A convenient route to pyridones, pyrazolo[2,3-a]pyrimidines and pyrazolo[5,1-c]triazines incorporating antipyrine moiety

Article abstract of DOI:10.1002/hc.20046

Condensation of 4-aminoantipyrine with ethyl acetoacetate, ethyl benzoylacetate, and ethyl cyanoacetate furnished the corresponding ethyl 3-(1,2-dihydro-1,5-dimethyl-2-phenyl-3-oxo-3H-pyrazol-4-yl)aminoacrylate and 2-cyano-N-[(1,2-dihydro-1,5-dimethyl-2-p

Full text of DOI:10.1002/hc.20046

Heteroatom Chemistry
Volume 15, Number 7, 2004
A Convenient Route to Pyridones,
Pyrazolo[2,3-a]pyrimidines
and Pyrazolo[5,1-c]triazines Incorporating
Antipyrine Moiety
Ahmad M. Farag, Kamal M. Dawood, and Hanan A. Elmenoufy
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
Received 16 March 2004
INTRODUCTION
ABSTRACT: Condensation of 4-aminoantipyrine
with ethyl acetoacetate, ethyl benzoylacetate, and ethyl
cyanoacetate furnished the corresponding ethyl 3-(1,2-
dihydro-1,5-dimethyl-2-phenyl-3-oxo-3H-pyrazol-4-
yl)aminoacrylate and 2-cyano-N-[(1,2-dihydro-1,5-
dimethyl-2-phenyl-3-oxo-3H-pyrazol-4-yl)]acetamide
derivatives. The aminoacrylates derivatives react with
acetonitrile and sodium hydride to give 2-amino-6-
methyl-1-(1,2-dihydro-1,5-dimethyl-2-phenyl-3-oxo-
3H-pyrazol-4-yl)-4-pyridone. Reaction of the cya-
noacetamide derivative with dimethylformamide-
dimethylacetal (DMF-DMA) afforded 2-cyano-N-[1,2-
dihydro-1,5-dimethyl-2-phenyl-3-oxo-pyrazol-4-yl]-2-
(N,N-dimethylamino)methylene acetamide in high
yield. Treatment of the latter with 5-aminopyrazole
derivatives afforded the corresponding pyrazolo[2,3-
a]pyrimidines. 2-cyano-N-[(1,2-dihydro-1,5-dimethyl-
2-phenyl-3-oxo-3H-pyrazol-4-yl)]acetamide also re-
acts with heterocyclic diazonium salts to give the
corresponding pyrazolo[5,1-c]-1,2,4-triazine deriva-
The synthesis of 1,2-dihydro-1,5-dimethyl-2-phenyl-
3H-pyrazol-3-one (antipyrine) derivatives has at-
tracted a great deal of attention in view of their
potent biological and pharmacological importance
[1–4]. In continuation of our interest in the synthe-
sis of heteroatom compounds for biological screen-
ing [5–8], this study was undertaken to utilize 4-
aminoantipyrine in the synthesis of a number of
pyridone, thiazole, pyrazolo[2,3-a]-pyrimidine, and
pyrazolo[5,1-c]-1,2,4-triazine derivatives having an
antipyrine moiety.
RESULTS AND DISCUSSION
Condensation of 4-aminoantipyrine (1) with ethyl
acetoacetate and ethyl benzoylacetate at refluxing
temperature afforded products that were character-
ized as ethyl 3-(1,2-dihydro-1,5-dimethyl-2-phenyl-
3-oxo-3H-pyrazol-4-yl)aminoacrylate derivatives 2a
and 2b, respectively (Scheme 1). Both products
showed ethyl ester protons as triplet and quartet sig-
nals around δ 1.3 and 4.2, in addition to an olefinic
CH singlet near δ 4.9 in their 1H NMR spectra. Their
IR spectra revealed absorption bands due to ester NH
functions and carbonyl near 3274 and 1674 cm−1,
respectively.
ꢀ
C
tives.
2004 Wiley Periodicals, Inc. Heteroatom Chem
15:508–514, 2004; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20046
When ethyl acrylate derivative 2a was treated
with acetonitrile in the presence of sodium hydride
by the Claisen condensation condition, it furnished
a single product identified as 2-amino-6-methyl-1-
Correspondence to: Ahmad M. Farag; e-mail: afarag@main-
ssc.cairo.edu.eg.
2004 Wiley Periodicals, Inc.
c
ꢀ
508

A Convenient Route to Pyridones, Pyrazolo[2,3-a]pyrimidines and Pyrazolo[5,1-c]triazines Incorporating Antipyrine Moiety 509
SCHEME 1
(1,2-dihydro-1,5-dimethyl-2-phenyl-3-oxo-3H-pyra-
2-phenyl-3-oxo-3H-pyrazol-4-yl)]acetamide (5) on
the basis of its elemental and spectral analyses in
addition to its chemical transformations outlined in
zol-4-yl)-4-pyridone (4a), which is assumed to be
formed through the in situ intramolecular cycliza-
tion of the nonisolable ꢀ-ketonitrile 3 (Scheme 1).
The structure of 4-pyridone derivative 4 was estab-
lished on the basis of its elemental analyses and
spectral data. For example, its IR spectrum showed
absorption bands at 3246, 3124, 1678, 1660 cm−1 due
to amino and two carbonyl functions, respectively,
and its mass spectrum showed a molecular ion peak
at m/z 310.
1
Scheme 2. The H NMR spectrum of compound 5
revealed a singlet signal at δ 3.24 due to methylene
protons. Reaction of the cyanoacetamide derivative
5 with dimethylformamide-dimethylacetal (DMF-
DMA), afforded the corresponding enaminonitrile
derivative 6 in a good yield (Scheme 2). Treatment
of the enaminonitrile derivative 6 with 5-aryl-3-
aminopyrazoles 7a,b resulted in the formation of the
1
Treatment of 4-aminoantipyrine (1) with ethyl
cyanoacetate afforded a single product that was
identified as 2-cyano-N-[(1,2-dihydro-1,5-dimethyl-
pyrazolo[2,3-a]pyrimidine derivatives 9a,b. The H
NMR spectrum of the enaminonitrile 6 exhibited a
singlet signal at δ 3.03 due to NMe2 protons, however,
SCHEME 2

510 Farag, Dawood, and Elmenoufy
1
synthesis from the reaction of 5 with the benzyliden-
emalononitriles 14a–c under similar reaction condi-
tions to give products identical in all respects (mp,
mixed mp, and spectra) with the obtained aminopy-
ridone derivatives 15a–c.
this signal disappeared in the H NMR spectra of
compounds 9a,b. The formation of the pyrazolo[2,3-
a]pyrimidine 9 from the enaminonitrile 6 is as-
sumed to take place through an intramolecular cy-
clization of the nonisolable intermediate 8 as shown
in Scheme 2.
Treatment of compound 5 with phenyl isothio-
cyanate, in dimethylformamide, and in the presence
of potassium hydroxide, at room temperature,
followed by treatment with dilute hydrochloric acid,
afforded a yellow-colored product that was identified
as 2-cyano-2-[carboxamido-N-[4-(1,2-dihydro-1,5-
dimethyl-2-phenyl-3-oxo-3H-pyrazol-4-yl)-2-yl]
thioacetanilide (16) (Scheme 5). The structure of the
latter was established on the basis of its elemental
analyses and spectral data. Its IR spectrum showed
absorption bands at 3346 and 2199 cm−1 due to
NH group and a nitrile functions, respectively. The
mass spectrum of the reaction product showed the
molecular ion peak at m/z 405.
In continuation of our interest in the synthesis of
bridged-head nitrogen heterocyclic systems [9–11],
we have found that diazotized heterocyclic amines
are excellent building blocks for the synthesis of
the target compounds. Thus, coupling of compound
5 with 3-phenylpyrazol-5-diazonium chloride (10),
afforded the corresponding pyrazolo[5,1-c]-1,2,4-
triazine derivative 12 via the nonisolable hydrazone
intermediate 11 (Scheme 3). The IR spectrum of the
isolated product showed three absorption bands at
3392, 3339, 3281 due to NH and NH2 functions be-
sides two carbonyl absorption bands at 1670 and
1618 cm−1. Its 1H NMR spectrum revealed two D2O-
exchangeable singlets at δ 9.1 and 10.9 due to NH and
NH2 protons, in addition to the two methyl protons
of the antipyrine ring at δ 2.26 and 3.12.
Compound 5 also reacted with some aromatic
aldehydes to afford the corresponding benzylidene
derivatives 13a–c (Scheme 4). Treatment of the lat-
ter compounds with malononitrile furnished the
aminopyridone derivatives 15a–c (Scheme 4). The
IR spectrum of compound 15a revealed absorption
bands at 3438, 3410, 2212, 1681, and 1651 cm−1due
to amino, nitrile, and two carbonyl functions, respec-
tively. The 1H NMR spectrum of 15a exhibited singlet
signals at δ 2.16 and 3.26 due to two methyl protons
in addition to a broad D2O-exchangeable signal at δ
8.47 due to amino protons. Formation of 15 is sup-
posed to proceed through the Michael type addition
followed by auto-oxidation of the intermediate 15c.
Additionally, the elucidation of structures of 15a–c
was supported chemically through their alternative
The thioacetanilide derivative 16 reacts with
phenacyl bromide (17) to afford the corresponding
thiazole derivative 18 (Scheme 5). The IR spectrum
of the isolated product showed absorption bands at
3408 and 2169 cm−1 characteristic for NH and nitrile
1
groups, respectively. Its H NMR spectrum showed
two singlet signals at δ 2.14, 3.05 due to two methyl
protons and thiazole-5-CH proton at δ 7.71. The fore-
going spectral data supported the proposed structure
18 and ruled out the other possible thiophene struc-
ture 19 (Scheme 5).
Similarly, compound 16 reacted with ethyl
chloroacetate under similar reaction conditions and
afforded the thiazolidinone derivative 21 as shown
in Scheme 5. Compound 21 was alternatively syn-
thesized by the reaction of the cyanothioacetanilide
derivative 16 with chloroacetonitrile, which afforded
the thiazolidinimine intermediate 20. The interme-
diate was readily converted into thiazolidinone 21
SCHEME 3

A Convenient Route to Pyridones, Pyrazolo[2,3-a]pyrimidines and Pyrazolo[5,1-c]triazines Incorporating Antipyrine Moiety 511
SCHEME 4
under the reaction condition (Scheme 5). The IR
EXPERIMENTAL
spectrum of compound 21 showed absorption bands
at 3311 and 2194 cm−1 due to amide-NH and nitrile
functions in addition to three carbonyl absorption
bands at 1660, 1637, and 1625 cm−1.
Melting points were measured with a Gallenkamp
apparatus and are uncorrected. IR spectra were
recorded on Shimadzu FT-IR 8101 PC infrared
SCHEME 5

512 Farag, Dawood, and Elmenoufy
spectrophotometer. 1H NMR spectra were deter-
mined at 300 MHz on a Varian Mercury VX 300 NMR
spectrometer using TMS as an internal standard.
Mass spectra were measured on a GCMS-QP1000
EX spectrometer at 70 eV. Elemental analyses were
carried out at the Microanalytical Center of Cairo
University. 3-Aryl-5-amino-(1H)-pyrazoles 7a,b [12],
3-phenyl-(1H)-pyrazole-5-diazonium chloride (10)
[13], benzylidenemalononitriles 14a–c [14,15], and
phenacyl bromide (17) [16] were prepared accord-
ing to the procedures reported in the literature.
2-Cyano-N-[1,2-dihydro-1,5-dimethyl-2-phenyl-
3-oxo-3H-pyrazol-4-yl]acetamide (5)
In a 250 mL three-necked round-bottomed flask, fit-
ted with an air condenser and a thermometer, ethyl
cyanoacetate (22.6 g, 21.26 mL, 200 mmol) was
placed. The flask was immersed in an oil bath heated
to 145–150◦C, then 4-aminoantipyrine (1) (40.6 g,
200 mmol) was added portionwise over a period of
30 min and heating was continued for an additional
15 min. The reaction flask was removed from the
oil bath, left to cool, and the product was triturated
with water. The solid product was filtered off, washed
with ethanol several times, dried, and finally recrys-
tallized from ethanol to afford the cyanoacetamide
derivative 5 in 60% yield, mp 218–220◦C, IR (KBr)
3188 (NH), 2360 (C N), 1701, 1639 (2C O) cm−1;
1H NMR (DMSO-d6) δ ppm 2.21 (s, 3H, CH3), 3.15
(s, 3H, NCH3), 3.24 (s, CH2), 7.27–7.57 (m, 5H, ArH),
9.91 (br s, 1H, D2O-exchangeable, NH); MS m/z, 271
(M+ + 1), 270 (M+), 231, 230, 202, 83, 68, 56. For
C14H14N4O2 Calcd: C, 62.21; H, 5.22; N, 20.73. Found:
C, 62.52; H, 5.01; N, 20.53%.
Synthesis of Ethyl 3-(1,2-dihydro-1,5-dimethyl-
2-phenyl-3-oxo-3H-pyrazol-4-yl)-aminoacrylate
Derivatives 2a,b
To hot neat ethyl acetoacetate or ethyl benzoylac-
etate (10 mmol) was added 4-aminoantipyrine (1)
(2.03 g, 10 mmol) portionwise over a period of 1 h,
keeping the reaction temperature at 150–160◦C. Af-
ter the addition was complete, the reaction mixture
was left to cool to room temperature then triturated
with methanol. The solid product was collected by
filtration, washed with cold ethanol, and finally re-
crystallized from ethanol to give the corresponding
ethyl acrylates 2a,b, respectively.
Synthesis of 2-Cyano-N-[1,2-dihydro-1,5-
dimethyl-2-phenyl-3-oxo-3H-pyrazol-4-yl]-2-
(N,N-dimethylamino)methylene Acetamide (6)
2a, yield (58%); mp 128–130◦C (Lit. mp 130◦C)
[17].
2b, yield (69%); mp 148–150◦C; IR (KBr) ꢁ 3274
A mixture of the cyanoacetamide derivative 5 (3.5 g,
13 mmol) and dimethylformamide-dimethylacetal
(DMF-DMA) (1.7 mL, 13 mmol) in dry xylene (30
mL) was refluxed for 4 h, then allowed to cool. The
precipitated product was filtered off, washed with
petroleum ether (60/80◦C), and dried. Recrystalliza-
tion from ethanol gave the enaminonitrile deriva-
tive 6 in 77% yield. mp 157–159◦C; IR (KBr) ꢁ 3325
(NH), 2183 (C N), 1660, 1612 (2C O) cm−1; 1H NMR
(CDCl3) δ 2.12 (s, 3H, CH3), 2.49 (s, 3H, CH3), 3.33
(s, 6H, NMe2), 7.30–7.49 (m, 5H, ArH), 8.61 (s, 1H),
10.07 (br s, 1H, NH); MS m/z, 325 (M+), 229, 123,
56. For C17H19N5O2 Calcd: C, 62.75; H, 5.89; N, 21.52.
Found: C, 62.51; H, 6.01; N, 21.71%.
(NH), 1674, 1632 (2C O) cm−1; 1H NMR (CDCl3)
δ
1.29 (t, 3H, J = 7.25 Hz), 1.87 (s, 3H), 2.79 (s, 3H),
4.17 (q, 2H, J = 7.25 Hz), 4.95 (s, 1H), 7.21–7.39 (m,
10H), 9.25 (s, 1H); MS m/z, 378 (M+ + 1), 377 (M+) ,
331, 304, 274, 105, 77, 56. For C22H23N3O3Calcd: C,
70.01; H, 6.14; N, 11.13. Found: C, 70.32; H, 6.42; N,
11.50%.
2-Amino-6-methyl-1-(1,2-dihydro-1,5-dimethyl-
2-phenyl-3-oxo-3H-pyrazol-4-yl)-4-pyridone (4a)
To a solution of the ethyl acrylate derivative 2a
(0.63 g, 2 mmol) in a mixture of dry benzene
(30 mL), acetonitrile (0.3 mL), and dimethylfor-
mamide (1 mL) was added sodium hydride (0.15 g)
portion-wise with stirring. After complete addition,
the reaction mixture was heated at refluxing temper-
ature for 2 h, then left to cool. The reaction mixture
was treated with water and the aqueous layer was
collected, then treated with dilute solution of HCl
(10%) to give the pyridone derivative 4a in 67% yield,
mp > 300◦C; IR (KBr) ꢁ 3246, 3124 (NH2), 1678, 1660
Reaction of the Enaminonitrile 6 with
5-aminopyrazoles 7a,b
To a mixture of the enaminonitrile 6 (0.5 g, 1.5 mmol)
and 5-aminopyrazoles 7a,b (1.5 mmol) in ethanol
(20 mL) was added few drops of piperidine as a cata-
lyst. The mixture was refluxed for 3 h, then left to cool
to room temperature. The solid that formed was col-
lected by filtration, washed with ethanol dried, and
finally recrystallized from ethanol to give the corre-
sponding pyrazolo[2,3-a]pyrimidine derivative 9a,b
in 62 and 68% yield, respectively.
1
(2C O) cm−1; H NMR (CDCl3) δ 1.92 (s, 3H, CH3),
2.22 (s, 3H, CH3), 3.06 (s, 3H, CH3), 7.25–7.47 (m,
7H), 9.38 (br, s, 2H, NH2); MS m/z, 311 (M+ + 1), 310
(M+), 269, 123, 56. For C17H18N4O2 Calcd: C, 65.79; H,
5.85; N, 18.05. Found: C, 65.53; H, 5.75; N, 18.30%.

A Convenient Route to Pyridones, Pyrazolo[2,3-a]pyrimidines and Pyrazolo[5,1-c]triazines Incorporating Antipyrine Moiety 513
9a: mp 252–253◦C; IR (KBr) ꢁ 3222, 3136 (NH2),
1662, 1627 (2C O) cm−1; 1H NMR (DMSO-d6) δ 2.22
(s, 3H), 3.10 (s, 3H), 6.82 (s, 1H), 7.03 (s, 1H), 7.21–
7.66 (m, 10H), 8.64 (br. s, 2H, NH2), 9.39 (s, 1H,
NH); MS m/z, 439 (M+), 348, 256, 159, 77, 56. For
C24H21N7O2Calcd: C, 65.59; H, 4.82; N, 22.31. Found:
C, 65.41; H, 4.57; N, 22.11%.
13b: Yield (75%), mp 230–231◦C; IR (KBr) ꢁ 3193
(NH), 2252 (C N), 1690, 1674 (2C O) cm−1; 1H NMR
(DMSO-d6) δ 2.25 (s, 3H, CH3), 2.48 (s, 3H, CH3),
3.19 (s, 3H, NCH3), 7.19–7.63 (m, 10H, ArH), 9.37 (s,
1H, NH). For C22H20N4O2 Calcd: C, 70.95; H, 5.41; N,
15.04. Found: C, 70.62; H, 5.18; N, 15.24%.
13c: Yield (88%), mp 214–216◦C; IR (KBr) ꢁ 3192
(NH), 2255 (C N), 1701, 1668 (2C O) cm−1; 1H NMR
(DMSO-d6) δ 2.95 (s, 3H, CH3), 3.20 (s, 3H, NCH3),
3.77 (s, 3H, OCH3), 7.23–7.57 (m, 10H, ArH), 9.38 (s,
1H, NH, D2O exchangeable). For C22H20N4O3 Calcd:
C, 68.03; H, 5.19; N, 14.42. Found: C, 68.30; H, 5.30;
N, 14.11%.
9b: mp 269–270◦C; IR (KBr) ꢁ 3209, 3132 (NH2),
1651, 1630 (2C O) cm−1; 1H NMR (DMSO-d6) δ 2.21
(s, 3H), 3.11 (s, 3H), 6.86 (s, 1H), 7.05 (s, 1H), 7.38–
8.13 (m, 9H), 8.68 (br. s, 2H, NH2), 9.48 (s, 1H, NH);
MS m/z, 475 (M+ + 2), 474 (M+ + 1), 473 (M+), 270,
203, 84, 56. For C24H20ClN7O2Calcd: C, 60.82; H, 4.25;
N, 20.69. Found: C, 60.63; H, 4.51; N, 20.46%.
Synthesis of 6-Amino-2-oxo-4-aryl-1-[1,2-
dihydro-1,5-dimethyl-2-phenyl-3-oxo-3H-
pyrazol-4-yl]pyridine-3,5-dicarbonitrile (15a–c)
Reaction of Cyanoacetamide Derivative 5 with
Pyrazole Diazonium Salt 7
To a stirred cold solution of cyanoacetamide deriva-
tive 5 (0.54 g, 2 mmol) in pyridine (25 mL) was
added the pyrazole diazonium salt 7 (2 mmol)
portionwise over a period of 30 min. The reaction
mixture was kept in an icebox overnight then
diluted with water. The solid that precipitated
was filtered off, washed with water, and dried.
Recrystallization from DMF gave 4-amino-3-[(1,2-
dihydro-1,5-dimethyl-2-phenyl-3-oxo-3H-pyrazol-
4-yl)-carboxamido]-7-phenylpyrazolo[5,1-c]-1,2,4-
triazine (12) in 61% yield, mp 254–256◦C; IR (KBr)
ꢁ 3392 (NH), 3339, 3281 (NH2), 1670, 1618 (2C O)
Method A. To a solution of the appropriate ben-
zylidenemalononitrile 14a–c (5 mmol) in ethanol
(20 mL) was added an equimolar amount of the
2-cyano-N-[1,2-dihydro-1,5-dimethyl-2-phenyl-3-
oxo-3H-pyrazol-4-yl]acetamide (5) (1.36 g, 5 mmol)
and few drops of piperidine and the reaction mixture
was heated under reflux for 2 h, then left to cool to
room temperature. The solid product that formed
was collected by filtration, washed with ethanol,
and then recrystallized from the EtOH/DMF to give
the corresponding pyridin-2-one derivatives 15a–c.
15a: Yield (76%), mp 210–211◦C; IR (KBr) ꢁ
3438, 3410 (NH2), 2212 (C N), 1681, 1651 (2C O)
1
cm−1; H NMR (DMSO-d6) δ 2.26 (s, 3H, CH3), 3.12
1
(s, 3H, CH3), 7.40–7.56 (m, 11H, ArH), 9.10 (s, 2H,
NH2), 10.90 (s, 1H, NH); MS m/z, 440 (M+), 329, 159,
130, 104, 77, 56. For C23H20N8O2 Calcd: C, 62.72; H,
4.58; N, 25.44. Found: C, 63.01; H, 4.56; N, 25.38%.
cm−1; H NMR (DMSO-d6) δ 2.16 (s, 3H, CH3), 3.26
(s, 3H, NCH3), 7.41–7.58 (m, 10H, ArH), 8.47 (s,
2H, NH2); MS m/z, 422 (M+), 303, 302, 77, 56. For
C24H18N6O2 Calcd: C, 68.24; H, 4.29; N, 19.89. Found:
C, 68.46; H, 4.50; N, 20.01%.
15b: Yield (75%), mp >300◦C; IR (KBr) ꢁ 3471,
3307 (NH2), 2185 (C N), 1682, 1662 (2C O) cm−1;
1H NMR (DMSO-d6) δ 2.16 (s, 3H, CH3), 2.41 (s, 3H,
CH3), 3.28 (s, 3H, NCH3), 7.40–7.46 (m, 9H, Ar-H),
8.53 (s, 2H, NH2); MS m/z, 437 (M+ + 1), 436 (M+),
316, 302, 179, 122, 83, 56. For C25H20N6O2 Calcd: C,
68.80; H, 4.62; N, 19.25. Found: C, 68.31; H, 4.91; N,
19.41%.
Reaction of Cyanoacetamide Derivative 5 with
Aromatic Aldehydes
General Procedure. To a solution of the cyanoac-
etamide derivative 5 (0.54 g, 2 mmol) and the
appropriate aromatic aldehyde (2 mmol), in ethanol
(20 mL), was added few drops of piperidine and the
reaction mixture was refluxed for 4 h then allowed
to cool. The precipitate that formed was filtered
off, washed with ethanol, and purified by recrysta-
llization from ethanol to afford the corresponding
2-cyano-2-arylmethylene-N-[1,2-dihydro-1,5-di-
methyl-2-phenyl-3-oxo-3H-pyrazol-4-yl]-acetamide
derivatives 13a–c.
15c: Yield (63%), mp >300◦C; IR (KBr) ꢁ 3278,
3194 (NH2), 2212 (C N), 1666 (C O), 1640 (C O)
1
cm−1; H NMR (DMSO-d6) δ 2.15 (s, 3H, CH3), 3.26
(s, 3H, NCH3), 3.85 (s, 3H, OCH3), 7.10–7.58 (m,
9H, ArH), 8.40 (s, 2H, NH2, D2O exchangeable). For
C25H20N6O3 Calcd: C, 66.36; H, 4.46; N, 18.57. Found:
C, 66.61; H, 4.61; N,18.27%.
13a:Yield (63%), mp 223–224◦C; IR (KBr) ꢁ 3202
(NH), 2225 (C N), 1708, 1675 (2C O) cm−1; MS m/z,
358 (M+), 281, 271, 231, 230, 229, 83, 77, 56. For
C21H18N4O2 Calcd: C, 70.38; H, 5.06; N, 15.63. Found:
C, 70.01; H, 5.41; N, 15.23%.
Method B. To a solution of the appropriate 2-
cyano-2-arylmethylene-N-(1,2-dihydro-1,5-dimethyl-
2-phvenyl-3-oxo-3H-pyrazol-4-yl]acetamide 13a–c

514 Farag, Dawood, and Elmenoufy
(5 mmol) in ethanol (20 mL) was added malononi-
trile (1.36 g, 5 mmol) and few drops of piperidine.
The reaction mixture was heated under reflux for
2 h then left to cool. The precipitated product
was collected by filtration, washed with ethanol,
and then recrystallized from the EtOH/DMF to
give products identical in all respects ([m.p, mixed
mp and spectra]) with those 15a–c obtained from
method A above.
18: Yield (64%), mp 255–257◦C; IR (KBr) ꢁ 3408
(NH), 2169 (C N), 1652, 1623 (C O) cm−1; 1H NMR
(DMSO-d6) δ 2.14 (s, 3H, CH3), 3.05 (s, 3H, NCH3),
7.18–7.50 (m, 15H, ArH), 7.71 (s, 1H, thiazole-H); MS
m/z, 506 (M+ + 1), 505 (M+), 276, 229, 134, 91, 56.
For C29H23N5O2S Calcd: C, 68.89; H, 4.59; N, 13.85.
Found: C, 68.90; H, 4.50; N, 13.91%.
21: Yield (69%), mp 268–269◦C; IR (KBr) ꢁ 3244
(NH), 2210 (C N), 1724, 1655 (2C O) cm−1; 1H NMR
(DMSO-d6) δ 2.16 (s, 3H, CH3), 3.08 (s, 3H, NCH3),
3.85 (s, 2H, CH2), 7.25–7.61 (m, 10H, ArH); MS m/z,
446 (M+ + 1), 445 (M+), 230, 229, 202, 83, 82, 56.
For C23H19N5O3S2 Calcd: C, 62.01; H, 4.30; N, 15.72.
Found: C, 61.90; H, 4.01; N, 15.46%.
Synthesis of the Thioacetanilide Derivative 16
To a stirred solution of potassium hydroxide (0.11 g,
2 mmol) in dimethylformamide (20 mL) was added
the cyanoacetamide derivative 5 (0.544 g, 2 mmol).
After stirring for 30 min, phenyl isothiocyanate
(0.27 g, 2 mmol) was added to the resulting mix-
ture. Stirring was continued for 6 h, then the reaction
mixture was poured over a cold solution of 0.5 N
hydrochloric acid. The solid product that formed
was filtered off, washed with water, dried, and fi-
nally recrystallized from ethanol to afford compound
16 in 64% yield, mp 154–155◦C; IR (KBr) ꢁ 3263,
3067 (2NH), 2174 (C N), 1724, 1686 (2C O) cm−1;
MS m/z, 405 (M+), 391, 372, 312, 229, 169, 105, 77.
For C21H19N5O2S Calcd: C, 62.20; H, 4.72; N, 17.27.
Found: C, 62.51; H, 4.62; N, 17.43%.
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Reaction of Thioacetanilide Derivative 16 with
ꢂ-Haloketones
General Procedure. To a solution of the thioac-
etanilide derivative16 (0.81 g, 2 mmol) in ethanol
(20 mL), the appropriate ꢂ-haloketone, phenacyl
bromide (17), ethyl chloroacetate or chloroacetoni-
trile (2 mmol) were added. Triethylamine (0.2 mL)
was added dropwise and the reaction mixture was
refluxed for 1 h then allowed to cool. The formed
solid was filtered off, washed with ethanol, and
recrystallized from EtOH/DMF to afford the corre-
sponding 2-cyano-2-(3,4-diphenyl-2-thiazolylidene)-
N-(antipyrin-4-yl)methylene acetamide (18) and 2-
cyano-2-(4-oxo-3-phenyl-2-thiazolylidene)-N-(anti-
pyrin-4-yl)methylene acetamide (21) derivatives
respectively.
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