Design and Synthesis of Fused and Spiro Pyrazole Derivatives

Article abstract of DOI:10.1134/S1070428020070192

Abstract: Condensation of 5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one with p-hydroxybenzaldehyde in alcoholic sodium hydroxide yielded (Z)-4-(4-hydroxybenzylidene)-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one which was treated with acetylacetone, hydrazine hydrate, ethyl cyanoacetate, and ethyl acetoacetate to afford pyranopyrazole, pyrazolopyrazole, pyrazolopyridine, and 6-aminopyrazolopyridine derivatives, respectively. 5-Methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was also reacted at the enamino carbon atom with 2,4-dichlorobenzoyl isothiocyanate, thiosemicarbazide, and hydrazine hydrate to produce pyrazolooxazine, pyrazolopyrazole, and spiro[pyrazole-3,3′-pyrazolo[3,4-c]pyrazole] derivatives.

Full text of DOI:10.1134/S1070428020070192

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 7, pp. 1245–1250. © Pleiades Publishing, Ltd., 2020.
Design and Synthesis of Fused and Spiro Pyrazole Derivatives
M. G. Assya,*, W. Shehtaa, and E. F. Abdelrahmana
a Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, 44519 Egypt
*e-mail: profmassy@yahoo.com
Received January 19, 2020; revised January 25, 2020; accepted January 29, 2020
Abstract—Condensation of 5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one with p-hydroxybenzaldehyde in
alcoholic sodium hydroxide yielded (Z)-4-(4-hydroxybenzylidene)-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-
3-one which was treated with acetylacetone, hydrazine hydrate, ethyl cyanoacetate, and ethyl acetoacetate to
afford pyranopyrazole, pyrazolopyrazole, pyrazolopyridine, and 6-aminopyrazolopyridine derivatives, respec-
tively. 5-Methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was also reacted at the enamino carbon atom with
2,4-dichlorobenzoyl isothiocyanate, thiosemicarbazide, and hydrazine hydrate to produce pyrazolooxazine,
pyrazolopyrazole, and spiro[pyrazole-3,3′-pyrazolo[3,4-c]pyrazole] derivatives.
Keywords: pyranopyrazole, pyrazolopyrazole, pyrazolopyridine, pyrazolooxazine
DOI: 10.1134/S1070428020070192
INTRODUCTION
and NH protons. Also, two doublets were observed at
δ 6.89–7.08 ppm with J = 8 Hz, which were assigned
to the cis-CH=CH protons. The 13C NMR spectrum
showed a signal at δC 163.06 ppm for the carbonyl
carbon. The mass spectrum of 4 showed the molecular
ion peak at m/z 278.32 and the base peak at m/z 77. The
IR spectrum of 5 displayed OH stretching band at
3411 cm–1 and carbonyl band at 1650 cm–1. Its
1H NMR spectrum showed singlets at δ 10.84 and
2.49 ppm corresponding to the OH and CH3 protons. In
the 13CNMR spectrum of 5, the carbonyl carbon
nucleus resonated at δC 163.06 ppm, and the CH3
signal was located at δC 13.16 ppm.
Pyrazolone derivatives constitute a significant class
of heterocyclic compounds found in many drugs and
synthetic products [1, 2]. These compounds exhibits
analgesic [3], antitubercular [4], antifungal, antibac-
terial [5], anti-inflammatory [6], antioxidant, and anti-
tumor activities [7]. A survey of literature on antimic-
robial studies revealed that the presence of pyrazole
ring in any molecule plays a significant role in im-
proving the activity [8–11]. This gave an extraordinary
impulse to look forward potential pharmacologically
active drugs carrying pyrazole substituents. On the
basis of this view, our study reports on the synthesis of
some new fused pyrazole derivatives such as pyrano-
pyrazole, pyrazolopyrazole, pyrazolopyridine, and
pyrazolooxazine.
The reaction of benzylidenepyrazole 5 with acetyl-
acetone in basic medium resulted in pyran cyclization
with the formation of pyranopyrazole 7, whereas no
indazole 8 was obtained. Compound 7 is likely to be
formed through non-isolable intermediate Michael
adduct 6 which undergoes intramolecular cyclodehy-
dration (Scheme 1). Compound 7 displayed IR peaks at
3402 and 1654 cm–1 due to OH and C=O groups. Its
1H NMR spectrum showed a downfield singlet (D2O
exchangeable) for the OH proton at δ 9.19 ppm,
a singlet at δ 4.83 ppm for the CH proton in the pyran
ring, and three methyl proton singlets at δ 2.70, 2.26,
RESULTS AND DISCUSSION
5-Methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one
(3) was synthesized by the reaction of ethyl aceto-
acetate with phenylhydrazine. The condensation of 3
with p-hydroxybenzaldehyde in basic medium afforded
pyrazolone 4 due to activation of the 5-methyl group
via protonation of endocyclic nitrogen atom. The
reaction of 3 with the same aldehyde in acidic medium
yielded pyrazolone 5 [12, 13] (Scheme 1). The IR
spectrum of 4 contained absorption bands at 3178 and
13
and 2.03 ppm. The C NMR spectrum of 7 contained
signals at δC 162.32 (C=O), 35.79 (pyran CH), and
32.34, 30.77, and 11.62 ppm (CH3). The mass spectrum
of 7 showed a peak at m/z 360 [M]+ corresponding to
the molecular ion.
1654 cm–1 due to NH and C=O groups. The H NMR
of 4 showed singlets at δ 10.83 and 10.59 ppm for OH
1
1245

ASSY et al.
1246
Scheme 1.
O
EtONa, EtOH
reflux
O
O
+
PhNHNH2
N
Ph
Me
OEt
Me
N
H
1
2
3
O
OH
4-HOC6H4CHO
AcONa, AcOH
Ph
N
N
HN
N
N2H4·H2O
BuOH
N
4
N
Ph
N
HO
Me
10
O
4-HOC6H4CHO
NaOH, EtOH
OH
N
O
O
Me
HO
N
Me
Me
EtONa
Me
Ph
N
5
O
O
O
Me
Me
6
Me
Me
HO
HO
N
N
N
N
Ph
Ph
O
O
O
Me
OH
Me
Me
7
8
The cyclization of 5 with hydrazine hydrate as
binucleophile involved conjugate addition, followed by
oxidation of intermediate adduct 9, to give pyrazolo-
pyrazole derivative 10 (Scheme 1). The IR spectrum of
10 lacked C=O absorption, but OH and C=N stretching
bands were present at 3452 and 1654 cm–1, respec-
attack of ammonia on the protonated pyran ring of 11
to give intermediate 12 and subsequent imine–enamine
tautomerization, ammonolysis, and oxidative aroma-
tization (Scheme 2) [14]. The IR spectrum of 13
revealed bands at 3066, 1640, and 1504 cm–1 due to
NH2, C=O, and C=N groups, respectively. Singlets at
1
1
tively. The H NMR spectrum of 10 displayed signals
9.17, 4.82, and 3.91 ppm in the H NMR spectrum of
at δ 10.33 (D2O exchangeable, OH), 4.80 (3-H), and
2.26 ppm (CH3). The C=N sp2-carbon signal was
located at δC 163.05 ppm in the 13C NMR spectrum.
The mass spectrum of 10 showed the molecular ion
peak at m/z 290 [M]+.
13 were assigned to the OH and two NH2 groups,
respectively. The carbonyl carbon signal appeared in
the 13C NMR spectrum of 13 at δC 162.32 ppm. The
molecular ion peak was present in its mass spectrum
at m/z 359.
Treatment of compound 5 with ethyl cyanoacetate
in presence of ammonium acetate in acetic acid af-
forded pyrazolopyridine 13 as the final product.
Presumably, compound 13 is formed via ring trans-
formation of pyranopyrazole 11 into pyrazolopyridine
13. The reaction mechanism involves nucleophilic
Likewise, the cyclocondensation of 5 with ethyl
acetoacetate in presence of ammonium acetate in acetic
acid gave pyrazolopyridine 15 (Scheme 2). The mecha-
nism of formation of 15 is similar to that proposed
above for the formation of 13. The IR spectrum of 15
revealed peaks for the OH and C=O groups at 3417 and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020

DESIGN AND SYNTHESIS OF FUSED AND SPIRO PYRAZOLE DERIVATIVES
1247
Scheme 2.
Me
Me
HO
HO
N
N
NCCH2COOEt
EtOH
N
N
Ph
Ph
NH4OAc, AcOH
5
O
NH
O
O
NH2
NH
OEt
11
OEt
12
Me
N
HO
(1) Ammonolysis
(2) Oxidation
N
Ph
N
O
NH2
NH2
13
O
O
Me
Me
HO
HO
N
N
Me
EtOH
OEt
N
N
Ph
Ph
NH4OAc, AcOH
5
O
N
O
O
Me
Me
OEt
14
NH2
15
1
1699 cm–1, respectively, and its H NMR spectrum
showed signals at δ 12.3 and 4.82 ppm for the OH and
NH2 protons.
goes intramolecular attack of the enamine carbon atom
on the C=S carbon atom with elimination of ammonia
and subsequent oxidation (Scheme 3). Pyrazolopyra-
zole 19 showed IR peaks for C=N and C=S groups at
Michael addition of the activated enamine carbon
atom of pyrazolone 3 to the electrophilic carbon of
2,4-dichlorobenzoyl isothiocyanate yielded thioamide
derivative 16 (Scheme 3). Compound 16 was found to
exist in solution as a mixture of thione and thiol
1
1616 and 1292 cm–1, respectively. Its H NMR spec-
trum displayed multiplet signals in the region δ 7.94–
7.26 ppm for aromatic protons and a singlet at
δ 2.49 ppm for the CH3 group.
1
tautomers, as indicated by IR and H NMR spectra.
Treatment of 3 with hydrazine hydrate in butan-1-ol
yielded spiropyrazole derivative 22. Presumably, the
reaction begins with the formation of bis-hydrazone 20,
followed by intramolecular addition of the endocyclic
enamine carbon atom to the hydrazone carbon atom of
the other ring and oxidation (Scheme 3). The C=N
stretching band was observed in the IR spectrum of 22
The IR spectrum of 16 showed peaks at 3375 (OH),
2245 (SH), 1647 (C=O), 1620 (C=O), and 1256 cm–1
(C=S). In the 1H NMR spectrum of 16, downfield D2O-
exchangeable singlets at δ 11.98, 11.65, and 9.58 ppm
were assigned to the SH, OH, and NH protons, respec-
tively. Base-catalyzed cyclization of 16 afforded pyra-
zolooxazine 17 (Scheme 3). We observed in the IR
spectrum of 17 peaks at 1651 and 1242 cm–1 assignable
to the C=N and C=S groups. The 1H NMR spectrum of
17 displayed a multiplet in the region δ 7.92–7.42 ppm
due to aromatic protons. The 13C NMR spectrum of 17
showed signals at δC 167.30 (C=S) and 135.9 ppm
(C=N). The mass spectrum of 17 contained the molec-
ular ion peak at m/z 390.29.
1
at 1616 cm–1. Its H NMR spectrum showed an aro-
matic multiplet at δ 7.75–7.17 ppm and two doublets in
the region δ 2.71–2.30 ppm for nonequivalent protons
of the CH2 group.
EXPERIMENTAL
The melting points were measured on a Gallenkamp
apparatus and are uncorrected. The IR spectra were
recorded in KBr on a Perkin Elmer FT/IR-400 spec-
By heating compound 3 with thiosemicarbazide in
the presence of sodium acetate we obtained pyrazolo-
pyrazole 19. The reaction is likely to involve interme-
diate formation of thiosemicarbazone 18 which under-
1
trometer. The H and 13C NMR spectra were recorded
on a Bruker Avance DPX 400 spectrometer at 400 and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020

ASSY et al.
1248
Scheme 3.
O
S
Me
N
NCS
S
O
Cl
Me
Cl
1,4-Dioxane
Cl
N
Cl
NaOH
–H2O
N
H
N
N
O
N
Ph
Cl
O
Ph
Cl
16
17
S
Me
Me
S
H2N
NHNH2
NH2
AcONa
[O]
–NH3, –H2
S
N
3
N
N
N
N
N
HN
N
Ph
Ph
18
19
Me
Me
Me
Me
Me
Me
N2H4·H2O, BuOH
[O]
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
NH
N
Ph
Ph
N
N
Ph
N
Ph
N
20
21
22
100 MHz, respectively, using DMSO-d6 as solvent.
The mass spectra were (electron impact, 70 eV) were
recorded on an MS-S988 instrument. Elemental
analyses were carried out at the Faculty of Science,
Mansoura University (Egypt).
5-Methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-
one (3) [12]. A solution of ethyl acetoacetate (1,
13 mL, 0.1 mol) and phenylhydrazine (2, 10 mL,
0.1 mol) in 3 mL of ethanol containing sodium ethoxide
(0.015 mol) was refluxed for 2 h. The mixture was
concentrated, and the precipitate was filtered off and
recrystallized from ethanol. Yield 85 %, pale yellow
crystals, mp 118–120°C; published data [12]: mp 126–
127°C. IR spectrum, ν, cm–1: 3414 (NH), 1604 (C=O).
1H NMR spectrum, δ, ppm: 2.09 s (3H, CH3), 5.36 s
(1H, =CH), 7.14–7.81 m (5H, Harom), 11.45 s (1H, NH).
9.77 s and 10.83 s (1H each, OH, NH, D2O exchange-
able). 13C NMR spectrum, δC, ppm: 73.10, 115.0,
118.2, 122.6, 124.3, 124.9, 128.8, 137.4, 138.4, 148.5,
151.8, 161.9, 163.06. Mass spectrum, m/z (Irel, %): 278
(45) [M]+, 185 (15), 145 (40), 127 (22), 115 (40),
91 (35), 77 (100), 51 (28). Found, %: C 73.35; H 5.05;
N 10.05. C17H14N2O2. Calculated, %: C 73.37; H 5.07;
N 10.07.
4-(4-Hydroxybenzylidene)-3-methyl-1-phenyl-
1H-pyrazol-5(4H)-one (5). A mixture of compound 3
(1.7 g, 0.01 mol), p-hydroxybenzaldehyde (1.2 g,
0.01 mol), and sodium hydroxide (0.4 g, 0.01 mol) in
ethanol (20 mL) was refluxed for 6 h. The mixture was
cooled to room temperature and poured into ice water,
and the precipitate was filtered off, dried, and recrystal-
lized from ethanol. Yield 70%, orange crystals,
mp 235–237°C; published data [13, 14]: mp 230.
IR spectrum, ν, cm–1: 3414 (OH), 1581 (C=O), 1500
5-[(Z)-2-(4-Hydroxyphenyl)ethenyl]-2-phenyl-
1,2-dihydro-3H-pyrazol-3-one (4). A mixture of
compound 3 (1.7 g, 0.01 mol), p-hydroxybenzaldehyde
(1.2 g, 0.01 mol), and sodium acetate (0.82 g,
0.01 mol) in acetic acid (10 mL) was refluxed for 3 h.
The mixture was cooled to room temperature and
poured into ice water, and the precipitate was filtered
off, dried, and recrystallized from ethanol. Yield 80%,
orange crystals, mp 230–233°C. IR spectrum, ν, cm–1:
1
(C=N). H NMR spectrum, δ, ppm: 2.31 s (3H, CH3),
6.63–8.64 m (10H, Harom, CH=),10.84 s (1H, OH,
D2O-exchangeable). 13C NMR spectrum, δC, ppm:
13.16, 115.8, 118.2, 122.6, 124.3, 124.9, 128.8, 137.4,
138.4, 148.5, 151.8, 161.9, 163.06. Mass spectrum, m/z
(Irel, %): 278 (10) [M]+, 264 (25), 186 (50), 145 (50),
127 (75), 116 (60), 77 (68), 51 (100). Found, %:
C 73.35; H 5.05; N 10.05. C17H14N2O2. Calculated, %:
C 73.37; H 5.07; N 10.07.
1
3178 (OH), 1654 (C=O), 1593 (C=N). H NMR spec-
trum, δ, ppm: 4.95 s (1H, 4-H), 6.91 d and 6.93 d
(1H each, J = 8 Hz, CH=CH), 7.16-8.63 m (9H, Harom),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020

DESIGN AND SYNTHESIS OF FUSED AND SPIRO PYRAZOLE DERIVATIVES
1249
Mass spectrum, m/z (Irel, %): 359 (20) [M]+, 248 (30),
143 (25), 115 (100), 78 (35), 63 (43), 50 (32).
Found, %: C 66.82; H 4.75; N 19.47. C20H17N5O2.
Calculated, %: C 66.84; H 4.77; N 19.49.
1-[4-(4-Hydroxyphenyl)-3,6-dimethyl-1-phenyl-
1,6-dihydropyrano[2,3-c]pyrazol-5-yl]ethanone (7).
A mixture of compound 5 (2 g, 0.01 mol), acetylacetone
(1.1 mL, 0.01 mol), and sodium ethoxide (0.01 mol) in
ethanol (20 mL) was refluxed for 4 h. The mixture was
cooled to room temperature and poured into ice water,
and the precipitate was filtered off, dried, and recrys-
tallized from ethanol. Yield 50%, dark brown crystals,
mp 200–202°C. IR spectrum, ν, cm–1: 3066 (OH), 1597
(C=O), 1504 (C=N) 1H NMR spectrum, δ, ppm: 2.28 s
(3H, CH3), 2.31 s (3H, CH3), 2.33 s (3H, CH3), 4.83 s
(1H, 4-H), 7.01–8.64 m (9H, Harom), 9.19 s (1H, OH,
D2O-exchangeable). 13C NMR spectrum, δC, ppm:
11.62, 30.77, 32.34, 35.79, 114.85, 120.49, 125.51,
128.10, 128.93, 132.27, 146.18, 155.49, 162.32. Mass
spectrum, m/z (Irel, %): 360 (10) [M]+, 302 (35), 185
(28), 174 (75), 115 (48), 76 (74), 44 (35). Found, %:
C 73.30; H 5.56; N 7.75 %. C22H20N2O3. Calculat-
ed, %: C 73.32; H 5.59; N 7.77.
4-(4-Hydroxyphenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-carboxamide (15). A mix-
ture of compound 5 (2 g, 0.01 mol), ethyl acetoacetate
(1.3 mL, 0.01 mol), and ammonium acetate (11 g) in
acetic acid (20 mL) was refluxed for 2 h. The mixture
was cooled to temperature and poured into ice water,
and the crystals were collected by filtration and recrys-
tallized from ethanol. Yield 45%, dark brown crystals,
mp. 100–102°C. IR spectrum, ν, cm–1: 3417 (NH2),
1
2978 (OH), 1701 (C=O), 1597 (C=N). H NMR spec-
trum, δ, ppm: 1.64 s and 2.09 s (3H each, CH3), 4.83 s
(2H, NH2), 6.42–8.69 m (9H, Harom),11.05 s (1H, OH,
D2O exchangeable). Mass spectrum, m/z (Irel, %): 358
(10) [M]+, 260 (20), 226 (22), 248 (30), 143 (25), 115
(100), 78 (35), 63 (43), 50 (32). Found, %: C 70.36;
H 5.04; N 15.60. C21H18N4O2. Calculated, %: C 70.38;
H 5.06; N 15.63.
4-(4-Methyl-6-phenyl-3,6-dihydropyrazolo-
[3,4-c]pyrazol-3-yl)phenol (10). A mixture of com-
pound 5 (2 g, 0.01 mol) and hydrazine hydrate
(0.5 mL, 0.01 mol) in butan-1-ol (20 mL) was heated
under reflux for 4 h. The mixture was cooled to room
temperature and poured into ice water, and the crystals
were collected by filtration and recrystallized from
ethanol. Yield 55%, light orange crystals, mp 210–
212°C. IR spectrum, ν, cm–1: 3452 (OH), 1654 (C=N).
1H NMR spectrum, δ, ppm: 2.30 s (3H, CH3), 4.80 s
(1H, 3-H), 6.62–8.63 m (9H, Harom), 10.83 s (1H, OH,
D2O exchangeable). 13C NMR spectrum, δC, ppm:
13.14, 69.50, 114.8, 115.8, 118.2, 120.4, 122.6, 124.3,
124.8, 128.7, 128.8, 137.42, 138.44, 148.53, 151.82,
161.97, 163.06. Mass spectrum, m/z (Irel, %): 290 (12)
[M]+, 246 (20), 190 (15), 177 (22), 115 (30), 77 (94),
42 (100). Found, %: C 70.30; H 4.82; N 19.28.
C17H14N4O. Calculated, %: C 70.33; H 4.86; N 19.30.
2,4-Dichloro-N-(3-methyl-5-oxo-1-phenyl-4,5-di-
hydro-1H-pyrazole-4-carbothioyl)benzamide (16).
A mixture of compound 3 (1.7 g, 0.01 mol), 2,4-di-
chlorobenzoyl isothiocyanate (0.01 mol), and 3 drops
of triethylamine in dioxane (20 mL) was heated under
reflux for 1 h. The mixture was allowed to cool to room
temperature and poured into ice-cooled aqueous acetic
acid, and the precipitate was filtered off, dried, and
recrystallized from DMF/H2O (80:20). Yield 60%,
brown crystals, mp 98–100°C. IR spectrum, ν, cm–1:
3375 (OH), 1647 (C=O), 1620 (C=O), 1589 (C=N),
1
1256 (C=S). H NMR spectrum, δ, ppm: 2.35 s (3H,
CH3), 7.15–8.25 m (8H, Harom); 9.58 s, 11.65 s, and
11.98 s (1H each, NH, OH, SH, D2O exchangeable).
Found, %: C 53.19; H 3.20; N 10.32. C18H13Cl2N3O2.
Calculated, %: C 53.21; H 3.23; N 10.34.
6-Amino-4-(4-hydroxyphenyl)-3-methyl-1-
phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
(13). A mixture of compound 5 (2 g, 0.01 mol), ethyl
cyanoacetate (1 mL, 0.01 mol), and ammonium acetate
(11 g) in acetic acid (20 mL ) was refluxed for 2 h. The
mixture was cooled to room temperature and poured
into ice water, and the crystals were collected by
filtration and recrystallized from ethanol. Yield 40%,
dark brown crystals, mp 180–182°C. IR spectrum, ν,
cm–1: 3066 (NH2), 2920 (OH), 1697 (C=O), 1504
6-(2,4-Dichlorophenyl)-3-methyl-1-phenyl-1,7a-
dihydropyrazolo[4,3-e][1,3]oxazine-4(3aH)-thione
(17). A mixture of compound 16 (0.01 mol) and sodium
hydroxide (0.01 mol) in ethanol (20 mL) was heated
under reflux for 2 h. The mixture was allowed to cool
to room temperature and poured into ice water, and the
precipitate was filtered off, dried, and recrystallized
from ethanol. Yield 55%, beige crystals, mp 190–
192°C. IR spectrum, ν, cm–1: 1651 (C=N), 1242 (C=S).
1H NMR spectrum, δ, ppm: 2.49 s (3H, CH3), 7.42–
7.92 m (8H, Harom). 13C NMR spectrum, δC, ppm:
13.14, 119.25, 120.45, 122.23, 125.22, 126.21, 127.01,
127.26, 129.15, 130.44, 130.91, 134.20, 135.9, 167.3.
Mass spectrum, m/z (Irel, %): 388 (100) [M]+, 353 (25),
338 (32), 109 (22), 80 (45), 67 (48), 57 (32), 44 (62).
1
(C=N). H NMR spectrum, δ, ppm: 2.29 s (3H, CH3),
3.91 s (2H, NH2), 4.87 s (2H, NH2), 6.65–7.94 m (9H,
Harom), 9.17 s (1H, OH, D2O exchangeable). 13C NMR
spectrum, δC, ppm: 11.65, 114.89, 115.8, 118.3, 120.5,
125.5, 128.8, 128.9, 132.3, 137.4, 146.2, 155.5, 162.3.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020

ASSY et al.
1250
2. Ragavan, R.V., Vijayakumar, V., and Kumari, N.S., Eur.
J. Med. Chem., 2009, vol. 44, p. 3852.
Found, %: C 55.66; H 2.84; N 10.79. C18H11Cl2N3OS.
Calculated, %: C 55.68; H 2.86; N 10.82.
https://doi.org/10.1016/j.ejmech.2009.04.010
4-Methyl-6-phenylpyrazolo[3,4-c]pyrazole-
3(6H)-thione (19). A mixture of compound 3 (1.7 g,
0.01 mol), thiosemicarbazide (0.91 g, 0.01 mol), and
sodium acetate (0.8 g, 0.01 mol) in acetic acid (10 mL)
was heated under reflux for 6 h. The mixture was
cooled to room temperature and poured into ice water,
and the precipitate was filtered off, dried, and recrys-
tallized from ethanol. Yield 40%, yellow crystals,
mp 195–196°C. IR spectrum, ν, cm–1: 1616 (C=N),
3. Gürsoy, A., Demirayak, Ş., Çapan, G., Erol, K., and
Vural, K., Eur. J. Med. Chem., 2000, vol. 35, p. 359.
https://doi.org/10.1016/S0223-5234(00)00117-3
4. Castagnolo, D., Manetti, F., Radi, M., Bechi, B.,
Pagano, M., De Logu, A., Meleddu, R., Saddi, M., and
Botta, M., Bioorg. Med. Chem., 2009, vol. 17, p. 5716.
https://doi.org/10.1016/j.bmc.2009.05.058
5. Parekh, N., Maheria, K., Patel, P., and Rathod, M., Int. J.
Pharm. Tech. Res., 2011, vol. 3, p. 540.
6. Mariappan, G., Saha, B., Sutharson, L., and Haldar, A.,
Indian J. Chem., Sect. B, 2010, vol. 49, p. 1671.
http://nopr.niscair.res.in/handle/123456789/10738
1
1292 (C=S). H NMR spectrum, δ, ppm: 2.30 s (3H,
CH3), 7.26–7.94 m (5H, Harom). Mass spectrum,
m/z (Irel, %): 230 (100) [M]+, 246 (20), 190 (15), 177
(22), 115 (30), 77 (2). Found, %: C 57.35; H 4.35;
N 24.30. C11H10N4S. Calculated, %: C 57.37; H 4.38;
N 24.33; S 13.92.
7. Kumar, P., Ravi, T., and Subbuchettiar, G., Acta Pharm.
Sci., 2009, vol. 59, p. 159.
8. Isloor, A.M., Kalluraya, B., and Shetty, P., Eur. J. Med.
Chem. 2009, vol. 44, p. 3784.
4′,5-Dimethyl-2,6′-diphenyl-2,4-dihydro-6′H-
spiro[pyrazole-3,3′-pyrazolo[3,4-c]pyrazole] (22).
A mixture of compound 3 (1.7 g, 0.01 mol) and
hydrazine hydrate (0.5 mL, 0.01 mol) in butan-1-ol
(20 mL) was refluxed for 6 h. The mixture was cooled
to room temperature and poured into ice water, and the
precipitate was filtered off, dried, and recrystallized
from ethanol. Yield 45 %, dark brown crystals,
mp 280–282°C. IR spectrum: ν 1616 cm–1 (C=N).
1H NMR spectrum, δ, ppm: 1.22 s and 0.85 s (3H each,
CH3), 2.30–2.71 d.d (2H, CH2), 7.17–7.75 m (10H,
https://doi.org/10.1016/j.ejmech.2009.04.038
9. Isloor, A.M., Kalluraya, B., and Pai, K.S., Eur. J. Med.
Chem., 2010, vol. 45, p. 825.
https://doi.org/10.1016/j.ejmech.2009.11.015
10. Chandrakantha, B., Shetty, P., Nambiyar, V., Isloor, N.,
and Isloor, A.M., Eur. J. Med. Chem., 2010, vol. 45,
p. 1206.
https://doi.org/10.1016/j.ejmech.2009.11.046
11. Rai, U.S., Isloor, A.M., Vijesh, A., Prabhu, N., Isloor, S.,
Thiageeswaran, M., and Fun, H.-K., Eur. J. Med. Chem.,
2010, vol. 45, p. 2695.
https://doi.org/10.1016/j.ejmech.2010.02.040
H
arom). Mass spectrum, m/z (Irel, %): 342 (12) [M]+,
12. Khan, R., Uddin, M.I., Alam, M.S., Hossain, M.M., and
Islam, M.R., Bangladesh J. Pharmacol., 2008, vol. 3,
p. 27.
327 (20), 131 (100), 105 (25), 77 (39). Found, %:
C 70.14; H 5.28; N 24.50. C20H18N6. Calculated, %:
C 70.16; H 5.30; N 24.54.
https://doi.org/10.3329/bjp.v3i1.834
13. Dube, P.N., Bule, S.S., Ushir, Y.V., Kumbhare, M.R.,
and Dighe, P.R., Med. Chem. Res., 2015, vol. 24,
p. 1070.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
https://doi.org/10.1007/s00044-014-1201-z
14. Seoane, C., Soto, J.L., Zamorano, P., and Quinteiro, M.,
J. Heterocycl. Chem., 1981, vol. 18, no. 2, p. 309.
https://doi.org/10.1002/jhet.5570180216
15. Atta-ur-Rahman, Choudhary, M.I., and Thomsen, W.J.,
Bioassay Techniques for Drug Development, London:
Harwood Academic, 2001.
1. Arnost, M., Pierce, A., Ter-Haar, E., Lauffer, D.,
Madden, J., Tanner, K., and Green, J., Bioorg. Med.
Chem. Lett., 2010, vol. 20, p. 1661.
https://doi.org/10.1016/j.bmcl.2010.01.072
https://doi.org/10.3109/9780203304532
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020