Synthesis and antioxidant assay of new nicotinonitrile analogues clubbed thiazole, pyrazole and/or pyridine ring systems

Article abstract of DOI:10.1002/jhet.3820

A series of novel nicotinonitrile derivatives were synthesized by hybridization with thiazole, pyrazole, and pyridine ring systems using 4-aminobenzohydrazide as link-bridge. The synthetic strategy of nicotinonitrile-thiazole analogues involves cyclizatio

Full text of DOI:10.1002/jhet.3820

Received: 20 September 2019
DOI: 10.1002/jhet.3820
Revised: 16 October 2019
Accepted: 27 October 2019
A R T I C L E
Synthesis and antioxidant assay of new nicotinonitrile
analogues clubbed thiazole, pyrazole and/or pyridine ring
systems
Hana M.A. Abumelha
Department of Chemistry, Faculty of
Abstract
Science, Princess Nourah Bint
Abdulrahman University, Riyadh, Saudi
Arabia
A series of novel nicotinonitrile derivatives were synthesized by hybridization
with thiazole, pyrazole, and pyridine ring systems using 4-
aminobenzohydrazide as link-bridge. The synthetic strategy of nicotinonitrile-
thiazole analogues involves cyclization of the precursor N-phenyl
thiosemicarbazide derivative 4 with chloroacetic acid and phenacyl bromide.
The reaction of hydrazide 3 with acetylacetone and/or ethyl acetoacetate was
applied as a synthetic route for accessing 2-((4-(pyrazole-1-carbonyl)phenyl)
amino)-nicotinonitrile derivatives 9–10. The 2-((4-(4-thiazolylidene-pyrazole-1-
carbonyl)-phenyl)amino)nicotinonitriles 14–15 were obtained via a nucleo-
philic addition of pyrazolone 10 to phenyl isothiocyanate followed by cycliza-
tion with chloroacetone, phenacyl chloride, and/or ethyl bromoacetate. The 6-
amino-4-aryl-3,5-dicyano-2-oxo-1-(4-substitutedbenzamido)-pyridines 19 were
synthesized by Knoevenagel condensation N0-(2-cyanoacetyl)-benzohydrazide
derivative 16 with substituted benzaldehydes followed by heating with
malononitrile. All synthesized products were evaluated for their antioxidant
potentialities using of 2,20-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)
(ABTS) radical cation delcolorization assay. The nicotinonitrile-thiazole hybrid
6b was found the most promising antioxidant agent with inhibition activ-
ity 86.27%.
Correspondence
Hana M. A. Abumelha, Department of
Chemistry, Faculty of Science, Princess
Nourah Bint Abdulrahman University,
Riyadh 84428, Saudi Arabia.
Email: hmaabumelha@gmail.com
Funding information
Deanship of Scientific Research at Princess
Nourah Bint Abdelulrahman University
through the Fast-track Research Funding
Program.
cholesterol and triglyceride regulator,[7] antitubercular,[8]
antidiabetic,[9] antihistaminic,[10] anti-inflammatory,[11]
1 | INTRODUCTION
antiproliferative,[12] and anticancer activities.[13–15] One
of the most important pyridine derivatives is
nicotinonitrile as a result of its exhibited unique biologi-
cal and pharmacological properties. 2-Amino-6-furanyl-
nicotinonitrile derivatives were reported as A2A adeno-
Pyridine is a key heterocyclic motif within a variety of
synthetic and naturally occurring bioactive com-
pounds.[1] Pyridine derivatives are distinct class of hetero-
cyclic-compounds. They display abroad spectrum of
bioactivities, making them attractive scaffolds for poten-
tial industrial pharmaceutical applications.[2,3] Many pyr-
idine-containing compounds display fabulous medicinal
potentialities, including hypnotic and sedative,[4] bone
sine
receptor
antagonists.[16]
2-Alkoxy-4-
aminonicotinonitrile derivatives were documented as
JNK inhibitors, serving as therapeutic methodology for
inflammatory diseases such as asthma, stroke, or
calcium
regulator,[5]
microtubule-destabilizing,[6]
J Heterocyclic Chem. 2020;1–12.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
ABUMELHA
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
The chlorine position of 2-chloronicotinonitrile derivative
1[39] was proved to be active toward nucleophilic
substitution by nitrogen-containing nucleophiles such as
ethyl 4-aminobenzoate to afford ethyl 4-(3-cyano-pyridin-
FIGURE 1 Nicotinonitrile containing-compounds as
phosphodiesterase-3 inhibitors
2-ylamino)benzoate
2 (Scheme 1). The compatible
elemental and spectral analyses supported the proposed
structure of benzoate 2. The hydrazide derivative 3 was
achieved by refluxing ethyl 4-(3-cyano-pyridin-2-
ylamino)benzoate 2 with hydrazine hydrate in ethyl alco-
hol for 2 hours. Subsequently, the conversion of hydra-
zide 3 into its conforming N-phenyl thiosemicarbazide
derivative 4 has been achieved through heating with phe-
nyl isothiocyanate in ethanol.
Alzheimer's disease.[17] Furthermore, many reports have
been published, demonstrating the inhibitory properties
of nicotinonitriles toward PKCq, a member of protein
kinase
C
family belongs to serine/threonine
kinases.[18–21] Additionally, Milrinone (A) and Olprinone
(B) were reported as phosphodiesterase-3 inhibitors and
cardiotonic agents (Figure 1).[22,23] Nicotinonitrile nucle-
osides have attracted attention because of their motivat-
The N-phenyl thiosemicarbazide derivative 4 was
employed as a starter for constructing thiazole ring
through its treatment with various α-halogenated car-
bonyl reagents. Derivative 4 was boiled with chloroacetic
acid in ethanol in the presence of sodium acetate to pro-
ing
pharmacological
activities
as
antiviral,[24]
antitumor,[25] antibacterial,[26] anticancer,[27] antioxi-
dants,[28,29] and other biological activity.[30–32] Moreover,
several thiazole,[33,34] pyrazole,[35,36] and pyridine[37,38]
moieties were reported to possess antioxidant activity.
Thus, the convergent synthetic strategy of the titled het-
erocyclic hybrids was carried out with three objectives.
(a) Synthesis of nicotinonitrile scaffold of the type 3,
which allow for further chemical modification through
its 4-aminobenzohydrazide moiety. (b) Molecular hybrid-
ization of nicotinonitrile nucleus with other effective
antioxidant moieties such as thiazole, pyrazole, and pyri-
dine. (c) Evaluating the antioxidant properties of the syn-
thesized nicotinonitrile-clubbed thiazole, pyrazole, and
pyridine hybrids.
duce
N0-(4-oxo-3-phenylthiazolidin-2-ylidene)-
benzohydrazide derivative 5, which undergoes
Knoevenagel condensation with variety of substituted
benzaldehydes (namely; 4-tolualdehyde, 4-anisaldehyde
and/or 4-chlorobenzaldehyde). Such condensation
requires heating the reaction mixture in acetic acid and
sodium acetate to furnish the corresponding 5-arylidene-
thiazolidin-4-one compounds 6a-c (Scheme 2). The reac-
tion of 4 with phenacyl bromide was performed in boiling
ethanol and triethylamine to yield 4-((3-cyano-4,6-dim-
ethylpyridin-2-yl)amino)-N0-(3,4-diphenylthiazol-2(3H)-
ylidene)-benzohydrazide (7). The fifth position of thia-
zole moiety in compound 7 is highly reactive toward elec-
trophilic coupling reactions with different diazotized
SCHEME 1 Synthesis of benzohydrazide and N-phenyl
thiosemicarbazide derivatives 3 and 4

ABUMELHA
3
substituted anilines (4-toluidine, 4-anisidine and/or 4-
chloroaniline). The diazo-coupling reactions were
achieved in pyridine at 0–5ꢀC to yield the corresponding
5-arylazo-3,4-diphenylthiazoles 8a-c.
Hydrazide 3 was boiled with acetyl acetone in ethanol
and in the presence of 1 mL acetic acid to afford, 2-((4-
(3,5-dimethyl-1H-pyrazole-1-carbonyl)phenyl)amino)-
4,6-dimethylnicotinonitrile (9). Similarly, the reaction of
hydrazide 3 with ethyl acetoacetate was carried out in
boiling ethanol and 1 mL of acetic acid to furnish the
corresponding 2-((4-(3-methyl-5-oxo-1H-pyrazole-1-car-
(Scheme 4). In situ addition of α-chloroketone reagents
(chloroacetone and phenacyl chloride) to the nonisolated
potassium salt 12 was achieved by stirring at room
temperature and yielded corresponding thiazoline
derivatives 14a and 14b, respectively. However, in situ
addition of ethyl bromoacetate to the nonisolated
potassium salt 12 afforded the corresponding
thiazolidine-4-one 15.
Cyanoacetylation of the hydrazide 3 was successfully
achieved by heating with 1-(cyanoacetyl)-3,5-dimethyl-
1H-pyrazole in dioxane to produce the conforming N0-(2-
cyanoacetyl)-benzohydrazide 16 (Scheme 5). The reaction
of 16 with mercaptoacetic acid has been accomplished in
boiling pyridine to produce the corresponding N0-(2-(4-
oxothiazolidin-2-ylidene)acetyl)benzohydrazide deriva-
tive 17. The methylene group of N0-(2-cyanoacetyl)-
benzohydrazide 16 was subjected toward Knoevenagel
condensation with substituted benzaldehydes (4-
bonyl)phenyl)amino)-nicotinonitrile
derivative
10
(Scheme 3). Diazocoupling of 10 with three types of diaz-
otized para substituted anilines (4-toluidine, 4-anisidine,
and/or 4-chloroaniline) was performed in ethanol and
sodium acetate to give the corresponding arylhydrazones
11a, 11b, and 11c, respectively.
Addition of 10 through its active methylene group to
phenyl isothiocyanate has been achieved by stirring in
dimethylformamide/potassium hydroxide to furnish the
nonisolated sulfide salt 12, which upon neutralization
with dilute HCl gave 2-((4-(4-(mercapto (phenylamino)
methylene)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-1-
carbonyl)phenyl)amino)-4,6-dimethylnicotinonitrile 13
tolualdehyde,
4-anisaldehyde,
and/or
4-chlo-
robenzaldehyde). The condensation proceeded success-
fully in boiling ethanol and piperidine to yield the
corresponding
N0-(2-cyano-3-arylacryloyl)-4-sub-
stitutedbenzohydrazide derivatives 18a-c, which were
heated with malononitrile in ethanol and piperidine to
SCHEME 2 Synthesis of nicotinonitrile-
thiazole hybrids 5–8

4
ABUMELHA
SCHEME 3 Synthesis of nicotinonitrile-pyrazole
hybrids 9–11
furnish the corresponding 6-amino-4-aryl-3,5-dicyano-2-
oxo-1-(4-substitutedbenzamido)-pyridines 19a-c. The
reaction mechanism started with the nucleophilic
Michael addition of malononitrile to the ß-carbon of the
unsaturated nitrile part to constitute the intermediate
Michael adduct, which undergoes intramolecular cycliza-
autoxidation of the tetrahydropyridine intermediate
furnished the final pyridine derivatives 19.
2.2 | Antioxidant activity
The antioxidant properties (Table 1) of the synthesized
nicotinonitrile-based compounds were screened by using
tion between the
NH and nitrile. Finally, air
SCHEME 4 Synthesis of nicotinonitrile-pyrazole-
thiazole hybrids 14 and 15

ABUMELHA
5
SCHEME 5 Synthesis of nicotinonitrile-
thiazole and nicotinonitrile-pyridone hybrids 17
and 19
the
2,20-azino-bis(3-ethylbenzothiazoline-6-sulphonic
3 | CONCLUSIONS
acid) (ABTS) radical cation decolorization assay.[40] The
results indicated that clubbing between the
nicotinonitrile moiety and thiazole ring in compounds
6a-c promoted the antioxidant activity to the highest per-
cent inhibition ranged from 82.15% to 86.27%. The inhibi-
tion of these 5-arylidene-thiazolidin-4-ones 6a-c was very
close to that observed by the reference antioxidant L-
Ascorbic acid (88.23%). Structure–activity analysis of the
three nicotinonitrile-clubbed thiazole compounds rev-
ealed that the presence of methoxy substituent in com-
pound 6b is correlated with the highest inhibition
(86.27%). Structural-analysis of compounds 15 and 17
reflected again that the combination between
nicotinonitrile and thiazole moieties was responsible for
the increment in the inhibition 81.96% and 79.60%,
respectively. The nicotinonitrile derivatives, N-(6-amino-
4-aryl-3,5-dicyano-2-oxopyridin-1(2H)-yl)-4-((3-cyano-4,6-
dimethylpyridin-2-yl)amino)benzamides 19a, 19b, and
19c promoted acceptable increment in the antioxidant
activity with percent inhibition from 74.50%, 79.21%, and
78.03%. The derivatives of 2-((4-(pyrazole-1-carbonyl)phe-
nyl)amino)-nicotinonitriles 9 and 10 displayed acceptable
antioxidant activity with percent inhibition 75.68% and
78.82%, respectively.
This article reports a facile synthesis, spectroscopic char-
acterization, and antioxidant evaluation of the
nicotinonitrile-thiazole, pyrazole, or pyridine hybrids.
The synthetic tactic started by preparation of the precur-
sor, 4-((3-cyanopyridin-2-yl)amino)benzohydrazide deriv-
ative 3. The synthesis of nicotinonitrile-thiazole hybrids
5–8 involves conversion of benzohydrazide 3 into N-phe-
nyl thiosemicarbazide derivative 4 followed by treatment
with chloroacetic acid and phenacyl bromide. The syn-
thesis of nicotinonitrile-pyrazole hybrids 9–10 was
accomplished by the reaction of benzohydrazide 3 with
acetylacetone
and/or
ethyl
acetoacetate.
The
benzohydrazide 3 was cyanoacetylated into the con-
forming N0-(2-cyanoacetyl)-benzohydrazide derivative 16,
which subjected to Knoevenagel condensation with
substituted benzaldehydes and the product, N0-(2-cyano-
3-arylacryloyl)-4-substitutedbenzohydrazides 18 were
heated with malononitrile to yield the corresponding 6-
amino-4-aryl-3,5-dicyano-2-oxo-1-(4-sub-
stitutedbenzamido)-pyridines 19. Among the tested
nicotinonitrile-based compounds, the best antioxidant
potentiality was displayed by 6b, followed by 6c, 6a,
and 15.

6
ABUMELHA
TABLE 1 Antioxidant properties of the synthesized
nicotinonitrile-based compounds
on Quadrupole GC–MS (DSQII) mass spectrometer at 70
eV. Elemental analyses of carbon, hydrogen, and nitro-
gen were estimated on Perkin Elmer 2400 analyzer. The
antioxidant assay has been performed at the microbiology
unit, Cairo University, Egypt.
ABTS inhibition (%) = [abs.
(control)−abs. (sample)] /abs.
Method
(control) × 100
Compound
number
Absorbance of
samples
%
inhibition
4.1 | Synthesis of ethyl 4-((3-cyano-4,6-
dimethylpyridin-2-yl)amino)-benzoate (2)
Control of ABTS
0.510
0.060
0.210
0.221
0.181
0.151
0.091
0.070
0.077
0.149
0.229
0.222
0.254
0.124
0.108
0.215
0.177
0.192
0.138
0.128
0.122
0.092
0.216
0.104
0.156
0.145
0.143
0.130
0.106
0.112
0
L-ascorbic acid
88.23
58.82
56.66
64.50
70.39
82.15
86.27
84.90
70.78
55.09
56.47
50.19
75.68
78.82
57.84
65.29
62.35
72.94
74.90
76.07
81.96
57.64
79.60
69.41
71.56
71.96
74.50
79.21
78.03
To a suspension of 2-chloro-4,6-dimethylnicotinonitrile
(1) (1.66 g, 0.01 mol) and ethyl p-aminobenzoate (1.65 g,
0.01 mol) in ethyl alcohol (30 mL), 1 mL conc. HCl was
added. The reaction mixture was subjected to heating
under reflux for 6 hours and then cooled to 25ꢀC. The
white precipitate was collected, dried, and recrystallized
from ethyl alcohol.
2
3
4
5
6a
6b
6c
White powder, yield = 60%, m.p. = 140–141ꢀC. IR:
1
3309 (N-H), 2222 (C N), 1712 cm−1 (C O). H NMR
7
(DMSO-d6): 1.31 (t, J = 7.00 Hz, 3H), 2.39 (s, 3H), 2.41 (s,
3H), 4.28 (q, J = 7.00 Hz, 2H, CH2), 6.87 (s, 1H, pyridine
H-5), 7.74 (d, J = 8.40 Hz, 2H), 7.87 (d, J = 8.40 Hz, 2H),
9.34 ppm (s, 1H, NH). MS m/z (%): 295 (M+, 65.48), 131
(100.00). Analysis for C17H17N3O2 (295): Calcd: C, 69.14;
H, 5.80; N, 14.23%. Found: C, 69.22; H, 5.78; N, 14.17%.
8a
8b
8c
9
10
11a
11b
11c
13
4.2 | Synthesis of 4-((3-cyano-4,6-
dimethylpyridin-2-yl)amino)-
benzohydrazide (3)
To a suspension of ethyl benzoate derivative 2 (2.95 g,
0.01 mol) in ethyl alcohol (30 mL), hydrazine hydrate
(1 mL, 0.02 mol) was added. The reaction components
was refluxed for 8 hours and then cooled to 25ꢀC. The
precipitate was collected by filtration and then rec-
rystallized from ethyl alcohol.
14a
14b
15
16
17
White crystals, yield = 52%, m.p. = 240–242ꢀC. IR:
3340, 3287 (NH2 and N-H), 2217 (C N), 1611 cm−1
18a
18b
18c
19a
19b
19c
1
(C O). H NMR (DMSO-d6): 2.35 (s, 3H), 2.37 (s, 3H),
4.44 (s, 2H, NH2), 6.80 (s, 1H, pyridine H-5), 7.65 (d, J =
9.00 Hz, 2H), 7.74 (d, J = 8.00 Hz, 2H), 9.14 (s, 1H, NH),
9.60 ppm (s, 1H, NH). Analysis for C15H15N5O (281):
Calcd: C, 64.04; H, 5.37; N, 24.90%. Found: C, 64.15; H,
5.34; N, 24.96%.
4 | EXPERIMENTAL
4.3 | Synthesis of 2-(4-((3-cyano-4,6-
dimethylpyridin-2-yl)amino)benzoyl)-N-
phenylhydrazine-1-carbothioamide (4)
Melting points were determined on Gallenkamp electric
device and were uncorrected. The infrared spectra (potas-
sium bromide discs) were registered on Thermo Scientific
Nicolet iS10 FTIR spectrometer. The 1H NMR spectra
were acquired in CDCl3 or DMSO-d6 on JEOL's spec-
trometer at 500 MHz. The mass spectra were determined
To a solution of benzohydrazide 3 (1.40 g, 0.005 mol) in
ethyl alcohol (30 mL), phenyl isothiocyanate (0.60 mL,
0.005 mol) was added. The reaction solution was kept
under reflux for 4 hours and then left to cool. The yellow

ABUMELHA
7
solid that formed was collected by filtration technique to
obtain the N-phenyl thiosemicarbazide derivative 4.
Yellow powder, yield = 64%, m.p. = 204–205ꢀC. IR:
3326, 3241, 3168 (N-H), 2212 (C N), 1644 cm−1 (C O).
1H NMR (DMSO-d6): 2.40 (s, 3H), 2.44 (s, 3H), 6.83 (s,
1H, pyridine H-5), 7.14–7.56 (m, 5H), 7.68 (d, J = 9.00
Hz, 2H), 7.77 (d, J = 8.50 Hz, 2H), 8.76 (s, 1H, NH), 9.58
(s, 1H, NH), 10.24 (s, 1H, NH), 11.62 ppm (s, 1H, NH).
MS m/z (%): 416 (M+, 32.17), 280 (100.00). Analysis for
C22H20N6OS (416): Calcd: C, 63.44; H, 4.84; N, 20.18%.
Found: C, 63.28; H, 4.91; N, 20.29%.
4.5.1 | 4-((3-Cyano-4,6-dimethylpyridin-2-
yl)amino)-N0-(5-(4-methylbenzylidene)-4-
oxo-3-phenylthiazolidin-2-ylidene)
benzohydrazide (6a)
Yellow solid, yield = 68%, m.p. = 294–296ꢀC. IR: 3254,
1
3168 (N H), 2211 (C N), 1660, 1692 cm−1 (C O). H
NMR (DMSO-d6): 2.39 (s, 3H), 2.43 (s, 6H, 2 CH3), 6.84
(s, 1H, pyridine H-5), 7.33–7.71 (m, 12H, Ar-H and ole-
finic HC C), 7.81 (d, J = 8.50 Hz, 2H), 10.62 (s, 1H, NH),
11.34 ppm (s, 1H, NH). MS m/z (%): 558 (M+, 22.36), 308
(100.00). Analysis for C32H26N6O2S (558): Calcd: C, 68.80;
H, 4.69; N, 15.04%. Found: C, 68.65; H, 4.75; N, 15.15%.
4.4 | Synthesis of 4-((3-cyano-4,6-
dimethylpyridin-2-yl)amino)-N0-(4-oxo-3-
phenylthiazolidin-2-ylidene)
benzohydrazide (5)
4.5.2 | 4-((3-Cyano-4,6-dimethylpyridin-2-
yl)amino)-N0-(5-(4-methoxybenzylidene)-4-
oxo-3-phenylthiazolidin-2-ylidene)
benzohydrazide (6b)
To a suspension of N-phenyl thiosemicarbazide derivative
4 (1.66 g, 0.004 mol) and anhydrous sodium acetate (0.6
g) in 40 mL ethanol, chloroacetic acid (0.38 g, 0.004 mol)
was added. The reaction components were refluxed for 6
hours and left to cool. The yellow powder that formed
was filtered and dried to give the target, 4-oxo-3-
phenylthiazolidin-2-ylidene)-benzohydrazide 5.
Yellow powder, yield = 74%, m.p. = 264–265ꢀC. IR:
3273, 3182 (N H), 2217 (C N), 1655, 1721 cm−1 (C O).
1H NMR (DMSO-d6): 2.39 (s, 3H), 2.43 (s, 3H), 4.02 (s,
2H, CH2), 6.91 (s, 1H, pyridine H-5), 7.31–7.58 (m, 5H),
7.64 (d, J = 8.50 Hz, 2H), 7.78 (d, J = 8.50 Hz, 2H), 10.67
(s, 1H, NH), 11.12 ppm (s, 1H, NH). MS m/z (%): 456
(M+, 14.78), 222 (100.00). Analysis for C24H20N6O2S
(456): Calcd: C, 63.14; H, 4.42; N, 18.41%. Found: C,
63.25; H, 4.48; N, 18.34%.
Yellow solid, yield = 71%, m.p. > 300ꢀC. IR: 3248, 3174
1
(N H), 2209 (C N), 1658, 1687 cm−1 (C O). H NMR
(DMSO-d6): 2.38 (s, 3H), 2.43 (s, 3H), 3.82 (s, 3H, OCH3),
6.88 (s, 1H, pyridine H-5), 7.02 (d, J = 8.00 Hz, 2H), 7.31–
7.68 (m, 10H, Ar-H and olefinic CH C), 7.77 (d, J = 8.50
Hz, 2H), 10.58 (s, 1H, NH), 11.09 ppm (s, 1H, NH). Anal-
ysis for C32H26N6O3S (574): Calcd: C, 66.88; H, 4.56; N,
14.62%. Found: C, 66.97; H, 4.54; N, 14.70%.
4.5.3 | N0-(5-(4-Chlorobenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)-4-((3-cyano-
4,6-dimethylpyridin-2-yl)amino)
benzohydrazide (6c)
Yellowish brown solid, yield = 61%, m.p. > 300ꢀC. IR:
3262, 3170 (N H), 2211 (C N), 1661, 1690 cm−1 (C O).
1H NMR (DMSO-d6): 2.39 (s, 3H), 2.42 (s, 3H), 6.87 (s,
1H, pyridine H-5), 7.38–7.70 (m, 12H, Ar-H and olefinic
CH C), 7.78 (d, J = 8.50 Hz, 2H), 10.58 (s, 1H, NH),
10.96 ppm (s, 1H, NH). Analysis for C31H23ClN6O2S
(578): Calcd: C, 64.30; H, 4.00; N, 14.51%. Found: C,
64.51; H, 4.09; N, 14.64%.
4.5 | Synthesis of N0-(5-arylidene-4-oxo-3-
phenylthiazolidin-2-ylidene)-4-((3-cyano-
4,6-dimethylpyridin-2-yl)amino)
benzohydrazides 6a-c
A suspension of 4-oxo-3-phenylthiazolidin-2-ylidene)-
benzohydrazide derivative 5 (0.91 g, 0.002 mol) and the
appropriate benzaldehyde derivative (namely; 4-
4.6 | Synthesis of 4-((3-cyano-4,6-
dimethylpyridin-2-yl)amino)-N0-(3,4-
diphenyl-thiazol-2(3H)-ylidene)
benzohydrazide (7)
tolualdehyde,
4-anisaldehyde
and/or
4-chlo-
robenzaldehyde) (0.002 mol) in 15 mL acetic acid and 0.5
g sodium acetate was refluxed for 4 hours. The reaction
solution was cooled and diluted with 10 g of crushed ice.
The solid that acquired was recrystallized from acetic
acid to furnish the corresponding 5-arylidene-thiazolidin-
4-ones 6a-c.
To a solution of N-phenyl thiosemicarbazide derivative 4
(1.66 g, 0.004 mol) in 30 mL of ethanol and 0.5 mL of
triethylamine, phenacyl bromide (0.79 g, 0.004 mol) was
added. The reaction components were refluxed for 3

8
ABUMELHA
hours. The precipitate that acquired on cooling was col-
lected to give the conforming N0-(3,4-diphenylthiazol-
2(3H)-ylidene)benzohydrazide 7.
Analysis for C37H30N8O2S (650): Calcd: C, 68.29; H, 4.65;
N, 17.22%. Found: C, 68.13; H, 4.68; N, 17.14%.
Yellow solid, yield = 82%, m.p. = 188–189ꢀC. IR: 3247,
4.7.3 | N0-(5-((p-Chlorophenyl)azo)-3,4-
diphenylthiazol-2(3H)-ylidene)-4-((3-cyano-
4,6-dimethylpyridin-2-yl)amino)
benzohydrazide (8c)
1
3196 (N H), 2217 (C N), 1651 cm−1 (C O). H NMR
(DMSO-d6): 2.37 (s, 3H), 2.41 (s, 3H), 6.87 (s, 1H, pyridine
H-5), 7.03 (s, 1H, thiazole-H5), 7.18–7.77 (m, 14H), 10.16
(s, 1H, NH), 10.78 ppm (s, 1H, NH). MS m/z (%): 516
(M+, 41.06), 132 (100.00). Analysis for C30H24N6OS (516):
Calcd: C, 69.75; H, 4.68; N, 16.27%. Found: C, 69.58; H,
4.60; N, 16.16%.
Reddish brown solid, yield = 73%, m.p. = 267–268ꢀC. IR:
1
3263, 3209 (N H), 2215 (C N), 1655 cm−1 (C O). H
NMR (DMSO-d6): 2.39 (s, 3H), 2.43 (s, 3H), 6.90 (s, 1H,
pyridine H-5), 7.18–7.78 (m, 18H), 10.41 (s, 1H, NH),
10.86 ppm (s, 1H, NH). Analysis for C36H27ClN8OS (654):
Calcd: C, 66.00; H, 4.15; N, 17.10%. Found: C, 66.22; H,
4.24; N, 17.14%.
4.7 | Synthesis of 4-((3-cyano-4,6-
dimethylpyridin-2-yl)amino)-N0-(3,4-
diphenyl-5-arylazo-thiazol-2(3H)-ylidene)
benzohydrazides 8a-c
4.8 | Synthesis of 2-((4-(3,5-dimethyl-1H-
pyrazole-1-carbonyl)phenyl)amino)-4,6-
dimethylnicotinonitrile (9)
The appropriate aniline derivative (4-toluidine, 4-
anisidine and/or 4-chloroaniline) (0.002 mol) was
suspended in 0.6 mL of conc. HCl at 0–5ꢀC and then
diazotized with NaNO2 solution (0.14 g in 10 mL water).
The diazonium salt that obtained was added to a solution
of 4-((3-cyano-4,6-dimethylpyridin-2-yl)amino)-N0-(3,4-
diphenylthiazol-2(3H)-ylidene)benzohydrazide (7) (1.03
g, 0.002 mol) in 15 mL of pyridine. The mixture was
stirred at 0–5ꢀC for 2 hours and then diluted with 10 mL
of ice water. The red solid that produced was separated
by filtration and recrystallized from ethanol to give con-
forming 5-arylazo-3,4-diphenylthiazoles 8a-c.
A
solution of 4-((3-cyano-4,6-dimethylpyridin-2-yl)
amino)-benzohydrazide (3) (1.40 g, 0.005 mol) and
acetylacetone (0.50 mL, 0.005 mol) in 40 mL of ethyl
alcohol and 1 mL of acetic acid was heated under reflux
for 5 hours. After cooling, white crystals were collected
by filtration and dried to give the conforming pyrazole-
nicotinonitrile derivative 9.
White crystals, yield 83%, m.p. = 188–189ꢀC. IR (KBr):
1
3308 (N H), 2217 (C N), 1660 cm−1 (C O). H NMR
(CDCl3): 2.30 (s, 6H, 2 CH3), 2.34 (s, 3H), 2.58 (s, 3H),
6.12 (s, 1H, pyrazole H-5), 6.57 (s, 1H, pyridine H-5), 7.78
(d, J = 8.40 Hz, 2H), 7.90 (d, J = 8.40 Hz, 2H), 11.48 ppm
(s, 1H, NH). Analysis for C20H19N5O (345): Calcd: C,
69.55; H, 5.54; N, 20.28%. Found: C, 69.66; H, 5.50;
N, 20.35%.
4.7.1 | 4-((3-Cyano-4,6-dimethylpyridin-2-
yl)amino)-N0-(3,4-diphenyl-5-(p-tolylazo)-
thiazol-2(3H)-ylidene)benzohydrazide (8a)
Red solid, yield = 66%, m.p. = 231–232ꢀC. IR: 3261, 3204
(N H), 2214 (C N), 1655 cm−1 (C O). 1H NMR
(DMSO-d6): 2.32 (s, 3H), 2.38 (s, 3H), 2.43 (s, 3H), 6.91 (s,
1H, pyridine H-5), 7.22–7.84 (m, 18H), 10.38 (s, 1H, NH),
10.81 ppm (s, 1H, NH). MS m/z (%): 634 (M+, 13.28), 132
(100.00). Analysis for C37H30N8OS (634): Calcd: C, 70.01;
H, 4.76; N, 17.65%. Found: C, 70.14; H, 4.70; N, 17.74%.
4.9 | Synthesis of 4,6-dimethyl-2-((4-(3-
methyl-5-oxo-4,5-dihydro-1H-pyrazole-1-
carbonyl)phenyl)amino)
nicotinonitrile (10)
A
solution of 4-((3-cyano-4,6-dimethylpyridin-2-yl)
amino)-benzohydrazide (3) (1.40 g, 0.005 mol) and ethyl
acetoacetate (0.65 mL, 0.005 mol) in 40 mL of ethyl alco-
hol and 1 mL of acetic acid was heated under reflux for 4
hours. The reaction mixture was cooled to 25ꢀC, and the
precipitate was collected by filtration and then rec-
rystallized from ethyl alcohol.
4.7.2 | N0-(5-(p-Anisylazo)-3,4-diphenyl-
thiazol-2(3H)-ylidene)-4-((3-cyano-4,6-
dimethylpyridin-2-yl)amino)-
benzohydrazide (8b)
Red solid, yield = 68%, m.p. = 253–254ꢀC. IR: 3252, 3188
(N H), 2217 (C N), 1656 cm−1 (C O). 1H NMR
(DMSO-d6): 2.38 (s, 3H), 2.44 (s, 3H), 3.82 (s, 3H, OCH3),
6.88 (s, 1H, pyridine H-5), 7.09 (d, J = 8.50 Hz, 2H), 7.22–
7.91 (m, 16H), 10.44 (s, 1H, NH), 10.89 ppm (s, 1H, NH).
White powder, yield 61%, m.p. = 170–172ꢀC. IR: 3353
1
(N H), 2219 (C N), 1735, 1648 cm−1 (C O). H NMR
(CDCl3): 2.11 (s, 3H), 2.30 (s, 3H), 2.33 (s, 3H), 3.31 (s,
2H, CH2), 6.58 (s, 1H, pyridine H-5), 7.76 (d, J = 8.40 Hz,

ABUMELHA
9
2H), 7.88 (d, J = 8.40 Hz, 2H), 11.73 ppm (s, 1H, NH).
Analysis for C19H17N5O2 (347): Calcd: C, 65.69; H, 4.93;
N, 20.16%. Found: C, 65.49; H, 4.86; N, 20.25%.
4.10.3 | 2-((4-(4-(2-(4-Chlorophenyl)
hydrazono)-3-methyl-5-oxo-4,5-dihydro-1H-
pyrazole-1-carbonyl)phenyl)amino)-4,6-
dimethylnicotinonitrile (11c)
Orange solid, yield 75%, m.p. = 238–239ꢀC. IR: 3294
4.10 | Synthesis of 4,6-dimethyl-2-((4-(3-
substituted-5-oxo-4-(2-(arylhydrazono)-4,5-
dihydro-1H-pyrazole-1-carbonyl)phenyl)-
amino)-nicotinonitriles 11a-c
1
(N H), 2214 (C N), 1708, 1655 cm−1 (C O). H NMR
(CDCl3): 2.36 (s, 3H), 2.43 (s, 3H), 2.49 (s, 3H), 6.62 (s,
1H, pyridine H-5), 7.16–7.24 (m, 4H), 7.71 (d, J = 8.50
Hz, 2H), 7.83 (d, J = 8.50 Hz, 2H), 11.48 (s, 1H, NH),
13.37 ppm (s, 1H, NH). Analysis for C25H20ClN7O2 (485):
Calcd: C, 61.79; H, 4.15; N, 20.18%. Found: C, 61.57; H,
4.25; N, 20.05%.
A suspension of aromatic amine (p-toluidine p-anisidine
and/or p-chloroaniline) (0.002 mol) in concentrated HCl
(0.6 mL) was cooled in an ice-bath at 0–5ꢀC, and then
diazotized with a solution of sodium nitrite (0.14 g in 15
mL of H2O) by stirring for 30 minutes. The diazonium
solution was added drop wisely to a solution of 4,6-
dimethyl-2-(4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-
1-carbonyl)phenyl)amino)-nicotinonitrile (10) (0.7 g,
0.002 mol) in 25 mL of pyridine with stirring in an ice-
bath at 0–5ꢀC for 2 hours. The obtained precipitate was
filtered and recrystallized from EtOH-DMF mixture (2:1)
to afford 11a, 11b, and 11c, respectively.
4.11 | Synthesis of 2-((4-(4-(mercapto
(phenylamino)methylene)-3-methyl-5-oxo-
4,5-dihydro-1H-pyrazole-1-carbonyl)phenyl)
amino)-4,6-dimethylnicotinonitrile (13)
To a stirred solution of 10 (0.69 g, 0.002 mol) and potas-
sium hydroxide (0.12 g, 0.002 mol) in 20 ml
dimethylformamide, phenyl isothiocyanate (0.24 mL,
0.002 mol) was added drop-wisely and permitted to stir at
ambient temperature for 6 hours. The reaction mixture
was then poured into ice water drop by drop and neutral-
ized by dilute HCl. The precipitate was collected and
purified by reprecipitation from ethyl acetate to afford
compound 13.
Yellow solid, yield 43%, m.p. = 170–172ꢀC. IR: 3349
(N H), 2211(C N), 1658 cm−1 (C O). 1H NMR (DMSO-
d6): 2.31 (s, 3H), 2.42 (s, 3H), 2.48 (s, 3H), 6.67 (s, 1H, pyr-
idine H-5), 7.12–7.78 (m, 9H), 10.46 (s, 1H, NH), 11.84
ppm (s, 1H, NH). Analysis for: C26H22N6O2S (482): Calcd:
C, 64.71; H, 4.60; N, 17.42%. Found: C, 64.48; H, 4.68;
N, 17.60%.
4.10.1 | 4,6-Dimethyl-2-((4-(3-methyl-5-oxo-
4-(2-(p-tolyl)hydrazono)-4,5-dihydro-1H-
pyrazole-1-carbonyl)phenyl)amino)
nicotinonitrile (11a)
Orange solid, yield 86%, m.p. = 230–232ꢀC. IR: 3316
1
(N H), 2208 (C N), 1711, 1657 cm−1 (C O). H NMR
(CDCl3): 2.34 (s, 6H, 2 CH3), 2.43 (s, 3H), 2.50 (s, 3H),
6.61 (s, 1H, pyridine H-5), 7.41–7.48 (m, 4H), 7.78 (d, J =
8.40 Hz, 2H), 7.88 (d, J = 8.40 Hz, 2H), 11.36 (s, 1H, NH),
13.28 ppm (s, 1H, NH). MS m/z (%): 465 (M+, 22.85), 310
(100.00). Analysis for C26H23N7O2 (465): Calcd: C, 67.08;
H, 4.98; N, 21.06%. Found: C, 67.19; H, 4.95; N, 20.97%.
4.12 | Synthesis of 2-((4-(4-(3-
phenylthiazolylidene)-3-methyl-5-oxo-4,5-
dihydro-1H-pyrazole-1-carbonyl)phenyl)
amino)-4,6-dimethyl-nicotinonitriles 14a,
14b and 15
4.10.2 | 2-((4-(4-(2-(4-Methoxyphenyl)
hydrazono)-3-methyl-5-oxo-4,5-dihydro-1H-
pyrazole-1-carbonyl)phenyl)amino)-4,6-
dimethylnicotinonitrile (11b)
To a stirred solution of 10 (0.69 g, 0.002 mol) and potas-
sium hydroxide (0.12 g, 0.002 mol) in 20 mL of
dimethylformamide, phenyl isothiocyanate (0.24 mL,
0.002 mol) was added drop wisely. The reaction mixture
was stirred at 30ꢀC for 6 hours. Subsequently, the appro-
priate α-halogenated reagent (chloroacetone, phenacyl
chloride, ethyl bromoacetate) (0.002 mol) was added, and
stirring was continued for additional 4 hours. The reac-
tion mixture was then poured drop by drop into ice
water. The precipitate that formed was collected and rec-
rystallized by heating in ethyl alcohol.
Orange solid, yield 83%, m.p. = 249–250ꢀC. IR: 3349
1
(N H), 2211 (C N), 1704, 1653 cm−1 (C O). H NMR
(CDCl3): 2.37 (s, 3H), 2.44 (s, 3H), 2.50 (s, 3H), 3.83 (s,
3H, OCH3), 6.65 (s, 1H, pyridine H-5), 6.95 (d, J = 8.40
Hz, 2H), 7.37 (d, J = 8.40 Hz, 2H), 7.82 (d, J = 8.40 Hz,
2H), 7.93 (d, J = 8.40 Hz, 2H), 11.53 (s, 1H, NH), 13.94
ppm (s, 1H, NH). Analysis for C26H23N7O3 (481): Calcd:
C, 64.85; H, 4.81; N, 20.36%. Found: C, 64.78; H, 4.75;
N, 20.45%.

10
ABUMELHA
8.00 Hz, 2H), 7.73 (d, J = 8.50 Hz, 2H), 9.56 (s, 1H, NH),
10.18 (s, 1H, NH), 10.71 ppm (s, 1H, NH). Analysis for
C18H16N6O2 (348): Calcd: C, 62.06; H, 4.63; N, 24.12%.
Found: C, 62.17; H, 4.66; N, 24.04%.
4.12.1 | 4,6-Dimethyl-2-((4-(3-methyl-4-(4-
methyl-3-phenylthiazol-2(3H)-ylidene)-5-
oxo-4,5-dihydro-1H-pyrazole-1-carbonyl)
phenyl)amino)-nicotinonitrile (14a)
Yellow solid, yield 54%, m.p. = 200–202ꢀC. IR: 3327
1
(N H), 2218 (C N), 1692, 1661 cm−1 (C O). H NMR
4.14 | Synthesis of 4-((3-cyano-4,6-
dimethylpyridin-2-yl)amino)-N0-(2-(4-
oxothiazolidin-2-ylidene)acetyl)
benzohydrazide (17)
To a suspension of N0-(2-cyanoacetyl)-benzohydrazide
derivative 16 (0.70 g, 0.002 mol) in 10 mL pyridine, mer-
captoacetic acid (0.18 mL, 0.002 mol) was added. The
reaction components were refluxed for 4 hours and then
diluted with 10 g of crushed ice and water. The yellow
solid that acquired was filtered and recrystallized from
ethanol.
Yellow solid, yield = 44%, m.p. = 256–257ꢀC. IR: 3324,
3252, 3160 (N H), 2207 (C N), 1688, 1658 cm−1 (C O).
1H NMR (DMSO-d6): 2.39 (s, 3H), 2.42 (s, 3H), 3.72 (s,
2H, CH2), 5.98 (s, 1H, CH C), 7.01 (s, 1H, pyridine H-5),
7.64 (d, J = 8.50 Hz, 2H), 7.75 (d, J = 8.50 Hz, 2H), 9.34
(s, 1H, NH), 10.52 (s, 1H, NH), 10.76 (s, 1H, NH), 11.47
ppm (s, 1H, NH). Analysis for C20H18N6O3S (422): Calcd:
C, 56.86; H, 4.29; N, 19.89%. Found: C, 56.68; H, 4.35;
N, 19.78%.
(DMSO-d6): 2.31 (s, 6H, 2 CH3), 2.40 (s, 6H, 2 CH3), 5.84
(s, 1H, thiazole H-5), 6.91 (s, 1H, pyridine H-5), 7.04–7.89
(m, 9H), 9.49 ppm (s, 1H, NH). MS m/z (%): 520 (M+,
31.09), 242 (100.00). Analysis for C29H24N6O2S (520):
Calcd: C, 66.91; H, 4.65; N, 16.14%. Found: C, 66.70; H,
4.56; N, 16.22%.
4.12.2 | 2-((4-(4-(3,4-Diphenylthiazol-
2(3H)-ylidene)-3-methyl-5-oxo-4,5-dihydro-
1H-pyrazole-1-carbonyl)phenyl)amino)-4,6-
dimethyl-nicotinonitrile (14b)
Yellow solid, yield 48%, m.p. = 290–291ꢀC. IR: 3326
1
(N H), 2212 (C N), 1703, 1658 cm−1 (C O). H NMR
(DMSO-d6): 2.20 (s, 3H), 2.36 (s, 3H), 2.37 (s, 3H), 5.66 (s,
1H, thiazole H-5), 6.79 (s, H, pyridine H-5), 7.65–7.91 (m,
10H), 9.33 ppm (s, 1H, NH). Analysis for C34H26N6O2S
(582): Calcd: C, 70.09; H, 4.50; N, 14.42%. Found: C,
70.31; H, 4.42; N, 14.54%.
4.12.3 | 4,6-Dimethyl-2-((4-(3-methyl-5-oxo-
4-(4-oxo-3-phenylthiazolidin-2-ylidene)-4,5-
dihydro-1H-pyrazole-1-carbonyl)phenyl)
amino)-nicotinonitrile (15)
4.15 | Synthesis of N0-(3-aryl-2-cyano-
acryloyl)-4-((3-cyano-pyridin-2-yl)amino)-
benzohydrazides 18a-c
To a solution of N0-(2-cyanoacetyl)-benzohydrazide deriv-
ative 16 (1.39 g, 0.004 mol) in 40 mL of ethanol, the
appropriate aldehyde (0.004 mol), and three drops of
piperidine were added. The reaction mixture was refluxed
for 2 hours and then allowed to cool. The yellow solid
was collected by filtration and dried.
Yellow solid, yield 42%, m.p. = 160–162ꢀC. IR: 3327
1
(N H), 2218 (C N), 1724, 1690 cm−1 (C O). H NMR
(DMSO-d6): 2.32 (s, 3H), 2.41 (s, 6H, 2 CH3), 4.15 (s, 2H,
thiazolidinone-CH2), 6.85 (s, 1H, pyridine H-5), 7.08–7.76
(m, 9H), 9.49 ppm (s, 1H, NH). Analysis for C28H22N6O3S
(522): Calcd: C, 64.35; H, 4.24; N, 16.08%. Found: C,
64.51; H, 4.30; N, 15.94%.
4.15.1 | N0-(2-Cyano-3-(p-tolyl)acryloyl)-4-
((3-cyano-4,6-dimethylpyridin-2-yl)-amino)-
benzohydrazide (18a)
4.13 | Synthesis of 4-((3-cyano-4,6-
dimethylpyridin-2-yl)amino)-N0-(2-
cyanoacetyl)-benzohydrazide (16)
Yellow solid, yield = 81%, m.p. = 244–245ꢀC. IR: 3285,
1
3211, 3153 (N-H), 2211 (C N), 1672 cm−1 (C O). H
A mixture of benzohydrazide 3 (1.40 g, 0.005 mol) and 1-
(cyanoacetyl)-3,5-dimethyl-1H-pyrazole (0.82 g, 0.005
mol) was boiled in 25 mL of dioxane for 2 hours. A white
solid was obtained upon cooling, collected by filtration,
and dried.
NMR (DMSO-d6): 2.34 (s, 6H, 2 CH3), 2.41 (s, 3H), 7.07
(s, 1H, pyridine H-5), 7.28 (d, J = 8.00 Hz, 2H), 7.61 (d, J
= 8.50 Hz, 2H), 7.74 (d, J = 8.50 Hz, 2H), 7.92 (d, J = 8.00
Hz, 2H), 8.36 (s, 1H, olefinic CH C), 9.77 (s, 1H, NH),
10.62 (s, 1H, NH), 11.33 ppm (s, 1H, NH). MS m/z (%):
450 (M+, 56.83), 280 (100.00). Analysis for C26H22N6O2
(450): Calcd: C, 69.32; H, 4.92; N, 18.66%. Found: C,
69.44; H, 4.88; N, 18.74%.
White solid, yield = 76%, m.p. = 211–212ꢀC. IR: 3289,
3234, 3171 (N H), 2258, 2214 (C N), 1682, 1661 cm−1
1
(C O). H NMR (DMSO-d6): 2.37 (s, 3H), 2.39 (s, 3H),
3.92 (s, 2H, CH2), 6.94 (s, 1H, pyridine H-5), 7.62 (d, J =

ABUMELHA
11
514 (M+, 22.69), 249 (100.00). Analysis for C29H22N8O2
(514): Calcd: C, 67.69; H, 4.31; N, 21.78%. Found: C,
67.88; H, 4.38; N, 21.74%.
4.15.2 | N0-(3-(p-Anisyl)-2-cyano-acryloyl)-
4-((3-cyano-4,6-dimethylpyridin-2-yl)
amino)-benzohydrazide (18b)
Yellow solid, yield = 78%, m.p. = 255–256ꢀC. IR: 3303,
1
3221, 3170 (N H), 2205 (C N), 1668 cm−1 (C O). H
4.16.2 | N-(6-Amino-4-(p-anisyl)-3,5-
dicyano-2-oxopyridin-1(2H)-yl)-4-((3-cyano-
4,6-dimethylpyridin-2-yl)amino)
benzamide (19b)
NMR (DMSO-d6): 2.34 (s, 3H), 2.39 (s, 3H), 3.87 (s, 3H,
OCH3), 7.06 (s, 1H, pyridine H-5), 7.00 (d, J = 9.00 Hz,
2H), 7.62 (d, J = 8.50 Hz, 2H), 7.74 (d, J = 8.50 Hz, 2H),
8.00 (d, J = 8.50 Hz, 2H), 8.32 (s, 1H, olefinic CH C),
9.58 (s, 1H, NH), 10.43 (s, 1H, NH), 11.42 ppm (s, 1H,
NH). Analysis for C26H22N6O3 (466): Calcd: C, 66.94; H,
4.75; N, 18.02%. Found: C, 66.85; H, 4.73; N, 18.11%.
Yellowish brown solid, yield = 61%, m.p. > 300ꢀC. IR:
3327, 3264, 3182 (NH2 and N H), 2212, 2191 (C N),
1662 cm−1 (C O). 1H NMR (DMSO-d6): 2.37 (s, 3H), 2.40
(s, 3H), 3.83 (s, 3H, OCH3), 6.66 (s, 2H, NH2), 7.07 (s, 1H,
pyridine H-5), 6.98 (d, J = 9.00 Hz, 2H), 7.55 (d, J = 9.00
Hz, 2H), 7.64 (d, J = 8.50 Hz, 2H), 7.77 (d, J = 8.50 Hz,
2H), 10.54 (s, 1H, NH), 13.11 ppm (s, 1H, NH). Analysis
for C29H22N8O3 (530): Calcd: C, 65.65; H, 4.18; N, 21.12%.
Found: C, 65.80; H, 4.24; N, 21.21%.
4.15.3 | N0-(3-(p-Chlorophenyl)-2-
cyanoacryloyl)-4-((3-cyano-4,6-
dimethylpyridin-2-yl)-amino)
benzohydrazide (18c)
Yellow solid, yield = 72%, m.p. = 261–262ꢀC. IR: 3291,
3202 (N H), 2216 (C N), 1671 cm−1 (C O). H NMR
1
4.16.3 | N-(6-Amino-4-(p-chlorophenyl)-
3,5-dicyano-2-oxopyridin-1(2H)-yl)-4-((3-
cyano-4,6-dimethylpyridin-2-yl)amino)
benzamide (19c)
(DMSO-d6): 2.37 (s, 3H), 2.42 (s, 3H), 7.06 (s, 1H, pyridine
H-5), 7.35 (d, J = 7.50 Hz, 2H), 7.55 (d, J = 7.50 Hz, 2H),
7.64 (d, J = 8.50 Hz, 2H), 7.77 (d, J = 8.50 Hz, 2H), 8.11
(s, 1H, olefinic CH C), 10.14 (s, 1H, NH), 10.78 (s, 1H,
NH), 11.56 ppm (s, 1H, NH). Analysis for C25H19ClN6O2
(470): Calcd: C, 63.76; H, 4.07; N, 17.85%. Found: C,
63.60; H, 4.00; N, 17.73%.
Brown solid, yield = 52%, m.p. = 278–280ꢀC. IR: 3281,
3219, 3163 (NH2 and N H), broad centered at 2202
1
(C N), 1668 cm−1 (C O). H NMR (DMSO-d6): 2.37 (s,
3H), 2.41 (s, 3H), 6.72 (s, 2H, NH2), 7.05 (s, 1H, pyridine
H-5), 7.31–7.42 (m, 4H), 7.68 (d, J = 8.50 Hz, 2H), 7.81 (d,
J = 8.50 Hz, 2H), 10.83 (s, 1H, NH), 14.06 ppm (s, 1H,
NH). Analysis for C28H19ClN8O2 (534): Calcd: C, 62.87;
H, 3.58; N, 20.95%. Found: C, 62.65; H, 3.69; N, 21.07%.
4.16 | Synthesis of N-(6-amino-4-aryl-3,5-
dicyano-2-oxo-pyridin-1(2H)-yl)-4-((3-
cyanopyridin-2-yl)amino)benzamides 19a-c
To a suspension of each N0-(2-cyano-3-arylacryloyl)-4-
substitutedbenzohydrazide derivative 18a, 18b, and/or
18c (0.002 mol) in 20 mL of ethanol, malononitrile (0.14
g, 0.002 mol), and three drops of piperidine were added.
The reaction mixture was refluxed for 4 hours. The reac-
tion mixture was cooled, and the formed solid was fil-
tered and dried.
ORCID
Hana M.A. Abumelha https://orcid.org/0000-0001-
8697-1585
REFERENCES AND NOTES
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R. S. Satkar, Eur. J. Pharm. Med. Res. 2018, 5, 184.
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Z. Zhu, J. Xu, Eur. J. Med. Chem. 2019, 173, 1.
4.16.1 | N-(6-Amino-3,5-dicyano-2-oxo-4-(p-
tolyl)pyridin-1(2H)-yl)-4-((3-cyano-4,6-
dimethylpyridin-2-yl)amino)
benzamide (19a)
Yellowish brown solid, Yield = 56%, m.p. = 292–293ꢀC.
IR: 3314, 3273, 3169 (NH2 and N H), 2217, 2193 (C N),
1664 cm−1 (C O). 1H NMR (DMSO-d6): 2.33 (s, 3H), 2.39
(s, 3H), 2.41 (s, 3H), 6.58 (s, 2H, NH2), 7.06 (s, 1H, pyri-
dine H-5), 7.17 (d, J = 8.00 Hz, 2H), 7.38 (d, J = 8.00 Hz,
2H), 7.64 (d, J = 8.50 Hz, 2H), 7.76 (d, J = 8.50 Hz, 2H),
10.68 (s, 1H, NH), 13.73 ppm (s, 1H, NH). MS m/z (%):
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How to cite this article: Abumelha HMA.
Synthesis and antioxidant assay of new
nicotinonitrile analogues clubbed thiazole,
pyrazole and/or pyridine ring systems.
J Heterocyclic Chem. 2020;1–12. https://doi.org/10.
1002/jhet.3820
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