Synthesis of pyrimidine, thiazolopyrimidine, pyrimidotriazine and triazolopyrimidine derivatives and their biological evaluation

Article abstract of DOI:10.1515/znb-1999-0614

Pyrimidin-4-one-2-thione (3) was synthesized via the reaction of thiourea (1) with ethyl henzoylacetate (2) and was taken as a starting material for the present study via its reactions with the halogen-containing reagents 6a-d and 10a-c to give the corresponding thiazolopyrimidines 8, 9 and 12a-c. The 2-hydrazino derivatives 5 were synthesized either via the reaction of 3 or 4 with hydrazine hydrate. Compound 5 reacted with 6a-c and 10a-c to give the corresponding pyrimidotriazines 17a-c and 19 respectively. Also, compound 5 reacted with the active methylene-containing reagents 13 and 2a,b to give the corresponding 2-pyrazolopyrimidines 15 and 22a,b respectively. On the other hand, the triazolopyrimidines 21a,b and 30a,b were also obtained via the reaction of 5 with each of formic acid, acetic anhydride, ethyl chloroformate and carbon disulfide respectively. Some of the newly synthesized heterocyclic derivatives were tested for their biological activity.

Full text of DOI:10.1515/znb-1999-0614

Synthesis of Pyrimidine, Thiazolopyrimidine, Pyrimidotriazine and
Triazolopyrimidine Derivatives and their Biological Evaluation
Fawzy A. Attaby3’* and Sanaa M. Eldinb
a Chemistry Department. Faculty of Science, Cairo University, Giza, Egypt
b Department of Pesticidal Chemistry, National Research Center. Dokki, Giza, Egypt
Z. Naturforsch. 54b, 788-798 (1999); received February 2, 1999
Thiazolopyrimidines, Pyrimidotriazines, 2-Pyrazolopyrimidines, Triazolopyrimidines.
Ethyl Benzoylacetate, Pyrimidin-4-one-2-thione
Pyrimidin-4-one-2-thione (3) was synthesized via the reaction of thiourea (1) with ethyl
benzoylacetate (2) and was taken as a starting material for the present study via its reactions
with the halogen-containing reagents 6a-d and lOa-c to give the corresponding thiazolopyri-
midines 8, 9 and 12a-c. The 2-hydrazino derivatives 5 were synthesized either via the reaction
of 3 or 4 with hydrazine hydrate. Compound 5 reacted with 6a-c and lOa-c to give the corre-
sponding pyrimidotriazines 17a-c and 19 respectively. Also, compound 5 reacted with the
active methylene-containing reagents 13 and 2a,b to give the corresponding 2-pyrazolopyri-
midines 15 and 22a,b respectively. On the other hand, the triazolopyrimidines 21a,b and 30a,b
were also obtained via the reaction of 5 with each of formic acid, acetic anhydride, ethyl
chloroformate and carbon disulfide respectively. Some of the newly synthesized heterocyclic
derivatives were tested for their biological activity.
Introduction
ide to give a product corresponding to dehydro-
chlorination. The IR of such product showed
bands of (C=0) and OH of the carboxyl group in
addition to the functional groups present in the
Although a number of publications [1-4] have
been appeared concerning the synthesis of pyrimi-
dine derivatives, no approach using ethyl benzo-
starting material. Its
NMR revealed signals
ylacetate (2 a) and thiourea ( ) as the starting ma-
1
of -C O O H and -C H 2-S- protons in addition to
the signals originally present in the starting mater-
ial (cf. Table II). By considering such results in
addition to elemental analyses data, compound 7a
could be formulated as 6-phenyl-2-S-carboxy-
terials has been reported. We now wish to report
a convenient and simple synthesis for 3 via the
reaction of thiourea ( ) with ethyl benzoylacetate
1
(2a) in ethanolic sodium acetate. Structure of 3
was established based on, both, spectral and ana-
lytical data (cf Tables I and II). Moreover, its mass
spectrum gave m/z=204, corresponding to the mo-
methylpyrimidine-4-one.
A good evidence for
structure 7a was given through its cyclization in
ethanolic hydrochloric acid to afford 4-phenylthia-
lecular weight of a molecular formula Ci
0
H8N2SO
zolo[3,2-a]pyrimidine-2,5-dione . The structure of
8
of the assigned structure (cf. Chart 1). In continua-
tion to our previous work [5] and due to the re-
ported biological activity [6-9] we were stim-
ulated to synthesize more derivatives of this ring
system. Compounds 3 and 5 were taken as the re-
active starting materials for the present study, ow-
ing to the presence of more than one active site in
both of them.
7a, and hence of 8 , was confirmed, based on IR,
’H NMR and elemental analyses (cf. Tables I and
II). Moreover, their mass spectra gave m /z=262
and 244, respectively which corresponded to the
molecular weights of the molecular formulas
Ci
2
H
1 0
N
2
SO
3
and C1 2
H
8
N
2
S 0
2
of the assigned
structures (cf. Chart 1).
In a similar manner, compound 3 reacted with
ethyl chloroacetate and chloroacetamide 6b,c to
afford the products 7b,c whose structures were
established, based on IR, *H NMR and elemental
analyses (cf. Tables I and II). Similar to the beha-
vior of 7a. 7b,c were cyclized under the same ex-
perimental conditions to afford products via elimi-
nation of ethanol and ammonia in a respective
Results and Discussion
It has been found that compound 3 reacted with
chloroacetic acid (6a) in ethanolic sodium ethox-
* Reprint requests to Dr. F. A. Attaby.
0932-0776/99/0600-0788 $06.00 © 1999 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
D
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789
F. A. Attabi and S. M. Eldin • Synthesis of Pyrimidine Derivatives
Table I. Physical and analytical data of the compound prepared.
Comp.
M.p.
(°C)
Yield
(%)
Molecular
formula
Analysis Calcd/Found (%)
H
N
S
C
3.92
4.2
4.58
4.4
4.95
5.2
3.82
4.0
4.83
5.0
4.21
4.3
4.35
4.3
3.28
3.5
3.95
4.1
4.62
4.4
4.63
4.8
4.81
5.0
4.13
3.9
4.22
4.5
4.45
4.2
5.26
5.4
5.42
5.6
5.33
5.6
5.45
5.6
5.00
5.3
4.96
4.7
5.12
5.4
4.61
4.8
5.55
5.8
5.01
5.3
4.13
4.3
3.77
4.0
4.42
4.6
4.24
4.5
15.69
15.4
14.67
14.4
-
-
12.21
12.5
11.03
11.2
12.26
12.4
9.94
10.2
13.11
13.4
10.53
10.3
12.31
12.5
10.59
10.7
9.63
9.7
13.22
13.4
11.26
11.5
10.19
10.3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
3
266
246
226
218
225
235
210
280
270
222
214
206
275
268
276
150
270
210
245
312
273
298
240
208
254
275
295
129
264
274
87
81
76
66
59
64
77
89
60
58
77
80
75
96
88
87
68
87
68
77
82
88
76
66
65
83
88
87
91
74
C1()H8N2SO
CuH 10N2SO
CiOH10N40
58.82
58.6
60.55
60.7
59.41
59.2
54.96
55.1
57.93
58.2
55.17
54.9
67.08
67.2
59.02
60.2
71.01
71.2
60.00
60.2
59.60
59.8
57.83
57.6
64.46
64.2
63.38
63.1
61.14
61.4
67.66
67.8
60.46
60.2
60.00
59.8
58.18
58.3
65.00
64.8
63.82
64.1
61.53
61.3
55.38
55.5
58.33
58.5
55.59
55.8
59.50
59.7
62.26
62.5
13.73
14.0
12.84
13.0
27.72
27.5
10.69
10.9
9.66
9.8
16.09
15.9
8.70
8.5
11.48
11.2
9.21
9.4
10.77
10.9
9.27
9.0
8.43
8.2
11.57
11.3
9.85
10.1
8.91
4
5
7a
C12H1oN2S03
C 14H 14N 2S O 3
C 12H uN 3S O 2
C 18H 14N 2S O 2
C 12H 8N 2S O 2
C 18H 12N 2SO
C 13H 12N 2S O 2
C 15H 14N 2S O 3
C 16H 16N 2S O 4
C 13H 10N 2SO
C 15H 12N 2S O 2
C 16H 14N 2S O 3
C 15H 14N 4O
7b
7c
7d
8
9
11a
lib
11c
12a
12b
12c
15
9.2
21.05
21.2
21.70
21.9
18.66
18.4
16.96
17.2
23.33
23.5
19.85
20.0
17.94
18.1
21.53
21.7
19.44
19.6
27.02
27.2
23.14
23.3
26.41
26.2
24.77
25.0
16.96
17.2
20.89
21.1
16a
16b
16c
17a
17b
17c
18a
18b
18c
19
C 13H 14N 4O 2
C 15H 16N 4O 3
Ci6H18N40 4
C 13H 12N 4O
Ci5H14N40 2
C 16H 16N 4O 3
C 12H 12N 4O 3
Ci4H16N40 3
Ci2H13N50 2
C 12H 10N 4O 2
C „ H 8N 4O
21a
21b
22a
22b
Ci2H 10N4O
63.71
63.5
69.09
69.2
62.68
62.9
C 19H 14N 4O 2
C 14H 12N 4O 2
4.47
4.6
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790
F. A. Attabi and S. M. Eldin • Synthesis of Pyrimidine Derivatives
Table I. (continued).
Comp.
M.p.
Yield
(%)
Molecular
formula
Analysis Calcd/Found (%)
(°C)
>300
272
H
N
S
C
25
57.99
58.2
70.34
70.1
62.86
63.0
60.81
61.0
57.89
58.1
54.09
54.2
4.08
4.3
26.02
26.2
76
88
80
86
76
69
C 13H „ N 5O 2
C 17H 14N40
C 17H 13N 4O C i
C 15H 12N 4S O
C u H 8N 4O 2
C „ H 8N 4S O
-
27a
27b
27c
30a
30b
4.82
5.0
19.31
19.1
-
-
-
295
4.00
4.2
17.25
17.5
>300
260
4.05
4.2
18.91
19.1
10.81
11.0
-
-
13.11
13.4
3.50
3.7
24.56
24.7
124
3.27
3.5
22.95
23.2
% of Cl for compound 27b Calcd/Found is 10.93/11.2.
All compounds are crystallized from ethanol except for compounds 15. 21b. 25 and 27a-c, which are crystallized
from acetic acid.
manner. The mass spectra of 7b,c gave m /z=290 kyl pyrimidinone derivative lla-c, respectively, via
and 261, respectively which corresponded to the dehydrochlorination in each case. The structures
of lla-c were established, based on IR, 'H NMR
and elemental analyses data (cf. Tables I and II).
A good evidence for structures lla-c arose from
molecular weights of the molecular formulas
S 0 and C^HnN^SC^ of the assigned
structures (cf Chart 1). It is remarkable to report
C
1 4
H
14
N
2
3
here that the cyclization product of the 7a-c was their cyclization in ethanolic hydrochloric acid, to
afford the corresponding thiazolo[3,2-a]pyrimid-
ines 12a-c, respectively. The above mentioned cycl-
similar in all aspects (m.p.. mixed m. p., IR, XH
NMR and mass spectra).
On the other hand, compound 3 reacted with a>- ization reactions most probably proceeded
through dehydration of lla-c. This results arose
from the mass spectra of lla-c which gave m/z=
bromoacetophenone 6d in ethanolic sodium
ethoxide to afford the corresponding -phenyl- -
6
2
S-benzoylmethylpyrimidine-4-one (7d) via dehy- 260, 302 and 332, while that of 12a-c gave m/z=
drobromination. Compound 7d was cyclized in 242, 284 and 314 which proved elimination of a
ethanolic hydrochloric acid to afford 4,5-diphenyl- water molecule in each case (cf. Chart 1).
The synthetic potentiality of 3 was investigated
further through its reaction with methyl iodide to
give the corresponding 6-phenyl-2-S-methylpyri-
midine-4-one (4). Compound 4 reacted with hydra-
zine hydrate to give the sulfur-free product 5. The
structures of, both, 4 and 5 were established based
on IR, ’H NMR and elemental analyses (cf. Tables
I and II). A good elucidation of structure 5 was
thiazolo[3,2-a]pyrimidine-2-one 9. The structures
7d and 9 were confirmed depending on the data of,
both, spectral and elemental analyses (cf. Tables I
and II). Moreover, their mass spectra gave m/z=
322 and 304 respectively which corresponded to
the molecular weights of the molecular formulas
Ci
8
H
14
N
2
S 0
2
and Ci
8
H 1 2 N2SO of the assigned
structure (cf. Chart 1). The m/z values of 7a-d were
262, 290, 261 and 322, while those of their cycliza- given through its preparation via another route.
tion products 8 and 9 were 244 and 304. This Thus, compound 3 reacted with hydrazine hydrate
proved that 7a-c cyclized via elimination of water, to give the same sulfur-free product 5, found iden-
ethanol and ammonia, respectively, to give the tical in all aspects (m.p., mixed m. p., IR, 'H NMR
and elemental analyses) with that given from the
reaction of 4 with hydrazine hydrate. Compound
cyclization product 8 while 7d cyclized via dehy-
dration to give the cyclization product 9.
5 was formulated as
dine-4-one by considering its mass spectrum (m/z=
) which corresponds to the molecular weight of
the molecular formula C ()H ()N40 of the assigned
2
-hydrazino-
6
-phenylpyrimi-
The synthon 3 reacted also with chloroacetone
(10 a), a-chloroacetylacetone (10 b) and ethyl a-
chloroacetoacetate (10 c) under similar experimen-
tal conditions to afford the corresponding 2-S-al-
2 0
2
1
1
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791
F. A. Attabi and S. M. Eldin • Synthesis of Pyrimidine Derivatives
S
I
H -N -C -N H ,
PhCOCH2COOEt
2
N H ,NH
i
12a-c
Chart 1.
structure (cf Chart 1). Compound 5 was taken as been found that compound 5 reacted with acetyl-
another synthon in the present study owing to the acetone (13) in ethanol containing the catalytic
presence of more than one active site. Thus, it has amount of triethylamine to afford the corres-
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Table II. Spectroscopic data of the newly synthesized compounds.
F. A. Attabi and S. M. Eldin • Synthesis of Pyrimidine Derivatives
Comp.
IR (cm *)
*H NMR (dppm)
3
4
5
3192(NH); 3076 (aromatic CH); 1678(C=0);
1603(C=C) and 1564(C=S).
3187(NH); 3069(aromatic CH); 2879(sat. CH);
1690(C=0); 1600(C=C) and 1558(C=S).
3379. 3297, 3278, 3189(NH, and NH);
3082(aromatic CH); 1691(C=0); 1614(C=N)
and 1600(C=C).
3.7(s, 1H. pyrimidine H-5); 7.0-7.9(m, 5H, ArH’s)
and 11.6(s, br., 2H. NH).
2.3(s, 3H. SCH3); 3.5(s. 1H, pyrimidine H-5); 5.2(s,
br., 1H, NH) and 7.0-7.9(m . 5H. ArH’s).
3.4(s, 1H, pyrimidine H-5); 5.0(s, br., 1H, NH py-
rimidine); 6.1(s, br., 1H, NH hydrazide); 7.0-
8.1 (m, 5H, ArH’s) and 9.3(s, br., 2H, NH2 hydraz-
ide).
7a
7b
3400-2400(H-bonded OH); 1712(C=0 acid);
1691(C=0 ring); 1613(C=N) and 1600(C=C).
3.1(s, 1H, pyrimidine H-5); 3.9(s, 2H, -SCH2-);
5.3(s, br., 1H, NH pyrimidine); 6.9-7.8(m , 5H,
ArH's) and 10.9(s, br., 1H, COOH).
1.0(t, 3H, C ^ C H t); 2.9(s, 1H. pyrimidine H-5);
3.7(s, 2H, -SCH2-); 4.0(q, 2H, CH3C //2-); 5.2(s,
br., 1H, NH pyrimidine); and 7.Ö-7.9(m, 5H,
ArH’s).
3180(NH); 3069(aromatic CH); 2987(sat. CH);
1739(C=0 ester); 1691(C=0 ring); 1617(C=N)
and 1605(C=C).
3.1 (s, 1H, pyrimidine H-5); 3.8(s, 2H, -SCH2 );
5.1(s, br., 1H, NH pyrimidine); 6.0(s, br., 2H,
NH2) and 7.0-8.1(m . 5H, ArH’s).
7c
3336, 3278, 3195(NH2 and NH); 3076(aromatic
CH); 2979(sat. CH); 1697(C=0); and 1605(C=
C).
7d
3187(NH); 3075(aromatic CH); 2977(sat. CH);
1709(C=0 ketone); 1695(C=0 ring); and
1605(C=C).
3.0(s, 1H, pyrimidine H-5); 3.9(s, 2H, -SCH2-);
5.4(s, br., 1H, NH pyrimidine); and 7.0-8.0(m ,
5H, ArH’s).
8
9
3083(aromatic CH); 2982(sat. CH); 1688(C=
O); and 1605(C=C).
3079(aromatic CH); 1700(C=0); 1613(C=N)
and 1602(C=C).
2.8(s, 1H, pyrimidine H-5); 4.1(s, 2H, -CH2- thia-
zole ring) and 7.0-7.9(m , 5H, ArH’s).
3.1(s, 1H, pyrimidine H-5); 4.6(s, 1H, -CH=) and
7 .0 -8 .l(m . 10H, ArH’s).
11a
3179(NH); 3078(aromatic CH); 2978(sat. CH);
1710 (C =0); 1610(C=N) and 1600(C=C).
2.2(s, 3H, -COCH3); 3.1(s, 1H, pyrimidine H-5);
3.9(s, 2H, -SCH.CO-); 5.3(s, br., 1H, NH) and
7.1 -7.8(m , 5H, ÄrH’s).
2.0(s, 6H, two -COCH3); 3.3(s, 1H, pyrimidine H-
5); 4.1 (s, H, -SCH); 5.3(s, br., 1H, NH) and 7.0-
8.1(m, 5H, ArH's).
l.l(t, 3H, CH3CH2-); 1.9(s, 3H, -COCH3); 2.8(s,
1H, pyrimidine H-5); 3.4(q. 2H, CH3CH2-); 4.1(s,
H, -SCH); 5.1(s, br., 1H, NH) and 7.0-8.1(m , 5H,
ArH’s).
11b
11c
3182(NH); 3075(aromatic CH); 2977(sat. CH);
1690 (C =0); 1612(C=N) and 1600(C=C).
3197(NH); 3083 aromatic CH); 2979(sat. CH);
1732(C=0 ester); 1708(C=0 ketone); 1687
(C =0 ring); 1615(C=N) and 1600(C=C).
12a
12b
3069 aromatic CH); 2976(sat. CH); 1689 (C=
O ring); 1611(C=N) and 1600(C=C).
3072 aromatic CH); 2977(sat. CH); 1715(C=0
ketone); 1687 (C = 0 ring); 1610(C=N) and
1601 (C=C).
I.l(t, 3H, CH3); 3.0(s, 1H, pyrimidine H-5); 4.5(s,
H, =CH-) and 7.1-7.9(m , 5H, ArH’s).
I.0(t, 3H, CH3); 2.1(S, 3H, COCH3); 3.2(s, 1H, py-
rimidine H-5) and 7.0-7.8(m , 5H, ArH’s).
0.9(t, 3H, CH3); l.l(t, 3H, C //3CH,-); 3.0(s, 1H,
pyrimidine H-5); 3.5(q, 2H, CH,C7/2-) and 6.9-
8.2(m, 5H, ArH’s).
1.3(s, 6 H, two CH3); 2.9(s, 1H, pyrimidine H-5);
3.4(s, 1H, pyrazole); 5.4(s, br., NH) and 7.0-
7.9(m, 5H, ArH’s).
12c
15
3079 aromatic CH); 2989(sat. CH); 1738(C=0
ester); 1690 (C =0 ring); 1616(C=N) and
1600(C=C).
3192(NH); 3083 aromatic CH); 2976(sat. CH);
1690 (C =0 ring); 1616(C=N) and 1603(C=C).
1.7(s, 3H. COCH3); 2.1 ( s, 2H, -COCH2-); 3.3(s,
1H, pyrimidine H-5); 4.9(s, br., three NH) and
7.0-7.8(m , 5H, ArH’s).
2.0(s, 6H, two COCH3); 2.3(s, 1H, -CH-); 3.1(s,
1H, pyrimidine H-5); 5.2(s, br., three NH) and
7.0-7.8 (m, 5H. ArH’s).
1.0(t, 3H, CH3CH2-); 2.1 (s, 3H, COCH3); 2.4(s,
1H, -CH-); 3.0(s, 1H, pyrimidine H-5); 3.5(q, 2H,
CH3CH2-); 5.1 (s, br., three NH) and 7.0-8.1(m .
5H. ArH’s).
16a
16b
16c
3222, 3190, 3168(NH); 3075 aromatic CH);
2988(sat. CH); 1711(C=0 ketone); 1673 (C =0
ring); 1611(C=N) and 1601(C=C).
3220, 3202, 3187(NH); 3077 aromatic CH);
2979 (sat. CH); 1687 (C =0) ; 1615(C=N) and
1600(C=C).
3231, 3217, 3193(NH); 3080 aromatic CH);
2978 (sat. CH); 1730(ester C =0); 1679 (ring
C = 0) ; 1610 (C=N) and 1600(C=C).
1.2(s, 3H. CH3); 3.1(s, 1H. pyrimidine H-5); 5.0(s,
1H. triazine H-3); 6.4(s. br., 2H, two NH) and
7.1 -8.2(m . 5H. ArH's).
17a
3223, 3189(NH); 3069 aromatic CH); 2978 (sat.
CH); 1688 (rins> C = 0)
1602(C=C).
; 1617(C=N) and
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F. A. Attabi and S. M. Eldin • Synthesis of Pyrimidine Derivatives____________________________________________793
Table II. (continued)
*H NMR (öppm)
IR ( c m 1)
Comp.
17b
1.0(s, 3H, CH-,); 1.9(s, 3H, COCH3); 3.2(s, 1H, py-
rimidine H-5); 6.1(s, br., 2H, two NH) and 7.0-
7.9(m, 5H, ArH’s).
3200, 3195(NH); 3079 aromatic CH); 2975 (sat.
CH); 1717(ketone C =0); 1692(C=0 ring);
1612 (C=N) and 1600(C=C).
1.0(s, 3H, CH3); 1.3(t, 3H, CH^CH2-); 3.1(s, 1H,
pyrimidine H-5); 3.5(q, 2H, CH3C //2-); 5.9(s, br.,
2H, two NH) and 6.9-7.8(m , 5H, ArH’s).
1.9(s, 2H, -COCHt ); 3.2(s, 1H, pyrimidine H-5);
5.4(s, br., 3H, three NH); 7.0-7.9(m , 5H, ArH’s)
and ll.l(s , br., 1H, COOH).
1.0(t, 3H, C //3CH2); 2.1 (s, 2H, -COCH2-); 3.0(s,
1H, pyrimidine H-5); 3.4(q, 2H, CH3C //2-); 5.2(s,
br., 3H, three NH) and 7.1-8.2(m , 5H, ÄrH’s).
2.0(s, 2H, -COCH2-); 3.2(s, 1H, pyrimidine H-5);
4.9(s, br., 3H, three NH); 6.0(s, br., 2H, NH2) and
7.0-8.1(m , 5H, ArH’s).
17c
18a
18b
18c
19
3217, 3195(NH); 3078 aromatic CH); 2977 (sat.
CH); 1737(ketone C =0); 1694(C=0 ring);
1613 (C=N) and 1603(C=C).
3400-2397(H-bonded OH); 1708(acid C=0);
1678(C=0 ring); 1611 (C=N) and 1601(C=C).
3320, 3276, 3193(NH); 3072(aromatic CH);
2978(sat., CH); 1732(ester C =0); 1689(C=0
ring); 1619(C=N) and 1603(C=C).
3340, 3310, 3226; 3189 (NH2 and NH); 3078
(arom- atic CH); 2977(sat., CH); 1690(C=0
ring); 1612 (C=N) and 1600(C=C).
3222, 3189 (NH); 3082 (aromatic CH);
2979(sat., CH); 1695(C=0); 1610 (C=N) and
1601(C=C).
2.1(s, 2H, -COCH2-); 3.2(s, 1H, pyrimidine H-5);
5.8(s, br., 2H, two NH) and 6.9-7.8(m , 5H,
ArH’s).
2.1(s, 2H, -COCHt ); 3.2(s, 1H, pyrimidine H-5);
6.0(s, br., 2H, two NH) and 6.9-7.8(m , 5H,
ArH’s).
21a
3197 (NH); 3077(aromatic CH); 1688(C=0);
1617 (C=N) and 1600(C=C).
21b
22a
22b
3188(NH); 2975(sat„ CH); 3079(aromatic
CH); 1690(C=0); 1615 (C=N) and 1604(C=C).
3182(NH); 3077(aromatic CH); 1692(C=0);
1617 (C=N) and 1601(C=C).
3190(NH); 3069(aromatic CH); 2978(sat„
CH); 1690 (C =0); 1615 (C=N) and 1600
(C=C).
l.l(s, 3H, CH3); 2.9(s, 1H, pyrimidine H-5) and
7.0-8.2(m , 6H, NH and ArH’s).
3.1(s, 1H, pyrimidine H-5); 4.2(s, 2H, -COCH2-);
5.3(s, br., 1H, NH) and 7.0-8.1(m , 10H, ArH’s).
1.0(s, 3H, CH3); 3.2(s, 1H, pyrimidine H-5); 4.4(s,
2H, -COCH2-); 5.5(S, br., 1H, NH) and 6.9-7.8(m ,
5H, ArH’s).
25
3379, 3282, 3190(NH2 NH) ; 3075(aromatic
CH); 1689 (C =0); 1617 (C=N) and 1600
(C=C).
2.8(s, 1H, pyrimidine H-5); 3.4(s, 1H, pyrazole H-
4); 4.8(s, br., 2H, two NH); 5.6(s, br., 2H, NH2)
and 7.0-7.9(m , 5H, ArH’s).
27a
27b
27c
3212, 3182(NH) ; 3070(aromatic CH); 1693
(C =0); 1612 (C=N) and 1600(C=C).
3.1(s, 1H, pyrimidine H-5); 4.9(s, br., 1H, pyrimi-
dine NH); 5.4(s, 1H, -CH=N-); 6.9-8.1(m , 10H,
ArH’s) and 9.8(s, br., 1H, NH, -NH-N=).
3.0(s, 1H, pyrimidine H-5); 5.1(s, br., 1H, pyrimi-
dine NH); 5.6(s, 1H, -CH=N-); 7.0-7.9(m , 9H,
ArH’s) and 9.9(s, br., 1H, NH, -NH-N=).
3.1(s, 1H, pyrimidine H-5); 4.8(s, br., 1H, pyrimi-
dine NH); 5.5(s, 1H, -CH=N-); 6.5-7.7(m , 8H,
furyl and ArH’s) and 10.1(s, br., 1H, NH, -NH-
3219, 3180(NH); 3079(aromatic CH); 1692
(C =0); 1616 (C=N) and 1600(C=C).
3223, 3193(NH); 3082(aromatic CH); 1689
(C =0); 1615 (C=N) and 1602(C=C).
N=).
3.0(s, 1H, pyrimidine H-5); 5.6(s, br., 2H, two NH)
and 6.9-7.8(m , 5H, ArH’s).
3.2(s, 1H, pyrimidine H-5) and 6.9-8.1(m , 7H,
two NH and ArH’s).
30a
30b
3223, 3187(NH); 3079(aromatic CH); 1695
(C =0); 1613 (C=N) and 1602(C=C).
3217, 3195(NH); 3082(aromatic CH); 1689
(C =0); 1615(C=N) and 1603(C=C).
Compound 5 reacted with chloroacetone (10a),
ponding 2-(3,,5,-dimethyl-l’-pyrazolyl)-6-phenyl-
pyrimidine-4-one (15) via the non-isolable inter- a-chloroacetylacetone (10 b) and ethyl a-chloroa-
cetoacetate (10 c) to afford compounds 16a-c,
respectively, via dehydrochlorination. Compounds
16a-c were cyclized in ethanolic sodium ethoxide
to afford the corresponding pyrimido[2,l-c]-l,2,4-
triazines 17a-c, respectively. Structures 16a-c and
mediate 14. The reaction is most probably
proceeded through dehydration in two successive
steps. By considering the data of IR, ‘H NMR
and elemental analyses, structure 15 was con-
firmed. Moreover, its mass spectrum gave m/z=
266, corresponding to the molecular weight of a 17a-c were established based on IR, ‘H NMR and
molecular formula C1 5
structure (cf. Chart 2).
H
1 4 N40 of the assigned elemental analyses (cf. Tables I and II). Moreover,
the mass spectra of 16a-c gave m /z-258, 300 and
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794
F. A. Attabi and S. M. Eldin • Synthesis of Pyrimidine Derivatives
N
A.
Ph
N
NH
Ph
N
NH
I
Cycl.
N
,J = i
21a, x=H
b, x=CH 3
19
(jH3
^H
N
r °
CH,
H,C
14
Cycl.
N
A
Ph
N
H
NH
I
/ NH
Cycl.
CH3-CO-CH
X
16a-c
15
Chart 2.
17a-c
330, corresponding to the molecular weights of the 2). The peaks at m /z-240, 282 and 312, of the 17a-c
confirmed that the cyclization of 16a-c proceeded
of the assigned structures (cf. Chart through dehydration in each case.
molecular formulas C1 3
Ci H i
H
14
N
4
0 2, Ci
5
H i
6
N
4
0
3
and
6
8
N
4
0
4
Similarly, compound 5 reacted with chloroacetic
acid (6 a), ethyl chloroacetate (6 b) and chloroacet-
amide (6 c) to afford compounds 18a-c via dehy-
drochlorination. Compounds 18a-c cyclized in eth-
anolic hydrochloric acid to afford one and the
2). The mass spectra of the cyclization products
17a-c gave ra/z=240, 282 and 312, respectively, cor-
responding to the molecular weights of the molec-
ular formulas
C
1 3
H
12
N
4
0,
C
1 5
H
1 4
N
4
0
2
and
Ci of the assigned structures (cf. Chart
6
H
16
N
4
0
3
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F. A. Attabi and S. M. Eldin • Synthesis of Pyrimidine Derivatives
795
same product 19. Depending on the data given structure (cf. Chart 2). The appearance of a peak
at m /z=242 for compound 19 confirmed that cycli-
I and II), compound 19 could be formulated as 4- zation of 18a-c proceeded via elimination of water,
from IR, ’H NMR and elemental analyses (Tables
ethanol and ammonia in a respective manner.
Furthermore, compound 5 reacted with, both,
formic acid and acetic anhydride under the same
experimental conditions to afford directly the cor-
phenylpyrimido[2,l-c]-l,2,4-triazine. The mass
spectra of 18a-c gave m /z=260, 288 and 259, corre-
sponding to the molecular weights of the mole-
cular formulas
of the assigned structures (cf. Chart
2). However, the mass spectrum of 19 gave m/z=
242, corresponding to the molecular weight of a trials to isolate the intermediates 20a,b failed un-
C
1 2
H
1 2
N
4
0 3,
C
1 4
H
1 6
N
4
0
3
and
responding
triazolo[4,3-a]pyrimidines
21a,b,
C
1 2
H
1 3
N
5
0
2
respectively. It is important to report here that all
der a variety of conditions. Structures 21a,b were
molecular formula Ci
2
H
1 0
N
4
O
2
of the assigned
Ar-CH= C(CN)2
26a, Ar=C6H5
b, Ar=C6H4-p-Cl
c, Ar=C4H3-S-a
pOOEt
Cl-COOEt
29
CH-iCOX
>
Ph
2 a, x= Ph
b, x= CH,
CS,
22a,b
CN
30 a, X= O
b, X=S
I
CH2-COOEt
23
Cycl.
NC-CH.
25
24
Chart 3.
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796
F. A. Attabi and S. M. Eldin • Synthesis of Pyrimidine Derivatives
established, based on IR, ]H NMR and elemental based on IR, 'H NMR and elemental analyses (cf.
analyses (Tables I and II). Tables I and II). Moreover, their mass spectra
The synthon 5 reacted with ethyl benzoylacetate gave m /z-228 and 244, corresponding to the mo-
(2 a) and ethyl acetoacetate (2 b) in ethanolic lecular weights of the molecular formulas
sodium ethoxide to afford directly the correspond-
Cn H
8
N
4 0
2
and Cn H N4SO of the assigned struc-
8
ing 2-(r-pyrazolyl)pyrimidine-4-one derivatives tures (cf Chart 3).
22a,b, respectively. Structure 22a,b was confirmed,
based on IR, *H NMR and elemental analyses (cf.
Tables I and II). Moreover, their mass spectra
Biological Activity
Using the disc-diffusion technique [10], some of
the newly synthesized heterocyclic derivatives
were tested in vitro against some Gram-positive,
Gram-negative bacteria, yeast and filamentous
fungi. The results obtained, indicated that some
compounds (9, 12b, 30b and 22a,b) were active
towards Gram-positive, some are active towards
Gram-negative bacteria (15 and 30b), while others
(8 and 11) are active towards both. On the other
hand, compounds 1 2 b and 16b were active toward
yeast, and compounds 5 and 15 showed antifungal
activity (cf. Table III).
gave m /z-330 and 268, representing the molecular
weights of the molecular formulas C1 9
and Ci of the assigned structures (cf.
Chart 3).
Furthermore, compound 5 reacted with ethyl cy-
anoacetate (23) under the same experimental con-
ditions to afford the corresponded 6-phenyl-2-(5’-
amino-r-pyrazol-3’-one)pyrimidine-4-one 25 via
the non-isolable open chain compound 24. The
structure 25 was established based on the data
given from IR, 'H NMR and elemental analyses
(icf. Tables I and II). Moreover, its mass spectrum
gave the same m /z=269 which corresponded to a
H
1 4
N
4 0 2
4
H
1 2
N
4
0
2
molecular weight of
for 25 (cf. Chart 3). It is remarkable
to report here that the IR spectrum of 25 has no
a
molecular formula
Experimental
C
1 3
H
1 1
N
5 0 2
All melting points are uncorrected. The IR
spectra in KBr discs were recorded on Perkin-El-
mer FT-IR type 4 and Pye Unicam SP-1100 spec-
trophotometers. The !H NMR spectra were re-
corded on Varian EM 390-90 MHz, Varian
Gemini, 200 and Brücker WP-80 spectrometers
bands of a CN group, while the newly bom NH
2
group was detected (cf Table II).
Work was extended to shed more light on the
chemical reactivity of 5. Thus, it has been found
that compound 5 reacted with the cinnamonitriles
26a-c to give the corresponding hydrazones 27a-c,
which were most probably formed via an arylidene
group exchange reaction. The formation of hydra-
zones 27a-c was confirmed by their preparation via
another route. Thus, compound 5 reacted with the
appropriate aromatic aldehydes 28a-c in ethanol
containing the catalytic amount of triethylamine
to afford the same previously obtained products
27a-c respectively The structures of 27a-c, ob-
tained from the two routes were confirmed based
on IR, ’H NMR and elemental analyses (cf. Tables
I and II).
Work was also directed to synthesize the biolo-
gically active triazolo[4,3-a]pyrimidine derivatives
30a,b through the reaction of 5 with ethyl chloro-
formate (29) and carbon disulfide. Thus, com-
pound 5 reacted with 29 in ethanolic sodium
ethoxide while with carbon disulfide in pyridine
the corresponded triazolopyrimidines 30a,b were
using CDC13, DMSO-d
and (CD3)2CO as solvents
6
and TMS as an internal standard. Chemical shifts
are expressed as d ppm units. Mass spectra were
recorded on Hewlett-Packard GC-MS type 2988
series A using the DIP technique at 70 eV. Micro-
analyses were performed at the Microanalytical
Center of Cairo University, using a Perkin-Elmer
2400 CHN Elemental Analyzer.
Synthesis o f 4, 7a-d, lla-c, 16a-c and 18a-c:
General procedure:
A solution of 3 and/or 5 (0.01 mole) and each
of ethyl iodide, 6 a-c and lOa-c in ethanolic sodium
ethoxide (prepared by dissolving 0 . 0 1 atom of so-
dium metal in 50 ml of ethanol) was heated under
reflux for 5 -7 h (TLC). The reaction mixture was
then cooled and poured onto ice-cold water. The
solid products obtained after acidification with hy-
drochloric acid were filtered off, washed with
water, then crystallized from ethanol, to afford 4,
7a-d. lla-c, 16a-c and 18a-c, respectively (cf. Ta-
obtained. The structures 30a,b were confirmed. bles I and II).
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F. A. Attabi and S. M. Eldin • Synthesis of Pyrimidine Derivatives
Table III. The antimicrobial activity of the tested new compounds.
797
Comp.
Filament, fungi
Asp. Asp. terr.
Gram + ve bacteria
Gram -ve
bacteria
Esch.
Yeast
Such.
cerv.
Staph.
A.
Bacil.
s.
Microco.
fum.
L.
coli.
-
+
-
_
-
-
++
+
++
+
+
++
+
++
++
+
+
+
+
+
+
++
++
+
4
5
7c
7d
8
9
lib
12b
15
16a
16b
17a
17b
19
21b
22a
22b
30a
30b
+
++
-
+
+
+
+
+
+
+
+
+
-
++
-
+
+
-
-
-
-
-
+
++
-
-
+
-
++
-
-
-
+
+
-
-
-
++
++
-
++
-
-
++
++
-
-
++
+
-
-
-
+++
+
-
++
-
++
-
-
-
-
++
-
+
-
-
-
+
-
-
++
+++
++
+
-
-
-
-
-
-
■
+
++
++
++
+++
+
-
+
+
+
++
+
+
+
-
++
+++
+
-
-
-
++
++
++
+
The minimal inhibitory concentration (MIC) has been used as a parameter to express the antimicrobial activity of
each compound as shown:
Activity
MIC
Highly active
Moderately active = ++
Slightly active
Inactive
= +++
10-30 fig / ml
35-50 fig / ml
55-75 fig / ml
= +
= -
> 75
fig / ml
Synthesis of 8, 9, 12a-c, 17a-c and 19.
General procedure:
obtained after pouring onto ice-cold water were
filtered off, washed with water and crystallized
from the proper solvent to afford 2 1 a,b respec-
tively (cf. Tables I and II).
A solution of 7a-c, 7d, lla-c, 16a-c and 18a-c in
ethanol (50 ml) and hydrochloric acid (3 ml) was
heated under reflux for 5 h. The reaction mixture
was cooled and then poured onto ice-cold water.
The separated products was then washed with
water and crystallized from ethanol to yield 8 , 9,
12a-c, 17a-c and 19 (cf Tables I and II).
Synthesis o f 15 and 22b:
A mixture of 5 (0.01 mole) and acetyl acetone
(13) and ethyl acetoacetate (2b) was heated, each
in a mixture of ethanol: acetic acid, 1:3, under re-
flux for 5 h. The solid products obtained after
cooling and pouring onto ice-cold water were fil-
tered off, washed with water and crystallized from
the proper solvent to give 15 and 22b respectively
0cf Tables I and II).
Synthesis of 5:
A mixture of 3 or 4 (0.01 mole) was heated un-
der reflux with excess of hydrazine hydrate (= 15
ml) until the odor of H2S or CH3SH ceased. The
solid product obtained after pouring onto ice-cold
water were filtered off and crystallized from etha-
nol to give 5 in each case {cf. Tables I and II).
Synthesis o f 30a:
A mixture of 5 (0.01 mole) and ethyl chloro-
formate (29), 0.01 mole, in absolute ethanol (50
Synthesis of 21a,b:
A mixture of 5 (0.01 mole) and each of formic ml), containing a catalytic amount of triethylamine
(0.5 ml), was heated under reflux for 5 h. The solid
product obtained after cooling and acidification
acid and acetic anhydride (35 ml of each) was
heated under reflux for 10 h. The solid products
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798
F. A. Attabi and S. M. Eldin • Synthesis of Pyrimidine Derivatives
ml) was heated under reflux for 5 h. The solid pro-
ducts obtained after cooling were filtered off,
washed with water and crystallized from the
proper solvent to afford 27a-c, 22a and 25 respec-
tively (cf Tables I and II).
with acetic acid was filtered off and crystallized
from ethanol to afford 30a (cf. Tables I and II).
Synthesis of 30b.
A mixture of 5 (0.01 mole) and carbon disulfide
in pyridine was heated under reflux for 5 h. The
reaction mixture was then cooled and acidified
with hydrochloric acid. Solid product obtained was
filtered off, washed with water and crystallized
from ethanol to afford 30b (cf Tables I and II).
Acknowledgement
Synthesis of 27a-c, 22a and 25:
General procedure:
Thanks are due to Prof. Dr. Y. E. Saleh, Depart-
ment of Botany, Faculty of Science, Cairo Univer-
A mixture of 5 (0.01 mole) and 26a-c, 2a and 23 sity for carrying out the biological activity of the
newly synthesized compounds.
each (0.01 mole of each) in glacial acetic acid (50
[6] V. J. Ram, A. Goel, M. Nath, P. Srivastava, Bioorg.
Med. Chem. Lett. 22, 2653 (1994); C. A. 122,
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24, 437 (1984); C. A. 103, 6300r (1985).
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Usachev, Yu. N. Portnov, Yu. M. Robotnikov, L. E.
Pchelintseva, Khim. Farm. Zh., (Russ.) 20. 556
(1986); C. A. 106, 119824u (1987).
[3] P. Vainilavicius and V. Sederaviciciute; Khim. Geter-
otsikl. Soedin. 12, 1655 (1987); C. A. 109. 92927c
(1988).
[4] S. V. Kluchko, B. M. Khutova, A. V. Rozhenko, E. A.
Romanenko, S. I. Vdovenko, L. I. Ribchenko. L. P.
Rrikazchikova, B. S. Drach, Khim. Geterotiskl. Soe-
din. (Russ.) 1. 95 (1992); C. A. 118. 213020y (1993).
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Pharm. Res. 20. 620 (1997).
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Chem. 25, 956 (1982); C. A. 97, 120198v (1982).
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