Utility of enaminonitriles in heterocyclic synthesis: Synthesis of some new pyrazole, pyridine, and pyrimidine derivatives

Article abstract of DOI:10.1002/jhet.855

The starting (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) carbonohydrazonoyl dicyanide (2) was used as key intermediate for the synthesis of 3-amino-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylazo)-[3- substituted]-1-yl-acryloni

Full text of DOI:10.1002/jhet.855

774
Utility of Enaminonitriles in Heterocyclic Synthesis: Synthesis of
Some New Pyrazole, Pyridine, and Pyrimidine Derivatives
Vol 49
*
Ahmed A. Fadda , Hassan A. Etman, Mohamed Y. El-Seidy
and Khaled M. Elattar
Department of Chemistry, Faculty of Science, Mansoura University, 35516 Mansoura, Egypt
*
E-mail: afadda2@yahoo.com
Received December 4, 2010
DOI 10.1002/jhet.855
View this article online at wileyonlinelibrary.com.
The starting (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbonohydrazonoyl dicyanide
(2) was used as key intermediate for the synthesis of 3-amino-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-ylazo)-[3-substituted]-1-yl-acrylonitrile derivatives (3–10). In addition, nitrile deriva-
tive 2 reacted with hydrazine hydrate or malononitrile to afford the corresponding 3,5-diaminopyrazole
11 and enaminonitrile derivative 13, respectively. On the other hand, compound 3 was subjected to
react with malononitrile, acetic anhydride, triethylorthoformate, N,N-dimethylformamide (DMF)-dime-
thylacetal, thiourea, and hydroxylamine hydrchloride to afford antipyrine derivatives 16–21. Moreover,
the reaction of enaminonitrile 3 with carbon disulfide in pyridine afforded the pyrimidine derivative 22,
whereas, in NaOH/DMF followed by the addition of dimethyl sulphate afforded methyl carbonodithioate
24. The reaction of enaminonitrile derivatives 3–5 with phenylisothiocyanate afforded the thiopyrimidine
derivatives 25a–c. Finally, the enaminonitrile 4 reacted with 3-(4-chloro-phenyl)-1-phenyl-propenone to
afford the pyridine derivative 27. The newly synthesized compounds were characterized by elemental
1
analyses and spectral data (IR, 13C-NMR, H–NMR, and MS).
J. Heterocyclic Chem., 49, 774 (2012).
INTRODUCTION
derivatives of antipyrine is 4-aminoantipyrine (4AAP),
which are used as a synthetic intermediate to prepare
polyfunctionally substituted heterocyclic moieties with
anticipated biological activity [8], analgesic [9,10], anti-
inflammatory [10], antimicrobial [11–13], and anticancer
[14] activities. It was of interest to study the reactivity
of antipyrinylhydrazonomalononitrile toward different
nitrogen nucleophiles as well as activated nitriles.
In continuation of our studies on the chemistry of
enamino and activated nitriles [1,3,15,16], and as a part
In recent years, there has been increasing interest
in the syntheses of heterocyclic compounds that have
biological and commercial importances. Antipyrine
compounds play an important role in modern organic
synthesis, not only because they constitute a particularly
useful class of heterocyclic compounds [1–3] but also
because they are of great biological interest. They have
been found to have biological [4], clinical [5], and phar-
macological [6,7], activities. One of the most important
© 2012 HeteroCorporation

July 2012
Utility of Enaminonitriles in Heterocyclic Synthesis: Synthesis of Some New Pyrazole,
Pyridine, and Pyrimidine Derivatives
775
Scheme 1
of our program directed toward developing new ap-
proaches to a variety of heterocycles incorporating the
antipyrine moiety [1,3] of potential biological activity,
we report here the scope and applicability of (1,5-
dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)
carbonohydrazonoyl dicyanide as a unique precursor
for the synthesis of some enaminonitriles and their
behavior toward different reagents in which a antipyrine
ring is incorporated.
malononitrile in refluxing sodium ethoxide to yield
the corresponding enaminonitrile derivative 13 via the
intermediate 12, which produced by nucleophilic addi-
tion of the active methylene group in malononitrile to
nitrile function in 2 followed by heterocyclization
(Scheme 2). The IR spectrum displayed the presence
of a broad absorption bands at 3336 and 3214 cmꢁ1
characteristic to the NH2 and NH functions. The
mass spectrum showed a molecular ion peak at m/z 346
(M+, 4.3%).
In addition, the reaction of enaminonitrile 3 with
malononitrile in ethanolic sodium ethoxide solution
afforded the corresponding pyrimidine derivative 16.
The 1H-NMR spectrum revealed singlet signal for two
methylene protons at d 4.13 ppm beside one amino
group at d 8.1 ppm as expected. Based on these data, it
seemed that compound 16 was formed via the interme-
diate 15 as shown in Scheme 3. Similar behavior has
been reported [20].
When compound 3 was heated in refluxing acetic
anhydride, the diacetyl derivative 17 was obtained.
Moreover, the reaction of enaminonitrile 3 with triethyl
orthoformate afforded the ethoxymethylideneamino deriv-
ative 18. The reaction of 3 with N,N-dimethylformamide-
dimethylacetal (DMF-DMA) in dry xylene afforded N,
N-dimethyl-formamidine derivative 19.
RESULTS AND DISCUSSION
The key precursor (1,5-dimethyl-3-oxo-2-phenyl-2,
3-dihydro-1H-pyrazol-4-yl)carbonohydrazonoyl dicyanide
(2) [1,17,18] was prepared by diazo-coupling of 4-
aminoantipyrine (1) with malononitrile in ethanolic so-
dium acetate solution at 0–5ꢀC. Compound 2 reacted
with different secondary amines namely; (piperidine,
morpholine, N-methylglucamine, pyrrolidine, diphenyl
amine, ethyl 2-(4-chlorophenylamino)acetate, pipera-
zine, and 1-phenylpiperazine) in refluxing ethanol to
afford the corresponding 1:1 acyclic enaminonitrile
adducts 3–10, respectively (Scheme 1).
Furthermore, we investigated the reactivity of 2
toward hydrazine hydrate to obtain the pyrazole deriva-
tives. Thus, an equimolar amount of hydrazine hydrate
reacted with nitrile derivative 2 to afford the corre-
sponding 3,5-diaminopyrazole derivative 11. Moreover,
we have also investigated the possible utility of com-
pound 2 to develop a facile and convenient route to
polyfunctionally pyridazine derivative 13 with expected
biological activities [19]. Thus, compound 2 reacted with
The reaction of 3 with thiourea in ethanol-DMF mix-
ture catalyzed by triethylamine afforded the pyrimidine
derivative 20 via H2S elimination. In a similar manner,
the reaction of 3 with hydroxyl amine hydrochloride in
ethanol catalyzed by triethylamine afforded the pyrazole
derivative 21 (Scheme 3).
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776
A. A. Fadda, H. A. Etman, M. Y. El-Seidy, and K. M. Elattar
Vol 49
Scheme 2
The reaction of 3 with carbon disulfide in pyridine pro-
[2-cyano-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-ylazo)-1-piperidin-1-yl-vinyl]-dithio-carbamic
acid methyl ester (24) (Scheme 4).
ceeded by the addition of carbon disulfide to the amino
group, followed by cyclization through nucleophilic attack
of the sulfur atom to the cyano group, which subsequently
underwent rearrangement to give the pyrimidinedithiole
derivative 22, similar behavior has been reported [21,22].
On the other hand, the reaction of 3 with carbon disulphide
in sodium hydroxide solution simultaneously in a vigorously
stirred solution of enaminonitrile 3 in dimethylformamide
led to the formation of the sodium salt of enaminonitrile
23, which was methylated with dimethyl sulphate to get
The enaminonitrile moiety in 3–5 proved to be highly
reactive toward nitrogen nucleophiles. Thus, compounds
3–5 were refluxed with phenyl isothiocyanate in ethanol/
DMF catalyzed by few drops of triethylamine to afford
the corresponding pyrimidinethione derivative 25a–c
(Scheme 5). The structures of 25a–c were elucidated
on the basis of elemental analyses and spectral data. The
1H-NMR spectra of 25a–c together with their mass spectra
Scheme 3
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July 2012
Utility of Enaminonitriles in Heterocyclic Synthesis: Synthesis of Some New Pyrazole,
Pyridine, and Pyrimidine Derivatives
777
Scheme 4
the calculated values. 2-[(1,5-Dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-yl)-hydrazono]-malononitrile (2) [1,17,18];
(93%), mp 140ꢀC; yellowish orange crystals; 1H-NMR (400
MHz, DMSO-d6): d, 2.26 (s, 3H, CH3), 3.25 (s, 3H, N―CH3),
7.35–7.56 (m, 5H, Ph), 12.1 (br, s, 1H, NH); ms: (m/z, %): 281
(M++1, 4.3), 280 (M+, 13.4), 188 (5.2), 91 (8.1), 56 (100.0).
Synthesis of 3-amino-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-ylazo)-[3-substituted]-1-yl-acrylonitrile
derivatives (3–10). General procedure. A mixture of (1,5-
dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbono-
hydrazonoyl dicyanide (2) (1.4 g, 5 mmol) and the appropriate
gives a more conformational data for the proposed struc-
tures (cf. Experimental section).
Finally, the pyridine derivative 27 was achieved via the
reaction of enaminonitrile 4 with 3-(4-chloro-phenyl)-1-
phenyl-propenone in DMF-EtOH catalyzed by triethylamine
(Fig. 1).
EXPERIMENTAL
All melting points are recorded on Gallenkamp electric melting
point apparatus. The IR spectra υ cmꢁ1 (KBr) were on Perkin
Elmer Infrared Spectrophotometer Model 157, Grating. The
13C-NMR and 1H-NMR spectra were run on Varian Spectropho-
tometer at 100 and 400 MHz using TMS as an internal reference
and DMSO-d6 as solvent. The mass spectra (EI) were run at 70
eV with JEOL JMS600 equipment and/or a Varian MAT 311 A
Spectrometer. Elemental analyses (C, H, and N) were carried
out at the Micro Analytical Center of Cairo Univ., Giza, Egypt.
The results were found to be in good agreement (ꢂ0.3%) with
secondary amine namely; piperidine (0.49 mL,
5 mmol),
morpholine (0.43 mL, 5 mmol), N-methylglucamine (0.98 g,
5 mmol), pyrrolidine (0.41 mL, 5 mmol), diphenyl amine (0.85 g,
5 mmol), ethyl 2-(4-chlorophenylamino)acetate (1.07 g, 5 mmol),
piperazine (0.43 g, 5 mmol), or 1-phenylpiperazine (0.81 g, 5
mmol) in ethanol (15 mL) was refluxed for 5 h. The reaction
mixture was left to cool, and the precipitated solid was filtered
off, dried, and recrystallized from EtOH-DMF (2:1) mixture to
afford the corresponding acyclic enaminonitrile derivatives 3–10.
Scheme 5
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A. A. Fadda, H. A. Etman, M. Y. El-Seidy, and K. M. Elattar
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Figure 1. Reaction of enaminonitrile 4 with 3-(4-chloro-phenyl)-1-phenyl-propenone: Synthesis of aminopyridine derivative 27.
3-Amino-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
3352, 3271 (NH2), 2179 (CN), 1644 (CO), 1472 (N═N);
pyrazol-4-ylazo)-3-piperidin-1-yl-acrylonitrile (3). Yield: 91%,
mp 209ꢀC; dark green crystals; IR (KBr) ύ (cmꢁ1), 3392, 3334
(NH2), 3189 (NH), 2960 (C―H, stretching), 2171 (CN),
1639 (CO), 1448 (N═N); 1H-NMR (400 MHz, DMSO-d6):
d, 1.58–1.69 (m, 6H, 3CH2, piperidine), 2.63 (s, 3H, CH3), 3.16
(s, 3H, N―CH3), 3.52–3.62 (m, 4H, 2CH2, piperidine), 7.13 (br.,
s, 2H, NH2), 7.31–7.52 (m, 5H, Ph); ms: (m/z, %): 367 (M+,
2.3), 366 (M+-1, 14.5), 338 (12.2), 280 (11.0), 215 (11.0), 189
(77.9), 152 (100.0), 86 (12.8), 63 (26.7). Anal. Calcd. for
C19H25N7O (367.45): C, 62.10; H, 6.86; N, 26.68%. Found: C,
62.23; H, 6.91; N, 26.76%.
3-Amino-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-ylazo)-3-morpholin-4-yl-acrylonitrile (4). Yield:
83%, mp 232ꢀC; light brown crystals; IR (KBr) ύ (cmꢁ1),
3385, 3337 (NH2), 3197 (NH), 2967 (C―H, stretching),
2186 (CN), 1637 (CO), 1470 (N═N); 1H-NMR (400 MHz,
DMSO-d6): d, 2.22–2.25 (m, 4H, 2CH2, morpholine), 2.44 (s,
3H, CH3), 3.10 (s, 3H, N―CH3), 3.58–3.74 (m, 4H, 2CH2,
morpholine), 7.24 (br, s, 2H, NH2), 7.36–7.51 (m, 5H, Ph); ms:
(m/z, %): 368 (M+-1, 6.7), 367 (M+-2, 15.5), 275 (7.7), 214
(13.4), 188 (14.6), 108 (24.6), 96 (17.8), 56 (100.0). Anal.
Calcd. for C18H23N7O2 (369.42): C, 58.52; H, 6.28; N, 26.54%.
Found: C, 58.61; H, 6.33; N, 26.61%.
1H-NMR (400 MHz, DMSO-d6): d, 2.42 (s, 3H, CH3),
3.18 (s, 3H, N―CH3), 6.63–7.54 (m, 15H, Ar-H), 8.14
(br, s, 2H, NH2). Anal. Calcd. for C26H25N7O (451.52):
C, 69.16; H, 5.58; N, 21.71%. Found: C, 69.27; H, 5.63;
N, 21.79%.
[1-Amino-2-cyano-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazol-4-ylazo)-vinyl]-(4-chloro-phenyl)-amino]-acetic
acid ethyl ester (8). Yield: 75%, mp 88–90ꢀC; light black
powder; IR (KBr) ύ (cmꢁ1), 3358, 3266 (NH2), 2183 (CN),
1740 (C═O, ester), 1648 (CO), 1479 (N═N); 1H-NMR (400
MHz, DMSO-d6): d, 1.29 (t, 3H, CH2CH3, J = 7.2 Hz),
2.41 (s, 3H, CH3), 3.18 (s, 3H, N―CH3), 3.82 (s, 2H,
CH2), 4.12 (q, 2H, CH2CH3, J = 7.2 Hz), 6.2 (br, s, 2H,
NH2), 7.01–8.12 (m, 9H, Ar-H); ms: (m/z, %): 495 (M+,
0.5), 447 (0.2), 214 (7.5), 212 (19.6), 141 (33.0), 139
(100.0), 56 (16.0). Anal. Calcd. for C24H26ClN7O3 (495.96):
C, 58.12; H, 5.28; N, 19.77%. Found: C, 58.21; H, 5.34; N,
19.81%.
3-Amino-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazol-4-ylazo)-3-piperazin-1-yl-acrylonitrile (9). Yield:
72%, mp 89–90ꢀC; dark red powder; IR (KBr) ύ (cmꢁ1), 3450,
3379 (NH2), 3159 (NH), 2929 (C―H, stretching), 2174
(CN), 1639 (CO), 1494 (N═N); ms: (m/z, %): 368 (M+, 0.4),
343 (1.0), 228 (2.9), 201 (6.9), 189 (10.0), 160 (17.5), 135
(69.5), 73 (100.0), 65 (20.8). Anal. Calcd. for C18H24N8O
(368.44): C, 58.68; H, 6.57; N, 30.41%. Found: C, 58.63; H,
6.51; N, 30.38%.
3-Amino-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-ylazo)-3-[methyl-(2,3,4,5,6-pentahydroxy-hexyl)-
amino]-acrylonitrile (5). Yield: 83%, mp 205ꢀC; dark yellow
crystals; IR (KBr) ύ (cmꢁ1), 3451, 3436 (OH), 3358, 3301
(NH2), 2954 (C―H, stretching), 2186 (CN), 1648 (CO), 1459
3-Amino-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazol-4-ylazo)-3-(4-phenyl-piperazin-1-yl)-acrylonitrile
1
(N═N); H-NMR (400 MHz, DMSO-d6): d, 2.47 (s, 3H, CH3),
(10).
Yield: 86%, mp 230ꢀC; yellow powder; IR (KBr) ύ
3.16 (s, 3H, N―CH3), 3.35–3.41 (m, 5H, CH2―N―CH3),
3.86–3.93 (m, 2H, CH2O), 4.36–5.14 (br, m, 5H, 5OH), 7.33
(br, s, 2H, NH2), 7.35-7.53 (m, 5H, Ph); ms: (m/z, %): 439
(M+-2-2H2O, 100.0), 438 (97.0), 282 (78.8), 279 (48.5), 241
(93.9), 178 (69.7), 163 (57.6), 144 (63.6), 104 (45.5), 94 (15.2),
57 (30.3). Anal. Calcd. for C21H31N7O6 (477.51): C, 52.82; H,
6.54; N, 20.53%. Found: C, 52.91; H, 6.59; N, 20.72%.
(cmꢁ1), 3390, 3334 (NH2), 2925, 2809 (C―H, aliphatic),
2173 (CN), 1610 (CO), 1490 (N═N); 1H-NMR (400 MHz,
DMSO-d6): d, 2.44 (s, 3H, CH3), 3.10 (s, 3H, N―CH3),
3.28–3.36 (m, 4H, 2CH2, piperazine), 3.72–3.82 (m, 4H,
2CH2, piperazine), 6.12 (br, s, 2H, NH2), 6.81-7.53 (m, 5H,
Ph); ms: (m/z, %): 444 (M+, 5.0), 375 (0.4), 228 (46.6), 214
(65.3), 188 (82.4), 162 (59.7), 132 (94.7), 120 (100.0), 99
(67.3), 88 (42.7), 73 (81.9), 66 (24.3). Anal. Calcd. for
C24H28N8O (444.53): C, 64.84; H, 6.35; N, 25.21%. Found:
C, 64.92; H, 6.39; N, 25.27%.
3-Amino-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-ylazo)-3-pyrrolidin-1-yl-acrylonitrile (6).
Yield:
88%, mp 229ꢀC; light brown sheets; IR (KBr) ύ (cmꢁ1), 3367,
3272 (NH2), 3183 (NH), 2944, 2875 (C―H, aliphatic), 2173
(CN), 1641 (CO), 1467 (N═N); 1H-NMR (400 MHz, DMSO-d6):
d, 1.92–2.09 (m, 4H, 2CH2, pyrrolidine), 2.44 (s, 3H, CH3), 3.10
(s, 3H, N―CH3), 3.50–3.69 (m, 4H, 2CH2, pyrrolidine), 6.73
(br., s, 2H, NH2), 7.31–7.51 (m, 5H, Ph). Anal. Calcd. for
C18H23N7O (353.42): C, 61.17; H, 6.56; N, 27.74%. Found: C,
61.26; H, 6.61; N, 27.83%.
Synthesis of 4-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)-
1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one (11). A solution
of 2 (1.4 g, 5 mmol) and hydrazine hydrate (0.24 mL, 5 mmol)
in ethanol (15 mL) was refluxed for 20 min. The reaction
mixture was left to cool, and the precipitated solid was filtered
off, dried, and recrystallized from a mixture of ethanol and
DMF (1:2) to afford compound 11 as yellow crystals (88%).
m.p.: > 300ꢀC; IR (KBr): 3450, 3480 (2NH2), 1640 (C═O);
1H-NMR (400 MHz, DMSO-d6): d, 2.47 (s, 3H, CH3), 3.20
3-Amino-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-ylazo)-3-diphenylamino-acrylonitrile (7). Yield:
75%, mp 98ꢀC; light black powder; IR (KBr) ύ (cmꢁ1),
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Utility of Enaminonitriles in Heterocyclic Synthesis: Synthesis of Some New Pyrazole,
Pyridine, and Pyrimidine Derivatives
779
(s, 3H, N―CH3), 5.74 (br., s, 4H, 2NH2), 7.34–7.54 (m, 5H,
Ph), 10.61 (br., s, 1H, NH); ms: (m/z, %): 313 (M++1, 3.1),
312 (M+, 14.8), 311 (M+-1, 4.2), 284 (0.6), 299 (0.5), 215
(1.1), 188 (2.7), 111 (6.8), 56 (100.0). Anal. Calcd. for
C14H16N8O (312.33): C, 53.84; H, 5.16; N, 35.88%. Found: C
53.74, H 5.19, N 35.84%.
(10 mL) was refluxed on a water bath for 3 h. The reaction
mixture was left to cool and poured into ice cold water.
The formed solid product was filtered, dried, and
crystallized from DMF-EtOH to yield 17 as brown powder
(62%). m.p.: 176ꢀC; IR (KBr): 2940 (C―H, stretching),
2934–2836 (CH, aliphatic), 2178 (CN), 1638 (CO), 1452
(N═N); ms: (m/z, %): 418 (M+-3, 0.5), 350 (5.2), 295
(8.2), 255 (12.2), 229 (16.7), 188 (100.0), 151 (33.7), 122
(17.0), 88 (44.1). Anal. Calcd. for C22H27N7O2 (421.50): C,
62.69; H, 6.46; N, 23.26%. Found: C, 62.76; H, 6.51; N,
23.33%.
Synthesis of 4-amino-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-yl)-6-imino-1,6-dihydropyridazine-3,5-
dicarbonitrile (13).
malononitrile (0.33 g, 5 mmol), and freshly prepared sodium
ethoxide [prepared by adding 1.0 sodium metal into
A mixture of 2 (1.4 g, 5 mmol),
g
Synthesis of N0-[2-cyano-2-(1,5-dimethyl-3-oxo-2-phenyl-
2,3-dihydro-1H-pyrazol-4-ylazo)-1-piperidin-1-yl-vinyl]-N,N-
ethanol (20 mL)] in ethanol (20 mL) was refluxed for 6 h.
The reaction mixture was left to cool and poured onto
water. The formed solid product was filtered off, dried, and
recrystallized from a mixture of ethanol and DMF (1:1) to
give compound 13 as brown powder (71%). m.p.: above
300ꢀC (dec); IR (KBr): 3336 (NH2), 3214 (NH), 2200 (CN),
1633 (CO); ms: (m/z, %): 346 (M+, 4.3), 313 (13.1), 185
(17.3), 83 (100.0). Anal. Calcd. for C17H14N8O (346.35): C,
58.95; H, 4.07; N, 32.35%. Found: C 58.89, H 4.13, N
32.42%.
dimethyl-formamidine (19).
(1.47 gm, 4 mmol) in xylene (15 mL), DMF-DMA (0.53 mL,
mmol) was added. The reaction mixture was heated
To a solution of compound 3
4
under reflux for 4 h, then filtered, and recrystallized from
DMF-EtOH mixture to give 19 as brown powder (51%). m.p.:
94ꢀC; IR (KBr): 2931, 2856 (C―H, aliphatic), 2177 (CN),
1637 (CO), 1616 (C═N); ms: (m/z, %): 419 (M+-1, 0.5), 349
(6.3), 228 (13.7), 202 (28.1), 188 (100.0), 118 (32.9), 88
(54.4), 73 (67.0). Anal. Calcd. for C22H28N8O (420.51): C,
62.84; H, 6.71; N, 26.65%. Found: C, 62.93; H, 6.78; N,
26.72%.
Synthesis of [4-amino-5-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-ylazo)-6-piperidin-1-yl-pyrimidin-2-yl]-
acetonitrile (16).
A mixture of 3 (1.84 g, 5 mmol) and
Synthesis of 4-(2,4-diamino-6-piperidin-1-yl-pyrimidin-
5-ylazo)-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (20).
A mixture of 3 (1.84 g, 5 mmol) and thiourea (0.38 g, 5mmol)
in ethanol-DMF mixture (20 mL) in the presence of catalytic
amount of triethylamine (5 drops) was refluxed for 19 h. The
reaction mixture was left to cool. The formed solid product
was filtered, dried, and crystallized from DMF-EtOH to
furnish 20 as dark yellow powder (74%). m.p.: 93ꢀC; IR
(KBr): 3431, 3372 (br, 2NH2), 1639 (CO), 1458 (N═N); ms:
(m/z, %): 405 (M+-2, 1.2), 349 (11.5), 308 (10.9), 294
(100.0), 265 (51.1), 238 (39.1), 226 (98.3), 197 (78.5), 143
(47.3), 78 (60.1). Anal. Calcd. for C20H25N9O (407.47): C,
58.95; H, 6.18; N, 30.94%. Found: C, 59.03; H, 6.24; N,
30.97%.
malononitrile (0.33 g, 5 mmol) was added to freshly prepared
sodium ethoxide solution [prepared by adding 1.0 g sodium
metal into ethanol (20 mL)], the reaction mixture was
refluxed for 8 h and left to cool overnight. The obtained solid
product was collected by filtration, washed, and crystallized
from ethanol to afford 16 as dark green crystals (78%). m.p.:
140–142ꢀC; IR (KBr): 3456 (br, NH2), 2209 (CN), 1650
(br, C═N, CO); 13C-NMR (100 MHz, DMSO-d6): d, 174.31,
171.42, 167.20, 163.52, 161.30, 159.93, 154.6, 136.21,
130.22, 126.5, 126.43, 123.43, 117.63, 115.49, 115.36, 92.40,
86.36, 85.40, 53.61, 53.63, 53.61, 42.50, 25.91, 25.66, 25.37,
22.14, 11.63; 1H-NMR (400 MHz, DMSO-d6): d, 1.53–1.67
(m, 6H, 3CH2, piperidine), 2.64 (s, 3H, CH3), 3.12 (s, 3H,
N―CH3), 3.52–3.67 (m, 4H, 2CH2, piperidine), 4.13 (s, 2H,
CH2), 7.35–7.59 (m, 5H, Ph), 8.1 (br., s, 2H, NH2); ms:
(m/z, %): 433 (M++2, 1.4), 391 (7.2), 375 (14.5), 343 (14.5),
278 (17.4), 254 (23.2), 213 (26.1), 186 (59.4), 129 (36.2), 84
(50.7), 73 (66.7), 57 (88.8). Anal. Calcd. for C22H25N9O
(431.49): C, 61.24; H, 5.84; N, 29.21%. Found: C, 61.29; H,
5.87; N, 29.26%.
Synthesis of 4-(5-amino-3-piperidin-1-yl-2H-[1,2,6]oxadiazin-
4-ylazo)-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (21).
A
mixture of 3 (1.84 g, 5 mmol) and hydroxylamine
hydrochloride (0.35 g, 5 mmol) in ethanol (15 mL) in the
presence of catalytic amount of triethylamine (four drops)
was refluxed for 14 h, and the reaction mixture was left to
cool. The formed solid product was filtered, dried, and
crystallized from ethanol to furnish 21 as yellow powder
(68%). m.p.: 124ꢀC; IR (KBr): 3346, 3298 (NH2), 3116
(NH), 2936, 2859 (C―H, aliphatic), 1647 (CO), 1623
(C═N); ms: (m/z, %): 382 (M++2, 3.1), 349 (13.8), 269
(41.5), 255 (19.4), 240 (100.0), 226 (35.7), 212 (43.2), 198
(22.9), 187 (62.2), 55(47.1). Anal. Calcd. for C19H24N8O
(380.45): C, 59.98; H, 6.36; N, 29.45%. Found: C, 60.06; H,
6.47; N, 29.53%.
Synthesis of N-acetyl-N-[2-cyano-2-(1,5-dimethyl-3-oxo-2-
phenyl-2,3-dihydro-1H-pyrazol-4-ylazo)-1-piperidin-1-yl-vinyl]-
acetamide (17). A mixture of 3 (1.84 g, 5 mmol) and acetic
anhydride (20 mL) was heated under reflux for 7 h. The
reaction mixture was poured into ice cold water, and the
formed solid product was filtered, washed with ethanol, dried,
and crystallized from ethanol to yield 17 as black crystals
(65%). m.p.: 218ꢀC; IR (KBr): 2960 (C―H, stretching), 2174
(CN), 1645 (CO), 1449 (N═N); ms: (m/z, %): 449 (M+, 0.3),
342 (57.2), 324 (10.3), 309 (100.0), 215 (14.8), 169 (21.8), 84
(24.8), 73 (34.9), 56 (22.0). Anal. Calcd. for C23H27N7O3
(449.51): C, 61.46; H, 6.05; N, 21.81%. Found: C, 61.55; H,
6.11; N, 21.87%.
Synthesis of 4-(2,4-dimercapto-6-piperidin-1-yl-pyrimidin-
5-ylazo)-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (22).
A solution of 3 (1.47 g, 4 mmol) in a mixture of dry pyridine
(25 mL) and carbon disulphide (10 mL) was refluxed on
Synthesis of N-[2-cyano-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-ylazo)-1-piperidin-1-yl-vinyl]-formimidic
acid ethyl ester (18). A mixture of 3 (1.84 g, 5 mmol) and
triethyl orthoformate (0.83 mL, 5 mmol) in acetic anhydride
a water bath for 8 h and allowed to stand at room
temperature for two days. The solution was then triturated
with aqueous ethanol (50 mL). The precipitated solid was
filtered off and recrystallized from DMF-EtOH mixture to
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

780
A. A. Fadda, H. A. Etman, M. Y. El-Seidy, and K. M. Elattar
Vol 49
afford 22 as dark red crystals (81%). m.p.: 167ꢀC; IR (KBr):
2573 (2SH), 1639 (CO), 1494 (N═N); 1H-NMR (400 MHz,
DMSO-d6): d, 1.58–1.68 (m, 6H, 3CH2, piperidine), 2.42
(s, 3H, CH3), 3.09 (s, 3H, N―CH3), 3.55–3.65 (m, 4H,
2CH2, piperidine), 7.17–7.52 (m, 7H, Ar-H, 2SH); ms:
(m/z, %): 438 (M+-3, 0.5), 342 (13.1), 187 (100.0), 144 (5.4),
121 (25.8), 88 (44.0), 56 (49.2). Anal. Calcd. for C20H23N7OS2
(441.57): C, 54.40; H, 5.25; N, 22.20%. Found: C, 54.51; H,
5.28; N, 22.27%.
6.93–7.51 (m, 5H, Ar-H), 10.81 (br, s, 2H, 2NH), ms:
(m/z, %): 503 (M+, 0.41), 286 (70.0), 271 (22.34), 229 (9.16),
200 (38.0), 168 (17.04), 86 (100.0), 77 (62.9). Anal. calcd for
C25H26N8O2S (502.59): C, 59.74; H, 5.21; N, 22.30%. Found:
C, 59.81; H, 5.29; N, 22.37%.
4-{6-Amino-4-[methyl-(2,3,4,5,6-pentahydroxy-hexyl)-amino]-
1-phenyl-2-thioxo-1,2-dihydro-pyrimidin-5-ylazo}-1,5-dimethyl-
2-phenyl-1,2-dihydro-pyrazol-3-one (25c). Yield (60%). m.p.
187ꢀC; IR (KBr) ύ (cmꢁ1), 3453, 3446 (OH), 3109 (NH),
2962 (C―H, stretching), 1658 (CO), 1446 (N═N), 1230
Synthesis of [2-cyano-2-(1,5-dimethyl-3-oxo-2-phenyl-
2,3-dihydro-1H-pyrazol-4-ylazo)-1-piperidin-1-yl-vinyl]-
1
(C═S); H-NMR (400 MHz, DMSO-d6): d, 2.47 (s, 3H, CH3),
3.16 (s, 3H, N―CH3), 3.01–4.52 (sugar moiety protons),
7.15–7.65 (m, 5H, Ph), 11.12 (br., s, 2H, 2NH); ms: (m/z, %):
590 [(M+-2)-H2O, 4.3], 589 (M+-3-H2O, 5.2), 181 (48.3), 136
(50.0), 93 (100.0), 51 (87.9). Anal. calcd for C28H34N8O6S
(610.68): C, 55.07; H, 5.61; N, 18.35%. Found: C, 55.13; H,
5.66; N, 18.40%.
dithiocarbamic acid methyl ester (24).
To a vigorously
stirred solution of enaminonitrile 3 (7.35 g, 0.02 mol) in
dimethylformamide (10 mL) at room temperature, carbon
disulphide (1.57 mL, 0.026 mol) and aqueous sodium hydroxide
(1.2 mL, 20 mol solution) were added simultaneously over
30 min. Stirring was continued for a further 30 min. Dimethyl
sulphate (1.9 mL g, 0.02 mol) was added dropwise to the
reaction mixture with stirring at 5–10ꢀC; it was further stirred
for 3 h and poured into ice-water; the solid obtained was
filtered, dried, and recrystallized from ethanol to afford 24 as
orange powder (88%). m.p. 152ꢀC; IR (KBr) cmꢁ1: 3151
(NH), 2173 (CN), 1641 (C═O), 1494 (N═N), 1178 (C═S);
1H-NMR (400 MHz, DMSO-d6): d, 1.59–1.71 (m, 6H, 3CH2,
piperidine), 2.44 (s, 3H, CH3), 2.91 (s, 3H, SCH3), 3.10
(s, 3H, N―CH3), 3.56–3.64 (m, 4H, 2CH2, piperidine),
7.15–7.50 (m, 5H, Ar-H), 7.97 (br, s, 1H, NH), ms: (m/z, %):
455 (M+, 29.6), 384 (30.4), 288 (24.2), 239 (60.1), 188 (43.5),
175 (57.8), 144 (47.8), 84 (78.8), 70 (45.2). Anal. calcd for
C21H25N7OS2 (455.60): C, 55.36; H, 5.53; N, 21.52%. Found:
C, 55.41; H, 5.58; N, 21.61%.
Synthesis of 4-((4-amino-5-benzoyl-6-(4-chlorophenyl)-2-
morpholinopyridin-3-yl)diazenyl)-1,5-dimethyl-2-phenyl-1H-
pyrazol-3(2H)-one (27). A mixture of 4 (1.85 g, 5 mmol) and
3-(4-chloro-phenyl)-1-phenyl-propenone (1.21 g, 5 mmol) in
DMF-EtOH mixture (15 mL, 1:3) in the presence of catalytic
amount of triethylamine (5 drops) was refluxed for 15 h. The
reaction mixture was poured into ice cold water, the formed solid
product was filtered, dried, and crystallized from DMF-EtOH
(1:4) to yield 27 as dark brown powder (67%). m.p.: 118–120ꢀC;
IR (KBr) ύ (cmꢁ1), 3388, 3346 (NH2), 1683, 1637 (2CO), 1493
1
(N═N); H-NMR (400 MHz, DMSO-d6): d, 2.43 (s, 3H, CH3),
3.17 (s, 3H, N―CH3), 3.55–3.93 (m, 8H, 4CH2, morpholine),
7.05–8.35 (m, 16H, Ar-H, NH2); ms: (m/z, %): 617 (M++7, 1.6),
342 (24.9), 241 (100.0), 215 (36.7), 177 (34.7), 136 (19.5), 114
(10.8), 99 (42.0), 73 (93.7). Anal. Calcd. for C33H30ClN7O3
(608.09): C, 65.18; H, 4.97; N, 16.12%. Found: C, 65.24; H,
5.03; N, 16.17%.
Synthesis of 4-(2-(4-(substituted)-6-imino-1-phenyl-2-
thioxotetrahydro-pyrimidin-5(6H)-ylidene)hydrazinyl)-1,5-
dimethyl-2-phenyl-1H-pyrazol-3(2H)-ones (25a–c). An equimolar
mixture of 3 (1.84 g, 5 mmol) or 4 (1.85 g, 5 mmol) or 5
(2.39 g, 5 mmol) and phenyl isothiocyanate (0.6 mL, 5
mmol) in EtOH-DMF mixture (3:1, 20 mL) in the presence
of catalytic amount of TEA (four drops) was refluxed for 21
h. The reaction mixture was left to cool and poured into
cold water for complete precipitation. The separated solid
was filtered off, washed with water, dried well, and
recrystallized from ethanol to yield pyrimidine derivatives
25a–c.
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Yield (50%). m.p. 157ꢀC; IR (KBr) ύ (cmꢁ1),
3193 (NH), 2964 (C―H, stretching), 1643 (CO), 1452 (N═N),
1
1216 (C═S); H-NMR (400 MHz, DMSO-d6): d, 1.55–1.67 (m,
6H, 3CH2, piperidine), 2.61 (s, 3H, CH3), 3.22 (s, 3H, N―CH3),
3.53–3.66 (m, 4H, 2CH2, piperidine), 7.38–7.56 (m, 5H, Ph),
10.86 (br, s, 2H, 2NH); ms: (m/z, %): 500 (M+, 0.21), 284 (9.13),
283 (8.57), 227 (8.13), 200 (7.77), 109 (13.5), 84 (100.0), 77
(90.0). Anal. calcd for C26H28N8OS (500.62): C, 62.38; H, 5.64;
N, 22.38%. Found: C, 62.46; H, 5.74; N, 22.43%.
4-(6-Amino-4-morpholin-4-yl-1-phenyl-2-thioxo-1,2-dihydro-
pyrimidin-5-ylazo)-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-
3-one (25b). Yield (57%). m.p. 193ꢀC; IR (KBr) ύ (cmꢁ1),
3183 (NH), 2958 (C―H, stretching), 1647 (CO), 1462
(N═N), 1209 (C═S); 1H-NMR (400 MHz, DMSO-d6): d,
2.24–2.29 (m, 4H, 2CH2, morpholine), 2.43 (s, 3H, CH3), 3.17
(s, 3H, N―CH3), 3.34–3.71 (m, 4H, 2CH2, morpholine),
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Utility of Enaminonitriles in Heterocyclic Synthesis: Synthesis of Some New Pyrazole,
Pyridine, and Pyrimidine Derivatives
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DOI 10.1002/jhet