Journal of the Chinese Chemical Society, 2004, 51, 779-784 779

2-Cyanoacetamide in the Synthesis of Heterocyclic Compounds:

Synthesis of New Polysubstituted Pyrazole, Pyridine and Pyrimidine
Derivatives

Eman A. El-Rady* and Mohamed A. Khalil

Chemistry Department, Faculty of Science, South Valley University, Aswan, Egypt

Phenylmethylenecyanoacetamide (1) was successfully transferred into polysubstituted pyrazole,

pyridine and pyrimidine derivatives in a one-pot reaction step. Hydrazine hydrate (2a,b), cyanoacetamide
(6a), cyanothioacetamide (6b), cyanoacetic acid hydrazide (6c), thiosemicarbazide (10), urea (14a), thiourea
(14b) and 2-phenylenediamine (24) were selected as amine nucleophile reagents.

Keywrods: Phenylmethylenecyanoacetamide; Pyrazole; Pyridine and pyrimidine.

INTRODUCTION formula (C17H16N4). The IR spectrum revealed the lack of the

The synthesis of pyrazole, pyridine and pyrimidine de-
rivatives that may have medicinal applications, is of inter-
est.1-10 They have been used as antipyretic drugs,11 as new in-
hibitors of inflammatory mediators in intact cells, 12 and as
antimicrobial agents.13 They have been used as inhibitors of
Pneumocystis carinii, Toxoplasma gondii, Mycobacterium
avium dihydrofolate reductase,14 and as anti-HIV agents.15 In
continuation with our previous interest in preparing five and
six membered ring systems,16-20 we herein report a simple ap-
proach to the synthesis of pyrazole, pyridine and pyrimidine
derivatives in a one-pot reaction step by reacting 2-phenyl-
methylenecyanoacetamide derivative (1) with some readily
available reagents.
RESULTS AND DISCUSSION
Compound 1 contains two reactive sites, a cyano group,
adjacent to the a-position of the a,b-unsaturated ketone
group itself. These groups render it susceptible to react either
via the well known reactions of a,b-unsaturated ketone, or
via a nucleophilic cycloaddition reactions onto the cyano
function. Thus, compound 1 reacted with hydrazine hydrate
2a, phenylhydrazine 2b in ethanolic solution at reflux in the
presence of drops of piperidine to give a colourless precipi-
tate after one hour. The mass spectrum of the product showed
a molecular ion at m/e at 276 (35), which may correspond to
two different molecular structures having the same molecular
characteristic absorption band corresponding to a cyano
group. The 1H NMR spectrum showed no signals due to dihy-
dropyrazole,21 instead, three singlet signals at d 2.5, 2.8 and
9.3 ppm were assigned for methyl, NH2 and NH protons, re-
spectively. Based on these data, it seems that the reaction was
proceeded to produce 5-aminopyrazole derivative 4a rather
than 5-phenylpyrazole 5a. Similarly, compound 1 reacted
with cyanoacetamide 6a, cyanothioacetamide 6b and cyano-
acetic acid hydrazide 6c under the same reaction conditions
to yield the corresponding 5-cyano-3-phenylmethylenepyri-
dines 8a-c. The isomers 3,5-dicyano-2,3-dihydropyridines 9
which have the same m/e as structures 8 are ruled out based
mainly on the spectral analysis. The IR spectra showed only
one absorption band corresponding to one cyano function,
and the 1H NMR of 8c showed no absorption at higher field
due to the two protons at C-2 and C-3; however, showed four
singlet signals at d 2.1, 2.9, 5.6 and 9.8 ppm assigned for CH3,
NH2, exocyclic NH and NH protons, respectively. Also, com-
pound 1 was reacted with thiosemicarbazide 10 to yield, upon
loss of water, the intermediate 11 which was cyclized via a
nucleophilic addition onto the cyano function to yield the
1,4-diaminopyrimidin-2-thione 13, rather than the isomeric
1-amino-4-phenyl-pyrimidin-2-thione 12 (Scheme I).
On the Contrary, the reaction of compound 1 with urea
14a and thiourea 14b was accomplished after a longer time of
reflux. As is shown in Scheme II, three plausible pathways
and different products could be expected. i) Condensation via
elimination of water would yield the intermediate 15, which
may be followed by a) nucleophilic addition of amino func-

Dedicated to Professor Dr. Dietrich Döpp on the occasion of his 65th birthday.
780 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004
Scheme I
tion onto the cyano group to yield 4-amino-5-phenylmethyl-
enepyrimidine 16, which has m/e = 320. b) Nucleophilic ad-
dition on the activated double bond to yield 5-cyanopyri-
midine 17, which has m/e = 304. ii) Successive two nucleo-
philic additions on the activated double bond and onto the
cyano function to yield 4-amino-6-phenylpyrimidine 19,
which has m/e = 302. However, the obtained mass spectrum
showed m/e at 434 (30) which is not compatible with any of
the above suggested structures; therefore, these structures are
El-Rady and Khalil
ruled out. It seems that the compound 1 loses benzaldehyde to
give in situ the compound 20, which then reacts once more
with 1 via Michael addition to give the intermediate 21 which
cyclized via 22 into the substituted pyridine 23 which has the
molecular formula C27H22N4O2 (434.50). The structure of 23
was chemically confirmed by fusion of cyanoacetamide with
p-toludine to give the compound 20 via losing ammonia, and
then reacted with compound 1 to yield compound 23 (Scheme
II).
2-Cyanoacetamide in the Synthesis of Heterocyclic Compounds J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 781

Scheme II
NH2
Ph CN
NH2 Ph
H 2O N
(i) ArHN N X
ArHN X
N
15 16
Ph
NC
NH

ArHN X
N
17
X Ph O Ph
14a,b O
(ii) HN NHAr
H2N-C-NH2 HN NHAr
1
EtOH/pip
reflux, 8h X NH2 CN O NH2
N
18 19
O
NC NHAr
CN
(1) Ph CN
(iii) + PhCHO
ArHN O ArHN O
20
21
O O
NC NC
N Ar
N Ar
Ph NH2
Ph NH
ArHN O
ArHN O
23
22
Ar = H3C-C6H4-

(1)

20 Fusion Cyanoacetamide + p-Toludine

Aimed at preparing 1,5-benzodiazepine derivatives, EXPERIMENTAL

the reaction with o-phenylenediamine 24 was undertaken un-
der the same reaction conditions. However, none of the ex-
pected seven-membered rings 26 and/or 27, 29 have been iso-
lated from any of the plausible intermediates 25, 28 (Scheme
III). Instead, compound 23 again was obtained, plausibly via
the same pathway presented in Scheme II. The above reac-
tions presented a facile one-pot reaction to prepare new poly-
substituted pyrazole, pyridine and pyrimidine derivatives
which might have pharmacological activity using readily and
cheap chemicals.
Melting points have been determined on a Gallen-
Kamp melting point apparatus and are uncorrected. The IR
spectra (potassium bromide, n in cm -1 ) were recorded on a
Pye-Unicam SP-1100 Spectrophotometer. 1H NMR spectra
(deuterochloroform and deuterodimethyl sulfoxide, d in
ppm) were run on a Varian EM-390 Spectrometer using
Tetramethylsilane as internal standard. Mass spectra were re-
corded on a Varian MAT 311 A spectrometer, and the elemen-
tal analyses were determined at the Microanalytical Center,
782 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 El-Rady and Khalil

Scheme III

HN N
HN NH2
27 Ph NH2
CN
Ph O
HN

H 3C HN O

28 CH3
29
NH2 EtOH / pip.
1 + 23
reflux / 5 h
NH2

24

CN
Ph NH2

H 3C HN N

25

NH2 Ph

Ph N NC NH

H 3C HN H 3C HN
N N

26 27

Cairo University, Egypt.
Synthesis of N-(P-toludyl)-2-phenylmethylene-2-cyano-
acetamide (1)
A solution of cyanoacetamide derivative (0.01 mol),
benzaldhyde (0.01 mol), and 0.1 mL of piperidine in 30 mL of
dry ethanol was refluxed for two hours. The solid formed dur-
ing reflux was collected by filtration, washed well with 2 mL
of methanol and crystallized from ethanol to give 1. Yield:
1.9 g (73%); mp: 140-142 °C; 1H-nmr (CDCl3): d 3.3 (s, 3H,
CH3), 10.3 (s, 1H, NH), 7.1-8.2 (m, 10H, Ar-H), m/z 262 (M+,
30%); ir: 3200-3290 (NH), 2220 (CN), 1715 (CO). Anal.
Calcd. for C 17 H 14 N 2 O (262.31): C, 77.84; H, 5.38; N,
10.68%. Found: C, 77.74; H, 5.27; N, 10.56%.
General Procedure for the synthesis of compounds
(4a,b)
A solution of 1 (1 g, 0.02 mol), hydrazine hydrate 2a
(0.24 g, 0.02 mol), and 0.1 mL of piperidine in 30 mL of dry
ethanol was warmed to reflux for two hours. The solid formed
during reflux was collected by filtration, washed with 3 mL
of methanol and crystallized from ethanol to give 4a. In anal-
ogy, 1 (1 g, 0.02 mol) reacted with phenyl hydrazine 2b (0.44
g, 0.02 mol) to give 4b.
5-Amino-4-phenylmethylene-3-(p-toludyl)pyrazole (4a)
Yield: 60 mg (60%); mp: 220-222 °C; 1H-nmr (CDCl3):
d 2.5 (s, 3H, CH3), 2.8 (s, 2H, NH2), 6.5-7.9 (m, 10H, Ar-H),
9.3 (s, 1H, NH); m/z 276 (M + , 35%); ir: 3200-3290 (NH 2 ),
(NH). Anal. Calcd. for C17H16N4 (276.34): C, 73.89; H, 5.84;
N, 20.28%. Found: C, 73.77; H, 5.69; N, 20.15%.
5-Imino-1-phenyl-4-phenylmethylene-3-(p-toludyl)pyrazole
(4b)
Yield: 60 mg (63%); mp: 120-122 °C; 1H-nmr (CDCl3):
d 2.7 (s, 3H, CH3), 5.3 (s, 1H, =NH), 6.9-8.0 (m, 15H, Ar-H),
2-Cyanoacetamide in the Synthesis of Heterocyclic Compounds
9.1 (s, 1H, NH); m/z 352 (M + , 30%); ir: 3200-3280 (NH).
Anal. Calcd. for C 23 H 20 N 4 (352.44): C, 78.38; H, 5.72; N,
15.90%. Found: C, 78.24; H, 5.59; N, 15.76%.
General Procedure for the synthesis of compounds
(8a-c)
A solution of 1 (1 g, 0.02 mol), cyanoacetamide 6a
(0.32 g, 0.02 mol), and 0.1 mL of piperidine in 30 mL of dry
ethanol was warmed to reflux for two hours and concentrated
under vacuum. The solid formed was triturated with 5 mL of
methanol, and then collected by filtration, and washed with
methanol to give 8a. Analogously, 1 was reacted with cyano-
thioacetamide 6b (0.4 g, 0.02 mol) to give 8b and with cyano-
acetic acid hydrazide 6c (0.38 g, 0.02 mol) to give 8c under
the same reaction conditions.
2-Amino-5-cyano-3-phenylmethylene-4-(p-toludyl)pyri-
dine-6(1H)-one (8a)
Yield: 75 mg (61%); mp: 235-237 °C; 1H-nmr (CDCl3):
d 2.5 (s, 3H, CH3), 2.8 (s, 2H, NH2), 6.5-7.9 (m, 10H, Ar-H),
9.6 (s, H, NH); m/z 328 (M+, 35%); ir: 1712 (CO), 2201 (CN),
3102 (NH), 3311-3414 (NH 2 ). Anal. Calcd. for C 20 H 16 N 4 O
(328.38): C, 73.15; H, 4.91; N, 17.06%. Found: C, 73.04; H,
4.77; N, 17.12%.
2-Amino-5-cyano-3-phenylmethylene-4-(p-toludyl)-6(1H)-
thiopyridine (8b)
Yield: 60 mg (46%); mp: 255-257 °C; 1H-nmr (CDCl3):
d 2.6 (s, 3H, CH3), 2.9 (s, 2H, NH2), 6.7-7.9 (m, 10H, Ar-H),
9.9 (s, 1H, NH); m/z 344 (M + , 30%); ir: 2209 (CN), 3109
(NH), 3321-3417 (NH2). Anal. Calcd. for C20H16N4S (344.44):
C, 69.74; H, 4.68; N, 16.27%. Found: C, 69.62; H, 4.54; N,
16.15%.
1-Amino-2-imino-5-cyano-3-phenylmethylene-4-(p-
toludyl)pyridine-6-one (8c)
Yield: 60 mg (50%); mp: 265-268 °C; 1H-nmr (DMSO):
d 2.1 (s, 3H, CH3), 2.9 (s, 2H, NH2), 5.6 (s, 1H, NH), 6.9 -8.0
(m, 10H, Ar-H), 9.8 (s, 1H, NH); m/z 345 (M+2, 35%); ir:
1673 (CO), 2210 (CN), 3300 (NH), 3389 (NH2). Anal. Calcd.
for C 20 H 17 N 5 O (343.39): C, 69.96; H, 4.99; N, 20.40%.
Found: C, 69.84; H, 4.87; N, 20.38%.
1,4-Diamino-5-phenylmethylene-6-(p-toludyl)-2(1H)-thio-
nepyrimidine (13)
A solution of 1 (1 g, 0.02 mol), thiosemicarbazide 10
(0.28 g, 0.02 mol), and 0.1 mL of piperidine in 30 mL of dry
ethanol was refluxed for seven hours and concentrated under
J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 783
vacuum. The solid formed after addition of cold diluted hy-
drochloric acid (1 mL, 20 mL H2O) was collected by filtra-
tion, washed well with 10 mL of cold water and crystallized
from methanol to give 13. Yield: 56 mg (44%); mp: 220-222
°C; 1H-nmr (CDCl3): d 2.5 (s, 3H, CH3), 3.1 (s, 2H, NH2), 5.1
(s, 2H, NH2), 6.5-7.9 (m, 10H, Ar-H); m/z 335 (M+, 30%); ir:
3310-3420 (NH2). Anal. Calcd. for C18H17N4S (335.97): C,
64.35; H, 5.10; N, 20.85%. Found: C, 64.23; H, 5.00; N,
20.73%.
Preparation of 2-amino-5-cyano-4-phenyl-6-oxo-1-(p-
toludyl)pyridine (23)
A solution of 1 (1 g, 0.02 mol), urea 14a (0.24 g, 0.02
mol), and 0.1 mL of piperidine in 30 mL of dry ethanol was
refluxed for eight hours and then concentrated under vacuum.
The solid formed after addition of cold diluted hydrochloric
acid (1 mL, 20 mL H2O) was collected by filtration, washed
with 100 mL of cold water and crystallized from methanol to
give 23. Analogously, 1 was reacted with thiourea 14b (0.3 g,
0.02 mol) and 2-phenylenediamine 24 (0.4 g, 0.02 mol) to
give 23.
Yield: 50 mg (31%); mp: 276-278 °C; 1H-nmr (CDCl3):
d 2.5 (s, 3H, CH3), 3.2 (s, 3H, CH3), 5.6 (s, 2H, NH2), 6.7-7.9
(m, 13H, Ar-H), 9.5 (s, 1H, NH); m/z 434 (M+, 30%); ir: 1650
(CO), 2211 (CN), 3318-3406 (NH, NH 2 ). Anal. Calcd. for
C27H22N4O2 (434.50): C, 74.64; H, 5.10; N, 12.89%. Found:
C, 74.52; H, 5.00; N, 12.77%.
Received August 14, 2003.
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