-2,5,6-triphenylpyrimidine 270b (Jello 1939, 1940 and
1942) .
O
OH
Ph
Ph
Ph
Ph
N
H
268
N OH
Ph
PCl
5
PCl
5
Ph
Ph
NH
2
Ph
N
H
O
269a
OH
N
NH
2
Ph heat
Zn/AcOH
Ph
Ph
N
270a
N
NH
2
N
Ph N
Ph N
270b
H
269b
O
Rearrangement of 1-benazyl and benzhydrazyl-3,5,dimethylpyrazole 271a,b in the presence sodium hydroxide at
150-155 o C followed by hydrolysis gave pyrimidine derivatives
272a,b (Bogachev and Tetrov 1980) .
Ph
Ph
81

CH
3
H
3
C CH
3
H N N
NaOH N
R
R
H
3
C N Ph
Ph
271a,b a, R= H b, R =Ph
H
272a,b
Hydrogenation of the 1,2,4-oxadiazole derivatives 273a-c followed by cyclization gave the pyrimidine derivatives 274a-c
(Rucia et al., 1974) .
EtO
2
C OH
R
'
N H
2
/Pd
N
O
N
R
R
'
N NHCOR
H
N
273a-c a, R=CH
3
R
'
=C
6
H
5
274a-c b, R=C
6
H
5
R
'
=CH
3 c, R=C
6
H
5
R
'
=C
6
H
5
nitriles undergo [4 + 2] cyclo addition to give pyrimidine 276
(Hees et al., 1990) via the initial formation of Dewar pyrimidine.
Kinetically stabilized azetes 275 and acceptor substituted
82

R
Bu t
Bu t
275
N
+
R Bu
R
1
-CN
CH
2
Cl
2
/CHCl
3
20 o
C
Bu t t
R
N
N
R
1
Bu
Bu
R=Bu t
, C
6
H
2
-2,4,6-Me
3
R
1
=COEt, CF
3
, C
6
H
4
-4-CF
3 t t
N
276
Aminolysis of 6-chloro-1,3-oxazine-2,4-diones 277 with primary aliphatic amines such as methyl amine gave 1,3dimethylbarbituric acid 278 (Yogo 1981) .
O O
N
R
1
R
1
R
2
CH
3
NH
2
R
1
N
R
2
O O Cl O N O
277
CH
3
278
The reaction of 1,3-oxazine 279 with dimethyl amine caused transformation to pyrimidine derivative 280 (Perronnet et al., 1981) .
83

O O O
O N
CH
3
NH
2
N CH
3
Ph N H
2
N N Ph
H
279
O H
280
Treatment of phenylazapyrylium salts 281 with ammonia resulted in ring transformation affording pyrimidine derivative
282 (Borodaev et al., 1991) .
R
'
R
''
R
R
'
O
281
N -
SbCl
6
Ph
+ NH
3
R=Ph, Me R
'
= Me R
''
=(CH
2
)
4
R
''
R
N
282
N
Ph
The reaction of 1,3-oxazine 283 with amides and thioamides resulted in ring transformation affording 6-alkyl and
6-aryl-5-acetyl-3-benzyluracil derivative 284 (Singh et al.,
1991) .
84

O O
CH
2
Ph
O
Me CH
2
Ph
N N
+ R-C-NH
2
O
283
O R N O
H
284
Heating of oxazole derivative 285 with aq. ammonia give
O-protected pyrimidine derivative 286 (Conner and Kostlan
1994) .
Me
3
C
CMe
3
N
R
'
O
Me
3
C
O
Me + NH
3
N
O
285
Me
3
C N
286
R
Reaction of 1,3-diaza-1,3-butadiene 288 with 2-phenyl-4methoxy-azoline-5-one 287 gave pyrimidine derivative 289
(Sain et al., 1992) .
O Ph
Me N
O
Ph +
Me
Me
N
Ph
CH= N- C= N
Ph
Ph
N
O
N
Me
NHPh
287 288
NMe
289
85

IV- Ring transformation of 1,3-thiazine into pyrimidine
Pyrimidine formation from thiazine may involve a
Dimroth like rearrangement of thiazinamine, an aminolytic displacement of the ring sulphur atom or combination of both, aqueous ethanol in methylamine converts 4-phenyl-5phenylsulfonyl-2H-1,3-thiazine-2,6(3H)-dithione 290 into pyrimidine 291 (Yamamoto and Muraoka 1988) by displacement of the ring sulfur and a nucleophilic substitution of the thioxo sulfur in the 2-position.
Ph Ph
PhSO
2
PhSO
2
NH
MeNH
2
, EtOH
H
2
O, r.t., 33%
N
S S S S N NHMe
290
H
291
5-Aryl or alkylsulphonyl 1,3-thiazine 292 on treatment with β-iminonitriles or sulfones in presence of sodium 1,1dimethyl peroxide in tetrahydrofurane gave 2,5,6-trisubstituted pyrimidine derivatives 293 (Otatsuo and Motomu 1982) .
H
N
HN
S
Ph
Ph S
Ph S
+ HN
N
CH
2
CN CN
H
3
CO
2
S
S
292
Ph
293
86

Oxoisoxazole derivative 293a underwent ring cleavage followed by condensation upon treating with isothiourea derivative, give pyrimidine carboxamide derivative 294 (Bossio et al., 1993) .
O OH
CO
2
R
R
N
Ph
O
293a
+ R
'
N
SMe
SMe
N
O
H
+
PhCOCl
Ph
150-180
N
Ph
RN
Ph
O
N
N
N
Ph
SMe
5-Amino-3-phenylisoxazole 293a was hydrogenated into
295, which then cyclized by warming in aqueous alkali to 4hydroxy-2,6-phenylpyrimidine 296 (Shaw and Sugowdz 1954) .
O
NH
2
OH
NH
2
O
N
R
'
294
293b
H
295
296
87

Pyrimidine is

-deficient because of electronegative Natom consequently the electron densities at the 2-, 4- and 6- positions are depleted, and these positions become strongly electrophilic and are here in referred to as the electrophilic position. The electron density at the 5-position is only slightly depleted the ring therefor retains benzenoid properties at this position this is indicated by the canonical forms for the pyrimidine ring.
N N N N
N i
N ii
N iii
N iv
N v
Electrophilic reagents almost invariably attack the pyrimidine ring at the position C-5, which is the carbon atom least, depleted in the electronic charge. For example pyrimidinebearing electron releasing group can be halogenated, nitrated, nitrosated and diazocoupled at position C-5.
N
88

1- Formylation
6-Amino-1,3-dimethyluracils 297 are readily formylated by dimethylform-amide (DMF), POCl
3
acylated by acid chlorides or converted into thiocarbamoyl derivatives by isothiocyanates 298 (Hirota et al., 1984; Wamhoff et al., 1992 and Tominaga et al., 1979) .
O
Z
O
N
Me
DMF, POCl
3
, RCOCL or R
'
CON=C=S
R
N
Me
H
2
N N O H
2
N N R
Me
297
R=H, alkyl Z=O
R=NHCOR Z=S
Me
298
2- Halogenation
Bromination can be achieved by bromine in aqueous medium or acetic acid solution 5-halogenated pyrimidines were obtained by using N-halogen succinimide. 2,4,6-Triflouropyrimidine 299 can be directly flourinated by sliver diflouride in hot perflourobutylamino into tetraflouropyrimidine 300
(Schroeder 1960 and Schroeder et al., 1962) .
F F
N
AgF
2
F
N
F N
299
F F N
300
F
89

The reaction of cytosine 301 with bromine in acetic acid yielded 5-bromocytosine 302 (Taguchi and Wang 1979) as a major product.
NH
2
NH
2
N
Br
2
/CH
3
COOH
Br
N
N O N O
H
301
H
302
Facile bromination of dihydropyrimidine 303a,b using bromine in acetic acid yielded the corresponding 5-bromopyrimidine derivatives 304a,b (Zagulyaeva et al., 1985) .
R R
NH
Br
2
/CH
3
COOH
Br
NH
CO
2
Et CO
2
Et
N N
303a,b
CN a, R=H b, R= C
6
H
5
304a,b CN
3- Nitration
The nitration of 2-hydroxypyrimidine 305 using potassium nitrate and sulfuric acid yielded the corresponding 5nitropyrimidine 306 (Wempen et al., 1969) .
90

N
KNO
3
/H
2
SO
4
100 o
C
O
2
N
N
N
305
OH N
306
OH
2,4-Dihydroxypyrimidine 307 was nitrated with fuming nitric acid at 100 o
C to yield 5-nitrouracil 308 (Brown et al.,
1954; Gabrial and Colman 1901 and Varvounis and
Giannopoulos 1966 ) .
OH OH
N fuming HNO
3
100 o
C
O
2
N
N
N
307
OH N
308
OH
4- Nitrosation
Isobarbaturic acid 309 and 2-amino-4,5-dihydroxypyrimidine 310 have been nitrosated at 6-position giving the nitrosopyrimidine 311, 312 (Chesterfield et al., 1964 and
Sadao et al., 1971 ) .
OH OH
HO
N
HNO
2
HO
N
N
309 R=OH
310 R=NH2
R ON N R
311 R=OH
312 R=NH2
91

Treatment of 2-phenyl-4-hydroxy-6-morpholinopyrimidine 313 with sodium nitrate in sulfuric acid yielded the 5nitrosopyrimidine derivatives 314 (Yoned et al., 1971) .
OH OH
ON
N
NaNO
2
/H
2
SO
4
N
R N
313
Ph
R= morphilino
R N
314
Ph
1,3-Dimethyl-6-hydroxylaminourail 315 has been nitrosted to give oxadiazolo-[3,4-d] uracil 316 (Remennikov et al., 1988) .
O
O
O
CH
3
CH
3
HOHN N
N
O
HNO
2 O
N
N
N
N
O
CH
3
315
CH
3
316
The 2-, 4- and 6-positions are activated for nucleophilic attack due to the presence of adjacent electron attracting nitrogen atom. The nucleophilic substitution at position 5 is comparable
92

to the reaction of aryl compounds and generally requires fairly vigorous reaction condition.
1- Alkylation:
(i)- Alkylation of nitropyrimidine derivatives 317 with methyl iodide in presence of aqueous potassium hydroxide yielded 5methyl-2-acetonyl-4,6-dimethoxypyrimidine 318 (Longsted and
Ludwikow 1982) .
NO
2
CH
3
H
3
CO OCH
3
H
3
CO OCH
3
CH
3
I/KOH
N N
CH
3
OH
N N
CH
2
COCH
3
317
CH
2
COCH
3
318
(ii)- Reaction with Grignard Reagent
5-Cyano-2-methylthiopyrimidine 319 alkylated by
Grignard reagent R Mg + X to give the dihydro derivative 320
(Boarland and Meomie 1951) .
93

CN CN
R
R-Mg
+
X
N N HN NH
SMe
319
2-Aminolysis
SMe
320
The aminolysis of 2,4-and/ or 6-chloropyrimidines yielded the corresponding dechloroaminated product. Thus 2chloropyrimidine 321 reacted with aniline to give 2anilinopyrimidine 322 (Assy 1996) .
N N
C
6
H
5
NH
2
C
6
H
5
N
321
Cl N
322
N
H
Treatment of 2-methylsulfonyl-4,6-dimethylpyrimidine
323 with cyclohexylamine or butylamine give the corresponding amino-pyrimidines 324a,b (Johanson et al., 1937) .
94

CH
3
CH
3
H
3
C
N N
RNH
2
SO
2
CH
3
H
3
C
R
N
323
N
324
N
H a, R=cyclohexyl b, R=butyl
2-Amino-4-anilino-6-methylpyrimidine 326 (Rao 1981) was obtained by the reaction of 2-amino-4-chloro-6methylpyrimidine 325 with aniline.
Cl NH-C
6
H
5
N N
C
6
H
5
NH
2
H
3
C N
325
NH
2
H
3
C N
326
NH
2
3- Ammonolysis
4-Amino-5-(3,4,5-trimethoxybenzyl)-2-thiopyrimidine
327 is aminated with NH
3
/ MeOH in presence of powdered Cu to give 2,4-diamino-5-(3,4,5-trimethoxybe-nzyl)pyrimidine 328
(Polina et al., 1985) .
95

OMe
OMe
MeO
MeO
MeO
NH
3
/MeOH
NH powdered Cu MeO N
H
2
N N
327
S
H
2
N
328
N
When 2,4-dichloropyrimidine 329 was treated with
NH
2 ammonia gas in methoxide/ methanol, a mixture of 4-amino-2methoxypyrimidine 330 and 2-amino-4-methoxypyrimidine 331
(Komoto et al., 1978) were obtained.
NH
2
Cl
N
N
329
N
Cl
NH
3
gas
MeONa/MeOH
N
330
OMe
OMe
N
N
331
NH
2
Treatment of 2,4,6-trichloro-5-methylthiopyrimidine 332 with 28% ammonium hydroxide in ethanol in a sealed tube at
96

100 o C for 6 hours yielded the 2,6-diaminopyrimidine 333
(Jaeyer 1981) .
Cl NH
2
H
3
CS
N
NH
4
OH/EtOH
H
3
CS
N
Cl N
332
Cl Cl N
333
Cl
The reaction of ethanolic ammonia with dichloropyrimidine 334 gave a mixture of 60% 2-amino-2-chloro-6methylpyrimidine335 and 40% of 4-amino-2-chloro-6-methylpyrimidine 336 (Johanson and Johan 1905 and Bvrman and
Vanderplas 1987) .
Cl Cl NH
2
N
NH
3
/EtOH N
H
3
C N
334
Cl H
3
C N
335
+
NH
2
H
3
C
When 4-t.butylpyrimidine 337 treated with liquid ammonia the amination occur in 2- and 6-position 338a,b
(Brown and Forc 1967) .
N
336
N
Cl
97

Bu t
Bu t
Bu t
N
337
N
K, NH
3
NH
4
Cl
N
+
N
N
338a 25%
NH
2
H
2
N N
338b 33%
4- Cyanation
When 2-methylsulphonylpyrimidine 339a was treated with potassium cyanide 2-cyanopyrimidine 340a (Daria et al.,
1972) was obtained.
N
N
KCN
N SO
2
CH
3 N CN
339a 340a
Treatment of the quaternary ammonium pyrimidine 339b with potassium cyanide gave the 2-cyanopyrimidine 340b
(Heinz et al., 1975) .
N
N
339b
N
Me
CH
3
.Cl
Me
KCN
N
N
340b
CN
98

5-Hydrazinolysis
Treatment of 6-chloropyrimidine derivative 341 with hydrazine hydrate derivative yielded the corresponding pyrimidopyridazine derivative 342 (El-Bahaie et al., 1990) .
OC
2
H
5
OC
2
H
5
CH
2
COCH
3
N N
RNHNH
2
N
H
5
C
2
N Cl H
5
C
6
N N
341
R=H, C
6
H
5
342 R with hydrazine hydrate yielded the pyrazolopyrimidine 344
(Biffin 1967) .
Hydrazinolysis of 4-methylthiopyrimidine derivative 343
CH
3
CH
3
CH
3 CH
3
CH
3
N O
NH
2
NH
2
N
N
H
5
C
2
N SCH
3
H
5
C
6
N
N
343 344
H hydrazine hydrate to give the dihydrazinopyrimidine 346
(Vanderhaeghe and Claeseno 1959) .
4,6-Dimethoxy-5-nitropyrimidine 345 reacted with
99

N
OMe
NO
2
N
NHNH
2
NO
2
NH
2
NH
2
N OMe N NHNH
2
345 346
Reaction of 2-Chloropyrimidine 347 with hydrazine hydrate gave 2-hydrazinopyrimidine 348 (El-Din and Hamid
1992) .
N N
NH
2
NH
2
Cl N H
2
NHN N
347 348
2-Methylmercaptopyrimidine 349 was reacted with hydrazine hydrate and produce 2-hydrazinopyrimidine 350
(Lawrence et al., 1983) with the evolution of methyl mercaptan.
NH
2
NH
2
CN CN
N
NH
2
NH
2
N
H
3
CS N
349
Ph H
2
NHN N
350
Ph
100

6-Hydrolysis
Selective hydrolysis of 2-amino-4,6-dichloropyrimidine-
5-carboxyaldehyde 351 yielded 2-amino-4-chloro-3,6-dihydro-6oxo-pyrimidine-5-carboyaldehyde 352 (El-Bahaie et al., 1991) .
Cl Cl
CHO CHO
N hydrolysis
HN
H
2
N N Cl H
2
NHN N O
351 352
Hydrolysis of the mercaptopyrimidine 353 with sodium hydroxide and hydrogen peroxide gave the hydroxypyrimidine
354 (Brown 1950) .
CH
3
CH
3
COMe
N
COMe
N
NaOH/H
2
O
2
Ph N
353
SH Ph N
354
OH
Hydrolysis of the 6-hydroxy-2-mercaptopyrimidine 355 with hydrochloric acid and chloroacetic acid mixture yielded a uracil 356 (Brown 1950 and Wheeler and Liddle 1908) .
101

OH OH
N N
HCl/Cl-CH
2
COOH
HS N HO N
355 356
The reaction of 4,6-dichloro-2-methylpyrimidine 357 with sodium hydroxide yielded 4-chloro-6-hydroxy-2-methylpyrimidine 358 (Henze et al., 1952) .
Cl OH
N N
NaOH
H
3
C N
357
Cl H
3
C N
358
Cl
When 2-aminopyrimidine 359 was allowed to react with nitrous acid the 2-hydroxy pyrimidine 360 (Brown 1952) was obtained.
N N
HNO
2
H
2
N N
359
HO N
360
102

Acidolysis of the 4-chloropyrimidine 361 using 98% formic acid or acetic acid yielded the hydroxy derivative 362
(El-Bahaie et al., 1991) .
CH
3 CH
3
COCH
3
N
COCH
3
98% HCOOH
N
H
5
C
6
N
361
Cl
H
5
C
6
N
362
OH
5-Cyano-2-methylthiopyrimidine 363 was oxidized with
Cl
2
followed by hydrolysis to give 2-hydroxy derivative 364
(Longsted and Ludwikow 1982) .
R N SMe R N OH
1. Cl
2
2. hydrolysis
N N
NC NC
363 364
7- Desulphurization
Desulphurization of 6-amino-5-cyano-4-(4-alkylbenzyl)-
2-thio-pyrimidine derivative 365 was achieved by the action of
H
2
O
2
to give hydroxypyrimidine derivative 366 (Daboun and
El-Reedy 1983) .
103

H
2
N
NC
N
N
SH
H
2
O
2
H
2
N
NC
N
N
OH
365 R 366 R
H
Ph N S Ph N
N
H
2
O
2
/ClCH
2
O
2
H
Br
2
/MeOH/CH
3
Cl
N
Ph
367
Ph
368
8- Reaction with oxygen nucleophile
4-Chloropyrimidine 369 react with 2,4-dinitrophenoxide and/ or sodium ethoxide in refluxing ethanol to give the corresponding ether 370a,b (El-Bahaie et al., 1991) .
104

Me Me
N
COMe
RO Na N
COMe
Ph N
369
Cl a, R= O
O
2
N
NO
2
Ph b, R=OC
2
H
5
N
370a,b
OR
9- Reaction with sulphur nucleophile
Treatment of 2-chloropyrimidine 371 with sodium hydrogen sulfide and/ or thiourea in methanol yielded 2mercaptopyrimidine 372 (Roblin and Clapp 1950) .
N
1 NaSH, CH
3
OH
2- NH
2
CSNH
2
N
Cl N
371
HS N
372
Similarly when 373 was treated with thiourea in refluxing methanol the corresponding mercaptopyrimidine 374 (El-Bahaie et al., 1991) was obtained.
105

Ph
Me
N
N
373
COMe
NH
2
CSNH
2
/MeOH
Cl
Me
N
Ph N
374
COMe
SH
106


Condensation of ethylcyanoacetate with

-unsaturated ketones in presence of excess ammonium acetate gave pyridones
376 (Sakurai and Midorikawa 1968) via the intermediate 375.
O R R
R
'
CN
CN CN
+
R
EtO O
R
'
N OH R
'
N O
375
H
376
Chittaranjan (1930) found that condensation of cyanoacetamide NCCH
2
CONH
2
with Ph-CH=CH-CO-Ph, p-
MeC
6
H
4
CO-CH=CH-Ph, Ph-CH=CH-CO-Me and Me-CO-
C(Me)=CH-Ph in the presence of piperidine or diethylamine
(Knoevenagel’s method) and in the presence of sodium ethoxide
(Michael’s method). It is found that (K’s method) gives a product that is not an open chain amide but closed-ring piperidine derivative 376 while M’s method give product of the type 376 which was converted into 377 by dry HCl or by heating with excess Ac
2
O.
107

O Ph Ph
CN
HO
CN CN
Ph
R
+
H
2
N O
R N O R N O
H
376
H
377
The condensation of 2-arylhydrazono-1,3-diphenylpropan-1,3-dione 378 with
 cyanothioacetamide in presence of sodium ethoxide to gave pyridinethione derivatives 379
(Elgemeie et al., 1992) .
Ph
O
CN
Ph
PhN=N CN
EtONa
Ph
O
278
NNHPh
+
H
2
N
S Ph N
H
279
S
Chalcones react with ethylcyanoacetate in the presence of ammonium acetate to give 3-cyano-4,6-diaryl-2-pyridones 380,
3-cyano-4,6-diarylhexahydro-2-pyridones 381 and ethyl-2amino-4,6-diaryl nicotinic acids 382 (Abdalla et al., 1977) .
108

O
Ar
'
Ar
'
Ar
'
Ar
'
CN
Amm acetate
CN CN CO
2
Et
Ar
EtO
+
O Ar N
+
O Ar N
+
O Ar N NH
2
H
380
H
381
382
Also, chalcones react with cyanoacetamide in the presence of sodiumethoxide to formation 3-cyano-4,6-di(p-chlorophenyl)-2(1H)-pyridinethione derivatives 383 (Ahmed and
Abd El-Salam 2001) .
O Ar
CN
CN
Ar
EtONa
+
Ar
H
2
N S
Ar N S
H
383
Pyridones 384, 386 and 388 were prepared by condensation of

-unsaturated ketone and cycloalkanones (385 and 387) with cyanoacetamide (Rastogi 1975) .
109

O
R
SMe
+
H
2
N
CN
SMe
CN
MeS
O
R N
H
384
O
O
CN
NC
(CH
2
)n
385
+
H
2
N O O N
H
386
(CH
2
)n
CN
+
SCH
3
C(SCH
3
)
2
H
2
N O N
O
387
388
O
Reaction of 3-aryl-2-cyanothiopropanamide 389 with cycloalkan-ones in methanol in presence of piperdine to give pyridinethione derivatives 390 (Elgemeie et al., 1994) .
110

O Ar
Ar CN
+
MeOH
NC
H
2
N S (CH
2
)n S N (CH
2
)n
389
H
390
Also, the 3-cyano-2(1H)-pyridinethione derivative 392 we obtaine frome reaction between arylidine thiocyanoacetamide
391 and cyclopentanone in ethanol containing a catalytic amount of piperdine (Bakhite et al., 2000) .
Ar Ar
CN
NC
EtOH
+
H
2
N S
O
S N
391
H
392
Benzyl cyanide react with benzal-p-methoxyacetophenone in the presence of sodium methoxide to give

-keto nitriles 393 which cyclies in presence of halogenic acid or bromine yielding dihydropyridones derivative 395. A trace of moisture is essential for the formation of the amide 394 after ring closure take place (Allen 1925, 1927 and Avery and Jorgensen
1930) . The mechanism of the reaction was explained as following:
111

O
Ph-CH=CH-C-C
6
H
4
-OCH3 + PhCH
2
CN
O
O
Ph
Ph-CH-CH
2
-C-C
6
H
4
-OCH3
AcOH
PhCHCN
396
Ph
Ph
HNO
2
Ph
Ph-CH-CH
2
-C-C
6
H
4
-OCH3
HBr
PhCHCONH
2
MeOH
4
C
6
N O MeOH
4
C
6
N
H
394
H
395
Also, condensation of 2-cinnamoyl benzimidazol with
O ethylcyanoacetate, cyanoacetamide or acetylacetamide gave the corresponding 2(1H)-pyridone derivatives 396, 397 and 398, respectively (Zoorob and Ismail 1976) .
Ph
NC
N CN
N
+
N
Ph
EtO O N N O
H O
H H
396
Ph
NC
N CN
N
N
+
Ph H
2
N O
N
H O
N O
H
397
H
112

Ph O
N
Me
O
N
N
+
Ph
H
2
N O N N O
H O
H H
398
The condensation of 2-thienyl-1,1,1-trifluoroacetone 399
Me with cyanothio-acetamide in refluxing ethanol in presence of piperidine gave pyridinethione derivatives 400 (Abd El-Monem et al., 2001) .
CF
3
CF
3
NC
CN
O
O
+
H
2
N S
EtOH piperidine
N S
S
399
S
H
400
The pyridone derivative 3-cyano-4-methyl-6-phenyl-
2(1H)-pyridone 401 was obtained by the reaction of benzoylacetonamine with cyanoacetamide (Rasu 1935) . The reaction can be represented as follows:
113

O
NC
CH
3
-C=CH-C-Ph +
NH
2
H
2
N
-NH
3
O
CH
3
-C-CH
2
-C-Ph
NC C-CONH
2
-H
2
O
Ph
Me
CN
O
N O
H
401
Thus, NCCH
2
CONH
2
and Et-(2,3,4-trimethoxybenzoyl)pyruvate in EtOH was refluxed 10 hours with a few dorps of piperdine to give 402 (Kametani et al., 1967) .
COOEt
O
R NC
R
R
CN
R R
EtO
+
O
H
2
N O
R=OCH
3
R
N
402
H
O
The reaction of 4-butoxybenzalcyanoacetic ester with cyano-acetamide yield 6-amino-4-(4-butoxyphenyl)-3,5dicyano-2(1H)-pyridinethione 403 (Dyachenkov and Litvinov
1998) .
114

OBu
BuO
RO
CN
+
NC
O H
2
N S
NC CN
H
2
N N S
H
403
The 2-amino-4-methylthio-5-cyano-6(1H)pyridinethione
404 has been prepared via treatment of 1,1-dimethylthio-1thiocarbamoyl-2-cyanoethylene with cyanoacetamide (Sharanin et al., 1987) .
S SMe
H
2
NC
CN
NC CN
+
MeS SMe
H
2
N S H
2
N N S
H
404
Gremer (1902) reported that the reaction between acetamide and malonamide gave another pyridone deivative 405.
115

O O Me O
Me
Me
+
H
2
N
NH
2
H
2
N O
-NH
3
Me N O
NH
2
H
405
2-Alkyl acroleines 406 react with triethylphosphonoacetate 407 yielding 4-alkyl-2,4-pentadienoate 408 as the main product. The latter is converted by the action of alkali to 4-alkyl-
2,4-pentadienoic acid 409 which reacts with ammonia yielding
5-alkyl-3,6-dihydro-2(1H)-pyridone 410 (Richard et al., 1967) .
O H O
P
(OEt)
2 R alkali
R
NH
3
R
H
2
C
406
R
+
CO
2
Et
407
CH
2
EtO
2
C
408
O
CH
2
HO
409
O
N
H
410
R=H, CH
3
or C
2
H
5
Also, the reaction between unsaturated N-dimethyl amine and ethylcyanoacetate produce pyridone derivative 411
(Krasnay 1973) .
O
116

O
R
CN
R CO
2
Et
Me
+ CH
2
-CO
2
Et
Me N O
N(Me)
2
H
411
2- From malonic acid derivative:
Reaction of diethyl malonate 412 (X = Et) or bistrichlorophenyl malonate 412 (X = C
6
H
2
Cl
3
) 245 with ethyl βaminocrotonate 413 in the presence of alkoxide to give ethyl 4hydroxy-6-methyl-2(1H)-pyridone-3-carboxylate 414 (Knoevenagel and Fries 1898 and Kappe et al., 1971) .
OH
CO
2
X H
3
C
NH
2
CO
2
Et
+
CO
2
X Me N O
CO
2
Et
412
413
X= C
2
H
5
, C
6
H
2
Cl
3
H
414
Condensation of diethylbenzylmalonate 415a with benzyl ether of propiophenone oxime 415b (Ziegler and Belegratica
1968) or malonylchloride 416a with nitrile 416b afforded 4hydroxy-2-pyridones 417 and 418, respectively (Davis et al.,
1962) .
117

CH
3
OH
H
3
C CH
2
C
6
H
5
C
6
H
5
CH
2
CO
2
Et
+
CO
2
Et
Ph
C
6
H
5
CH
2
X
N
O
Ph N O
415a 415b
OH
O
Cl
R
R
+
CN
416a
O
416b
Cl Cl N
H
418
O
On the other hand, the 3-(un) substituted 4-hydroxy-2pyridones 420 (Kappe et al., 1988) could be obtained in good yield by condensation of enamines or azomethines 419a with diethylmalonate 419b (R 4 = Et) or with bis-trichlorophenylmalonate 419c (R 4 = C
6
H
2
Cl
3
).
OH
O
H
417
R
3
R
3
R
4
+
R
4
R
2
N
419 a
R
1
X
O
419 b,c
R
2
N
R
1
420
O
118

Condensation of substituted diethyl malonate 421b with
3-aminocrotononitrile 421a to yielded 3-substituted 4-hydroxy-
6-methyl-2(1H)-pyridone-5-carbonitriles 422 (Kappe and
Kappe 1989) .
OH
O
NC
OEt
NC R
+ R
H
3
C NH
2
OEt H
3
C N O
421a
O
421b
H
422
The reaction between arylmethylenecyanoacetamide 423 with acetoacetate and acetylacetone 424a,b to formation the corresponding 3-cyano-2(1H)pyridinethione derivatives 425
(Elgemeie et al., 1998) .
Ar
H
3
C
CN
O
H
3
COC
Ar
CN
+
H
2
N
423
S
O
R
424a,b
R N
H
425a,b
S a) R= CH
3
, b) R=OC
2
H
5
119

3- From heterocyclic compounds:
The replacement of the ring oxygen of

-pyrones by nitrogen leads to the formation of 2(1H)-pyridones. This reaction is usually carried out by warming the pyrone derivatives in aqueous solution with ammonia or with primary amines, or by heating with ammonium acetate in glacial acetic acid (Leben
1896; Fried and El-Derfield 1941 and Hradetzky and Ziegler
1966) .
Thus, methyl coumarate if treated with aqueous ammonia and then boiled with dilute sodium hydroxide, forms 2-hydroxy pyridine-5- carboxylic acid 423 (Pechman and Flsh 1884) .
H
3
CO
2
C HO
2
C
O O N
426
OH
Reaction of 1,3-oxazin-4-one 427 with active methylene compounds in presence of a base afforded 4-hydroxy-2-pyridone
428 (Kato et al., 1975) .
120

O OH
HO
2
C COMe
N
+ CH(CO
2
Et)
2
Ph O Me Ph N O
427
H
428
Treatment of 4-Hydroxy-2-pyrones 429 with ammonia or methylamine give 4-hydroxy-2-pyridone derivatives 430
(Brenneisen et al., 1964; Acker et al., 1966 and Salemink
1961) .
OH OH
R R
NH
3 or CH
3
NH
2
R O O R N O
429
H
430
Reaction of hydroxylamine and hydrazine hydrate with 2pyrone derivative 431 yielded 1-hydroxy, and 1-amino-2pyridone derivatives 432 and 433, respectively (Lohaus 1973;
El-Koly et al., 1959 and Hoegerle 1959) .
121

R
2
R
1
R
3
NH
2
OH
R
1
R
2
R
3
R N
OH
432
R
2
O
R O
431
O
R
1
R
3
NH
2
NH
2
R N O
NH
2
433
Also, the thipopyrane derivative 434 was converted into the pyridinethione 435 by refluxing in ethanol and triethylamine solution (Elnagdi et al., 1991) .
R R
EtOH/N(Et)
3 reflux
O S N S
434
H
435
On the other hand, pyidones can also be prepared from corresponding pyridine-N-oxide. For example, when pyridine-N-
122

oxide 436 is heated with acetic anhydride, N-acetylation takes place. This is followed by rearrangement to the acetoxypyridine
437 which is hydrolysed to 2-pyridone 438 (Shine 1967; Ochiai
1967; Katritzky 1956 and Markgraf et al., 1963) .
Ac
2
O
N N N OAc N
O
436
OAc
437
H
438
Treatment of ethoxypyridine-N-oxide 439 with aqueous halogen acids yielded N-hydroxy-2-pyridone 441 (Hamana and
Yamozaki 1962 and Newbold and Spring 1948) . The reaction can be explained on the basis of the formation of a protonated species 440, which is capable of rapid conversion to the pyridone via nucleophilic attack at the alkoxy group, by halide ion
O
HX X
CH
2
N OEt N O CH
3
N O
O
439
OH
440
OH
441
Takeda et al., (1952) reported that pyridine-N-oxide 442 reacts with 2-bromo-pyridine at 100 o C yielding 1-(2-pyridyl)-2-
123

pyidone 443 in addition to 1-(2-pyidyl)-3-bromopyridone 444 and 2(1H)-pyridone 445.
Br
N
442
+
Br
N
O
100 o
C
N
N
O
+
443
N
N
O
+
444
N
H
445
O
124

2-Pyridone forms salt with sodium ethoxide and with strong acids. These salts are derived from the resonancestabilized ion 446 and 447 (Ramirez and Ostwalden 1959) .
N O N O N OH N OH
446 H
447
H
2-Pyridone can behave as such as 2-hydroxypyridine towards chemical reagents, and reaction at nitrogen and oxygen are in competition with each other. For example, 2-pyridone with acetic anhydride gives a 9:1 mixture of 2-acetoxy pyridine and 1acetyl-2-pyridone. With methyl iodide it gives 1-methyl-2pyridone while with diazomethane a mixture of 1-methy-2pyridone and 2-methyl pyridone is formed (Kornblum and
Coffey 1966) .
125

Cl
PCl
5
POCl
3
MeONa
N N
H
CH
2
N
2
O
MeI
N OMe
35% 55%
N
MeI
O
X
N OMe
H
When alkyl halides (Fuks 1970; Takahashi and Kashiro
1961 and Cook et al., 1961) or dialkyl sulfate (Simchen 1970;
Ban and Wakamatsu 1964 and Dornow et al., 1966) , were fused with salts of pyridones 448, N-alkylation appears to predominate to yield 449. On the other hand, it has been shown that both N-alkyl-2-pyridones 450 and 2-alkoxy pyridines 451 were formed from the reaction of 2-pyridones 448 with diazoalkanes (Pieters and Hertog 1962; Peresleni et al., 1967 and Karnblum and Coffey 1966) .
126

R
3
R
4
R
2
RI or
(R)
2
SO
4
R
3
R
1
R
2
R
4
N O
R
1
N O
R
449
R
2
R
2
H
448
RCHN
2
R
3
R
1
R
3
R
1
+
R
4
N O R
4
N
R
450
451
Photolysis of 1-methyl-2-pyridone in ether solution
OR yields 452, presumably via the diradical 453, which dimerises to
454 if formed in concentrated solution (Gorey and Streich
1964) .
Me h

O N
N O N O
N +
Me Me
Me
N
452 453
454
Me
4-Hydroxy-2-pyridone 455 has been methylated with diazomethane affording a mixture of 2,4-dimethoxy pyridines
O
127

456 and 4-methoxy-N-methyl-2-pyridones 457 (Dornow and
Plessen 1966 and Takahashi et al., 1966) .
OH OMe OMe
R
2
R
1
CH
2
N
2
R
2
R
1
R
2
R
1
R
3
N O R
3
N OMe
+
R
3
N O
H
455 456
Me
457
Alkylation of 6-methyl-4-methoxymethy-3-cyano-2(1H)pyridinethione 457 with halogen derivatives in the presence of potassium hydroxide gave the S-alkyl derivatives 559
(Kaigorodova et al., 1996) .
CH
2
OCH
3
CN
CH
2
OCH
3
CN
+ RX
KOH
H
3
C N S
H
3
C N SR
H
458 459
2-Displacement by halogen
4-Hydroxy-2-pyridone 460 (R = H) were converted into dichloro-pyridines 461 by the reaction with phosphorus
128

oxychlotide (Kappe and Kappe 1948; Davis 1962; Elvidge and Zaidi 1968; Chum-Shan 1970; Mittelbaach 1988 and
Signor et al., 1963) , a mixture of phosphorus pentchloride
(Gorey and Streich 1967) and phosphorus oxychloride with dimethylaniline (Davis 1962) .
Treatment of 4-hydroxy-N-phenyl pyridones 460 (R = Ph) with phosphorus oxychloride give a mixture of 2chloropyridones 462a and 4-chloropyridones 462b (Kappe et al., 1988) .
Cl
R
2
R
1
OH
POCl
3
/PCl
5
R=H
R
2
R
1
R
3
N
461
Cl
R
3
N
R
460
O
R
2
O
R
1
R
2
Cl
R
1
POCl
3
R=Ph
+
R
3
N Cl R
3
N
R
462a
R
462b
The reaction of 3-cyano-4,6-di(p-chloropheny)-
2(1H)pyridine-thione derivative 463 with Cl
2
gas in HCl or acetic acid yield the corresponding 2-chloro-3-cyano-pyridine
O
129

derivatives 464, and the sulfonyl chloride derivatives 465
(Ahmed and Abd El-Salam 2001) , respectively.
Ar Ar
CN CN
Cl
2
HCl
Ar N S Ar N Cl
H
463 464
Ar
R
Ar
CN CN
Cl
2
CH
3
COOH
Ar N S Ar N
465
SO
2
Cl
H
Also, the sulfonyl chloride of 3-cyanopyridine derivative
467 (Deeb et al., 1990) can be prepared by oxidations of pyridinethione derivative 466 with Cl
2 in water (H
2
O).
R
CN CN
R
'
N S
Cl
2
H
2
O
R
'
N SO
2
Cl
H
466
467
130

3- Nitration
3,5-Dinitro-2-pyridones 469 are usually prepared by direct nitration of 2-pyridones 468 with fuming nitric acid
(Mittelbaach 1988) . 3-Nitro-4-pyridones 471 were prepared by treatment of the 4-pyridones 470 with a mixture of nitric acid and sulphuric acid (Albert and Barlin 1963 and Nantka-
Namirski 1961), but 4-hydroxy-2-pyridones 472 are usually nitrated at the 3-position with nitric acid affording 4-hydroxy-3nitro-2-pyridones 473 (Salemink 1961; Kaigorodova 1996;
Davis et al., 1962 and Elvidge and Zaidi 1968) .
R
2
R
2
O
2
N NO
2
HNO
3
fuming
R
1
O R
1
O N
H
4 68
N
H
469
O O
R
2
R
3
R
1
HNO
3
/H
2
SO
4
R
2
R
3
NO
2
R
1
N
H
470
N
H
471
131

OH OH
NO
2
HNO
3
R N O R N O
H
472
H
473
A number of pyridones has demonstrated medicinal activity. For example, clopidol 474 was used as antiparasitic agent (Dow. Chem. Co. Neth 1963) . Diodon 475 and its npropyl ester are used as X-ray contrast media (Beecham Group
Ltd 1974) .
O O
Cl Cl I I
Me N Me N
H
474
H
475
Chloropyridine are useful intermediates for many pharmaceutical products. For example 476, which was used for treatment of inflammation in rheumatism, osteoporosis, collagen diseases,
132

bursitis and gout was prepared from 3-chloronicotinic acid
(Scherico Ltd. 1967) .
COH
N N N Cl
H
476
Amino pyridines have been reported to have important pharmaceutical propertis, for example 2-amino-4-picoline 477 is reported as analgetic (Haxthausen et al., 1959) .
Phenyramidol 478 based on 2-aminopyridine is used in treatment of muscular rheumatism.
CH
3
N
477
NH
2
N
478
Ph
NH.CH
2
.CH
OH
133

All melting points are uncorrected. The IR spectra were recorded on Perkin Elmer 883 spectrophotometer using KBr discs. 1 H NMR spectra (DMSO-d
6
) were carried out on Jeol FX-
100, FT-NMR with TMS as internal standard and chemical shifts are expressed as (ppm). Microanalyses were carried out at the
Microanalytical Unit, Cairo University. Analytical and physical data listed in Table 1 and Table 2.
Method A:
A mixture of furfural or thiophen-2-aldehyde (0.01 mole), ethyl cyanoacetate (0.01 mole), thiourea (0.01 mole) or urea
(0.01 mole) and potassium carbonate (0.01 mole) in ethanol was heated under reflux for 6h. The solid precipitated during the reaction, was collected, stirred in water and acidified with acetic acid. The deposited precipitate was collected, washed with water and crystallized from the proper solvent to give 3a-d (Table 1).
Method B:
A mixture of ethyl(2E)-2-cyano-3-(2-aryl)prop-2-enoate
(1) (0.01 mole) and thiourea (0.01 mole) or urea (0.01 mole) in
134

pyridine (30 ml) was refluxed for 6 h. The precipitate was collected and recrystallized from the proper solvent (Table1) .
2
2
Add H
2
O
2
(15 ml, 38%) drop wise with stirring to a mixture of 3a and/ or 3b an potassium carbonate (0.01 mole) in water. The reaction mixture was left overnight at room temperature, the solid formed was filtered off and crystallized from DMF to produce 3c and 3d (Table 1).
Method A:
A mixture of 3a and/or 3b (0.01 mole), methyliodide
(0.01 mole) and potassium carbonate (0.01 mole) in ethanol (40 ml) was heated under reflux for 5h., allowed to cool and diluted with water. The solid produced was filtered off and recrystallized from dioxane to form 4a,b.
Compound 4c was prepared as described above by using ethylbromide instead of methyliodide with 3c (Table 1).
Method B:
A mixture of S-methylisothiourea sulphate (0.01 mole), ethylcyanoacetate (0.01 mole) and potassium carbonate (0.02
135

mole) in ethanol (60 ml) was heated under reflux for 6h., the reaction mixture was allowed to cool. The separated solid was filtered off, washed with water, dried and recrystallized from dioxane to from 4a,b.
A solution of 4a-c (0.01 mole) in dioxane (40 ml) was treated with phosphorous oxychloride (20 ml) and heated under reflux for 4 h. The reaction mixture was cooled and poured into ice water. The solid formed was collected, dried and recrystallized from the proper solvent to give 6a-c (Table 1).
A mixture of 6a-c (0.01 mole) and thiourea (0.01 mole) in ethanol was heated under reflux for 6 h., the reaction mixture was left to cool, the solid formed was filtered and recrystallized from the proper solvent to give 7a-c.
A stream of dry ammonia gas was bubbled slowly through a solution of one gram of 6a-c and in anhydrous dioxane (20 ml). The solution was warmed for 20 min, cooled and then poured into cold water. The collected precipitate
136

dried and recrystallized from the proper solvent to yield 8ac.
A solution of 6a-c (0.01 mole) in anhydrous dioxane (40 ml) was treated with hydrazine hydrate (0.01 mole, 99%) and refluxed for 2 h. The solution was concentrated and cooled. The solid separated was collected and recrystallized from the proper solvent to yield 9a,b.
A solution of 9a,b (2 g) in anhydrous dioxane (20 ml) was heated under reflux for 5 h., the solid precipitated after cooling was filtered and recrystallized from the proper solvent into10a,b.
A solution of 6a-c (0.01 mole) in n-butanol (20 ml) was treated with phenylhydrazine (0.01 mole) and refluxed for 10 h.
The solution was left to cool the solid separated was collected and recrystallized from the proper solvent to yield 11a-c (Table
1).
137

A solution of 9a,b (1 g), carbon disulphide (4 ml) and potassium hydroxide (0.4 g) in ethanol (20 ml) was refluxed for 5 h. After removal of the ethanol, water was added and the alkaline solution was filtered. The clear filtrate was acidified with dilute hydrochloric acid. The solid produced was filtered and recrystallized from the proper solvent to give 13a,b.
A solution of 9a,b (1 g), in acetic acid (30 ml) was cooled to 0 o C and a cold solution of sodium nitrite (0.8 g) in water (10 ml) was gradually added. The reaction mixture was kept at 0-5 o C while stirring for 3h. left overnight, and then diluted with water.
The precipitated solid was collected, washed with water, filtered and recrystallized from DMF to give 4-[aza(methyldiazenyl)methylene]-6-(2-furyl)-5,3a-dihydro-1,2,3,4-tetraazolo[1,5-e]pyrimidine-7-carbonitrile 14a and 4-[aza(methyldiazenyl)methylene]-6-(2-thienyl)-5,3a-dihydro-1,2,3,4-tetraazolo[1,5-e]pyrimidine-7-carbonitrile 14b.
A mixture of 6a-c (0.01 mole) and aroylhydrazines, namely benzoyl and 2-chlorobenzoylhydrazine (0.01 mole) in nbutanol (30 ml) was refluxed for 10 h. The solid that separated
138

after cooling was collected and recrystallized from the proper solvent to give the products 15a-f.
To a solution of 7a-c (0.01 mole) in dry acetone (30 ml) potassium carbonate (0.01 mole) and chloroacetone (0.012 mole)
(0.013 mol) were added. The reaction mixture was heated on water bath for 20 h. After cooling, the reaction mixture was diluted with water. The precipitate, so formed was filtered off, dried and recrystallized from the proper solve to gave 16a-c.
A mixture of 16a-c (0.01 mole), benzaldehyde (0.01 mole) and sodium ethoxide (0.01 mole) in ethanol (30 ml) was heated under reflux for 3h. The solid produced after cooling was filtered off, dried and recrystallized from the proper solvent 17ac.
To a solution of 7c (0.01 mole) in dry acetone (30 ml) potassium carbonate (0.01 mole) and ethylchloroacetate (0.013 mole) were added. The reaction mixture was heated on water bath for 20 h. After cooling, the reaction mixture was diluted with water. The precipitate, so formed was filtered off, dried and recrystallized from ethanol and gave 19.
139

A solution of 19 (0.01 mole) in 20% alcoholic KOH (60 ml) was refluxed for 24h. The solution was concentrated by heating under vacuum to 1/3 of it’s volume and the solid produced was dried to yield 20.
A mixture of 20 (0.01 mole) and acetic anhydride (0.013 mole) in dry pyridine was refluxed for 10h. The reaction mixture was poured on ice-acetic acid mixture. The solid produced was dried to yield 21.
A solution of 6a,c (0.01 mole) in acetic acid (50 ml), anthranilic acid (0.02 omle) was added. The solution was refluxed for 7h. Compounds 21a,b which precipitated during reflux were collected and recystallized from the proper solvent to yield 21a,b.
140

A solution of 21a,b (1 g) in acetic anhydride (15 ml) was heated under reflux for 8h. The separated solid, after cooling was collected and recystallized from acetic acid to give 22a,b.
A mixture of 7c (0.01 mole) and pchlorophenylisothiocyanate (0.01 mole) in dry acetone (40 ml) was refluxed for 6h. The solid that separated after cooling was filtered; dried and crystallized from acetone into 23.
A mixture of cyanoacetamide (0.01 mole), ammonium acetate (0.02 mole) and [4,6-bis(4-chlorophenyl)-2-thioxo-3hydropyridine-3-carbonitrile] (0.01 mole) fused on oil bath for
4hours at 160-180 o
C, poured on ice water and gave brownish precipitate. Shake well with methanol and filter. The filtered which contain the aliphatic compound was concentrated and left to cool yield aliphatic undesirable part. The yellow precipitate, which insoluble in methanol was dried and recrystallized from benzene into 25 (Table 2).
2
2
141

To a solution of 25 (0.01 mole) in conc. HCl and/ or acetic acid, Cl
2
gas was bubbled at 0 o c. After 2h the resulting solid was filtered, washed with water and dried to yield 26 and
29, respectively.
2-Sulfonylchloride derivative 26 (0.01 mole) was added to conc. NH
4
OH (100 ml). The reaction mixture was heated on a steambath for 6h, the volume was reduced to the half, then neutralized with 6N HCl and then resulting solid was washed with water, dried and then treated with acetic acid. It was divided into two parts; an acetic acid soluble part and an acetic acid insoluble part. The acetic acid solution was concentrated to obtain 28. The acetic acid insoluble part was crystallized into 27
(Table 2).
To a solution of 25, 26 and/ or 29 (0.01 mole) in nbutanol (25 ml) was added hydrazine hydrate (0.012 mole), the reaction mixture was refluxed for 15h, then cooled and the solid produced was crystallized from n-butanol to give 30 (Table 2).
2
4
142

Compound 25 (0.01 mole) was dissolved in conc H
2
SO
4
(30 ml) and heated on steam-bath for 6h, poured over crushed ice and the resulting solid was dried 31 (Table 2).
2
To a solution of 31 (0.01 mole) in benzene (25 ml) was added iodine (0.02 mole) in benzene (20 ml) and the solution was refluxed for 10h. After cooling add saturated solution of
KOH to destroy the excess iodine, the solid produced was filtered and dried (Table 2).
Compound 25 (0.01 mole) was added to a solution of sodium hypochloride (20 ml). The reaction mixture was stirred at
30 o for 4h. Ammonium hydroxide (40 ml) was added to the reaction mixture, and stirred for an additional 1h at room temperature, the precipitate of 33 was filtered and washed with water several times to yield 33 (Table 2).
To solution of 33 (0.01 mole) in acetone (20 ml) was added a solution of potassium permanganate (0.02 mole) in water (60 ml) portion-wise and the solution was stirred at room temperature for 12h. The excess permanganate was destroyed
143

with sulfur dioxide and the solution filtered to remove the precipitated manganese dioxide. The aqueous solution was made strongly alkaline with sodium hydroxide pellets (2g) and then extracted with chloroform (3x20 ml). Evaporation of the dried
(Na
2
SO
4
) chloroform extract gave 28. The compound had a melting point and spectral properties identical to those of a sample obtained in the previous experiment (Table 2).
To a solution of 25 (0.01 mole) in dry acetone (40 ml),
K
2
CO
3
(0.01 mol), chloroacetone (0.01 mole) and/ or ethyl bromoacetate (0.013 mol) were added. The reaction mixture was heated on water-bath for 48h, then cooled and diluted with water.
The resulting solid was dried to yield the products 34 and 36, respectively.
A mixture of 34 (0.01 mole) aromatic aldehydes
(benzaldehyde and 2-chlorobenzaldehyde) (0.01 mole) and sodium ethoxide (0.01 mol) in ethanol (40 ml) was refluxed for
3h. The solid produced after cooling was dried to yield 35a,b
(Table 2).
144

A solution of 36 (0.01 mole) in 20% alcoholic KOH (60 ml) was refluxed for 24h. The solution was concentrated under vacuum to 1/3 of it’s original volume and the solid produced was dried into 37 (Table 2).
A mixture of 37 (0.01 mole) and acetic anhydride (0.013 mole) in dry pyridine was refluxed for 10h. The reaction mixture was poured on ice-acetic acid mixture. The solid produced was dried to yield 38 (Table 2).
A solution of 25 was added to a solution of ammonium thiocyanate (0.01 mole) in acetone (30 ml), equimolar amount of aroylchloride (benzoylchloride and p-chlorobenzoyl-chloride) was added dropwise with shaking. After heating the mixture on a steambath for 2h, the solvent was distilled and the residue was treated with ice-cold water. The solid that separated was filtered, dried and crystallized from the proper solvent to give 39a,b
(Table 2).
To a solution of 25, 26 and /or 29 (0.01 mole) was added aroylhydrazines (benzoyl and p-chlorobenzoyl hydrazine) (0.01
145

mole) in n-butanol (30 ml) and the mixture was heated under reflux for 20h. The solid that separated after cooling was crystallized from the proper solvent into 40a,b (Table 2).
146

147

Table 1. Analytical and Physical Data for Pyrimidine Derivatives from 3a-6b.
Comp.
No. m.p o
C
Yield
%
Solv. Mol.formula
Mol.wt
3a
3b
4a
248
265
290
48
75
DMF
DMF
C
9
H
5
N
3
O
2
S
219.2
C
9
H
5
N
3
OS
2
235.29
55 dioxane C
10
H
7
N
3
O
2
S
233.25
C
49.31
(49.76)
45.94
(46.07)
51.49
(51.37)
Analysis Calc. (found) %
H N
2.30
(2.17)
2.14
(2.11)
3.02
(2.11)
19.17
(19.42)
17.86
(17.62)
18.02
(18.32)
S
14.63
(14.39)
27.26
(27.50)
13.75
(14.0)
4b 253
4c
6a
6b
190
155
172
63
60
DMF
DMF
C
10
H
7
N
3
OS
2
249.31
C
11
H
9
N
3
OS
2
263.34
70 BuOH C
10
H
6
ClN
3
OS
251.7
52 DMF C
10
H
6
ClN
3
S
2
267.76
48.18
(48.11)
50.17
(50.21)
47.72
(47.78)
44.86
(44.59)
2.83
(2.96)
3.44
(3.52)
2.4
(2.52)
2.26
(2.17)
16.85
(16.75)
15.96
(15.88)
16.69
(17.03)
15.69
(15.6)
25.72
(26.01)
24.35
(24.55)
12.74
(12.63)
23.95
(24.08)
148

Table 1. Analytical and Physical Data for Pyrimidine Derivatives from 6c-8c.
Comp.
No. m.p o C
Yield
%
Solv. Mol.formula
Mol.wt C
Analysis Calc. (found) %
H N
6c
7a
7b
132
245
Dec.
185
58
63
43
DMF
EtOH
EtOH
C
11
C
H
10
8
H
7
ClN
N
3
3
281.79
OS
249.31
OS
C
10
H
7
N
3
S
3
265.38
2
46.89
(47.01)
48.18
(48.2)
45.26
(45.12)
2.86
(2.93)
2.83
(2.78)
2.66
(2.87)
14.91
(14.53)
16.85
(16.92)
15.83
(16.05)
S
22.76
(22.83)
6.42
(6.63)
36.25
(36.43)
7c 220 53 acetone
8a
8b
8c
Dec.
140
241
175-
177
44
68
57
BuOH dioxane
DMF
C
11
H
9
N
3
S
3
279.41
C
10
H
8
N
4
OS
232.27
C
10
H
8
N
4
S
248.33
2
C
11
H
10
N
4
S
2
262.36
47.29
(47.18)
51.71
(52.0)
48.37
(48.35)
50.36
(50.13)
3.25
(3.41)
3.47
(3.65)
3.25
(3.33)
3.84
(4.03)
15.04
(15.55)
24.12
(23.84)
22.56
(23.02)
21.36
(21.26)
34.43
(34.5)
13.8
(13.73)
25.82
(26.08)
24.44
(24.09)
149

Table 1. Analytical and Physical Data for Pyrimidine Derivatives from 9a-13a.
Comp.
No. m.p. oC
Yield
%
Solv. Mol.formula
Mol.wt
Analysis Calc. (found) %
9a 325 45 DMF C
9
H
9
N
7
O
231.22
C
46.75
(46.76)
H
3.92
(4.08)
N
42.4
(42.72)
9b
12a
215-
217
Dec.
120
48 DMF C
9
H
9
N
7
S
247.28
56 BuOH C
17
H
14
N
4
O
2
S
338.39
43.72
(43.99)
60.34
(60.3)
3.67
(3.51)
4.17
(4.43)
39.65
(40.0)
16.56
(16.13)
S
-
-
12.97
(13.31)
9.48
(9.78)
12b
12c
13a
Dec.
80
168-
70
262-
264
35 AcOH C
17
H
14
N
4
OS
2
41
45
DMF
DMF
C
18
354.36
H
16
N
4
OS
368.48
C
9
H
3
N
9
O
253.18
2
57.61
(57.91)
58.67
(50.48)
42.70
(42.96)
3.98
(3.66)
3.38
(3.72)
1.19
(1.63)
15.81
(16.02)
15.20
(15.38)
49.79
(50.04)
18.09
(17.86)
17.4
(17.75)
150

Table 1. Analytical and Physical Data for Pyrimidine Derivatives from 13b-15d.
Comp.
No. m.p o C
Yield
%
Solv. Mol.formula
Mol.wt C
Analysis Calc. (found) %
H N
13b Dec.2
14b
60
165
54
14a >300 59
62
EtOH
DMF
DMF
C
C
10
9
H
269.25
H
6
3
N
N
6
9
S
O
274.26
2
S
C
10
H
6
N
6
OS
2
290.33
40.15
(39.95)
43.79
(43.98)
41.37
(41.59)
1.12
(1.32)
2.21
(2.62)
2.08
(2.48)
46.82
(46.42)
30.64
(30.88)
28.95
(28.69)
S
11.91
(12.22)
11.69
(11.65)
22.09
(22.58)
15a 170 55 EtOH
15b 207-
208
15c 187
15d 210
57
46
51
DMF
BuOH
C
17
H
11
N
5
OS
333.37
C
17
H
11
N
5
S
2
349.44
C
18
H
13
N
5
S
2
363.47
EtOH C
17
H
10
ClN
5
OS
368.82
61.25
(61.52)
58.43
(58.78)
59.48
(59.97)
55.51
(55.48)
3.33
(3.87)
3.17
(3.41)
3.61
(3.36)
2.74
(2.9)
21.01
(20.85)
20.04
(20.55)
19.27
(19.67)
19.04
(19.42
9.62
(9.83)
18.35
(18.15)
17.64
(17.83)
8.72
(8.88)
151

Table 1. Analytical and Physical Data for Pyrimidine Derivatives from 15e- 17a.
Comp.
No. m.p. oC
Yield
%
Solv. Mol.formula
Mol.wt C
Analysis Calc. (found) %
H N
15e
15d
15e
236
210
236
67
51
AcOH
EtOH
C
C
17
17
H
H
10
10
ClN
ClN
5
383.88
368.82
5
OS
OS
2
67 AcOH C
17
H
10
ClN
5
OS
2
383.88
53.19
(53.17)
55.51
(55.48)
53.19
(53.17)
2.63
(2.77)
2.74
(2.9)
2.63
(2.77)
18.24
(18.1)
19.04
(19.42
18.24
(18.1)
S
16.71
(16.54)
8.72
(8.88)
16.71
(16.54)
15f 208
16a 137-
39
16b 150
55 BuOH C
18
H
12
ClN
5
S
2
397.91
40 EtOH C
13
H
11
N
3
O
2
S
2
305.38
70 EtOH C
13
H
11
N
3
OS
321.44
3
54.33
(54.66)
51.13
(51.19)
48.58
(48.23)
3.04
(3.28)
3.63
(3.95)
3.45
(3.63)
17.6
(17.72)
13.76
(13.48)
13.07
(13.53)
16.12
(16.03)
21.0
(21.41)
29.92
(30.09)
17a >300 50 DMF C
20
H
13
N
3
O
2
S
2
391.47
61.36
(16.31)
3.35
(3.66)
10.73
(10.84)
16.38
(16.11)
152

Comp.
No.
Table 1. Analytical and Physical Data for Primidine Derivatives from 17b-22a. m.p. o C
Yield
%
Solv. Mol.formula
Mol.wt C
Analysis Calc. (found) %
H N
17b Dec.2
60
18 112-
19
114
220
39
65
EtOH C
20
H
13
N
3
OS
3
407.54
EtOH C
15
H
15
N
3
O
2
S
3
365.5
44 MeOH C
13
H
10
KN
3
O
2
S
3
375.54
58.94
(59.22)
49.29
(49.09)
41.58
(41.18)
3.22
(3.54)
4.14
(4.37)
2.68
(2.94)
10.31
(10.19)
11.5
(11.78)
11.19
(11.37)
S
23.6
(23.96)
26.32
(26.62)
25.61
(25.68)
20 230
21a
21b
268-
270
219-
220
22a 255
48 AcOH C
15
H
11
N
3
O
2
S
3
361.47
60 BuOH C
17
H
12
N
4
O
3
S
352.37
47 DMF C
18
H
14
N
4
O
382.47
2
S
2
52 AcOH C
17
H
10
N
4
O
334.45
2
S
49.84
(50.19)
57.95
(58.13)
56.53
(56.22)
61.07
(61.24)
3.07
(3.25)
3.43
(3.76)
3.69
(3.52)
3.01
(3.51)
11.62
(11.87)
15.9
(15.48)
14.65
(14.86)
16.76
(17.08)
26.61
(26.31)
9.1
(9.32)
16.77
(17.01)
9.59
(9.83)
153

Table 1. Analytical and Physical Data for Primidine Derivatives from 22b-23.
Comp.
No. m.p. o C
Yield
%
Solv. Mol.formula
Mol.wt C
Analysis Calc. (found) %
H N
22b
23
207
255-
257
57 AcOH C
18
H
12
N
4
OS
364.45
2
55 acetone C
18
H
11
ClN
4
OS
4
463.02
59.32
(59.14)
46.69
(46.44)
3.32
(3.81)
2.39
(2.78)
15.37
(15.88)
12.1
(12.39)
S
17.6
(17.46)
27.7
(28.06)
154

Table 2. Analytical and Physical Data for Pyridinethione Derivatives from 25-31.
Comp.
No. m.p. oC
Yield
%
Solv. Mol.formula
Mol.wt C
Analysis Calc. (found) %
H N
25
26
240
162
65 Benz. C
18
H
10
Cl
2
N
2
S
357.26
59 MeOH C
18
H
9
Cl
3
N
2
O
2
S
423.71
27 >300 55 AcOH C
18
H
11
Cl
2
N
3
O
2
S
404.28
60.52
(60.23)
51.03
(51.39)
53.48
(53.88)
2.82
(2.96)
2.14
(2.64)
2.74
(2.85)
7.84
(7.74)
6.61
(6.37)
10.39
(10.63)
S
8.97
(9.11)
7.57
(7.91)
7.93
(8.24)
28
29
196
120
40 EtOH C
18
H
11
Cl
2
N
3
O
2
S
404.28
52 MeOH C
18
H
9
Cl
3
359.64
N
2
53.48
(53.88)
60.12
(59.88)
2.74
(2.85)
2.52
(2.72)
10.39
(10.63)
7.79
(7.96)
7.93
(8.24)
30
31
243
215
56 BuOH C
18
H
12
Cl
2
N
4
355.23
42 MeOH C
18
H
12
Cl
2
N
2
OS
375.28
60.86
(61.03)
57.61
(57.56)
3.41
(3.22)
3.22
(3.39)
15.77
(15.33)
7.46
(7.17)
8.54
(8.87)
155

Table 2. Analytical and Physical Data for Pyridinethione Derivatives from 32-37.
Comp.
No. m.p. oC
Yield
%
Solv. Mol.formula
Mol.wt C
Analysis Calc. (found) %
H N
32 250
33
34
35a
35b
178
138
235
223
34 acetone C
18
H
10
Cl
2
N
2
OS
373.26
47 EtOH C
18
H
11
Cl
2
N
372.26
3
S
59 Benz. C
21
H
14
Cl
2
N
2
OS
413.33
53
58
EtOH C
28
H
16
Cl
2
N
2
OS
499.42
EtOH C
28
H
15
Cl
3
N
2
OS
533.87
57.92
(58.17)
58.07
(57.91)
61.03
(60.79)
67.34
(67.71)
63.0
(63.35)
2.7
(2.97)
2.98
(2.79)
3.41
(3.67)
3.23
(3.49)
2.83
(3.0)
7.5
(7.84)
11.28
(11.05)
6.78
(6.54)
5.61
(5.24)
7.84
(7.94)
S
8.59
(9.0)
8.61
(8.48)
7.67
(7.46)
6.42
(6.33)
6.01
(6.38)
36
37
147
257
53 Tolu. C
22
H
16
Cl
2
N
2
O
2
S
443.36
52 MeOH C
20
H
11
Cl
2
KN
2
O
2
S
453.39
59.6
(59.54)
52.98
(53.37)
3.64
(3.81)
2.45
(2.27)
6.32
(6.5)
6.18
(6.45)
7.23
(7.12)
7.07
(7.27)
156

Table 2. Analytical and Physical Data for Pyridine Derivatives from 38-40b.
Comp.
m.p
o Yield Solv. Mol.formula Analysis Calc. (found) %
No.
38
39a
C
>
300
210
%
61
65
AcOH
EtOH
C
C
22
26
H
H
Mol.wt
12
439.32
15
Cl
Cl
2
2
N
N
520.46
2
3
O
2
OS
S
2
C
60.15
(60.0)
60.0
(59.78)
H
2.75
(2.86)
2.91
(3.11)
N
6.38
(6.64)
8.07
(8.49)
S
7.30
(7.06)
12.32
(12.17)
39b 195
40a 208
62 MeOH C
26
H
14
Cl
3
N
3
OS
2
554.91
47 BuOH C
25
H
14
Cl
2
441.32
N
4
56.28
(56.69)
68.04
(68.48)
2.54
(2.91)
3.2
(3.53)
7.57
(7.22)
12.7
(12.74)
11.56
(11.78)
40b 185 53 BuOH C
25
H
13
Cl
3
475.77
N
4
63.11
(63.28)
2.75
(2.62)
11.78
(12.08)
157

Pyrimidine and its thione derivatives have a wide range of application in medicine due to their pronounced biological activity. Many of these compounds have provide to be active antiviral (Fauci 1988; Rice et al., 1988 and El-Bendary and
Badria 2000) , antimicrobial (El-Bahaie and Assy 1990; Fasoli and Kerridge 1990; and Kalil et al., 1988) , antifungi (Abd El-
Ad et al., 1955) , antibacterial (Ghorab and Hassan 1998) , as inhibitor of bovine liver dihydrofolate reductase (Taylor et al.,
1983) , anticancer (Ingram et al., 1992) , herbicides (Christoph et al., 1992 and Kevin et al., 1992) , antitumour (Zhohua et al.,
2001) , antihistamine (Chamanlal et al., 2000) and as tyrosine kinase inhibitor (Smaill et al., 2000) .
This stimulated our interest for the synthesis of new 2hydroxy-, 2-mercapto- and 2-alkylmercaptopyrimidine derivatives via the reaction of aromatic aldehydes (heterocyclic aromatic aldehydes) e.g. furfural, thiophen-2-aldehyde, ethyl cyanoacetate with urea, thiourea and S-methylisothiourea, respectively. The reaction products were utilized for the synthesis of other new azolopyrimidine (Scheme 1).
158

Heating under reflux, a ternary mixture of furfural and/or thiophene-2-aldehyde, ethylcyanoacetate and thiourea or urea in ethanol in presence of potassium carbonate, the 3,4-dihydro-2mercapto-4-oxo-6-(aryl)- pyrimidine-5-carbonitrile and hydroxy analogue 3a-d were obtained via Michael addition followed by cyclization and autoxidation to give the final isolable 3a-c (Assy and Moustafa 1997) (Scheme 1).
Ar-CHO +
CN
CH
2
CO
2
C
2
H
5
X
H
2
N-C-NH
2
O
NC
NH
CN
Ar-CH=C-CO
2
C
2
H
5
1a,b
X
H
2
N-C-NH
2
NC
O
Ar N XH
OC
2
H
5
NH
2
Ar N
H
X
NC
Ar
O
N
3a-d
O
NC
NH
XH
[O]
Ar
NH -
C
2
H
5
OH
N
2a-d
X a) Ar= , X= S b) Ar= , X= S
O S c) Ar= , X= O d) Ar= , X= O
S
O
Scheme 1
159

Reaction of 3a,b with alkylhalides, namely methyliodide and ethylbromide in aqueous ethanolic potassium carbonate gave the S-alkyl derivatives 4a-c. The above alkylation took place at the sulfur atom was proved by: (I) preparation of 4a-c by two other different alternative routes, reaction of S-alkylisothiourea 5 with either of compounds 1a,b or a mixture of furfural or thiophene-2-aldehyde, and ethylcyanoacetate (Scheme 2).
Reaction of 3a with methyl chloride afforded 4a, while 3b reacted with methyl chloride and ethyl bromide and gave the alkyl products 4a,b respectively.
O OH
NC
NH
+
RX
K
2
CO
3
EtOH
NC
N
Ar N
3a,b
SR Ar N
4a-c a) Ar= , R= CH
3
O c) Ar= , R= C
2
H
5
S b) Ar= , R= CH
3
S
The structure of compound 4a-c was elucidated from (a) their correct analytical and spectral data . 1 HNMR of 4a showed a chemical shift at δ: 2.34 (s, 3H, CH
3
) and 6.8-8.1 (m , 3H, ArH).
IR spectra of 4a-c gave characteristic bands at the regions 3340
(broad, OH, NH), 2230 (CN) and 1650 cm -1 (C=N).
SR
160

CN
Ar-CHO + CH
2
CO
2
C
2
H
5 +
H
2
N
SR
5
NH
1 + 5 4a-c
3a,b + RX
Scheme 2
Reaction of compounds 4a-c with phosphorous oxychloride in dioxane produced the 4-chloropyrimidine derivatives 6a-c.
O OH Cl
NC
NH
NC
N
+ POCl
3
NC
N
Ar N SR Ar N SR Ar N SR
4a-c 6a-c a) Ar= , R= CH
3
O c) Ar= , R= C
2
H
5
S b) Ar= , R= CH
3
S
161

1 HNMR of 6a, δ: 2.62 (s, 3H, CH
3
) and 6.7-8.2 (m , 3H,
ArH). IR spectra of compounds 6a-c indicate the absence of any band at the NH or OH and CO regions and the presence of absorption bands at the C=N region at 1630 cm -1 and at the CN region at 2220 cm -1 . The above compounds 6a-c reacted with thiourea and gave the compounds 6-mercapto-2-alkylthio-4-(2aryl)primidine-5-carbonitrile 7a-c (Scheme 3). IR spectra of these compounds showed the absence of any absorption bands at the OH and CO regions and the presence of absorption bands in the CN region, νmax 2240 cm -1 .
On the other hand, treatment of compounds 6a-c with ammonia afforded 6-amino-2-alkyl-4-(2-aryl)pyrimidine-5carbonitriles 8a-c, due to the distinct activity of position 4
(Scheme 3).
1
HNMR of 8a, δ: 2.6 (s, 3H, CH
3
), 6.5-8 (m , 3H,
ArH) and 9.2 (s, 2H, NH
2
); 8c: δ: 2.56 (t, 3H, CH
3
), 4.3 (q, 2H,
CH
2
), 6.3-7.9 (m , 3H, ArH) and 9.4 (s, 2H, NH
2
). IR spectra of compounds 8a-c showed absorption bands at the region at 3350 cm
-1
(NH
2
) and 2220 cm
-1
(CN).
Also, compounds 6a-c reacted with hydrazine hydrate in boiling butanol and gave 2,6-dihydrazino-4-(2-alkyl)pyrimidine-
5-carbonitriles 9a,b ( El-Bahaie and Assy 1990) (Scheme 3).
The structure of compounds 9a,b was confirmed from their correct analytical and spectral data , thus IR spectra showed absorption bands at the regions 3340-3050 cm -1 (broad, NH,
NH
2
) and 2215 cm -1 (CN); 1 HNMR spectra showed a chemical
162

shift at δ: 5.2
(br, 4H, 2NH
2
), 8.7-9.8 (br, 2H, 2NH) and 7.6-7.1
(m , 3H, Arm).
The dihydrazino compounds 9a,b easily cyclized by further refluxing in butanol into 6-hydrazino-4-(2-aryl)pyrazolo-
[5,4-d]pyrimid-ine-3-yl amine 10a,b (Scheme 3). 1 HNMR spectra of compounds 10a,b showed a chemical shift at the regions δ: 5.1 (br, 4H, 2NH
2
), 8.7-9.7 (br, 2H, 2NH) and 6.8-7.9
(m , 3H, ArH).
SH
S
H
2
NCNH
2
NH
3
NC
NC
NH
2
N
Ar N
N
7a-c
SR
Ar N
8a-c
SR
NC
Ar
Cl
N
6a-c
N
NC
H
2
NNHN
2
SR butanol
Ar
PhNHNH
2
RS
N
Ar
N
NHNH
2
H
2
N
N
9a,b
N butanol
NHNH
2
Ar
N N
H
N
N
HN
NHNH
2
Ar
H
N N
H
N
10a,b
N
NHNH
2
C N
NHNHPh
Ar
NH a) Ar=
O b) Ar=
S
Ar
O
RS
N
H
2
O
N
N Ph N Ph
N
11a-c
N
H
RS N
12a-c
N
H a) Ar= , R= CH
3
O c) Ar= , R= C
2
H
5
S b) Ar= , R= CH
3
S
Scheme 3
163

In contrast to the action of hydrazine hydrate, phenylhydrazine reacted with 6a-c under the same experimental conditions to directly yield 2,3-dihydro-5-alkylthio-1-oxo-2phenyl-7-aryl-1H-pyrazolo-[3,4-d]pyrimidines 12a,b (Atsushi et al., 1994) (Scheme 3) via the non isolable compounds 1la-c.
1 HNMR spectrum of compound 12a showed signal at δ: 2.68 (s,
3H, CH
3
), 5.65 (br.s, 1H, NH) and 6.8-7.6 ppm (m, 3H, ArH).
The IR spectra of compounds 12a-c indicated no absorption bands in the cyano region, furthermore, it displayed a carbonyl absorption band at 1690 cm -1 .
Treatment of compounds 9a,b with nitrous acid at 0 o C resulted in the formation of the ditetrazopyrimidine derivatives
13a,b (El-Assiery and Al-Haiza 1998) (Scheme 4). The structure of 13a,b was elucidated from analytical and spectral data; thus
1
HNMR spectra showed signals at δ: 6.8-8.1 (m , 3H,
ArH). The IR spectra displayed an absorption bands at 2240 cm
-1
(CN) and revealed no absorption in the NH region
Also, when compounds 9a,b reacted with carbon disulphide in ethanolic Potassium hydroxide solution gave
1,2,7,8-tetrahydro-6-oxo-1-thioxo-5-(aryl)-6H-pyrazolo[3 ,4-d]-
1,2,4-triazolo[3,4-b]pyrimidine 14a,b ( Ahmed 2000 ).
1
HNMR spectra of 14a,b showed signals at δ: 5.9
(br, s, 1H, NH), 6.8-8.3
(m,3H ArH), 10.2 (br, s, 1H, CSNH) and 12 ppm (br, s, 1H,
164

CONH); IR spectra revealed no absorption band at (CN) region, but it displayed absorption bands at 3340, 3180 (NH) and 1690 cm -1 (CO).
NC
NHNH
2
N
+ HONO
NC
NH
N
N
N
NC
H
N
N
N
N
Ar N
9a-b
NHNH
2
Ar N
N
NH
N
Ar N
N N
N
H
NC
N N
N
N
Ar N
N
N
13a,b
N a) Ar=
O b) Ar=
S
-2H
+
Scheme 4
NC
Ar
NHNH
2
N
9a,b
N
+
CS
2
NHNH
2
HN
H
N N
H
N H
2
O
O
H
N N
H
N
Ar
S
N
N
N
H a) Ar=
O
Ar b) Ar=
S
S
N
14a,b
N
N
H
165

NC
The mechanism of the reaction can be explained as follow
(Scheme 5):
NHNH
2
H
N N
H
H
N N
H
HN O
N N
H
2
O
N
Ar N
9a-b
NHNH
2
Ar N NHNH
2
Ar N NH
NH
2
O
H
N N
H
N
O
-H
2
S
H
N N
H
N
O
H
N N
H
S
S
C
N
Ar
S
N
N
N
H
14a,b
Ar N
HS
N
C
NH
S
H Ar N
HS
NH
C
NH
S a) Ar=
O b) Ar=
S
Scheme 5
On the other hand, when compounds 6a-c were allowed to react with aroylhydrazines, namely benzoyl and 4chlorobenzoylhydrazine in n-butanol it gave 1,2,4-triazolo[4,3a]pyrimidine derivatives 15a-f (Scheme 6).
1 HNMR spectra of compound 15a showed signals at δ 2.6 (s, 3H, CH
3
) and 6.2-8.4 ppm (m, 8H, Arm); IR spectra of compounds 15a-f gave
166

absorption bands at the regions 2230 cm -1 (CN) and 1640 cm -1
(C=N).
NC
Cl
N
O
H
2
..
NNHCAr
'
NC
H
N
N
NH
C
Ar
'
O
NC
N N
N
H
Ar
'
OH
Ar N
6a-c
SR Ar N SR Ar N SR
N N
NC Ar
'
N
-H
2
O
Ar N
15a-f
SR a) R = CH
3
, Ar = Ar
'
O
= C
6
H
5 c) R = C
2
H
5
, Ar = Ar
'
= C
S
6
H
5 e) R = CH
3
, Ar = Ar
'
S
= p-Cl.C
6
H
4 b) R = CH
3
, Ar = Ar
'
S
= C
6
H
5 d) R = CH
3
, Ar = Ar
'
O
= p-Cl.C
6
H
4 f) R = C
2
H
5
, Ar = Ar
S
'
= p-Cl.C
6
H
4
Scheme 6
Compounds 7a-c reacted with chloroacetone in presence of anhydrous sodium carbonate and gave 1-(5-amino-2alkylthio-4-(2-aryl)thiopheno[2,3-d]pyrimidin-6-yl) ethan-1-one
16a-c, which reacted with benzaldehyde yielded 2-alkylthio-6phenyl-4-(2-aryl)-5-hydropyri-midino-[5′,4′-5,4]thiopheno[3,2b]pyridin-8-one 17a-c (Scheme 7). The structure of compounds
167

17a-c was elucidated from their correct analytical and spectral data. Thus 1 HNMR spectra of 17a, δ: 1.62 (s, 3H, CH
3
), 11.9 (br, s, 1H, NH) and 6.85-8.22 ppm (m, 8H, Arm) and for 17c, δ: 2.7
(s, 3H, CH
3
), 4.2 (q, 2H, CH
2
), 11.87 (br, s, 1H, NH) and 6.73-
8.42 (m, 8H, Arm). IR spectra of compounds 17a-c showed
NC
Ar absorption bands at the regions 3250 (NH), 1700 (CO) and 1100 cm -1 (-S-).
H
3
COC
SH SCH
2
COCH
3
S
NC
N ClCH
2
COCH
3 acetone
N
H
2
N
N
N
7a-c
SR Ar N SR
Ar
16a-c
N SR
PhCHO
O
Ph-CH=HCOC
O
S N SR Ph S
S
H
2
N
Ph N
N
[O]
H
N
N
N
H Ar Ar N SR
Ar N
17a-c
SR a) R = CH
3
, Ar =
O c) R = C
2
H
5
, Ar =
S b) R = CH
3
, Ar =
S
Scheme 7
Also, compound 7c reacted with ethyl chloroacetate to yield the alkyl products 18, which hydrolyzed by using aqueous potassium hydroxide into 19 (Scheme 8).
168

Compound 19 were cyclized by refluxing with acetic anhydride to give 1-ethylthio-10-oxo-3-(2-thienyl)-10-hydropyrimidino[6,1-b]quinazoline-4-carbonitrile
20 (Scheme 8).
The structure of the compound 20 was confirmed from their correct analytical and spectral data, thus 1 HNMR spectrum of compound 20 showed a chemical shift at the regions δ: 2.22
(t, 3H, CH
3
), 4.1 (q, 2H, CH
2
), 2.41(s, 3H, CH
3
) and 7.4-7.9 ppm
(m , 3H, Arm). IR spectrum of compound 20 gave absorption bands at the 1620 (C=N) and 1695 cm -1 (CO).
EtS
N
Ar
N
7c
Ar
CN
SH
ClCH
2
CO
2
C
2
H
5 acetone
EtS
N
N
18
Ar
CN
Na
2
CO
3
SCH
2
CO
2
Et EtS
N
N
C N
S-CHCO
2
Et
EtS
N
Ar
N
Ar
S
O
NH-C-CH
3
O
(CH
3
CO)
2
O
N
COK
EtS
Ar
N
19
OH
N=C-CH
3
N
EtS N
S
COK
O EtS
S
NH
2
O
COK
N
Ar
N S
20
Ar =
S
Scheme8
KOH N
EtS
N
O
O
Ar
N
CH
3
S
NH
2
CO
2
Et
169

On the other hand, when compounds 6a,c were allowed to react with anthranilic acid it gave 2-[(5-cyano-2-alkylthio-6-(2aryl) pyrimi-dine-4-yl)amino] benzoic acid 2la,b, which cyclized by refluxing with acetic anhydride to gave 3-(2-furyl)-1methylthio-10-oxo-10a-hydropyri-midino[6,1-b]quinazoline-4carbonitrile 22a and 1-ethylthio-10-oxo-3-(2-thienyl)-10ahydropyrimidino[6,1-b]quinazoline-4-carbonitrile 22b (Scheme
9).
The structure of the compounds 21a,b was confirmed from their correct analytical and spectral data, thus 1 HNMR spectrum of compound 21a showed a chemical shift at the regions δ: 2.63 (s, 3H, CH
3
), 8.67 (br.,s, 1H, NH), 6.7-8.15 (m ,
7H, Arm) and 11.85 ppm (s, 1H, COOH); 21c, δ: 1.39 (t, 3H,
CH
3
), 3.47 (q, 2H, CH
2
), 3.62 (br, s, 1H, NH), 7.3-8.0 (m , 7H,
Arm) and 11.8 ppm (s, 1H, COOH). IR spectra of compounds
21a,b gave absorption bands in the region 3400-3100 broad (NH and OH), 2222 (CN) and 1685 cm
-1
(C=O).
The structure of the compounds 22a,b was confirmed from their correct analytical and spectral data, thus
1
HNMR spectrum of compound 22a showed a chemical shift at the regions δ: 2.62 (s, 3H, CH
3
), and 6.9-7.8 (m , 7H, Arm); 22b, δ:
1.32 (t, 3H, CH
3
), 3.4 (q, 2H, CH
2
) and 7.23-8.2 ppm (m , 7H,
Arm). The IR spectra of compounds 22a,b gave absorption bands at the 2230 (CN), 1710 (C=O) and 1630 cm -1 (C=N).
170

RS
Cl Ar
N
CN COOH CN
N
+
N
6a,c
Ar
Ar
CN
NH
2
Ar
CN
RS N
HO
C
O
21a,b
NH
N
N
RS
O
N N -H
2
O
RS N
HO
C
O
N
22a,b a) R = CH
3
, Ar =
O b) R = C
2
H
5
, Ar =
S
H
Scheme9
Compound 7b reacted with p-chlorophenylisothiocyanate in dry acetone and gave (4-chlorophenyl)-N-[(5-cyano-2-methylthio-6-(2-thienyl)pyrimidin-4-ylthio)thioxomethyl]carboxamide
23. The structure of compounds 23 was elucidated from their correct analytical and spectral data. Thus
1
HNMR spectrum of
23, δ: 2.45 (s, 3H, CH
3
), 7.31-7.95 ppm (m, 7H, Arm) and 9.92
(br, 1H, NH). IR spectra of compound 23 showed absorption bands at the regions 3340-3220 (NH), 2225 (CN), 1690 (CO),
1600 (C=N) and 1525 cm -1 (C=S).
171

Ar Ar
RS
N
N
7b
CN
+
O
Ar
'
-C-N=C=S
N
SH RS N
23
R = CH
3
, Ar = Ar
'
S
= p-Cl.C
6
H
4
CN
S O
S-C-NH-C-Ar
'
The considerable biological activity of 1,2-benzothiazole-
3(2H)-one-1,1-dioxide 24 as fungicide, antiviral and antibacterial agent (Davis 1972; Baggaley 1978 and Welter et al., 1982) has prompted considerable interest in synthesis and chemistry of these compounds. As a part of program directed for developing new compounds for utility as antischitosomal agent we become interested in synthesizing derivatives of 24 in which the benzene ring is replaced by a nitrogen hetero-aromatic ring. Also, a wide range of pharmacological activities pyridinethione and its derivatives such as antifungi (Klimesova et al., 1999 and Bond and Jones 2000) antimicrobial (Attaby et al., 1999) , antitumor virus (Attia et al., 1995) , bacterial (Ghorab and Hassan 1998) and some derivatives possess positive intropic activity (Rumler and Hagen 1990) .
172

O O
SO
2
NR
S
NR
24
O O
In the present investigation, 3-cyano-4,6-di(p-chlorophenyl)-2(1H)-pyridinethione 25 was synthesized following the literature procedure (Abdalla et al., 1977) and used as starting material for the synthesis of several new thienopyridine and pyrazolopyridine derivatives.
Ar Ar
O
Ar-CH=CH-C-Ar
+
CN
CH
2
-C-NH
2
C
2
H
5
ONa
S Ar
CN
[O]
N S Ar N
H
Ar = p-Cl-C
6
H
4
H
25
It has been found that when 25 was treated with chlorine gas in presence of 10% acetic acid at 0 o
C the corresponding sulfonyl chloride 26 was obtained, which on direct amonolysis with NH
4
OH (Ainsworth 1953) afforded, 3-amino-4,6-di(pchlorophenyl)isothiazolo[5,4-b] pyridine-1,1-dioxide 27 (Ahmed
1994) and 3-amino-4,6-di(p-chlorophenyl)pyridine-2-sulfonamide 28 (Ahmed 1996) .
CN
S
173

Ar Ar
Ar
Ar
Ar N
H
25
CN
Cl
2
S
CH
3
COOH
Ar N
CN
NH
4
OH
SO
2
Cl
Ar N
O
S
N
O
27
NH
2
+
Ar N
CN
SO
2
NH
2
26
Ar
28
CN
Cl
2
HCl
Ar N
29
Cl
The structure of compounds 27 and 28 was elucidated from their correct analytical and spectral data, thus IR spectrum of compound 27 showed absorption bands at the region 3300 cm -
1 (NH
2
) and 1360 cm -1 (SO
2
), 1 HNMR,δ 8.3-7.5 (m , 9H, ArH) and 28, 6.4 (br, 2H, NH
2
). IR spectrum of 28 showed absorption bands at 3400-3300 cm -1 (NH
2
), 2210 cm -1 (CN) and 1360 cm -
1 (SO
2
).
Treatment of 25 with chlorine gas in the presence of HCl at 0 o C gave 2-chloro-3-cyano-4,6-di(p-chlorophenyl)pyridine 29
(Ainsworth 1953 and Ahmed 1996) . The structure of 29 was confirmed from it’s correct analytical and spectral data, IR spectrum showed absorption bands at the regions 2240 cm
-1
(CN) and the absence of any bands in the (SH) region.
1
HNMR showed band at δ: 7.8-6.7 (m , 9H, ArH).
174

On the other hand, compound 25 was obtained when compound 29 was allowed to react with thiourea (Lawson and
Tnkler 1970) .
Ar Ar
CN S CN n.butanol
+
H
2
N-C-NH
2
Ar N
29
Cl
Ar = p-Cl-C
6
H
4
Ar N
25
SH
Also when compound 25 when reacted with hydrazine hydrate in boiling n-butanol gave 4,6-bis(4chlorophenyl)pyrazolo[5,4-b]pyridine-3-yl amine 30 (Lawson and Tnkler 1970) .
Ar Ar
CN C N
+
NH
2
NH
2 n.butanol
Ar N
25
SH
Ar
Ar N NH
NH
2
NH
2
Ar N
30
N
N
H
175

Structure of 30 was confirmed (a): by Analytical and spectral data. Thus IR spectrum of 30 showed absorption bands at 1600 cm -1 (C=N), a broad band at 3400-3200 cm -1 (NH
2
and
NH) and the absence of any band at 2200 cm -1 due to the absence of (CN) group. 1 HNMR showed a bands at δ: 8.73 (br, s, 1H,
NH), 6.9-7.8 (m, 9H, ArH) and 5.8 ppm (br, s, 2H, NH
2
).
(b): Chemically: by synthesis from the chloropyridine derivative 29 and hydrazine hydrate (in refluxing butanol).
The author has prepared 4,6-bis(4-chlorophenyl)-2thioxohydro-pyridine-3-carboxamide 31 by acidic hydrolysis of
25 (Coffey 1984) . The IR spectrum showed absorption bands at
3320 (NH
2
), 1140 cm -1 (-S-); 1 NHMR δ: 8.5
(s,1H, SH), 7.9-6.6
(m, 9H, ArH) and 6.3 (br., s, 2H, NH
2
).
Compound 31 was treated with iodine in benzene at reflux temperature to gave 3-oxo-2,3-dihydroisothiazolo[5,4b]pyridine derivatives 32.
Ar Ar Ar
O
Ar N
CN
S
H
2
SO
4 hydrolysis
Ar N
CONH
2
I
2
S Ar N
S
NH
H
25
H
31 32
176

The structure of 32 was confirmed from it’s correct analytical and spectral data, thus IR spectrum showed absorption bands at the regions 3300 (NH), 1680 (C=O) and 1150 cm -1 (-S-
); 1 HNMR δ: 9.7 (br, s, 1H, NH) and 8.1-6.7 (m, 9H, ArH).
On the other hand when compound 25 was treated with sodium hypochlorite followed by ammonium hydroxide, it yields
2-sulphenamide derivative 33 which can be oxidized by potassium permanganate into the corresponding sulphonamide
28.
Ar
Ar Ar
CN i)NaOCl
S ii)NH
4
OH
Ar
CN
KMnO
4
CN
Ar N
N SNH
2
Ar N SO
2
NH
2
H
25
28
33
The structure of the sulphenamide derivative 33 was elucidated from it’s correct analytical and spectral data, thus IR spectrum showed absorption bands at the region 2230 cm -1 (CN) and 3350 cm -1 (NH
2
); 1 HNMR showed a chemical shift at δ 8.2-
7.11 (m , 9H, ArH), 6.2 (br, 2H, NH
2
).
Furthermore, when compound 25 was allowed to react with chloroacetone it gave the corresponding thieno[2,3-
177

b]pyridine derivative 34 (Kaigorodova 1999) . The IR spectrum showed absorption bands at the regions 3340 (NH
2
), 1640 (CO) and 1130 cm -1 (-S-); 1 HNMR showed a chemical shift at δ: 1.3
(s, 3H, CH
3
), 6.1 (br, s, 2H, NH
2
) and 8.2-7.1 (m , 9H, ArH).
Compound 34 was easily condensed with aromatic aldehydes, namely, benzaldehyde and 2-chlorobenzaldehyde giving the tricyclic compounds 35a,b.
Ar Ar Ar
Ar N
CN
S Ar N
CN O
SH
ClCH
2
CCH
3
K
2
CO
3
Ar N
C N
O
S-CH
2
-C-CH
3
H
25
Ar Ar
NH
2
C N
K
2
CO
3
Ar
CH
3
N S Ar N S-CH-COCH
3
34
O
K
The structure of compounds 35a,b was elucidated from their correct analytical and spectral data, IR spectrum of 35a showed the absorption bands at the regions 3300 cm -1 (NH),1650
(C=O) and 1130 cm -1 (-S-); 1 HNMR of 35a showed a chemical shift at δ: 8.9 (br, s,1H, NH), 8.4-6.8 (m , 14H, ArH). IR spectrum of 35b showed the absorption bands at 3360 (NH),
178

Ar
1660 (CO) and1140 cm -1 (-S-); 1 HNMR of 35b, δ: 9.2 (br, s, 1H,
NH) and 8.3-6.9 (m , 13H, ArH).
Ar
Ar
N
34
S
NH
2
CH
3
+
O
Ar
'
-CH
O
Ar N S
NH
2
CH=CH-Ar
'
O
Ar H
N Ar
'
Ar H
N Ar
'
[O]
Ar N S Ar N S
35a,b
O O a) Ar
'
=C
6
H
5 b) Ar
'
= 2-ClC
6
H
4
Similarly, when compound 25 was allowed to react with ethyl bromoacetate, it gave the corresponding thieno[2,3b]pyridine derivative 36. IR spectrum gave characteristic bands at the regions 3310 (NH
2
), 1760 (CO) and 1120 cm -1 (-S-).
1 HNMR showed a chemical shift at δ: 1.75 (t, 3H, CH
3
), 2.85 (q,
2H, CH
2
), 5.85
(br, 2H, NH
2
) and 7.8-6.7 (m , 9H, ArH).
Treatment of 36 with alcoholic potassium hydroxide afforded 3-amino-4,6-di(p-chlorophenyl)thieno[2,3-b]pyridine-
2-carboxylate 37. IR spectrum of 37 showed absorption bands at
179

3320 (NH
2
), 1780 (C=O) and 1100 cm -1 (-S-); 1 HNMR δ: 6.5
(br, 2H, NH
2
) and 7.7-6.7 (m , 9H, ArH).
Compound 37 reacted with acetic anhydride to give the tricyclic compound 38. The IR spectrum of 38 showed the absorption bands at the regions 1670 (C=O) and 1120 cm -1 (-S-);
1 HNMR showed a chemical shift at δ: 2.4 (s, 3H, CH
3
) and 8.1-
7.2 (m , 9H, ArH).
On the other hand compound 25 reacted with aroylisothiocyanate, namely benzoylisothiocyanate and 4chlorobenzoylisothiocyanate in dry acetone and gave the pyridinedithiocarbamate derivatives 39a,b.
The structure of 39a,b was confirmed from their correct analytical and spectral data, thus IR spectrum of compound 39a gave characteristic bands at 3360-3300 (NH), 2220 (CN), 1670
(C=O) and 1520 cm
-1
(C=S);
1
HNMR showed a chemical shift at
δ: 10.65 (br, 1H, NH) and 7.8-7.0 (m
, 14H, ArH). IR spectrum of 39b showed absorption bands at 3350-3250(NH), 2230
(C≡N), 1720 (C=O), 1600 (C=N) and 1530 cm -1
(C=S);
1
HNMR of 17b showed chemical shift at δ: 9.6(br,1H, NH) and 8.1-7.3
(m , 13H, ArH).
180

Ar Ar Ar
N
H
CN CN O
SH
ClCH
2
COC
2
H
5
K
2
CO
3
Ar
C N
Ar S
25
Ar N N S-CH
2
CO
2
C
2
H
5
Ar Ar
NH
2
C N
K
2
CO
3
Ar
Ar
Ar N
36
KOH EtOH
Ar
S
NH
2
O
OC
2
H
5
(CH
3
CO)
2
O
OK
N S
37
O
Ar
Ar
N CH
3
-KOH
O
N S
38
O
Ar
Ar
N
Ar
N S
Ar
N
S-CH-CO
2
C
2
H
5
K
S
H O
N CCH
3
O
OH
N CCH
3
O
OK
OK
181

Ar Ar
Ar N
CN
S
+
O
Ar
'
-CNCS
Ar N
CN
S O
S-C-NH-C-Ar
'
H
25 a) Ar
'
= C
6
H
5
39a,b b) Ar
'
= p-Cl-C
6
H
4
The triazolopyridine derivatives 40a,b were obtained by reaction of 25, 26 and 29 with benzoylhydrazine and 4chlorobenzoylhydrazine in refluxing butanol.
The structure of the triazolopyridine derivatives 40a,b was confirmed from their correct analytical and spectral data, IR spectrum of 40a: showed absorption bands at the regions 2210
(CN) and 1560 cm -1 (C=N).
1 HNMR δ: 8.1-6.6 (m , 14H, ArH). IR spectrum of 40b: gave characteristic bands at 2230 (CN) and 1540 cm -1 (C=N);
1 HNMR δ: 8.3-6.9 (m , 13H, ArH).
182

Ar
Ar
N
25
Ar
Ar
CN
+
O
Ar
'
-CNHNH
2
SH
Ar
CN
Ar
N
Ar
'
O
CN
NH
Ar
NH
N
Ar
'
OH
CN
NH
N
O
29 + Ar
'
-CNHNH
2 a) Ar
'
= C
6
H
5
Ar N b) Ar
'
= 4-C
6
H
4
Ar
'
40a,b
N
N H
2
O
183

Pyrimidine and its thione derivatives have a wide range of application in medicine due to their pronounced biological activity. Many of these compounds have provide to be active antiviral (Fauci 1988; Rice et al., 1988 and El-Bendary and
Badria 2000) , antimicrobial (El-Bahaie and Assy 1990; Fasoli and Kerridge 1990; and Kalil et al., 1988) , antifungi (Abd El-
Ad et al., 1955) , antibacterial (Ghorab and Hassan 1998) , as inhibitor of bovine liver dihydrofolate reductase (Taylor et al.,
1983) , anticancer (Ingram et al., 1992) , herbicides (Christoph et al., 1992 and Kevin et al., 1992) , antitumour (Zhohua et al.,
2001) , antihistamine (Chamanlal et al., 2000) and as tyrosine kinase inhibitor (Smaill et al., 2000) .
This stimulated our interest for the synthesis of new 2hydroxy-, 2-mercapto- and 2-alkylmercaptopyrimidine derivatives via the reaction of aromatic aldehydes (heterocyclic aromatic aldehydes) e.g. furfural, thiophen-2-aldehyde, ethyl cyanoacetate with urea, thiourea and S-methylisothiourea, respectively. The reaction products were utilized for the synthesis of other new azolopyrimidine (Scheme 1).
184

Heating under reflux, a ternary mixture of furfural and/or thiophene-2-aldehyde, ethylcyanoacetate and thiourea or urea in ethanol in presence of potassium carbonate, the 3,4-dihydro-2mercapto-4-oxo-6-(aryl)- pyrimidine-5-carbonitrile and hydroxy analogue 3a-d were obtained via Michael addition followed by cyclization and autoxidation to give the final isolable 3a-c (Assy and Moustafa 1997) (Scheme 1).
Ar-CHO +
CN
CH
2
CO
2
C
2
H
5
X
H
2
N-C-NH
2
O
NC
NH
CN
Ar-CH=C-CO
2
C
2
H
5
1a,b
X
H
2
N-C-NH
2
NC
O
Ar N XH
OC
2
H
5
NH
2
Ar N
H
X
NC
Ar
O
N
3a-d
O
NC
NH
XH
[O]
Ar
NH -
C
2
H
5
OH
N
2a-d
X a) Ar= , X= S b) Ar= , X= S
O S c) Ar= , X= O d) Ar= , X= O
S
O
Scheme 1
185

Reaction of 3a,b with alkylhalides, namely methyliodide and ethylbromide in aqueous ethanolic potassium carbonate gave the S-alkyl derivatives 4a-c. The above alkylation took place at the sulfur atom was proved by: (I) preparation of 4a-c by two other different alternative routes, reaction of S-alkylisothiourea 5 with either of compounds 1a,b or a mixture of furfural or thiophene-2-aldehyde, and ethylcyanoacetate (Scheme 2).
Reaction of 3a with methyl chloride afforded 4a, while 3b reacted with methyl chloride and ethyl bromide and gave the alkyl products 4a,b respectively.
O OH
NC
NH
+
RX
K
2
CO
3
EtOH
NC
N
Ar N
3a,b
SR Ar N
4a-c a) Ar= , R= CH
3
O c) Ar= , R= C
2
H
5
S b) Ar= , R= CH
3
S
The structure of compound 4a-c was elucidated from (a) their correct analytical and spectral data . 1 HNMR of 4a showed a chemical shift at δ: 2.34 (s, 3H, CH
3
) and 6.8-8.1 (m , 3H, ArH).
IR spectra of 4a-c gave characteristic bands at the regions 3340
(broad, OH, NH), 2230 (CN) and 1650 cm -1 (C=N).
SR
186

CN
Ar-CHO + CH
2
CO
2
C
2
H
5 +
H
2
N
SR
5
NH
1 + 5 4a-c
3a,b + RX
Scheme 2
Reaction of compounds 4a-c with phosphorous oxychloride in dioxane produced the 4-chloropyrimidine derivatives 6a-c.
O OH Cl
NC
NH
NC
N
+ POCl
3
NC
N
Ar N SR Ar N SR Ar N SR
4a-c 6a-c a) Ar= , R= CH
3
O c) Ar= , R= C
2
H
5
S b) Ar= , R= CH
3
S
187

1 HNMR of 6a, δ: 2.62 (s, 3H, CH
3
) and 6.7-8.2 (m , 3H,
ArH). IR spectra of compounds 6a-c indicate the absence of any band at the NH or OH and CO regions and the presence of absorption bands at the C=N region at 1630 cm -1 and at the CN region at 2220 cm -1 . The above compounds 6a-c reacted with thiourea and gave the compounds 6-mercapto-2-alkylthio-4-(2aryl)primidine-5-carbonitrile 7a-c (Scheme 3). IR spectra of these compounds showed the absence of any absorption bands at the OH and CO regions and the presence of absorption bands in the CN region, νmax 2240 cm -1 .
On the other hand, treatment of compounds 6a-c with ammonia afforded 6-amino-2-alkyl-4-(2-aryl)pyrimidine-5carbonitriles 8a-c, due to the distinct activity of position 4
(Scheme 3).
1
HNMR of 8a, δ: 2.6 (s, 3H, CH
3
), 6.5-8 (m , 3H,
ArH) and 9.2 (s, 2H, NH
2
); 8c: δ: 2.56 (t, 3H, CH
3
), 4.3 (q, 2H,
CH
2
), 6.3-7.9 (m , 3H, ArH) and 9.4 (s, 2H, NH
2
). IR spectra of compounds 8a-c showed absorption bands at the region at 3350 cm
-1
(NH
2
) and 2220 cm
-1
(CN).
Also, compounds 6a-c reacted with hydrazine hydrate in boiling butanol and gave 2,6-dihydrazino-4-(2-alkyl)pyrimidine-
5-carbonitriles 9a,b ( El-Bahaie and Assy 1990) (Scheme 3).
The structure of compounds 9a,b was confirmed from their correct analytical and spectral data , thus IR spectra showed absorption bands at the regions 3340-3050 cm -1 (broad, NH,
NH
2
) and 2215 cm -1 (CN); 1 HNMR spectra showed a chemical
188

shift at δ: 5.2
(br, 4H, 2NH
2
), 8.7-9.8 (br, 2H, 2NH) and 7.6-7.1
(m , 3H, Arm).
The dihydrazino compounds 9a,b easily cyclized by further refluxing in butanol into 6-hydrazino-4-(2-aryl)pyrazolo-
[5,4-d]pyrimid-ine-3-yl amine 10a,b (Scheme 3). 1 HNMR spectra of compounds 10a,b showed a chemical shift at the regions δ: 5.1 (br, 4H, 2NH
2
), 8.7-9.7 (br, 2H, 2NH) and 6.8-7.9
(m , 3H, ArH).
SH
S
H
2
NCNH
2
NH
3
NC
NC
NH
2
N
Ar N
N
7a-c
SR
Ar N
8a-c
SR
NC
Ar
Cl
N
6a-c
N
NC
H
2
NNHN
2
SR butanol
Ar
PhNHNH
2
RS
N
Ar
N
NHNH
2
H
2
N
N
9a,b
N butanol
NHNH
2
Ar
N N
H
N
N
HN
NHNH
2
Ar
H
N N
H
N
10a,b
N
NHNH
2
C N
NHNHPh
Ar
NH a) Ar=
O b) Ar=
S
Ar
O
RS
N
H
2
O
N
N Ph N Ph
N
11a-c
N
H
RS N
12a-c
N
H a) Ar= , R= CH
3
O c) Ar= , R= C
2
H
5
S b) Ar= , R= CH
3
S
Scheme 3
189

In contrast to the action of hydrazine hydrate, phenylhydrazine reacted with 6a-c under the same experimental conditions to directly yield 2,3-dihydro-5-alkylthio-1-oxo-2phenyl-7-aryl-1H-pyrazolo-[3,4-d]pyrimidines 12a,b (Atsushi et al., 1994) (Scheme 3) via the non isolable compounds 1la-c.
1 HNMR spectrum of compound 12a showed signal at δ: 2.68 (s,
3H, CH
3
), 5.65 (br.s, 1H, NH) and 6.8-7.6 ppm (m, 3H, ArH).
The IR spectra of compounds 12a-c indicated no absorption bands in the cyano region, furthermore, it displayed a carbonyl absorption band at 1690 cm -1 .
Treatment of compounds 9a,b with nitrous acid at 0 o C resulted in the formation of the ditetrazopyrimidine derivatives
13a,b (El-Assiery and Al-Haiza 1998) (Scheme 4). The structure of 13a,b was elucidated from analytical and spectral data; thus
1
HNMR spectra showed signals at δ: 6.8-8.1 (m , 3H,
ArH). The IR spectra displayed an absorption bands at 2240 cm
-1
(CN) and revealed no absorption in the NH region
Also, when compounds 9a,b reacted with carbon disulphide in ethanolic Potassium hydroxide solution gave
1,2,7,8-tetrahydro-6-oxo-1-thioxo-5-(aryl)-6H-pyrazolo[3 ,4-d]-
1,2,4-triazolo[3,4-b]pyrimidine 14a,b ( Ahmed 2000 ).
1
HNMR spectra of 14a,b showed signals at δ: 5.9
(br, s, 1H, NH), 6.8-8.3
(m,3H ArH), 10.2 (br, s, 1H, CSNH) and 12 ppm (br, s, 1H,
190

CONH); IR spectra revealed no absorption band at (CN) region, but it displayed absorption bands at 3340, 3180 (NH) and 1690 cm -1 (CO).
NC
NHNH
2
N
+ HONO
NC
NH
N
N
N
NC
H
N
N
N
N
Ar N
9a-b
NHNH
2
Ar N
N
NH
N
Ar N
N N
N
H
NC
N N
N
N
Ar N
N
N
13a,b
N a) Ar=
O b) Ar=
S
-2H
+
Scheme 4
NC
Ar
NHNH
2
N
9a,b
N
+
CS
2
NHNH
2
HN
H
N N
H
N H
2
O
O
H
N N
H
N
Ar
S
N
N
N
H a) Ar=
O
Ar b) Ar=
S
S
N
14a,b
N
N
H
191

NC
The mechanism of the reaction can be explained as follow
(Scheme 5):
NHNH
2
H
N N
H
H
N N
H
HN O
N N
H
2
O
N
Ar N
9a-b
NHNH
2
Ar N NHNH
2
Ar N NH
NH
2
O
H
N N
H
N
O
-H
2
S
H
N N
H
N
O
H
N N
H
S
S
C
N
Ar
S
N
N
N
H
14a,b
Ar N
HS
N
C
NH
S
H Ar N
HS
NH
C
NH
S a) Ar=
O b) Ar=
S
Scheme 5
On the other hand, when compounds 6a-c were allowed to react with aroylhydrazines, namely benzoyl and 4chlorobenzoylhydrazine in n-butanol it gave 1,2,4-triazolo[4,3a]pyrimidine derivatives 15a-f (Scheme 6).
1 HNMR spectra of compound 15a showed signals at δ 2.6 (s, 3H, CH
3
) and 6.2-8.4 ppm (m, 8H, Arm); IR spectra of compounds 15a-f gave
192

absorption bands at the regions 2230 cm -1 (CN) and 1640 cm -1
(C=N).
NC
Cl
N
O
H
2
..
NNHCAr
'
NC
H
N
N
NH
C
Ar
'
O
NC
N N
N
H
Ar
'
OH
Ar N
6a-c
SR Ar N SR Ar N SR
N N
NC Ar
'
N
-H
2
O
Ar N
15a-f
SR a) R = CH
3
, Ar = Ar
'
O
= C
6
H
5 c) R = C
2
H
5
, Ar = Ar
'
= C
S
6
H
5 e) R = CH
3
, Ar = Ar
'
S
= p-Cl.C
6
H
4 b) R = CH
3
, Ar = Ar
'
S
= C
6
H
5 d) R = CH
3
, Ar = Ar
'
O
= p-Cl.C
6
H
4 f) R = C
2
H
5
, Ar = Ar
S
'
= p-Cl.C
6
H
4
Scheme 6
Compounds 7a-c reacted with chloroacetone in presence of anhydrous sodium carbonate and gave 1-(5-amino-2alkylthio-4-(2-aryl)thiopheno[2,3-d]pyrimidin-6-yl) ethan-1-one
16a-c, which reacted with benzaldehyde yielded 2-alkylthio-6phenyl-4-(2-aryl)-5-hydropyri-midino-[5′,4′-5,4]thiopheno[3,2b]pyridin-8-one 17a-c (Scheme 7). The structure of compounds
193

17a-c was elucidated from their correct analytical and spectral data. Thus 1 HNMR spectra of 17a, δ: 1.62 (s, 3H, CH
3
), 11.9 (br, s, 1H, NH) and 6.85-8.22 ppm (m, 8H, Arm) and for 17c, δ: 2.7
(s, 3H, CH
3
), 4.2 (q, 2H, CH
2
), 11.87 (br, s, 1H, NH) and 6.73-
8.42 (m, 8H, Arm). IR spectra of compounds 17a-c showed
NC
Ar absorption bands at the regions 3250 (NH), 1700 (CO) and 1100 cm -1 (-S-).
H
3
COC
SH SCH
2
COCH
3
S
NC
N ClCH
2
COCH
3 acetone
N
H
2
N
N
N
7a-c
SR Ar N SR
Ar
16a-c
N SR
PhCHO
O
Ph-CH=HCOC
O
S N SR Ph S
S
H
2
N
Ph N
N
[O]
H
N
N
N
H Ar Ar N SR
Ar N
17a-c
SR a) R = CH
3
, Ar =
O c) R = C
2
H
5
, Ar =
S b) R = CH
3
, Ar =
S
Scheme 7
Also, compound 7c reacted with ethyl chloroacetate to yield the alkyl products 18, which hydrolyzed by using aqueous potassium hydroxide into 19 (Scheme 8).
194

Compound 19 were cyclized by refluxing with acetic anhydride to give 1-ethylthio-10-oxo-3-(2-thienyl)-10-hydropyrimidino[6,1-b]quinazoline-4-carbonitrile
20 (Scheme 8).
The structure of the compound 20 was confirmed from their correct analytical and spectral data, thus 1 HNMR spectrum of compound 20 showed a chemical shift at the regions δ: 2.22
(t, 3H, CH
3
), 4.1 (q, 2H, CH
2
), 2.41(s, 3H, CH
3
) and 7.4-7.9 ppm
(m , 3H, Arm). IR spectrum of compound 20 gave absorption bands at the 1620 (C=N) and 1695 cm -1 (CO).
EtS
N
Ar
N
7c
Ar
CN
SH
ClCH
2
CO
2
C
2
H
5 acetone
EtS
N
N
18
Ar
CN
Na
2
CO
3
SCH
2
CO
2
Et EtS
N
N
C N
S-CHCO
2
Et
EtS
N
Ar
N
Ar
S
O
NH-C-CH
3
O
(CH
3
CO)
2
O
N
COK
EtS
Ar
N
19
OH
N=C-CH
3
N
EtS N
S
COK
O EtS
S
NH
2
O
COK
N
Ar
N S
20
Ar =
S
Scheme8
KOH N
EtS
N
O
O
Ar
N
CH
3
S
NH
2
CO
2
Et
195

On the other hand, when compounds 6a,c were allowed to react with anthranilic acid it gave 2-[(5-cyano-2-alkylthio-6-(2aryl) pyrimi-dine-4-yl)amino] benzoic acid 2la,b, which cyclized by refluxing with acetic anhydride to gave 3-(2-furyl)-1methylthio-10-oxo-10a-hydropyri-midino[6,1-b]quinazoline-4carbonitrile 22a and 1-ethylthio-10-oxo-3-(2-thienyl)-10ahydropyrimidino[6,1-b]quinazoline-4-carbonitrile 22b (Scheme
9).
The structure of the compounds 21a,b was confirmed from their correct analytical and spectral data, thus 1 HNMR spectrum of compound 21a showed a chemical shift at the regions δ: 2.63 (s, 3H, CH
3
), 8.67 (br.,s, 1H, NH), 6.7-8.15 (m ,
7H, Arm) and 11.85 ppm (s, 1H, COOH); 21c, δ: 1.39 (t, 3H,
CH
3
), 3.47 (q, 2H, CH
2
), 3.62 (br, s, 1H, NH), 7.3-8.0 (m , 7H,
Arm) and 11.8 ppm (s, 1H, COOH). IR spectra of compounds
21a,b gave absorption bands in the region 3400-3100 broad (NH and OH), 2222 (CN) and 1685 cm
-1
(C=O).
The structure of the compounds 22a,b was confirmed from their correct analytical and spectral data, thus
1
HNMR spectrum of compound 22a showed a chemical shift at the regions δ: 2.62 (s, 3H, CH
3
), and 6.9-7.8 (m , 7H, Arm); 22b, δ:
1.32 (t, 3H, CH
3
), 3.4 (q, 2H, CH
2
) and 7.23-8.2 ppm (m , 7H,
Arm). The IR spectra of compounds 22a,b gave absorption bands at the 2230 (CN), 1710 (C=O) and 1630 cm -1 (C=N).
196

RS
Cl Ar
N
CN COOH CN
N
+
N
6a,c
Ar
Ar
CN
NH
2
Ar
CN
RS N
HO
C
O
21a,b
NH
N
N
RS
O
N N -H
2
O
RS N
HO
C
O
N
22a,b a) R = CH
3
, Ar =
O b) R = C
2
H
5
, Ar =
S
H
Scheme9
Compound 7b reacted with p-chlorophenylisothiocyanate in dry acetone and gave (4-chlorophenyl)-N-[(5-cyano-2-methylthio-6-(2-thienyl)pyrimidin-4-ylthio)thioxomethyl]carboxamide
23. The structure of compounds 23 was elucidated from their correct analytical and spectral data. Thus
1
HNMR spectrum of
23, δ: 2.45 (s, 3H, CH
3
), 7.31-7.95 ppm (m, 7H, Arm) and 9.92
(br, 1H, NH). IR spectra of compound 23 showed absorption bands at the regions 3340-3220 (NH), 2225 (CN), 1690 (CO),
1600 (C=N) and 1525 cm -1 (C=S).
197

Ar Ar
RS
N
N
7b
CN
+
O
Ar
'
-C-N=C=S
N
SH RS N
23
R = CH
3
, Ar = Ar
'
S
= p-Cl.C
6
H
4
CN
S O
S-C-NH-C-Ar
'
The considerable biological activity of 1,2-benzothiazole-
3(2H)-one-1,1-dioxide 24 as fungicide, antiviral and antibacterial agent (Davis 1972; Baggaley 1978 and Welter et al., 1982) has prompted considerable interest in synthesis and chemistry of these compounds. As a part of program directed for developing new compounds for utility as antischitosomal agent we become interested in synthesizing derivatives of 24 in which the benzene ring is replaced by a nitrogen hetero-aromatic ring. Also, a wide range of pharmacological activities pyridinethione and its derivatives such as antifungi (Klimesova et al., 1999 and Bond and Jones 2000) antimicrobial (Attaby et al., 1999) , antitumor virus (Attia et al., 1995) , bacterial (Ghorab and Hassan 1998) and some derivatives possess positive intropic activity (Rumler and Hagen 1990) .
198

O O
SO
2
NR
S
NR
24
O O
In the present investigation, 3-cyano-4,6-di(p-chlorophenyl)-2(1H)-pyridinethione 25 was synthesized following the literature procedure (Abdalla et al., 1977) and used as starting material for the synthesis of several new thienopyridine and pyrazolopyridine derivatives.
Ar Ar
O
Ar-CH=CH-C-Ar
+
CN
CH
2
-C-NH
2
C
2
H
5
ONa
S Ar
CN
[O]
N S Ar N
H
Ar = p-Cl-C
6
H
4
H
25
It has been found that when 25 was treated with chlorine gas in presence of 10% acetic acid at 0 o
C the corresponding sulfonyl chloride 26 was obtained, which on direct amonolysis with NH
4
OH (Ainsworth 1953) afforded, 3-amino-4,6-di(pchlorophenyl)isothiazolo[5,4-b] pyridine-1,1-dioxide 27 (Ahmed
1994) and 3-amino-4,6-di(p-chlorophenyl)pyridine-2-sulfonamide 28 (Ahmed 1996) .
CN
S
199

Ar Ar
Ar
Ar
Ar N
H
25
CN
Cl
2
S
CH
3
COOH
Ar N
CN
NH
4
OH
SO
2
Cl
Ar N
O
S
N
O
27
NH
2
+
Ar N
CN
SO
2
NH
2
26
Ar
28
CN
Cl
2
HCl
Ar N
29
Cl
The structure of compounds 27 and 28 was elucidated from their correct analytical and spectral data, thus IR spectrum of compound 27 showed absorption bands at the region 3300 cm -
1 (NH
2
) and 1360 cm -1 (SO
2
), 1 HNMR,δ 8.3-7.5 (m , 9H, ArH) and 28, 6.4 (br, 2H, NH
2
). IR spectrum of 28 showed absorption bands at 3400-3300 cm -1 (NH
2
), 2210 cm -1 (CN) and 1360 cm -
1 (SO
2
).
Treatment of 25 with chlorine gas in the presence of HCl at 0 o C gave 2-chloro-3-cyano-4,6-di(p-chlorophenyl)pyridine 29
(Ainsworth 1953 and Ahmed 1996) . The structure of 29 was confirmed from it’s correct analytical and spectral data, IR spectrum showed absorption bands at the regions 2240 cm
-1
(CN) and the absence of any bands in the (SH) region.
1
HNMR showed band at δ: 7.8-6.7 (m , 9H, ArH).
200

On the other hand, compound 25 was obtained when compound 29 was allowed to react with thiourea (Lawson and
Tnkler 1970) .
Ar Ar
CN S CN n.butanol
+
H
2
N-C-NH
2
Ar N
29
Cl
Ar = p-Cl-C
6
H
4
Ar N
25
SH
Also when compound 25 when reacted with hydrazine hydrate in boiling n-butanol gave 4,6-bis(4chlorophenyl)pyrazolo[5,4-b]pyridine-3-yl amine 30 (Lawson and Tnkler 1970) .
Ar Ar
CN C N
+
NH
2
NH
2 n.butanol
Ar N
25
SH
Ar
Ar N NH
NH
2
NH
2
Ar N
30
N
N
H
201

Structure of 30 was confirmed (a): by Analytical and spectral data. Thus IR spectrum of 30 showed absorption bands at 1600 cm -1 (C=N), a broad band at 3400-3200 cm -1 (NH
2
and
NH) and the absence of any band at 2200 cm -1 due to the absence of (CN) group. 1 HNMR showed a bands at δ: 8.73 (br, s, 1H,
NH), 6.9-7.8 (m, 9H, ArH) and 5.8 ppm (br, s, 2H, NH
2
).
(b): Chemically: by synthesis from the chloropyridine derivative 29 and hydrazine hydrate (in refluxing butanol).
The author has prepared 4,6-bis(4-chlorophenyl)-2thioxohydro-pyridine-3-carboxamide 31 by acidic hydrolysis of
25 (Coffey 1984) . The IR spectrum showed absorption bands at
3320 (NH
2
), 1140 cm -1 (-S-); 1 NHMR δ: 8.5
(s,1H, SH), 7.9-6.6
(m, 9H, ArH) and 6.3 (br., s, 2H, NH
2
).
Compound 31 was treated with iodine in benzene at reflux temperature to gave 3-oxo-2,3-dihydroisothiazolo[5,4b]pyridine derivatives 32.
Ar Ar Ar
O
Ar N
CN
S
H
2
SO
4 hydrolysis
Ar N
CONH
2
I
2
S Ar N
S
NH
H
25
H
31 32
202

The structure of 32 was confirmed from it’s correct analytical and spectral data, thus IR spectrum showed absorption bands at the regions 3300 (NH), 1680 (C=O) and 1150 cm -1 (-S-
); 1 HNMR δ: 9.7 (br, s, 1H, NH) and 8.1-6.7 (m, 9H, ArH).
On the other hand when compound 25 was treated with sodium hypochlorite followed by ammonium hydroxide, it yields
2-sulphenamide derivative 33 which can be oxidized by potassium permanganate into the corresponding sulphonamide
28.
Ar
Ar Ar
CN i)NaOCl
S ii)NH
4
OH
Ar
CN
KMnO
4
CN
Ar N
N SNH
2
Ar N SO
2
NH
2
H
25
28
33
The structure of the sulphenamide derivative 33 was elucidated from it’s correct analytical and spectral data, thus IR spectrum showed absorption bands at the region 2230 cm -1 (CN) and 3350 cm -1 (NH
2
); 1 HNMR showed a chemical shift at δ 8.2-
7.11 (m , 9H, ArH), 6.2 (br, 2H, NH
2
).
Furthermore, when compound 25 was allowed to react with chloroacetone it gave the corresponding thieno[2,3-
203

b]pyridine derivative 34 (Kaigorodova 1999) . The IR spectrum showed absorption bands at the regions 3340 (NH
2
), 1640 (CO) and 1130 cm -1 (-S-); 1 HNMR showed a chemical shift at δ: 1.3
(s, 3H, CH
3
), 6.1 (br, s, 2H, NH
2
) and 8.2-7.1 (m , 9H, ArH).
Compound 34 was easily condensed with aromatic aldehydes, namely, benzaldehyde and 2-chlorobenzaldehyde giving the tricyclic compounds 35a,b.
Ar Ar Ar
Ar N
CN
S Ar N
CN O
SH
ClCH
2
CCH
3
K
2
CO
3
Ar N
C N
O
S-CH
2
-C-CH
3
H
25
Ar Ar
NH
2
C N
K
2
CO
3
Ar
CH
3
N S Ar N S-CH-COCH
3
34
O
K
The structure of compounds 35a,b was elucidated from their correct analytical and spectral data, IR spectrum of 35a showed the absorption bands at the regions 3300 cm -1 (NH),1650
(C=O) and 1130 cm -1 (-S-); 1 HNMR of 35a showed a chemical shift at δ: 8.9 (br, s,1H, NH), 8.4-6.8 (m , 14H, ArH). IR spectrum of 35b showed the absorption bands at 3360 (NH),
204

Ar
1660 (CO) and1140 cm -1 (-S-); 1 HNMR of 35b, δ: 9.2 (br, s, 1H,
NH) and 8.3-6.9 (m , 13H, ArH).
Ar
Ar
N
34
S
NH
2
CH
3
+
O
Ar
'
-CH
O
Ar N S
NH
2
CH=CH-Ar
'
O
Ar H
N Ar
'
Ar H
N Ar
'
[O]
Ar N S Ar N S
35a,b
O O a) Ar
'
=C
6
H
5 b) Ar
'
= 2-ClC
6
H
4
Similarly, when compound 25 was allowed to react with ethyl bromoacetate, it gave the corresponding thieno[2,3b]pyridine derivative 36. IR spectrum gave characteristic bands at the regions 3310 (NH
2
), 1760 (CO) and 1120 cm -1 (-S-).
1 HNMR showed a chemical shift at δ: 1.75 (t, 3H, CH
3
), 2.85 (q,
2H, CH
2
), 5.85
(br, 2H, NH
2
) and 7.8-6.7 (m , 9H, ArH).
Treatment of 36 with alcoholic potassium hydroxide afforded 3-amino-4,6-di(p-chlorophenyl)thieno[2,3-b]pyridine-
2-carboxylate 37. IR spectrum of 37 showed absorption bands at
205

3320 (NH
2
), 1780 (C=O) and 1100 cm -1 (-S-); 1 HNMR δ: 6.5
(br, 2H, NH
2
) and 7.7-6.7 (m , 9H, ArH).
Compound 37 reacted with acetic anhydride to give the tricyclic compound 38. The IR spectrum of 38 showed the absorption bands at the regions 1670 (C=O) and 1120 cm -1 (-S-);
1 HNMR showed a chemical shift at δ: 2.4 (s, 3H, CH
3
) and 8.1-
7.2 (m , 9H, ArH).
On the other hand compound 25 reacted with aroylisothiocyanate, namely benzoylisothiocyanate and 4chlorobenzoylisothiocyanate in dry acetone and gave the pyridinedithiocarbamate derivatives 39a,b.
The structure of 39a,b was confirmed from their correct analytical and spectral data, thus IR spectrum of compound 39a gave characteristic bands at 3360-3300 (NH), 2220 (CN), 1670
(C=O) and 1520 cm
-1
(C=S);
1
HNMR showed a chemical shift at
δ: 10.65 (br, 1H, NH) and 7.8-7.0 (m
, 14H, ArH). IR spectrum of 39b showed absorption bands at 3350-3250(NH), 2230
(C≡N), 1720 (C=O), 1600 (C=N) and 1530 cm -1
(C=S);
1
HNMR of 17b showed chemical shift at δ: 9.6(br,1H, NH) and 8.1-7.3
(m , 13H, ArH).
206

Ar Ar Ar
N
H
CN CN O
SH
ClCH
2
COC
2
H
5
K
2
CO
3
Ar
C N
Ar S
25
Ar N N S-CH
2
CO
2
C
2
H
5
Ar Ar
NH
2
C N
K
2
CO
3
Ar
Ar
Ar N
36
KOH EtOH
Ar
S
NH
2
O
OC
2
H
5
(CH
3
CO)
2
O
OK
N S
37
O
Ar
Ar
N CH
3
-KOH
O
N S
38
O
Ar
Ar
N
Ar
N S
Ar
N
S-CH-CO
2
C
2
H
5
K
S
H O
N CCH
3
O
OH
N CCH
3
O
OK
OK
207

Ar Ar
Ar N
CN
S
+
O
Ar
'
-CNCS
Ar N
CN
S O
S-C-NH-C-Ar
'
H
25 a) Ar
'
= C
6
H
5
39a,b b) Ar
'
= p-Cl-C
6
H
4
The triazolopyridine derivatives 40a,b were obtained by reaction of 25, 26 and 29 with benzoylhydrazine and 4chlorobenzoylhydrazine in refluxing butanol.
The structure of the triazolopyridine derivatives 40a,b was confirmed from their correct analytical and spectral data, IR spectrum of 40a: showed absorption bands at the regions 2210
(CN) and 1560 cm -1 (C=N).
1 HNMR δ: 8.1-6.6 (m , 14H, ArH). IR spectrum of 40b: gave characteristic bands at 2230 (CN) and 1540 cm -1 (C=N);
1 HNMR δ: 8.3-6.9 (m , 13H, ArH).
208

Ar
Ar
N
25
Ar
Ar
CN
+
O
Ar
'
-CNHNH
2
SH
Ar
CN
Ar
N
Ar
'
O
CN
NH
Ar
NH
N
Ar
'
OH
CN
NH
N
O
29 + Ar
'
-CNHNH
2 a) Ar
'
= C
6
H
5
Ar N b) Ar
'
= 4-C
6
H
4
Ar
'
40a,b
N
N H
2
O
209

210

211

Fig. 3. IR spectra of compound No.6a
212

Fig. 4. IR spectra of compound No.7a
213

Fig. 5. IR spectra of compound No.10b
214

Fig. 6. IR spectra of compound No.12a
215

Fig. 7. IR spectra of compound No.13a
216

Fig.8. IR spectra of compound No.13b
217

Fig. 9. IR spectra of compound No.14a
218

Fig. 10. IR spectra of compound No.15e
219

Fig. 11. IR spectra of compound No.21a
220

Fig. 12. IR spectra of compound No.22a
221

Fig.13. IR spectra of compound No.23
222

Fig.14. IR spectra of compound No.27
223

224

225

226

227

1
1
228

Fig. 21. 1 HNMR spectra of compound No. 6a
Fig. 22.
1
HNMR spectra of compound No. 7a
229

Fig. 23.
1
HNMR spectra of compound No. 10b
Fig. 24.
1
HNMR spectra of compound No. 12a
230

Fig. 25. 1 HNMR spectra of compound No. 13a
Fig.26. 1 HNMR spectra of compound No. 34
231

Fig. 27. 1 HNMR spectra of compound No. 14a
Fig. 28. 1 HNMR spectra of compound No. 15e
232

Fig. 29. 1 HNMR spectra of compound No. 21a
Fig. 30. 1 HNMR spectra of compound No. 22a
233

Fig.31. 1 HNMR spectra of compound No. 23
Fig.32.
1
HNMR spectra of compound No. 27
234

1
1
235

1
1
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261

ةةةة ي لا بةةةة ي ي ةةةة ني رةةةةا رلبةةةةريضل رورةةةةسرللا ر ةةةةا ةيلا رةةةةطخلا
بةة يللا رةةضملا ةةاأ نرةة اللا با ةة ل ي لاو ر ةة اللا با ةة ي لاو ةة ل ي لاو
قةةةةة ملا بت ةةةةة رةةةةةمي ةةةةةلك ا ا قةةةةة ملكا ا ةةةةة لبا بت ةةةةة قا خ ةةةةةربب
تةطواو هرفةررفلا ة هرض يةا وا أة باهو ةب تضوبفي ي لا
4a-c
3a,b
ل ي بر بب ي
بةةة ر كا ةةة قةةة أةةة
8a-c
6a-c
ن
6a-c
ل ي لا هرض بت
ةةة ل ي لا ةةة هرض بت ةةة قةةةوبفي ةةةاوو
ةة ل ي برا كا بت ةة تةة رمي ناه ةة ا قةة ا فلاو ت ه ةة ا ناه ةة هلاو
نيلار لا ضو
12a-c
ن ل ي برلوناي لاو
9a,b
ل ي برا ناه ا يا لاو
تةطواو نربيملا ي يةباثو نوي الا ضلح أ
9a,b
ب يللا تضوبفي
ةةضو
14a,b
ةة ل ي برلونب ايي رةةلوناي بو
13a,b
ةة ل ي بوناي ي يا بت ةة
تة رميو تبةلحكا ا ة ناه ا أة
6a-c
نب يي لا
ل ي لا هرض بت ق قوبفي
بت ةةةةة تةةةةةطوا نر ةةةةةركا ةةةةة هرض أةةةةة
ن
15a-f
7a-c
ل ي برلونب اي لا بت
بةةةةة يللا رةةةةةضوبف و
قا خ ةةربب
16a-c
بةة يلضل رةةا ب
ن
للا يةة ر رةةتلرنلاو
17a-c
16a-c
ن ةة ل ي برا ر ثلا
بتضنلا ر ثلاث ب ي ت رمي ا لازا لا
ييةلاو
18
بة يللا ج و ق ث كا ب را هرض أ
7c
ب يللا قوبفي ًب ا
ضةلح قةضن لا جيبة قةوبفي تةث قر ةربير ل ا وه ا لرضن رجو ي ها خا ب قضن
ن
20
ل ي ب را ر ثلا ب ي ج ا ل يةب لالا ك ضخلا
كةة ض ايث كا ضةةلح أةة تةةضوبفي
6a,c
بةة يللا نبةة ايةةفا رةة حب ةة و
ن
22a,b
جيارالا ت رميو
وا كة ضخضل ضةلح رةجو ية هرةضملا نبغب
ن
29
ةة ي بوهرض و
26
25
نر ث ي لا ق ر لبأ و
ةة ي ب ق رفضةةروهرض يةطأ هةة ب ك هرض وه ةة هلا ضةلح
ق ة و
27
ة ي لارلونب ثوز ا ج ة و قر ر كا ا وه ا أ
26
با ةةةرر ثوز ا قةةة وهاو ت ه ةةة ا ناه ةةة هلا ةةة قةةة أةةة
25
ب يللا قوبفيو
ن
28
ب رفضالا
بةةة يللا قةةةوبفيو
بةةةة ببي ر ثو
30
ةةةة ي برلوناي لا بت ةةةة تةةةة رمي تبةةةةلحكا ا ةةةة ناه او
ن
40a,b
ي برلونب اي لاو
39a,b
ي لا
قرة ر كا ةا و ا رةجو ي قر رصلا هرض ر هب
ةلك قر ةربير لا بةا ا يب رطةرارب هي ةا ا تلي ييلاو
25
33
ب يللا ر لبأ و
ا فضالا ق طوا
ةة ا نرةةم كةة ي ملا ضةةلح رطةةرارب
ن
32
ي برلونب ثوز ك
25
ن
28
ب رفضالا ق
بةة يلضل يةة لنلا قةةضن لا نا ةةجو ةةقو
ا ق نرم ل ر لبب هي ا ا م ا ييلاو
31
ضلنلا
262

ب ةةراوهرض قةة ث كو نر ةةركا ةة هرض ةة قةة أةة
ا ةةة ا لكا
34
بةةة يللا قةةةوبفي ةةةاوو نيلارةةة لا ةةةضو
25
بةة يللا قةةوبفيو
36
و
34
جيارةةةالا يةةةطواو
رةجو ية
36
بة يللا قضن بلا ب
35a,b
بتضنلا ر ثلاث ب ي ت رمي ر يب وهلآا
بة يللا ةلك يةب لالا ك ضخلا ضلح رجو ي جيب تت لرح تث قر ربير لا ا وه ا
ن
38
263

264

265

266