2-Cyano-N′-[(1,3-diphenyl-1H-pyrazol-4-yl)methylidene]acetohydrazide in the Synthesis of Nitrogen Heterocycles

Article abstract of DOI:10.1134/S1070428019120224

Some interesting nitrogen heterocycles, as well as other products, were synthesized by reactions of 2-cyano-N′-[(1,3-diphenyl-1H-pyrazol-4-yl)methylidene]acetohydrazide with phenyl isothiocyanate/elemental sulfur, 3,4,5-trimethoxybenzaldehyde, 4-hydroxy-1

Full text of DOI:10.1134/S1070428019120224

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 12, pp. 1940–1945. © Pleiades Publishing, Ltd., 2019.
2-Cyano-N′-[(1,3-diphenyl-1H-pyrazol-4-yl)methylidene]aceto-
hydrazide in the Synthesis of Nitrogen Heterocycles
S. K. Ramadana,* E. A. E. El-Helwa, and M. E. Azaba
a Chemistry Department, Faculty of Science, Ain Shams University, Abassia, Cairo, 11566 Egypt
*e-mail: sayed.karam2008@sci.asu.edu.eg
Received June 20, 2019; revised October 9, 2019; accepted October 23, 2019
Abstract—Some interesting nitrogen heterocycles, as well as other products, were synthesized by reactions of
2-cyano-N′-[(1,3-diphenyl-1H-pyrazol-4-yl)methylidene]acetohydrazide with phenyl isothiocyanate/elemental
sulfur, 3,4,5-trimethoxybenzaldehyde, 4-hydroxy-1,1′-biphenyl-3-carbaldehyde, 2-oxoquinoline-3-caraldehyde,
triethyl orthoformate, ethyl cyanoacetate, and thiosemicarbazide. The structures of all isolated compounds were
established from their analytical and spectral data.
Keywords: 1,3-diphenylpyrazole, thiazolidine, chromene, pyridine, quinolinone.
DOI: 10.1134/S1070428019120224
Pyrazoles are synthetically versatile substrates that
display diverse biological and pharmacological prop-
erties [1–6]. Several compounds containing a pyrazole
moiety have been reported to possess antibacterial,
antifungal, anticonvulsant, anti-inflammatory, and
anti-HIV activities. Among a number of commercially
availble substituted hydrazines, 2-cyanoacetohydrazide
is a versatile and convenient intermediate product for
the synthesis of a wide variety of heterocyclic com-
pounds. Herein, we report the synthesis of some nitro-
gen heterocycles containing a pyrazole moiety starting
from cyanoacetohydrazide and 1,3-diphenyl-1H-pyra-
zole-4-carboxaldehyde.
spectrum revealed the absence of C≡N group and the
presence of characteristic absorption bands due to C=O,
1
C=N, and C=S stretchings. The H NMR spectrum
of 2 was consistent with the assigned structure. The
Knoevenagel condensation of 1 with 3,4,5-trimethoxy-
benzaldehyde in 10% ethanolic potassium hydroxide
under reflux afforded α,β-unsaturated carbonyl com-
pound 3 (Scheme 1). The IR spectrum of 3 exhibited
absorption bands due to NH, C≡N, and C=O groups.
The reduced C≡N stretching frequency (in comparison
to 1) was attributed to conjugation with the C=C double
bond. Treatment of 1 with 5-phenylsalicylaldehyde and
2-oxoquinoline-3-carbaldehyde in the presence of tri-
ethylamine led to the formation of chromenone 4 and
pyranoquinoline derivative 5, respectively (Scheme 1).
The IR spectra of compounds 4 and 5 lacked C≡N
stretching band (see Experimental).
In continuation of our previous work [1–3, 5–10]
and as a part of our program focusing on the synthesis
of some valuable heterocyclic compounds with antici-
pated biological activity, 2-cyano-N′-[(1,3-diphenyl-
1H-pyrazol-4-yl)methylidene]acetohydrazide (1) [11]
was selected as starting material to build up some
biologically active N-heterocycles. The carbonyl and
cyano functions in molecule 1 are suitably situated to
enable reactions with common reagents to construct
a variety of N-heterocyclic compounds. In addition, the
active methylene group of 1 can be involved in con-
densation and substitution reactions.
It seemed interesting that the reaction of 1 with tri-
ethyl orthoformate led to the formation of triazepinone
derivative 7 instead of expected condensation product 6
(Scheme 2). The structure of 7 was deduced from its
analytical and spectral data. The IR spectrum of 7
showed OH, C≡N, C=O, and C=N absorption bands.
1
The H NMR spectrum displayed an upfield singlet
from the methine proton and was devoid of triplet and
quartet signals typical of ethyl group, which ruled out
structure 6. Scheme 3 outlines a plausible mechanism
for the formation of compound 7.
Indeed, the cyclocondensation of 1 with phenyl
isothiocyanate and elemental sulfur in the presence of
triethylamine as a base led to the formation of thiazo-
lidine derivative 2 (Scheme 1). The structure of 2 was
inferred from its analytical and spectral data. The IR
The reaction of 1 with ethyl cyanoacetate in boiling
DMF in the presence of triethylamine furnished dihy-
1940

2-CYANO-N′-[(1,3-DIPHENYL-1H-PYRAZOL-4-YL)METHYLIDENE]ACETOHYDRAZIDE
1941
Scheme 1.
Ar
OH
O
N
H
O
N
Ph
CHO
PhNCS/S8, Et3N
dioxane, 60°C
NH
N
Et3N, dioxane, r.t.
Ph
S
N
NH
O
H
N
S
Ph
N
5'
N
Ar
Ph
2
N
O
4
MeO
MeO
CHO
HN
OMe
CHO
Ph
N
O
N
OMe
OMe
H
OMe
10% KOH/EtOH
reflux, 1 h
Ar
N
O
CN
O
H
1
Et3N, dioxane, r.t.
N
HN
NH
N
CN
O
Ar
3
5
5'
Ph
N
Ar =
N
Ph
droxypyridine derivative 8 (Scheme 2). The IR spec-
trum of compound 8 lacked absorption bands assign-
able to C=O and NH2 groups, and three D2O-exchange-
able one-proton singlets were observed in the 1H NMR
spectrum due to two OH protons and one NH proton.
The formation of compound 8 could be explained by
Scheme 4.
spectral data. The IR spectrum displayed the absence
of carbonyl absorption, but absorption bands for NH,
C≡N, and C=S groups were present. Compound 10 was
converted to N-chloroacetyl derivative 11 by treatment
with chloroacetyl chloride in dioxane containing few
drops of triethylamine at room temperature (Scheme 5).
The IR spectrum of compound 11 showed C=O stretch-
ing band at 1694 cm–1, whose increased frequency may
be attributed to field effect of the chlorine atom.
Treatment of 1 with acetyl chloride afforded pyrazo-
lone 9 which was obtained previously by cyclization of
1 in ethanol under reflux in the presence of a few drops
of piperidine [11] (Scheme 5). Treatment of 9 with
phosphorus pentasulfide in refluxing toluene gave
pyrazolethione derivative 10 (Scheme 5). The structure
of compound 10 was determined from its analytical and
In the reaction of hydrazone 1 with thiosemicarba-
zide we isolated thiosemicarbazone 13 instead of the
expected cyclization product, aminothiadiazole 12
(Scheme 6). The structure of 13 was supported by
spectral data, as well as by direct comparison with
Scheme 2.
O
Ar
N
CN
N
H
H
N
OEt
O
NCCH2COOEt
DMF, Et3N, reflux, 8 h
6
CH(OEt)3, reflux, 4 h
Ar
N
CN
OH
1
Ar
O
CN
HN
N
O
8
N
Ar
H
N
N
7
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 12 2019

RAMADAN et al.
1942
Scheme 3.
O
H
N
Ar
N
CN
Ar
Ar
N
CN
N
H
H
N
O
Ar
N
CN
1
HN
–H+
O
NH
NC
Ar
O
Ar
O
O
CN
CN
1,7-exo-trig cyclization, ~H+
N
N
N
N
Ar
Ar
–MeCN, –H2
H
H
O
N
O
N
N
H
N
7
NC
Scheme 4.
O
O
O
H
N
H
CN
1,6-exo-dig, ~H+
Ar
N
CN
O
Ar
N
EtO
N
H
N
CN
Ar
N
CN
1
–H+
–EtOH
H
N
O
HN
O
H
O
O
~H+
~H+
Ar
N
N
CN
Ar
N
N
CN
OH
HN
O
HN
8
an authentic sample prepared by the condensation of
1,3-diphenyl-1H-pyrazole-4-carbaldehyde with thio-
semicarbazide in refluxing dioxane [1]. Presumably,
compound 13 is formed via nucleophilic attack of the
free NH2 group of thiosemicarbazide on the CH=N
carbon atom of 1, followed by elimination of 2-cyano-
acetohydrazide.
EXPERIMENTAL
All melting points were measured on a Gallenkamp
electric melting point apparatus and are uncorrected.
The IR spectra were recorded using KBr disks on
a Thermo Electron Nicolet iS10 spectrometer (USA)
at the Chemistry Department Laboratory, Faculty of
1
Science, Ain Shams University. The H NMR spectra
In summary, we have synthesized and characterized
some nitrogen-containing heterocycles of the thiazoli-
dine, chromenone, pyranoquinoline, and pyridine series
with potential biological activity using 2-cyano-N′-
[(1,3-diphenyl-1H-pyrazol-4-yl)methylidene]acetohy-
drazide as the key building block.
were run at 400 MHz on a Bruker spectrometer (USA)
using tetramethylsilane as internal standard and
DMSO-d6 as solvent at the Faculty of Pharmacy, Ain
Shams University. Elemental analyses were carried out
at the microanalytical unit, Cairo University, Giza,
Scheme 5.
N
Ph
Ph
Cl
N
NC
Ar
NC
Ar
NC
ClCOCH2C(O)Cl
Et3N, dioxane, r.t.
P2S5, PhH
reflux, 1 h
AcCl, 60°C
1
NH
NH
N
O
S
S
N
N
N
H
H
H
O
9
10
11
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 12 2019

2-CYANO-N′-[(1,3-DIPHENYL-1H-PYRAZOL-4-YL)METHYLIDENE]ACETOHYDRAZIDE
1943
Scheme 6.
N
N
H
NH2
N
S
N
Ph
N
O
N
Ph
S
Dioxane
reflux, 6 h
12
H2N
1
+
N
NH2
Ph
H
CHO
Ph
H2NC(=S)NHNH
2
N
S
dioxane, reflux, 4 h
N
N
N
Ph
N
H
NH2
N
Ph
13
Egypt. The reactions were monitored by thin layer
chromatography (TLC) using Merck Kieselgel 60 F254
analytical sheets (Fluka).
Compounds 4 and 5 (general procedure). A solu-
tion of 1 (2 mmol) and 4-hydroxy-1,1′-biphenyl-3-
carbaldehyde or 2-oxo-1,2-dihydroquinoline-3-carb-
aldehyde (2 mmol) in dioxane (20 mL) containing
2 drops of piperidine was stirred at room temperature
for 3 h. The solid product was filtered off and recrystal-
lized from an appropriate solvent.
N′-[(1,3-Diphenyl-1H-pyrazol-4-yl)methylidene]-
4-imino-3-phenyl-2-sulfanylidene-5-carbohydrazide
(2). Phenyl isothiocyanate (2 mmol) and elemental
sulfur (2 mmol) were added to a solution of hydrazide 1
(2 mmol) in N,N-dimethylformamide (10 mL) contain-
ing triethylamine (0.5 mL). The mixture was heated at
60°C for 5 h with continuous stirring. After cooling, the
mixture was acidified with cold 10% aqueous HCl, and
the separated solid was collected by filtration, washed
several times with water, dried, and recrystallized from
petroleum ether (bp 60–80°C)–benzene (1:1). Yield
63%, yellow crystals, mp 200–202°C. IR spectrum, ν,
cm–1: 3445, 3209 (NH), 1686 (C=O), 1631 (C=N),
N′-[(1,3-Diphenyl-1H-pyrazol-4-yl)methylidene]-
2-imino-6-phenyl-2H-chromene-3-carbohydrazide
(4). Yield 67%, orange crystals, mp 238–240°C (from
benzene). IR spectrum, ν, cm–1: 3442 (NH, H-bonded),
1682 (C=O), 1628 (C=N). 1H NMR spectrum, δ, ppm:
11.33 s (1H, =NH, exchangeable), 11.21 s (1H, NHCO,
exchangeable), 9.16 s (1H, CH=N), 9.10 s (1H, 5′-H),
8.97 s (1H, 4-H), 8.81 s (1H, 5-H), 8.02–6.84 m
(17H, Harom). Found, %: C 75.30; H 4.41; N 13.79.
C32H23N5O2. Calculated, %: C 75.43; H 4.55; N 13.74.
1
1245 (C=S). H NMR spectrum, δ, ppm: 11.61 s (1H,
=NH, exchangeable), 11.36 s (1H, NHCO, exchange-
able), 9.02 s (1H, CH=N), 8.76 s (1H, 5′-H), 8.27–
7.16 m (15H, Ph), 4.12 s (1H, CH). Found, %: C 62.64;
H 3.89; N 16.95. C26H20N6OS2. Calculated, %:
C 62.88; H 4.06; N 16.92.
N′-[(1,3-Diphenyl-1H-pyrazol-4-yl)methylidene]-
2-imino-2H-pyrano[2,3-b]quinoline-3-carbohydra-
zide (5). Yield 57%, yellow crystals, mp 275–277°C
(from EtOH–dioxane, 1:1). IR spectrum, ν, cm–1: 3419
1
(NH, H-bonded), 1650 (C=O), 1616 (C=N). H NMR
2-Cyano-N′-[(1,3-diphenyl-1H-pyrazol-4-yl)-
methylidene]-3-(3,4,5-trimethoxyphenyl)prop-2-
enehydrazide (3). 3,4,5-Trimethoxybenzaldehyde
(2 mmol) was added to a solution of 1 (2 mmol) in
10% ethanolic KOH (10 mL), and the mixture was
refluxed for 1 h. After cooling, the precipitate was
collected by filtration, washed with ethanol, dried, and
recrystallized from dioxane. Yield 69%, beige crystals,
mp >360°C. IR spectrum, ν, cm–1: 3416 (NH), 2206
spectrum, δ, ppm: 11.34 s (1H, =NH, exchangeable),
11.23 s (1H, NHCO, exchangeable), 9.17 s (1H,
CH=N), 9.13 s (1H, 5′-H), 8.95 s (1H, 4-H), 8.84 s
(1H, 5-H), 8.00–7.02 m (14H, Harom). Found, %:
C 71.61; H 3.89; N 17.30. C29H20N6O2. Calculated, %:
C 71.89; H 4.16; N 17.35.
7-(1,3-Diphenyl-1H-pyrazol-4-yl)-4-{[(1,3-di-
phenyl-1H-pyrazol-4-yl)methylidene]amino}-3-hy-
droxy-5-oxo-5,6-dihydro-4H-1,2,4-triazepine-6-
carbonitrile (7). A suspension of 1 (2 mmol) in triethyl
orthoformate (5 mL) was refluxed for 3 h. Excess
solvent was evaporated under rediced pressure, the
residue was triturated with light petroleum, and the
1
(C≡N), 1650 (C=O), 1617 (C=N). H NMR spectrum,
δ, ppm: 11.84 s (1H, NH, exchangeable), 9.12 s (1H,
CH=N), 9.03 s (1H, 5′-H), 7.88–7.20 m (13H, Harom
,
CH=). Found, %: C 68.42; H 4.79; N 13.78.
C29H25N5O4. Calculated, %: C 68.63; H 4.97; N 13.80.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 12 2019

RAMADAN et al.
1944
precipitate was filtered off and recrystallized from
ethanol–dioxane (1:1). Yield 76%, yellow crystals,
mp 306–308°C. IR spectrum, ν, cm–1: 3422 (OH), 2207
nitrile (11). Chloroacetyl chloride (2.1 mmol) was
added dropwise with stirring at room temperature to
a solution of 10 (2 mmol) in dioxane (10 mL) containing
2 drops of triethylamine. The mixture was stirred for
2 h, and the solid product was collected by filtration
and recrystallized from ethanol–dioxane (2:1). Yield
64%, yellow crystals, mp 272–274°C. IR spectrum, ν,
cm–1: 3442 (NH), 2220 (C≡N), 1694 (C=O), 1619
1
(C≡N), 1679 (C=O), 1614 (C=N). H NMR spectrum:
11.75 s (1H, OH, exchangeable), 9.28 s (1H, CH=N),
8.98 s (1H, 5′-H), 8.77 s (1H, 5″-H), 8.14–7.30 m
(20H, Harom), 3.59 s (1H, CH). Found, %: C 69.97;
H 3.87; N 20.42. C36H25N9O2. Calculated, %: C 70.23;
H 4.09; N 20.48.
1
(C=N), 1233 (C=S). H NMR spectrum, δ, ppm:
11.80 s (1H, NHCS, exchangeable), 9.01 s (1H, 5′-H),
7.94–7.11 m (10H, Harom), 4.02 s (2H, CH2). Found, %:
C 59.82; H 3.17; N 16.71. C21H14ClN5OS. Calculated,
%: C 60.07; H 3.36; N 16.68.
1-{[(1,3-Diphenyl-1H-pyrazol-4-yl)methylidene]-
amino}-2,4-dihydroxy-6-imino-1,6-dihydropyri-
dine-3-carbonitrile (8). Ethyl cyanoacetate (2 mmol)
was added to a solution of 1 (2 mmol) in DMF (10 mL)
containing 2 drops of triethylamine, and the mixture
was refluxed for 8 h. After cooling, the mixture was
acidified with cold 10% aqueous HCl, and the precip-
itate was filtered off, dried, and recrystallized from
ethanol. Yield 55%, yellow crystals, mp 250–252°C. IR
spectrum, ν, cm–1: 3335 br (OH, NH), 2217 (C≡N),
Reaction of compound 1 with thiosemicarbazide.
A solution of 1 (2 mmol) and thiosemicarbazide
(2 mmol) in dioxane (10 mL) was refluxed for 2 h.
After cooling, the obtained solid was filtered off and
recrystallized from ethanol–dioxane (1:1). The product
was identified as 2-[(1,3-diphenyl-1H-pyrazol-4-yl)-
methylidene]hydrazine-1-carbothioamide (13), yellow
crystals, mp 232–234°C. It was identical in IR spec-
trum, melting point, mixed melting point, and TLC data
with an authentic sample prepared by the condensation
of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde with thio-
semicarbazide in refluxing dioxane [1].
1
1628 (C=N). H NMR spectrum, δ, ppm: 11.87 s (1H,
NH, exchangeable), 10.71 br.s (2H, OH, exchangeable),
9.09 s (1H, CH=N), 9.01 s (1H, 5′-H), 7.85–7.14 m
(11H, Harom, 5-H). Found, %: C 66.42; H 3.81; N 21.18.
C22H16N6O2. Calculated, %: C 66.66; H 4.07; N 21.20.
Cyclization of compound 1. A solution of hydra-
zone 1 (2 mmol) in acetyl chloride (5 mL) was heated
at 60°C for 2 h. Excess acetyl chloride was evaporated,
the residue was triturated with light petroleum, and
the precipitate was recrystallized from dioxane. The
product was identified as 5-oxo-1′,3′-diphenyl-2,5-
dihydro-1H,1′H-[3,4′-bipyrazole]-4-carbonitrile (9);
yellow crystals, mp 250–252°C; published data [11]:
mp 247–248°C.
CONFLICT OF INTERESTS
The authors declare no conflict of interests.
REFERENCES
1. Ramadan, S.K. and Sallam, H.A., J. Heterocycl. Chem.,
2018, vol. 55, p. 1942.
https://doi.org/10.1002/jhet.3232
1′,3′-Diphenyl-5-sulfanylidene-2,5-dihydro-
1H,1′H-[3,4′-bipyrazole]-4-carbonitrile (10). A mix-
ture of 9 (2 mmol) and phosphorus pentasulfide
(1 mmol) in anhydrous toluene (10 mL) was refluxed
for 1 h. The precipitate was filtered off from the hot
mixture and recrystallized from toluene. Yield 71%,
yellow crystals, mp 240–242°C. IR spectrum, ν, cm–1:
3417 (NH), 2209 (C≡N), 1623 (C=N), 1235 (C=S).
1H NMR spectrum, δ, ppm: 11.82 s (1H, NHCS, ex-
changeable), 8.01 s (1H, NH, exchangeable), 9.11 s
(1H, 5′-H), 7.95–7.15 m (10H, Harom). Found, %:
C 66.27; H 3.65; N 20.35. C19H13N5S. Calculated, %:
C 66.45; H 3.82; N 20.39.
2. Ramadan, S.K. and Abou-Elmagd, W.S.I., Synth.
Commun., 2018, vol. 48, no. 18, p. 2409.
https://doi.org/10.1080/00397911.2018.1491995
3. Abou-Elmagd, W.S.I., El-Ziaty, A.K., Elzahar, M.I.,
Ramadan, S.K., and Hashem, A.I., Synth. Commun.,
2016, vol. 46, no. 14, p. 1197.
https://doi.org/10.1080/00397911.2016.1193755
4. Hashem, A.I., Youssef, A.S., Kandeel, K.A., and Abou-
Elmagd, W.S.I., Eur. J. Med. Chem., 2007, vol. 42,
p. 934.
https://doi.org/10.1016/j.ejmech.2006.12.032
5. El-Ziaty, A.K., Abou-Elmagd, W.S.I., Ramadan, S.K., and
Hashem, A.I., Synth. Commun., 2017, vol. 47, no. 5,
p. 471.
2-(2-Chloroacetyl)-1′,3′-diphenyl-5-sulfanyli-
dene-2,5-dihydro-1H,1′H-[3,4′-bipyrazole]-4-carbo-
https://doi.org/10.1080/00397911.2016.1271896
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 12 2019

2-CYANO-N′-[(1,3-DIPHENYL-1H-PYRAZOL-4-YL)METHYLIDENE]ACETOHYDRAZIDE
1945
6. Ramadan, S.K. and El-Helw, E.A.E., J. Chem. Res., 2018,
vol. 42, no. 6, p. 332.
9. El-Helw, E.A.E., Sallam, H.A., and Elgubbi, A.S., Synth.
Commun., 2019, vol. 49, no. 20, p. 2651.
https://doi.org/10.3184/174751918X15295796734379
https://doi.org/10.1080/00397911.2019.1638938
7. Hashem, A.I., Abou-Elmagd, W.S.I., El-Ziaty, A.K., and
Ramadan, S.K., J. Heterocycl. Chem., 2017, vol. 54,
p. 3711.
10. El-Helw, E.A.E., Derbala, H.A., El-Shahawi, M.M.,
Salem, M.S., and Ali, M.M., Russ. J. Bioorg. Chem.,
2019, vol. 45, p. 42.
https://doi.org/10.1002/jhet.2937
https://doi.org/10.1134/S1068162019010047
8. Youssef, A.M., El-Ziaty, A.K., Abou-Elmagd, W.S.I.,
and Ramadan, S.K., J. Heterocycl. Chem., 2015, vol. 52,
p. 278.
11. Atta-Allah, S.R., Abou-Elmagd, W.S.I., Kandeel, K.A.,
Hemdan, M.M., Haneen, D.S., and Youssef, A.S.,
J. Chem. Res., 2017, vol. 41, p. 617.
https://doi.org/10.1002/jhet.1943
https://doi.org/10.3184/174751917X15065183733150
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