Synthesis of Pyrano, Pyrido, Oxazino, and Spiro Pyrazole Derivatives and Their Antimicrobial Activity

Article abstract of DOI:10.1134/S1070428020100267

Abstract: Condensation of 5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one with 4-hydroxybenzaldhyde in alcoholic sodium hydroxide yielded 4-(4-hydroxybenzylidene)-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, and treatment of the latter with acetylacetone, hydrazine hydrate, ethyl cyanoacetate, and ethyl acetoacetate gave pyranopyrazole, pyrazolopyrazole, and pyrazolopyridine derivatives. 5-Methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was reacted with 2,4-dichlorobenzoyl isothiocyanate, thiosemicarbazide, and hydrazine hydrate to afford pyrazolooxazine, pyrazolopyrazole, and spiro[pyrazole-3,3′-pyrazolo[3,4-c]pyrazole] derivatives. Some of the newly synthesized compounds showed high antimicrobial activity against three microbial strains (S. aureus, E. coli, C. albicans).

Full text of DOI:10.1134/S1070428020100267

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 10, pp. 1832–1839. © Pleiades Publishing, Ltd., 2020.
Synthesis of Pyrano, Pyrido, Oxazino, and Spiro Pyrazole
Derivatives and Their Antimicrobial Activity
E. F. Abdelrahmana,*, W. Shehtaa, M. G. M. Assya, and M. E. Farhana
a Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, 44519 Egypt
*e-mail: feman3553@gmail.com
Received December 20, 2019; revised July 24, 2020; accepted July 31, 2020
Abstract—Condensation of 5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one with 4-hydroxybenzaldhyde in
alcoholic sodium hydroxide yielded 4-(4-hydroxybenzylidene)-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-
one, and treatment of the latter with acetylacetone, hydrazine hydrate, ethyl cyanoacetate, and ethyl acetoacetate
gave pyranopyrazole, pyrazolopyrazole, and pyrazolopyridine derivatives. 5-Methyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one was reacted with 2,4-dichlorobenzoyl isothiocyanate, thiosemicarbazide, and hydrazine hydrate
to afford pyrazolooxazine, pyrazolopyrazole, and spiro[pyrazole-3,3′-pyrazolo[3,4-c]pyrazole] derivatives.
Some of the newly synthesized compounds showed high antimicrobial activity against three microbial strains
(S. aureus, E. coli, C. albicans).
Keywords: pyranopyrazole, pyrazolopyrazole, pyrazolopyridine, pyrazolooxazine, antimicrobial activity
DOI: 10.1134/S1070428020100267
INTRODUCTION
Herein we report the synthesis and antimicrobial
activity of some new fused pyrazole derivatives such
as pyranopyrazole, pyrazolopyrazole, pyrazolopyridine,
and pyrazolooxazine.
In recent years, much attention has been focused on
the synthesis of nitrogen heterocycles because of their
biological and medicinal importance. Pyrazolones and
their derivatives constitute a significant class of hetero-
cyclic compounds which can be found in many natural
and synthetic products and medicinally active mole-
cules [1, 2]. They are interesting because of their sub-
stantial pharmacological and biological activities such
as antioxidant, antiplatelet, anti-inflammatory, anti-
tumor, enzyme inhibitory, analgesic, antifungal, and
antibacterial [3–10]. Therefore, the synthesis of func-
tionalized pyrazolone structures is a hot topic in
synthetic chemistry, and a great deal of work has been
reported on this subject [11–14].
RESULTS AND DISCUSSION
5-Methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one
(3) was synthesized by the condensation of ethyl
acetoacetate (1) with phenylhydrazine (2). The reaction
of 3 with 4-hydroxybenzaldehyde in acetic acid in the
presence of sodium acetate afforded pyrazolone 4 due
to the activation of the 5-CH3 group via protonation of
the endocyclic nitrogen atom, whereas pyrazolone 5
was obtained under basic conditions [18, 19]
(Scheme 1). The IR spectrum of 4 contained bands at
3178 and 1654 cm–1 for N–H and C=O stretching
1
Increasing antibiotic resistance in microbial popula-
tions requires search for alternate cellular targets for
new antimicrobial agents. It is well known that small
modifications in the structure of targets change their
biological character and physiochemical properties.
A survey of literature on antimicrobial activity of
various types of compounds revealed that the presence
of certain pharmacophore such as pyrazole in any
molecule plays an important role in improving the
activity [15–17].
vibrations, respectively, The H NMR spectrum of 4
showed singlets at δ 10.83 and 10.59 ppm for OH and
NH protons and two doublets at δ 6.89–7.08 ppm with
J = 8 Hz, which were assigned to cis-oriented protons
at the exocyclic C=C double bond. In the 13C NMR
spectrum of 4, the carbonyl carbon atom resonated at
δC 163.06 ppm. The mass spectrum of 4 showed the
molecular ion peak at m/z 278.32 and the base peak at
m/z 77 [Ph]+. In the IR spectrum of 5 we observed OH
and C=O peaks at 3411 and 1650 cm–1, respectively. Its
1832

SYNTHESIS OF PYRANO, PYRIDO, OXAZINO, AND SPIRO PYRAZOLE DERIVATIVES
1833
Scheme 1.
4-HOC6H4CHO
AcONa, AcOH
NH
O
N
Ph
O
OH
Me
O
O
EtONa, EtOH
4
Me
+ PhNHNH2
N
N
H
Me
OEt
Ph
4-HOC6H4CHO
NaOH, EtOH
1
2
3
N
N
HO
O
Ph
5
Scheme 2.
Me
Me
O
O
Ph
Me
N
O
O
Me
O
N
Me
EtONa
Me
O
HO
Me
O
N
7
Ph
N
Me
OH
HO
Me
O
6
Ph
N
5
N
HO
Me
8
NH
N
HN
N
Ph
Ph
N2H4·H2O, BuOH
Oxidation
N
N
N
N
HO
HO
Me
Me
9
10
1HNMR spectrum showed singlets at δ 10.84 (OH) and
2.49 ppm (CH3), and the 13C NMR spectrum contained
signals at δC 163.06 (C=O) and 13.16 ppm (CH3).
and three methyl proton singlets at δ 2.70, 2.26, and
2.03 ppm. The 13C NMR spectrum of 7 contained
signals at δС 162.32 ppm (C=O) and at δC 35.79, 32.34,
30.77, and 11.62 ppm for sp3-carbons (CH, CH3). The
mass spectrum of 7 showed the molecular ion peak at
m/z 360 [M]+.
The reaction of benzylidenepyrazole 5 with acetyl-
acetone in basic medium resulted in cyclization to
pyranopyrazole derivative 7, whereas no indazole 8
was formed. Obviously, compound 7 is formed via in-
tramolecular cyclodehydration of intermediate Michael
adduct 6 which could not be isolated (Scheme 2).
Compound 7 displayed IR peaks at 3402 and 1654 cm–1
due to O–H and C=O stretchings, respectively. Its
1H NMR spectrum showed a downfield D2O exchange-
able singlet at δ 9.19 ppm for the OH proton, a singlet
at δ 4.83 ppm from the CH proton of the pyran ring,
Intermolecular cyclization via conjugate addition of
hydrazine hydrate to compound 5, followed by oxida-
tion of intermediate 9, afforded pyrazolopyrazole
derivative 10 (Scheme 2). The IR spectrum of 10
lacked C=O absorption, but OH and C=N peaks were
observed at 3452 and 1654 cm–1, respectively. The OH
1
proton of 10 resonated in the H NMR spectrum at
δ 10.33 ppm as a D2O-exchangeable singlet, and the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

ABDELRAHMAN et al.
1834
Scheme 3.
O
OEt NH2
EtO
O
N
NC
OEt
O
O
OH
EtOH
5
Ph
N
Ph
N
N
N
HO
HO
Me
Me
11
HN
OEt NH
NH2 NH2
EtO
O
NH2
O
AcONH4
AcOH
(1) Ammonolysis
(2) Aromatization
O
NH
O
N
Ph
Ph
N
N
Ph
N
N
N
N
HO
HO
HO
Me
Me
Me
13
12
CH and methyl proton signals were located at
δ 4.80 and 2.26 ppm, respectively. The 13C NMR
spectrum of 10 showed C=N carbon signals at
δC 163.05 ppm. The mass spectrum contained the
molecular ion peak at m/z 290 [M]+.
mechanism of formation of 15 is likely to be similar to
that proposed for compound 13. In the IR spectrum of
15 we observed absorption peaks at 3417 (OH), and
1699 cm–1 (C=O), and signals at δ 12.3 (OH) and
4.82 ppm (NH2) were present in its 1H NMR.
Treatment of 5 with ethyl cyanoacetate in presence
of ammonium acetate in acetic acid afforded pyrazolo-
pyridine 13 as final product. The reaction is likely to
involve initial formation of pyranopyrazole 11 and its
recyclization to pyrazolopyridine 13 through interme-
diate 12, followed by imine–enamine tautomerization,
ammonolysis, and aromatization [20] (Scheme 3). The
IR spectrum of 13 showed bands at 3066, 1640, and
1504 cm–1 for NH2, C=O, and C=N groups. Its
1H NMR spectrum revealed the presence of singlets
at δ 9.17, 4.82, and 3.91 ppm assignable for OH and
two NH2 protons. In the 13C NMR spectrum of 13, the
carbonyl carbon resonated at δC 162.32 ppm. Its mass
spectrum contained the molecular ion peak at m/z 359.
Michael addition of the activated enamino carbon
atom of pyrazolone 3 to the electrophilic carbon atom
of 2,4-dichlorobenzoyl isothiocyanate yielded thio-
amide derivative 16 (Scheme 5). It should be noted that
thioamide derivative 16 exist in solution as a mixture
of thione and thiol tautomers (Scheme 6) as indicated
1
by its IR and H NMR spectra. The IR spectrum of
16 revealed peaks at 3375, 2245, 1647, 1620, and
1256 cm–1 assignable to OH, SH, C=O, and C=S
1
groups. The H NMR spectrum of 16 showed down-
field D2O exchangeable singlets at δ 11.98, 11.65, and
9.58 ppm for SH, OH, and NH protons.
Base-catalyzed cyclization of 16 afforded pyrazolo-
oxazine 17 (Scheme 5) which displayed IR absorption
bands at 1651 (C=N) and 1242 cm–1 (C=S). Aromatic
protons of 17 resonated as a multiplet signal at δ 7.92–
Likewise, the cyclocondensation of 5 with ethyl
acetoacetate in the presence of ammonium acetate in
acetic acid gave pyrazolopyridine 15 (Scheme 4). The
1
7.42 ppm in the H NMR spectrum. In the 13C NMR
Scheme 4.
O
O
OEt Me
NH2 Me
Me
EtOH
OEt
O
O
O
N
AcONH4, AcOH
5
Ph
Ph
N
N
N
N
HO
HO
Me
Me
14
15
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

SYNTHESIS OF PYRANO, PYRIDO, OXAZINO, AND SPIRO PYRAZOLE DERIVATIVES
1835
Scheme 5.
S
Me
O
S
OH
N
2,4-Cl2C6H3C(O)NCS
NaOH
N
N
H
Ph
N
N
N
O
Ph
Cl
Cl
Me
Cl
Cl
16
17
Ph
Me
H2NC(=S)NHNH2
AcONa
N
N
H
N
NH2
3
N
N
N
N
–NH3, –H2
N
S
Ph
S
Me
18
19
Me
Me
Me
N
N
N
N
N2H4·H2O
BuOH
N
Me
N
Me
N
Oxidation
N
Me
Ph
Ph
N
N
NH
N
N
N
Ph
N
N
H
N
N
Ph
20
Me
Me
21
22
Scheme 6.
O
S
O
S
O
SH
O
N
OH
OH
H
N
H
N
H
N
Ph
Ph
Ph
N
N
N
N
N
Cl
Cl
Cl
Cl
Cl
Cl
Me
Me
Me
16
spectrum of 17, signals at δC 167.30 (C=S) and
135.9 ppm (C=N) were present. The mass spectrum of
17 showed a peak at m/z 390.29 corresponding to its
molecular ion.
underwent intramolecular cyclization via addition of
enamino carbon atom of one pyrazole fragment to the
hydrazone carbon atom of the other pyrazole fragment,
followed by oxidation (Scheme 5). In the IR spectrum
of 22, an absorption band at 1616 cm–1 (C=N) was
observed. Its H NMR spectrum showed a multiplet at
δ 7.75–7.17 ppm for aromatic protons and two doublets
at δ 2.71–2.30 ppm for methylene protons.
The reaction of 3 with thiosemicarbazide in acetic
acid in the presence of sodium acetate yielded pyra-
zolopyrazole 19. Compound 19 is likely to be formed
as a result of intramolecular cyclization of intermediate
thiosemicarbazone 18 via attack of the enamino carbon
atom on the thioxo group with extrusion of ammonia
molecule and subsequent oxidation (Scheme 5). Pyr-
azolopyrazole 19 showed IR peaks for C=N and
C=S groups at 1616 and 1292 cm–1, respectively. Its
1H NMR spectrum (DMSO-d6) revealed multiplet
signals at δ 7.94–7.26 ppm for aromatic protons and
a singlet at δ 2.49 ppm for CH3 group. Treatment of 3
with hydrazine hydrate afforded spiro pyrazole deriva-
tive 22. Presumably, initially formed bis-hydrazone 20
1
Antimicrobial activity. The synthesized com-
pounds were evaluated for their in vitro antimicrobial
activity against three microbial strains (S. aureus,
E. coli, and C. albicans) by using agar diffusion assay,
and the results for each tested compound were repre-
sented as inhibition zone diameters in mm (Table 1).
Compounds 16 and 17 containing a 2,4-dichlorophenyl
moiety showed high antibacterial activity against
S. aureus and E. coli, whereas compounds 4, 5, 7, 10,
13, 15, 19 and 22 were weakly active against the same
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

ABDELRAHMAN et al.
1836
Table 1. Inhibition zone diametersa (d) and activity indices (I) for the newly synthesized compounds against some bacterial
and fungal strains
E. coli
S. aureus
C. albicans
Compd. no.
d, mm
I, %
11
d, mm
I, %
17
d, mm
I, %
26
4
3
4
7
5
8
9
10
13
7
42
55
30
76
67
79
88
58
37
100
–
15
18
9
56
67
34
82
48
45
12
55
63
–
31
7
35
12
10
3
13
11
12
20
22
10
7
43
46
80
82
38
26
18
16
19
21
14
9
22
13
12
3
15
16
17
19
15
17
NA
27
22
Ampicillin
Clotrimazole
24
NA
26
NA
100
–
100
a
NA stands for no activity.
bacterial strains. Compound 13 showed the highest
antifungal activity against C. albicans; the other com-
pounds exhibited weak activity against C. albicans.
(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:
3406 (O–H), 3178 (N–H), 3070 (C–Harom), 1654
EXPERIMENTAL
The melting points were measured on a Gallenkamp
apparatus and are uncorrected. The IR spectra were re-
corded in KBr on a Perkin Elmer FT/IR-400 spectro-
1
(C=O), 1593 (C=N), 1543 (C=C). H NMR spectrum,
δ, ppm: 4.95 s (1H, 4-H), 6.90 d (1H, J = 8 Hz,
CH=CH), 6.98 d (2H, J = 8 Hz, Harom), 7.14–7.68 m
(3H, Harom), 7.74 d (1H, J = 8 Hz, CH=CH), 7.84 d
(2H, J = 8 Hz, Harom), 8.56–8.60 m (2H, Harom), 9.77 s
(1H, NH, D2O exchangeable),10.83 s (1H, OH, D2O
exchangeable). 13C NMR spectrum, δC, ppm: 73.1,
115.85, 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. M 278.
1
photometer. The H and 13C NMR were recorded on
a Bruker spectrometer at 400 and 100 MHz, respec-
tively, using DMSO-d6 as solvent. The mass spectra
(electron impact, 70 eV) were run on an MS-S988
instrument. Elemental analyses and antimicrobial study
were carried out at the Faculty of Science, Mansoura
University (Egypt).
5-Methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-
one (3) [18]. A solution of ethyl acetoacetate (1, 13 mL,
0.1 mol) and phenylhydrazine (2, 10 mL, 0.1 mol) in
ethanolic sodium ethoxide (0.015 mol in 3 mL of
ethanol) was refluxed for 2 h. The mixture was concen-
trated, and the precipitate was filtered off and recrys-
tallized from ethanol. Yield 85%, pale yellow solid,
mp 118–120°C; published data [20]: mp 126–127°C.
IR spectrum, ν, cm–1: 3414 (N–H), 3055 (C–Harom),
(Z)-4-(4-Hydroxybenzylidene)-5-methyl-2-
phenyl-2,4-dihydro-3H-pyrazol-3-one (5). A mixture
of compound 3 (1.7 g, 0.01 mol) and 4-hydroxylbenz-
aldhyde (1.2 g, 0.01 mol) in a solution of sodium
hydroxide (0.4 g, 0.01 mol) in ethanol (20 mL) was
refluxed for 6 h. The mixture was cooled to room tem-
perature and poured into ice water, and the precipitate
was filtered off, dried, and recrystallized from ethanol.
Yield 70%, orange crystals, mp 235–237°C; published
data [18, 19]: mp 230°C. IR spectrum, ν, cm–1: 3414
(O–H), 3170 (C–Harom), 2800 (C–Haliph), 1581 (C=O),
1
2924 (C–Haliph), 1604 (C=O), 1519 (C=C). H 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).
5-[(Z)-2-(4-Hydroxyphenyl)ethenyl]-2-phenyl-
1,2-dihydro-3H-pyrazol-3-one (4). A mixture of com-
pound 3 (1.7 g, 0.01 mol), 4-hydroxybenzaldehyde
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

SYNTHESIS OF PYRANO, PYRIDO, OXAZINO, AND SPIRO PYRAZOLE DERIVATIVES
1837
1
1500 (C=N). H NMR spectrum, δ, ppm: 2.31 s (3H,
CH3), 6.61–6.64 m (3H, Harom), 6.80 d (2H, J = 8 Hz,
Harom), 7.00 d (2H, J = 8 Hz, Harom), 7.16-8.57 m (3H,
Harom), 7.73 s (1H, =CH), 10.84 s (1H, OH, D2O ex-
changeable). 13CNMR 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. M 278.
Found, %: C 70.30; H 4.82; N 19.28. C17H14N4O.
Calculated, %: C 70.33; H 4.86; N 19.30. M 290.
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 filtra-
tion and recrystallized from ethanol. Yield 40%, dark
brown crystals, mp 180–182°C. IR spectrum, ν, cm–1:
3417 (O–H), 3136 (NH2), 3066 (C–Harom), 2920
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: 3402 (O–H),
3066 (C–Harom), 1597 (C=O), 1504 (C=N), 1249
1
(C–Haliph), 1654 (C=O), 1597 (C=N). H NMR spec-
trum, δ, ppm: 2.29 s (3H, CH3), 3.91 br.s (2H, NH2),
4.87 s, 2H, NH2), 6.66 d (2H, J = 8 Hz, Harom), 7.04 d
(2H, J = 8 Hz, Harom), 7.21–7.94 m (5H, Ph), 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, 137.44, 146.2, 155.54, 162.32. 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.
M 359.
1
(C–O). H 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),
6.53–6.65 m (3H, Ph), 6.98 d (2H, J = 8 Hz, Harom),
7.02 d (2H, J = 8 Hz, Harom), 7.23–7.94 m (2H, Ph),
9.19 s (1H, OH, D2O exchangeable). 13C NMR spec-
trum, 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. Calculated, %: C 73.32; H 5.59; N 7.77.
M 360.
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 acetooacetate
(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 room temperature and poured into ice
water, and the crystals were collected by filtration and
recrystallized from ethanol. Yield 45%, dark brown
crystals mp 100–102°C. IR spectrum, ν, cm–1: 3417
(O–H), 3197 (NH2), 3066 (C–Harom), 2904 (C–Haliph),
1701 (C=O), 1597 (C=N). 1H NMR spectrum, δ, ppm:
1.64 s (3H, CH3), 2.09 s (3H, CH3), 4.83 s (2H, NH2),
6.66 d (2H, J = 8 Hz, Harom), 7.04 d (2H, J = 8 Hz,
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 refluxed
for 4 h. The mixture was cooled to room temperature
and poured into ice water, and the crystals were col-
lected by filtration and recrystallized from ethanol.
Yield 55%, light orange crystals, mp 210–212°C. IR
spectrum, ν, cm–1: 3421 (O–H), 3066 (C–Harom), 2920
H
arom), 7.21–7.94 m (5H, Ph), 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. M 358.
1
(C–Haliph), 1654 (C=N), 1597 (C=C). H NMR spec-
2,4-Dichloro-N-(3-methyl-5-oxo-1-phenyl-4,5-
dihydro-1H-pyrazole-4-carbothioyl)benzamide (16).
A mixture of compound 3 (1.7 g, 0.01 mol) and 2,4-di-
chlorobenzoyl isothiocyanate (0.01 mol) in dioxane
(20 mL) was refluxed for 1 h. The mixture was allowed
to cool to room temperature and poured into an ice-
cooled mixture of water and acetic acid, and the pre-
cipitate was filtered off, dried, and recrystallized from
water and DMF. Yield 60%, brown crystals, mp 98–
trum, δ, ppm: 2.30 s (3H, CH3), 4.80 s (1H, 3-H),
6.63 d (2H, J = 8 Hz, Harom), 6.92–7.90 m (5H, Ph),
8.62 d (2H, J = 8 Hz, Harom), 10.83 s (1H, OH, D2O ex-
changeable). 13C NMR spectrum, δC, ppm: 13.14, 69.5,
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).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

ABDELRAHMAN et al.
1838
100°C. IR spectrum, ν, cm–1: 3375 (O–H), 3186
(C–Harom), 3062 (C–Haliph), 1647 (C=O), 1620 (C=O),
1589 (C=N), 1554 (C=C), 1256 (C=S). 1H NMR spec-
trum, δ, ppm: 2.35 s (3H, CH3), 7.15–7.45 m (5H, Ph),
7.65–8.25 m (3H, Harom), 9.58 s (1H, NH, D2O ex-
changeable), 11.65 s (1H, OH, D2O exchangeable),
11.98 s (1H, SH, D2O exchangeable). Found, %:
C 53.19; H 3.20; N 10.32; S 7.87. C18H13Cl2N3O2.
Calculated, %: C 53.21; H 3.23; N 10.34; S 7.89.
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, cm–1: 3066 (C–Harom),
1
2688 (C–Haliph), 1597 (C=N), 1558 (C=C). H NMR
spectrum, δ, ppm: 0.85 s (3H, CH3), 1.22 s (3H, CH3),
2.50 d.d (2H, CH2), 7.75–7.17 m (10H, Ph). Mass
spectrum, m/z (Irel, %): 342 (12) [M]+, 327 (20), 131
(100), 105 (25), 77 (39), 77 (100). Found, %: C 70.14;
H 5.28; N 24.50. C20H18N6. Calculated, %: C 70.16;
H 5.30; N 24.54. M 342.
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 refluxed
for 2 h. The mixture was allowed to cool to room tem-
perature and poured into ice water, and the precipitate
was filtered off, dried, and recrystallized from ethanol.
Yield 55%, rose crystals, mp 190–192°C. IR spectrum,
ν, cm–1: 3186 (C–Harom), 2904 (C–Haliph), 1651 (C=N),
Antimicrobial evaluation. The synthesized com-
pounds were evaluated against gram positive
(S. aureus) and gram negative bacteria (E. coli), as well
as fungi (C. albicans). Each compound was dissolved
in DMSO to a concentration of 1 mg/mL. Whatman
filter paper discs with a standard size (5 cm) were
prepared and sterilized in an autoclave. The paper discs
were soaked in a solution of a compound to be tested
with a required concentration and were placed asep-
tically in Petri dishes containing nutrient agar media
(agar 20 g + beef extract 3g + peptone 5 g) seeded with
S. aureus, E. coli, or C. albicans. The Petri dishes were
incubated at 36°C, and the inhibition zones were
measured after incubation for 24 h. Each treatment was
replicated three times. Ampicillin and clotrimazole
were used as reference drugs [21]. The activity index
was calculated as the percent ratio of the inhibition
zone diameters for a test compound and standard drug.
1
1620 (C=C), 1242 (C=S). H NMR spectrum, δ, ppm:
2.49 s (3H, CH3), 7.42–7.48 m (5H, Ph), 7.61–7.92 m
(3H, Harom). 13CNMR 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]+, 390 (50)
[M + 2]+, 392 (10) [M + 4]+, 353 (25), 338 (32), 109
(22), 80 (45), 67 (48), 57 (32), 44 (62). Found, %:
C 55.66; H 2.84; N 10.79; S 8.24. C18H11Cl2N3OS.
Calculated, %: C 55.68; H 2.86; N 10.82; S 8.26.
M 388.
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 refluxed for 6 h. The mixture was cooled to room
temperature and poured into ice water, and the precip-
itate was filtered off, dried, and recrystallized from
ethanol. Yield 40%, yellow crystals, mp 195–196°C.
IR spectrum, ν, cm–1: 3059 (C–Harom), 2908 (C–Haliph),
1616 (C=N), 1496 (C=C), 1292 (C=S). 1H NMR spec-
trum, δ, ppm: 2.30 s (3H, CH3), 7.26–7.94 m (5H, Ph).
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; S 13.90. C11H10N4S.
Calculated, %: C 57.37; H 4.38; N 24.33; S 13.92.
M 230.
CONFLICT OF INTEREST
The authors declared the absence of conflict of interest.
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