Synthesis and biological evaluation of some new pyrimidine derivatives

Article abstract of DOI:10.3987/COM-13-12663

Reaction of 2-mercaptopyrimidine 1 with ethyl chloroacetate afforded isomeric pyrimidines 2 and 3. Interaction of 3 with bifunctional nitrogen nucleophiles yielded pyrimidotriazine 5 and 7. Hydrazinolysis of 2 by hydrazine hydrate afforded hydrazinopyrimi

Full text of DOI:10.3987/COM-13-12663

HETEROCYCLES, Vol. 87, No. 4, 2013
841
HETEROCYCLES, Vol. 87, No. 4, 2013, pp. 841 - 851. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 8th January, 2013, Accepted, 30th January, 2013, Published online, 13th February, 2013
DOI: 10.3987/COM-13-12663
SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NEW
PYRIMIDINE DERIVATIVES
Kamelia M. El-mahdy and Azza M. El-Kazak*
Department of Chemistry, Faculty of Education, Ain Shams University, Roxy,
11711, Cairo, Egypt
*Corresponding Author: Email: az_azelkazak@yahoo.com
Abstract – Reaction of 2-mercaptopyrimidine 1 with ethyl chloroacetate afforded
isomeric pyrimidines 2 and 3. Interaction of 3 with bifunctional nitrogen
nucleophiles yielded pyrimidotriazine 5 and 7. Hydrazinolysis of 2 by hydrazine
hydrate afforded hydrazinopyrimidine 8. Treatment of 8 with acetophenone gave
9. Cyclization of 9 with Vilsmeier reagent afforded the pyrazole carbaldehyde 10.
Interaction of 8 with benzylidenemalononitrile and/or ethyl ethoxymethylene-
cyanoacetate afforded the pyrazoles 11 and 12. The reaction of 8 with p-
chlorobenzaldehyde yielded 13, which was cyclized with thioglycolic acid to give
thiazolidinone 14. The biological activity of selected compounds was investigated.
The synthesis of dihydropyrimidine derivatives have been attracting extensive attention as a wide range
of such compounds played an important role in the field of medicinal chemistry as antiviral,1
antibacterial,2 antimalarial,3 antihypertensive4 and anti-inflammatory agents.5 In addition, pyrimidine
derivatives form the basis of a large number of pharmacological products with anticancer and protein
kinase inhibitory activity.6,7 The Biginelli reaction8 is a simple one-pot condensation of an aldehyde, keto
ester, and urea or thiourea in the presence of catalytic amount of acid to produce 3,4-dihydropyrimidin-
2(1H)-ones. Dihydropyrimidinones (DHPMs) and their derivatives exhibit wide range of biological
activities such as antibacterial, antiviral, antitumour, and anti-inflamatory actions.9 Biginelli compounds
exhibit pharmacological activities as calcium channel blockers, antihypertensive agents, α-1a–antagonists,
and neuro peptide Y(NPY) antagonists.10-12 Biological activities of some marine alkaloids isolated were
also found to contain the dihydropyrimidinone-5-carboxylate core.13-16

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HETEROCYCLES, Vol. 87, No. 4, 2013
The versatile biological properties of pyrimidine derivatives prompted us to synthesize some novel
pyrimidine and fused heterocyclic pyrimidine derivatives for biological screening.
On heating of ethyl 2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxylate
(1)17 under reflux with ethyl chloroacetate in ethanolic potassium hydroxide solution, ethyl 2-(2-ethoxy-
2-oxoethyl)-2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxylate (2) and
ethyl
1-(2-ethoxy-2-oxoethyl)-2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-
carboxylate (3) were obtained (Scheme 1).
Ar
Ar
Ar
EtO2C
NH
EtO2C
Me
EtO2C
Me
NH
EtOH/KOH
CH2CO2Et
SH
ClCH2CO2Et
+
SH
N
+
Me
N
N
SCH2CO2Et
1
N
3
2
Ar= p-MeOC6H4
75%
10%
Scheme 1
As depicted in Scheme 1, the reaction proceeded through S-alkylation18 to give S-alkylated product 2 as
the major reaction product in 75% yield. In addition, this reaction was accompanied by a second, minor
product, 3, which was obtained in 10% yield. The structures of compounds 2 and 3 were confirmed on the
basis of their elemental analysis, IR, 1H NMR and mass spectral analysis.
Treatment of compound 3 with ethyl carbazate, in refluxing ethanol in the presence of a catalytic amount
of piperidine, furnished a single product identified as diethyl pyrimido[2,1-c][1,2,4]triazine-4,7-
dicarboxylate 5. The formation of 5 may be attributed to the intermediacy of the non-isolable
transamination adduct 4, which underwent cyclization via loss of ethanol molecule. Also, compound 3
was allowed to react with hydrazine hydrate in boiling ethanol, it yielded the respective pyrimido[2,1-c]-
[1,2,4]triazine-7-carbohydrazide 7. The direct formation of 7 indicates that the initially formed product
namely
ethyl
1-(2-ethoxy-2-oxoethyl)-2-hydrazino-6-(p-methoxyphenyl)-4-methyl-1,6-
dihydropyrimidine-5-carboxylate (6) underwent in situ cyclization via loss of ethanol molecule to give
pyrimido[2,1-c][1,2,4]triazine 7 (Scheme 2).

HETEROCYCLES, Vol. 87, No. 4, 2013
843
Ar
Ar
N
CO2Et
-
EtO2C
Me
CH2CO2Et
N
EtO2C
Me
O
H2NHNCO2Et
N
OEt
N
SH
EtOH/piperidine
-H2S
NH
N
H
3
Ar= p-MeOC6H4
4
N2H4
-H2S
-EtOH
EtOH
Ar
N
CO2Et
Ar
EtO2C
Me
EtO2C
O
CH2CO2Et
N
N
NH
Me
N
H
N
6
NHNH2
-EtOH
Ar
Ar
CO2Et
EtO2C
Me
OH
H2NHNOC
Me
O
N
N
NH
NH
N
N
N
N
H
H
5
7
70%
70%
Scheme 2
The structures of compounds 5 and 7 were characterized from their spectroscopic as well as elemental
analytical data. Thus, compound 5 showed absorption bands at 3243, 1704 and 1648 cm-1 corresponding
to NH and two C=O functions, respectively. Its 1H NMR spectrum revealed a triplet signal at δ 1.09 ppm
with coupling constant (J = 6.6 Hz) due to CH3 protons, a quartet signal at δ 3.99 ppm with coupling
constant (J = 6.9 Hz) due to CH2 protons, two D2O-exchangeable signals at δ 6.88 and 7.15 due two NH
protons in addition to D2O-exchangeable signal at δ 9.13 corresponding to OH proton. The IR spectrum
of compound 6 revealed bands at 3431, 3250 and 1632 cm-1 corresponding to NH2, NH and C=O groups,
respectively. Its 1H NMR spectrum showed the absence of CH3 and CH2 protons of ethoxycarbonyl group
and showed D2O-exchangeable signal at δ 3.39 ppm due to NH2 protons. It showed also three D2O-
exchangeable signals at δ 7.65, 7.81 and 7.82 ppm corresponding to three NH protons, in addition to
aromatic protons.
When the thioglycolate 2 was treated with hydrazine hydrate, it afforded 2-hydrazino-6-(p-
methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carbohydrazide
(8).
2-hydrazinopyrimidine
carbohydrazide 8 could be used as versatile building blocks in the synthesis of new heterocyclic systems.

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HETEROCYCLES, Vol. 87, No. 4, 2013
Thus, condensation of 2-hydrazinopyrimidine 8 with acetophenone in boiling ethanol and few drops of
acetic acid were added, it gave N-[(1-phenylethylidene)-2-[2-(1-phenylethylidene)hydrazino]-1,6-
dihydropyrimidine 9, which on treatment with POCl3/DMF under Vilsmeier reaction condition yielded
the final product 1-{5-[(4-formyl-3-phenyl-1H-pyrazol-1-yl)carbonyl]-6-(p-methoxyphenyl)-4-methyl-
1,6-dihydro pyrimidin-2-yl}-3-phenyl-1H-pyrazole-4-carbaldehyde (10) (Scheme 3).
Ar
Ar
EtO2C
Me
H2NHNOC
NH
NH
N2H4
+
-HSCH2CO2Et
SCH2CO2Et
Me
N
N
NHNH2
80%
8
2
PhCOMe
EtOH/AcOH
72%
Ar= p-MeOC6H4
Ar
Ph
Ph
NHNCO
Me
N
Ar
N
NH
Me
N
Ph
CO
POCl3/DMF
60%
NH
OHC
N
NHN
N
Me
Me
N
Ph
9
10
CHO
Scheme 3
The structures of compounds 9 and 10 were characterized from their spectroscopic as well as elemental
1
analytical data. The IR and H NMR spectrum of compound 9 lacked an absorption band and protons
corresponding to NH2 groups. While, the IR spectrum of compound 10 showed bands at 1717 and 1680
due to formyl and exocyclic C=O groups, its 1H NMR spectrum were characterized by the appearance of
single broad signal at 13 ppm attributed to formyl proton.
Furthermore, cyclocondensation of 2-hydrazinopyrimidine 8 with (p-methoxybenzylidene)malononitrile
in pyridine gave the corresponding aminopyrazolecarbonitrile 11. Also, interaction of 8 with ethyl
ethoxymethylenecyanoacetate in DMF led to the formation of the ethyl pyrazolecarboxylate 12. Finally,
the amino functionality of 2-hydrazinopyrimidine carbohydrazide 8 was reacted with carbon electrophiles
such p-chlorobenzaldehyde to afford 2-[2-(p-chlorobenzylidene)hydrazine]-N-[1-(p-chlorophenyl)-
methylene]-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carbohydrazide (13). Compound 13
was formed by nucleophilic attack of the amino group on the electronically deficient carbonyl carbon
atom of the aldehyde followed by dehydration. It is of interest to investigate the behavior of 13 which

HETEROCYCLES, Vol. 87, No. 4, 2013
845
contain an activated C=N bond towards aliphatic mercaptan. Thus, cyclocondensation of 13 with
thioglycolic acid in dioxane gave the thiazolidinone derivative 14 (Scheme 4).
H2N
NC
H2N
C(CN)CO2Et
N
Ar
N
N
Ar
N
EtOCH
Ar CH C(CN)2
O
C
CO
N
8
NH
Ar
DMF
60%
NH
pyridine
60%
EtO2C
Ar
N
N
N
Me
Ar1
N
N
Me
CHO
NH2
NH2
AcOH
90%
12
CN
CO2Et
11
Ar
Ar1 CH
OCNHN
NH
CH Ar1
Me
N
NH2
13
HSCH2CO2H
dioxane
90%
Ar1
Ar
O
H
O
Ar1
N
N
C
NH
S
O
Me
N
N
N
H
S
14
1
p-MeOC H ,
p-ClC H
6
A =
Ar =
6
4
4
Scheme 4
1
The structures of compounds 11 and 12 were confirmed on the basis of their elemental analysis, IR, H
NMR, and the mass spectral data. The IR spectrum of compound 11 showed characteristic bands at 2208
attributed to C≡N group. While, the IR spectrum of compound 12 revealed absorption peaks at 1721 and
1
1693 cm-1 due to ester and exocyclic C=O group. The H NMR spectrum of compound 11 was
characterized by the appearance of douplet douplet signals at δ 6.95 ppm with coupling constant (J = 8.7
Hz), 7 ppm with coupling constant (J = 8.4 Hz), 7.08 ppm with coupling constant (J = 6.9 Hz), 7.13 ppm
with coupling constant (J = 6.9 Hz), 7.42 ppm with coupling constant (J = 8.4 Hz), and 7.75 ppm with
1
coupling constant (J = 8.7 Hz), assignable to aromatic protons. While, the H NMR spectrum of
compound 12 was characterized by the appearance of CH3 and CH2 protons of ethoxycarbonyl groups.
The mass spectrum of compound 12 showed a molecular ion peak (M+) at m/z = 536 which is in an
agreement with the molecular formula C25H28N8O6.
Also, the structures of compounds 13 and 14 were confirmed on the basis of their elemental analysis, IR,
1
1H NMR and mass spectral analysis. The IR and H NMR spectrum of compounds 13 and 14 lacked an

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HETEROCYCLES, Vol. 87, No. 4, 2013
1
absorption band and protons corresponding to NH2 group. H NMR spectrum of compound 13 revealed
singlet signal at δ 8.71 assigned to the CH=N. The mass spectrum of 14 showed a molecular ion peak
(M+) at m/z = 683 corresponding to a molecular formula C31H28Cl2N6O4S2.
EXPERIMENTAL
Melting points are uncorrected and were recorded in open capillary tubes on a Stuart SMP3 melting point
apparatus. Infrared spectra were recorded on FT-IR Bruker Vector 22 spectrophotometer using KBr wafer
1
technique. The H NMR and 13C NMR spectra were recorded in DMSO-d6 or CDCl3 on Gemini
1
13
spectrometer (300 MHz for H NMR and 75 MHz for C NMR) and the chemical shift in δ downfield
from TMS as an internal standard. Elemental microanalyses were performed at the Main Laboratories of
the War Chemical. Mass spectra were obtained using gas chromatography GCMS qp-2010 plus
Schimadzu instrument mass spectrometer (70 eV) were performed at the Cairo University
Microanalytical Center.
Ethyl 2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxylate (1). This
compound was prepared according to the reported method.17
Ethyl 2-(2-ethoxy-2-oxoethyl)-2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-
carboxylate (2) and ethyl 1-(2-ethoxy-2-oxoethyl)-2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-
dihydropyrimidine-5-carboxylate (3). A mixture of compound 1 (3 g, 0.01 mol) and ethyl chloroacetate
(1.6 mL, 0.015 mol) in ethanolic potassium hydroxide solution (prepared by dissolving 0.56 g, 0.01 mol
of KOH in 50 mL EtOH) was heated under reflux for 3 h and cooled. The solid obtained was filtered off
and recrystallized from dilute dioxane to give compound 3 as yellow crystals (0.3 g, yield 10%): mp >300
°C; IR (ν cm-1) 3114 (CH aromatic), 2979, 2956 (CH aliphatic), 1704 (C=O), 1648 (C=O), 1611 (C=N);
1H NMR (DMSO-d6) δ 1.09 (t, 6H, CH2 CH3, J = 6.9 Hz), 2.23 (s, 3H, CH3), 3.35 (s, 2H, NCH2), 3.71 (s,
3H, OCH3), 3.96 (q, 4H, CH2 CH3, J = 6.9 Hz), 5.09 (s, 1H, pyrimidine-H-6), 6.86 (d, 2H, ArH’s, J = 9
Hz), 7.14 (d, 2H, ArH’s, J = 9 Hz), 9.16 (s, 1H, D2O-exchangeable, SH); MS m/z (%): [M+-CH2] 378
(5.8), 351 (21.8), 328 (28.8), 302 (25.3), 234 (20.2), 232 (4.2), 218 (18.9), 195 (19.9), 155 (100), 151
(20.8), 123 (9.3), 97 (8.9); Anal. Calcd for C19H24N2O5S (%): C, 58.15; H, 6.16; N, 7.14. Found C, 58.18;
H, 6.16; N, 7.10%.
On the other hand, the filtrate of the above reaction was poured gradually onto crushed ice. The solid was
filtered off and recrystallized from EtOH to give compound 2 as yellow crystals (2.25 g, yield 75%): mp
180-182 °C; IR (ν cm-1) 3114 (CH aromatic), 2979, 2956 (CH aliphatic), 1704 (C=O), 1648 (C=O), 1611
(C=N); 1H NMR (DMSO-d6) δ 1.09 (t, 6H, CH2CH3, J = 6.9 Hz), 2.23 (s, 3H, CH3), 3.35 (s, 2H, NCH2),
3.71 (s, 3H, OCH3), 3.96 (q, 4H, CH2CH3, J = 6.9 Hz), 5.09 (s, 1H, pyrimidine-H-6), 6.86 (d, 2H, ArH’s,
J = 9 Hz), 7.14 (d, 2H, ArH’s, J = 9 Hz ), 9.16 (s, 1H, D2O-exchangeable, NH); MS m/z (%): [M+-CH2]

HETEROCYCLES, Vol. 87, No. 4, 2013
847
378 (22.4), 348 (5.5), 290 (21.2), 275 (11.8), 261 (100), 244 (20.2), 217 (63.5), 183 (42.1), 155 (39.1),
137 (43.1), 77 (42.6); Anal. Calcd for C19H24N2O5S (%): C, 58.15; H, 6.16; N, 7.14. Found C, 58.20; H,
6.14; N, 7.18%.
Diethyl 3-hydroxy-6-(p-methoxyphenyl)-8-methyl-1,6-dihydro-2H-pyrimido[2,1-c][1,2,4]triazine-
4,7-dicarboxylate (5). A mixture of compound 3 (0.392 g, 0.001 mol) and ethyl carbazate (0.104 g, 0.001
mol) in EtOH (10 mL) and few drops of piperidine was refluxed for 2 h. The solid thus obtained was
filtered off and recrystallized from EtOH to give compound 5 as yellow crystals (0.274 g, yield 70%): mp
248-250 °C; IR (ν cm-1) 3243 (NH), 3113 (CH aromatic), 2979, 2955 (CH aliphatic), 1704, 1648 (C=O),
1
1612 (C=N); H NMR (DMSO-d6) δ 1.09 (t, 6H, CH2CH3, J = 6.6 Hz), 2.23 (s, 3H, CH3), 3.71 (s, 3H,
OCH3), 3.99 (q, 4H, CH2CH3, J = 6.9 Hz), 5.08 (s, 1H, pyrimidine-H-6), 6.85 (d, 2H, ArH’s, J = 8.1 Hz),
7.12 (d, 2H, ArH’s, J =9 Hz), 6.88, 7.15 (s, 2H, D2O-exchangeable, NH), 9.13 (s, 1H, D2O-exchangeable,
OH); MS m/z (%): [M+] 416 (34.3), 415 (32.5), 403 (32.5), 373 (38.5), 340 (34.3), 308 (36.7), 284 (51.5),
274 (42), 183 (45), 137 (100), 84 (88.7), 58 (52.6); Anal. Calcd for C20H24N4O6 (%): C, 57.68; H, 5.81;
N, 13.45. Found C, 57.70; H, 5.80; N, 13.50%.
6-(p-Methoxyphenyl)-8-methyl-3-oxo-1,3,4,6-tetrahydro-2H-pyrimido[2,1-c][1,2,4]triazine-7-carbo-
hydrazide (7). A suspension of compound 3 (0.392 g, 0.001 mol) and hydrazine hydrate (4 mL, 99%) in
EtOH (10 mL) was refluxed for 2 h and cooled. The solid separated was filtered off and recrystallized
from dioxane to give compound 7 as yellow crystals (0.274 g, yield 70%): mp 258-260 °C; IR (ν cm-1)
1
3431, 3250 (NH2, NH), 3050 (CH aromatic), 2925 (CH aliphatic), 1632 (C=O); H NMR (DMSO-d6) δ
2.28 (s, 3H, CH3), 3.39 (brs, 2H, D2O-exchangeable, NH2), 3.77 (s, 3H, OCH3), 3.79 (s, 2H, CH2), 6.82
(s, 1H, pyrimidine-H-6), 7.03 (d, 2H, ArH’s, J = 8.7 Hz), 7.79 (d, 2H, ArH’s, J = 8.7 Hz), 7.65, 7.81, 7.82
(s, 3H, D2O-exchangeable, NH); MS m/z (%): [M+] 330 (55.3), [M++1] 331 (82.9), 302 (61.7), 286 (61.7),
274 (15), 252 (70.2), 206 (61.7), 172 (74.5), 92 (100), 78 (80), 58 (46.8); Anal. Calcd for C15H18N6O3
(%): C, 54.54; H, 5.49; N, 25.44. Found C, 54.60; H, 5.50; N, 25.40%.
2-Hydrazino-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carbohydrazide (8).
A mixture of compound 2 (0.392 g, 0.001 mol) and hydrazine hydrate (5 mL, 99%) was heated under
reflux for 2 h. The reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained
was filtered off and recrystallized from EtOH to give compound 8 as yellow crystals (0.31 g, yield 80%):
mp 168-170 °C; IR (ν cm-1) 3243, 3139 (NH2, NH), 3034 (CH aromatic), 2981 (CH aliphatic), 1625
1
(C=O), 1602 (C=N); H NMR (DMSO-d6) δ 2.24 (s, 3H, CH3), 3.69 (s, 3H, OCH3), 4.71 (s, 4H, D2O-
exchangeable, NH2), 6.83 (s, 1H, pyrimidine-H-6), 7.02 (d, 2H, ArH’s, J = 8.4 Hz), 7.56 (s, 1H, D2O-
exchangeable, NH), 7.59 (s, 1H, D2O-exchangeable, NH), 7.77 (d, 2H, ArH’s, J = 8.4 Hz), 8.20 (s, 1H,
D2O-exchangeable, NH); MS m/z (%): [M++1] 291 (16.1), [M+] 290 (17.8), 275 (19.2), 264 (20.9), 234
(25.1), 219 (21.4), 172 (24.2), 135 (29.9), 134 (22), 75 (100), 60 (9.6), 52(8.4); Anal. Calcd for

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HETEROCYCLES, Vol. 87, No. 4, 2013
C13H18N6O2 (%): C, 53.78; H, 6.25; N, 28.95. Found C, 53.72; H, 6.20; N, 28.90%.
6-(p-Methoxyphenyl)-4-methyl-N-[(1-phenylethylidene)-2-[2-(1-phenylethylidene)hydrazino]-1,6-
dihydropyrimidine-5-carbohydrazide (9). To a solution of 8 (0.29 g, 0.001 mol) in hot EtOH,
acetophenone (0.22 mL, 0.002 mol) and few drops of acetic acid were added. The solid that separated on
warming for 30 min on a water-bath was filtered off and recrystallized from MeOH to give compound 9
as yellow crystals (0.2 g, yield 72%): mp 128-129 °C; IR (ν cm-1) 3350 (NH), 3056 (CH aromatic), 2958
1
(CH aliphatic), 1679 (C=O), 1602 (C=N); H NMR (DMSO-d6) δ 2.22 (s, 3H, CH3), 2.27 (s, 6H,
CH3C=N), 3.62 (s, 3H, OCH3), 7.45-7.91 (m, 15H, ArH’s and pyrimidine-H-6), 7.92, 7.93 (s, 3H, D2O-
exchangeable, NH); MS m/z (%): [M+] 494 (28.7), [M+-1] 493 (3.9), 412 (44), 387 (31.1), 334 (18.8), 320
(41.5), 214 (42.5), 187 (28.7), 174 (36.1), 131 (83.6), 101 (100), 73 (29.7), 66 (34.1); Anal. Calcd for
C29H30N6O2 (%): C, 70.42; H, 6.11; N, 16.99. Found C, 70.40; H, 6.10; N, 16.70%.
1-{5-[(4-Formyl-3-phenyl-1H-pyrazol-1-yl)carbonyl]-6-(p-methoxyphenyl)-4-methyl-1,6-dihydro-
pyrimidin-2-yl}-3-phenyl-1H-pyrazole-4-carbaldehyde (10). To the Vilsmeier reagent [prepared from
DMF (10 mL) and POCl3 (1.1 mL, 0.012 mol)], compound 9 (1.1 g, 0.004 mol) in DMF was added and
then the reaction mixture stirred at 60-65 °C for 2 h. The reaction mixture was cooled and poured
gradually onto crushed ice. The solid obtained was filtered off and recrystallized from dilute dioxane to
give compound 10 as yellow crystals (0.66 g, yield 60%): mp 288-290 °C; IR (ν cm-1) 3430 (NH), 3057
(CH aromatic), 2926 (CH aliphatic), 1717, 1680 (C=O), 1628 (C=N); 1H NMR (DMSO-d6) δ 2.23 (s, 3H,
CH3), 3.73 (s, 3H, OCH3), 6.68 (s, 1H, pyrimidine-H-6), 7.03-8.57 (m, 16H, ArH’s and pyrazole-H-5),
8.21 (s, 1H, D2O-exchangeable, NH), 13 (s, br, 2H, CHO); MS m/z (%): [M++1] 571 (0.71), [M+] 570
(0.20), 549 (6.50), 537 (8.87), 532 (6.63), 509 (5.57), 492 (2.72), 480 (3.09), 423 (3.97), 313 (14.62), 236
(21.37), 150 (100), 64 (43.14), 55 (38.83); Anal. Calcd for C33H26N6O4 (%): C, 69.46; H, 4.59; N, 14.73.
Found C, 69.40; H, 4.54; N, 14.70%.
3-Amino-1-{(5-[(3-amino-4-cyano-5-(p-methoxyphenyl)-1H-pyrazol-1-yl)carbonyl]}-6-(p-methoxy-
phenyl)-4-methyl-1,6-dihydropyrimidin-2-yl)-5-(p-methoxyphenyl)-1H-pyrazole-4-carbonitrile (11).
A mixture of 8 (0.29 g, 0.001 mol) and (p-methoxybenzylidene)malononitrile (0.368 g, 0.002 mol) in
pyridine (10 mL) was heated under reflux for 3h. The reaction mixture was cooled, poured gradually onto
crushed ice and neutralized with diluted HCl. The solid obtained was filtered off and recrystallized from
MeOH to give compound 11 as brown crystals (0.17 g, yield 60%): mp 130-132 °C; IR (ν cm-1) 3320,
1
3205 (NH2, NH), 3006 (CH aromatic), 2930 (CH aliphatic), 2208 (C≡N), 1670 (C=O), 1603 (C=N); H
NMR (DMSO-d6) δ 2.48 (s, 3H, CH3), 3.32 (s, br, 4H, NH2), 3.82 (s, 9H, OCH3), 6.75 (s, 1H, pyrimidine-
H-6), 6.95 (d, 2H, ArH’s, J = 8.7 Hz), 7 (d, 2H, ArH’s, J = 8.4 Hz), 7.08 (d, 2H, ArH’s, J = 6.9 Hz), 7.13
(d, 2H, ArH’s, J = 6.9 Hz), 7.42 (d, 2H, ArH’s, J = 8.4 Hz), 7.75 (d, 2H, ArH’s, J = 8.7 Hz), 9.10 (s, 1H,
D2O-exchangeable, NH); MS m/z (%): [M++1] 655 (56.7), [M+] 654 (61.2), 518 (80.1), 490 (73.8), 401

HETEROCYCLES, Vol. 87, No. 4, 2013
849
(75.6), 398 (72.9), 345 (66.6), 321 (100), 318 (59.4), 297 (70.2), 271 (81), 260 (88.2), 229 (65.7), 191
(63), 145 (70.2), 73 (63.9); Anal. Calcd for C35H30N10O4 (%): C, 64.21; H, 4.62; N, 21.39. Found C,
64.20; H, 4.60; N, 21.36%.
Ethyl
3-amino-1-(5-{[(3-amino-4-(ethoxycarbonyl)-1H-pyrazol-1-yl)carbonyl]}-6-(p-methoxy-
phenyl)-4-methyl-1,6-dihydropyrimidin-2-yl)-1H-pyrazole-4-carboxylate (12). Equimolar mixture of
compound 8 (0.29 g, 0.001 mol) and ethyl ethoxymethylenecyanoacetate (0.338 g, 0.002 mol) in DMF
(10 mL) was refluxed for 4 h then cooled and diluted with cooled water. The solid obtained was filtered
off and recrystallized from EtOH to give compound 12 as yellow crystals (0.17 g, yield 60%): mp 185-
186 °C; IR (ν cm-1) ν 3392, 3279, 3124 (NH2, NH), 3090 (CH aromatic), 2933, 2904 (CH aliphatic), 1721,
1
1693 (C=O), 1635 (C=N); H NMR (DMSO-d6) δ 1.32 (t, 6H, CH2CH3, J = 6.9 Hz), 2.49 (s, 3H, CH3),
3.31 (s, 3H, OCH3), 4.24 (s, 2H, D2O-exchangeable, NH2), 4.31 (q, 4H, CH2CH3, J = 6.9 Hz), 4.39 (s, 2H,
D2O-exchangeable, NH2), 5.20 (s, 1H, pyrimidine-H-6), 8.57-8.79 (m, 6H, ArH’s and pyrazole-H-5), 9 (s,
1H, D2O-exchangeable, NH); MS m/z (%): [M+] 536 (59.7), [M+-1] 535 (77.1), 515 (93.4), 499 (89.1),
465 (85.8), 429 (61,9), 381 (59.7), 355 (88), 307 (77.1), 284 (76), 241 (100), 201 (93.4), 155 (13),
101(80.4), 81 (46.7), 56 (28.2); Anal. Calcd for C25H28N8O6 (%): C, 55.96; H, 5.26; N, 20.88. Found C,
55.90; H, 5.24; N, 20.90%.
2-[2-(p-Chlorobenzylidene)hydrazine]-N-[1-(p-chlorophenyl)methylene]-6-(p-methoxyphenyl)-4-
methyl-1,6-dihydropyrimidine-5-carbohydrazide (13). A mixture of 8 (0.29 g, 0.001 mol) and p-
chlorobenzaldehyde (0.28 g, 0.002 mol) in glacial acetic acid (10 mL) was heated under reflux for 2 h.
The reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained was filtered
off and recrystallized from EtOH to give compound 13 as yellow crystals (0.26 g, yield 90%): mp 208-
210 °C; IR (ν cm-1) 3429 (NH), 3027 (CH aromatic), 2931 (CH aliphatic), 1664 (C=O), 1624 (C=N); 1H
NMR (DMSO-d6) δ 2.49 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 6.90 (s, 1H, pyrimidine-H-6), 7.56-7.89 (m,
12H, ArH’s), 7.91 (s, 3H, D2O-exchangeable, NH), 8.71 (s, 2H, CH=N); MS m/z (%): [M++2] 537 (62),
[M+] 535 (21), 446 (86), 427 (73), 413 (54), 364 (78), 319 (86.), 309 (57), 294 (78), 226 (73), 157 (92),
117 (100), 68 (58), 55 (79); Anal. Calcd for C27H24Cl2N6O2 (%): C, 60.57; H, 4.52; N, 15.70. Found C,
60.54; H, 4.50; N, 15.78%.
N-[(4-(p-Chlorophenyl)-5-oxo-1,3-thiazolidin-3-yl)-2-[(4-(p-chlorophenyl)-5-oxo-1,3-thiazolidin-3-
yl)amino]-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxamide (14). A mixture of
13 (0.535 g, 0.001 mol) and thioglycolic acid (0.69 mL, 0.01 mol) in dioxane (10 mL) was refluxed for
10 h. The solid obtained was filtered off and recrystallized from EtOH to give compound 14 as yellow
crystals (0.48 g, yield 90%): mp 197-199 °C; IR (ν cm-1) 3434 (NH), 3090 (CH aromatic), 2981, 2925
1
(CH aliphatic), 1670, 1654 (C=O), 1624 (C=N); H NMR (DMSO-d6) δ 2.08 (s, 3H, CH3), 3.78 (s, 3H,
OCH3), 3.83 (s, 2H, NCH2S), 3.97 (s, 2H, NCH2S), 6.48 (s, 1H, pyrimidine-H-6), 7.38-7.89 (m, 14H,

850
HETEROCYCLES, Vol. 87, No. 4, 2013
ArH’s and thiazolidinone-H-4), 7.92 (s, 3H, D2O-exchangeable, NH); MS m/z (%): [M++2] 685 (29.5),
[M++1] 684 (39.5), [M+] 683 (28.6), 667 (25.9), 655 (30), 627 (35.4), 586 (42.7), 534 (35.4), 454 (44),
405 (46.3), 364 (45.4), 289 (40.9), 258 (14.1), 195 (46.8), 72 (100), 58 (14.5); Anal. Calcd for
C31H28Cl2N6O4S2 (%): C, 54.46; H, 4.13; N, 12.29. Found C, 54.40; H, 4.10; N, 12.20%.
BIOLOGICAL ACTIVITIES
The results depicted in Table 1, showed various activities against all species of microorganisms which
suggest that the variations in the structures affect on the growth of the microorganisms. Thus, we can
conclude from these results that, some of the prepared compounds showed a low to high antimicrobial
activity towards Gram positive bacteria, Gram negative bacteria and the fungal strain (Table 1).
Table 1. The antimicrobial activity of the newly synthesized compounds
Compound
Diameter of inhibition zonea
(mm), Conc. (100 µg mL-1)
No.
S. aureus
B. subtilis
E. coli
C. albicans
(Gram +ve)
(Gram +ve)
(Gram –ve)
(Fungal strain)
2
3
-
-
-
-
-
-
-
-
5
7
8
9
10
18
11
-
-
8
12
16
20
-
21
20
-
22
28
-
11
12
-
-
-
-
-
-
21
-
13
14
-
-
3
-
15
3
-
-
16
19
35
Controlb
38
a12 mm or less: resistant or no inhibition, 13–19 mm: moderate inhibition, 20 mm or more: strong inhibition.
bChloramphencol in the case of Gram-positive bacteria, Cephalothin in the case of Gram-negative bacteria and
Cycloheximide in the case of fungi.
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