Synthesis and Modification of Hetero-Fused Pyrazoles Derived from Methyl 1-(2-Oxo-2-phenylethyl)-3-phenyl-1H-pyrazole-5-carboxylate

Article abstract of DOI:10.1134/S1070428020040144

Abstract: A modified procedure has been proposed for the synthesis of2,7-diphenyl-5,8-dihydro-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one, and the possibility of transformation ofthe latter to the pyrazolo[1,5-a]pyrazinesystem has been demonstrated. Functionalization of2,7-diphenyl-5,8-dihydro-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one at the 4-position and fusion of a tetrazoleor triazole ring at theC⁴–N⁵ bond have beenperformed.

Full text of DOI:10.1134/S1070428020040144

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 4, pp. 654–661. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 4, pp. 619–627.
Synthesis and Modification of Hetero-Fused Pyrazoles
Derived from Methyl 1-(2-Oxo-2-phenylethyl)-
3-phenyl-1H-pyrazole-5-carboxylate
A. O. Kharanekoa, T. M. Pekhterevaa, and O. I. Kharanekoa,*
a Litvinenko Institute of Physical Organic and Coal Chemistry, Donetsk, 83114 Ukraine
*e-mail: o_kharaneko@mail.ru
Received October 1, 2019; revised February 10, 2020; accepted February 18, 2020
Abstract—A modified procedure has been proposed for the synthesis of 2,7-diphenyl-5,8-dihydro-4H-pyra-
zolo[5,1-d][1,2,5]triazepin-4-one, and the possibility of transformation of the latter to the pyrazolo[1,5-a]pyra-
zine system has been demonstrated. Functionalization of 2,7-diphenyl-5,8-dihydro-4H-pyrazolo[5,1-d][1,2,5]-
triazepin-4-one at the 4-position and fusion of a tetrazole or triazole ring at the C4–N5 bond have been
performed.
Keywords: 5,8-dihydro-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one, pyrazolo[1,5-a]pyrazin-4-ol, pyrazolo-
[1,5-a]pyrazin-4(5H)-one, 5-aminopyrazolo[1,5-a]pyrazin-4(5H)-one, 5,8-dihydro-4H-pyrazolo[5,1-d][1,2,5]-
triazepine-4-thione, 4-(methylsulfanyl)-8H-pyrazolo[5,1-d][1,2,5]triazepine, 4-(morpholin-4-yl)-8H-pyrazolo-
[5,1-d][1,2,5]triazepine, 4-hydrazinyl-8H-pyrazolo[5,1-d][1,2,5]triazepine, 7H-pyrazolo[5,1-d][1,2,4]triazolo-
[4,3-b][1,2,5]triazepine, 7H-pyrazolo[5,1-d]tetrazolo[1,5-b][1,2,5]triazepine
DOI: 10.1134/S1070428020040144
Methyl 1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-car-
boxylate derivatives can formally be regarded as
1,5-dicarbonyl compounds which offer great potential
for molecular design and synthesis of new fused
heterocyclic compounds as candidates for biological
screening. In particular, pyrazolo[5,1-c][1,4]oxazines
and pyrazolo[5,1-d][1,2,5]triazepin-4-ones containing
an aryl, methyl, or carbohydrazide substituents in the
2-position have been reported [1–3]. 2,7-Diaryl-5,8-di-
hydro-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-ones were
found to inhibit endothelial cell apoptosis [2].
modify the structure of 2,7-diphenyl-5,8-dihydro-4H-
pyrazolo[5,1-d][1,2,5]triazepin-4-one at the seven-
membered ring, specifically at the C4–N5 bond.
2,7-Diaryl-5,8-dihydro-4H-pyrazolo[5,1-d][1,2,5]-
triazepin-4-ones were synthesized for the first time in
68–82% yields by reaction of 2,6-diaryl-4H-pyrazolo-
[1,5-a][1,4]oxazin-4-ones with hydrazine hydrate
[1, 2]. We have found that, apart from pyrazolotriazepi-
none 4, 7-hydrazinyl-2,7-diphenyl-5,6,7,8-tetrahydro-
4H-pyrazolo[5,1-d][1,2,5]-triazepin-4-on (3) is also
formed as minor product in the reaction of 2,6-di-
phenyl-4H-pyrazolo[1,5-a][1,4]oxazin-4-one (2) with
hydrazine hydrate and that compound 3 is transformed
to 4 on further heating in the presence of acetic acid.
These findings prompted us to modify the procedure
described in [2]; as a result, the yield of 4 was
improved to 96% (Scheme 1).
In continuation of our studies on the synthetic
potential of methyl 1-(2-oxo-2-phenylethyl)-1H-pyra-
zole-5-carboxylate, the present work was aimed at syn-
thesizing pyrazolo[1,5-a]pyrazines, taking into account
the ability of 1,5-dicarbonyl compounds to undergo
heterocyclization to pyridine derivatives. Pyrazolo-
[1,5-a]pyrazine derivatives attract much interest as
some of them have been found to exhibit anti-HIV-1
activity and be efficient in the prevention and treatment
of some hematological diseases and diabetes [4, 5].
Like 1,2-diazepinones, 1,2,5-triazepinones are
known to undergo ring contraction by the action of
hydrochloric acid to give six-membered N-aminopyr-
azine derivatives [6, 7]. However, as we showed previ-
ously [3], 1,2,5-triazepinone ring fused to a pyrazole
ring did not change on heating in aqueous HCl. On the
other hand, by heating pyrazolotriazepinone 4 in 85%
Thus, the goal of this work was to study reactions of
methyl 1-(2-oxo-2-phenylethyl)-3-phenyl-1H-pyra-
zole-5-carboxylate (1) with nitrogen nucleophiles and
654

SYNTHESIS AND MODIFICATION OF HETERO-FUSED PYRAZOLES
655
Scheme 1.
AcOH
Ph
O
O
O
O
(1) NaOH
(2) Ac2O
N
NH
NH
NHNH2
NH
N
O
OMe
N2H4·H2O
O
+
Ph
Ph
N
Ph
N
N
Ph
N
N
N
N
Ph
Ph
Ph
1
2
3 (~15%)
4 (~85%)
H3PO4
140°C
HCONH2
HCONHMe
OH
N
O
O
O
Me
Ph
Me
N
NH2
Ph
N
N
+
Ph
Ph
Ph
Ph
N
N
N
N
N
N
N
N
Ph
Ph
5
6
7
8
H3PO4 at 140°C for 1 h we obtained the corresponding
ring contraction product, 5-amino-2,6-diphenylpyra-
zolo[1,5-a]pyrazin-4(5H)-one (8). This reaction can be
regarded as a new method of synthesis of pyrazolo-
[1,5-a]pyrazine derivatives.
Pyrazolo[1,5-a]pyrazines can also be obtained
directly from pyrazole 1. The latter was quantitatively
converted to 2,6-diphenylpyrazolo[1,5-a]pyrazin-4-ol
(5) on heating for 1 h in boiling formamide, and
compound 5 remained unchanged on further heating.
When pyrazole 1 was refluxed in N-methylformamide
for 1 h, a mixture of 5-methyl-2,6-diphenylpyrazolo-
[1,5-a]pyrazin-4(5H)-one (6) and 5-methyl-2,6-di-
phenyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
(7) at a ratio of ~72:28 was formed. The proportion of
7 increased on further heating, and the ratio 6:7
changed to the opposite (~30:70) after 20 h. In fact,
this is the result of Leuckart–Wallach reaction. Pre-
sumably, the rate of reduction of 6 to 7 is determined
by the rate of ring opening of pyrazinone 6, which is
followed by reduction and ring closure to pyrazinone 7
(Scheme 3).
Balci et al. [6] proposed a mechanism for tri-
azepinone ring contraction in 4-methyl-2,5-dihydro-
1H-pyrolo[2,1-d][1,2,5]triazepin-1-one by the action of
trace amount of acid present in chloroform. The authors
presumed initial protonation of the carbonyl oxygen
atom, though protonation of N3 seemed to be more
probable since the N3 atom possesses the highest elec-
tron density. Scheme 2 shows an alternative mechanism
for acid-catalyzed triazepine ring contraction in 5,8-di-
hydro-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-ones. We
believe that initial protonation of the pyrazole nitrogen
atom is responsible for the high stability of pyrazolo-
triazepinone 4 in acid medium in comparison to pyr-
rolo[2,1-d][1,2,5]triazepin-1-one and 2,5-dihydro-1H-
2,3-benzodiazepin-1-ones [7].
Hetero-fused 1,2,5-triazepinethiones were reported
[8] to be more reactive than their oxygen analogs.
Therefore, it could be possible to perform their struc-
Scheme 2.
O
O
O
O
NH
N
NH
N
NH
NH
NH
NH
H+
–H+
N
N
N
N
N
N
N
N
H
O
O
O
H
NH2
NH
N
N
H+
H
H
N
N
–H+
N
N
N
H
H
N
N
N
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

KHARANEKO et al.
656
Scheme 3.
O
Me
Ph
–MeNH2
Ph
N
Ph
Ph
N
O
O
MeNH2
N
N
6
N
N
MeNH2
N
O
N
OMe
NHMe
Ph
O
O
Ph
Ph
Me
Ph
N
N
HCONHMe
NMe
NHMe
Ph
1
–MeNH2
N
N
Ph
NHMe
7
tural modifications at both sulfur atom and C4–N5 bond
and thus extend the range of pyrazolo[1,2,5]triazepine
derivatives. 2,7-Diphenyl-5,8-dihydro-4H-pyrazolo-
[5,1-d][1,2,5]triazepine-4-thione (9) was synthesized in
high yield by treatment of 4 with Lawessonʼs reagent
(Scheme 4). The alkylation of 9 with dimethyl sulfate
gave 4-(methylsulfanyl)-2,7-diphenyl-8H-pyrazolo-
1
[5,1-d][1,2,5]triazepine (10). In the H NMR spectrum
of 10, ortho protons in the phenyl ring on C7 appeared
as two doublets in the region δ 7.91–8.00 ppm with
Scheme 4.
MeS
N
(MeO)2SO2
Ph
N
N
N
Ph
10
O
N
N
S
N
R
O
NH
N
N
N
HN
LR
RC(O)Cl
4
Ph
Ph
N
Ph
N
N
N
N
N
N
N
Ph
Ph
Ph
9
11
13a, 13b
NH2
N
N
N
HN
N
N
N
N2H4·H2O
HNO2
Ph
Ph
N
N
N
N
N
Ph
Ph
14
12
Me
N
O
O
Me
1,4-dioxane
Me
Me
N
N
Ph
N
N
N
Ph
15
R = Me (a), 4-MeOC6H4 (b); LR stands for Lawessonʼs reagent.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

SYNTHESIS AND MODIFICATION OF HETERO-FUSED PYRAZOLES
657
Scheme 5.
Ph
Ph
N
O
O
N
N
Me
Me
H
EtOCH2CH2OH
9
N
N
N
13a
12
N
H
N
N
N
Ph
Ph
16
3
a coupling constant J of 6.8 Hz, indicating their non-
equivalence. Protons in the para and meta positions of
the same phenyl substituent resonated as a narrow
multiplet at δ 7.45–7.48 ppm.
polar and nonpolar solvent. In 2-ethoxyethanol, ketone
cleavage of the pentane-2,4-dione hydrazone is accom-
panied by closure of triazole ring and elimination of
acetone molecule (Scheme 6). Although the basicity of
hydrazine 12 is not high, the configuration of nitrogen
atoms therein is likely to favor the observed cleavage
of pentane-2,4-dione hydrazone.
The sulfur atom in pyrazolotriazepinethione 9 is
readily replaced by a secondary amine moiety; for
example, 4-(morpholin-4-yl)-2,7-diphenyl-8H-pyra-
zolo[5,1-d][1,2,5]triazepine (11) was obtained in the
reaction of 9 with morpholine. The reaction of 9 with
hydrazine hydrate afforded 4-hydrazinyl-2,7-diphenyl-
8H-pyrazolo[5,1-d][1,2,5]triazepine (12), and the latter
reacted with acetyl chloride and 4-methoxybenzoyl
chloride to produce 3-methyl-6,10-diphenyl-7H-pyra-
zolo[5,1-d][1,2,4]triazolo[4,3-b][1,2,5]triazepine (13a)
and 3-(4-methoxyphenyl)-6,10-diphenyl-7H-pyrazolo-
[5,1-d][1,2,4]triazolo[4,3-b][1,2,5]triazepine (13b),
respectively (Scheme 4). 6,10-Diphenyl-7H-pyrazolo-
[5,1-d]tetrazolo[1,5-b][1,2,5]triazepine (14) was isolat-
ed in the reaction of 12 with sodium nitrite in acetic
acid. The condensation of 12 with pentane-2,4-dione in
1,4-dioxane gave 4-(3,5-dimethyl-1H-pyrazol-1-yl)-
2,7-diphenyl-8H-pyrazolo[5,1-d][1,2,5]triazepine (15)
(Scheme 5), whereas the reaction in 2-ethoxyethanol
unexpectedly afforded pyrazolotriazolotriazepine 13a.
Pyrazolotriazepinethione 9 reacted with hydrazine
12 to give 4,4′-(hydrazine-1,2-diyl)bis(2,7-diphenyl-
8H-pyrazolo[5,1-d][1,2,5]triazepine (16) (Scheme 5).
This should be taken into account while synthesizing
compound 12 from thione 9, and no less than 20 equiv
of hydrazine hydrate should be used.
Thus, we have improved the procedure for synthesis
of pyrazolotriazepinone 4, found conditions for ring
contraction of the triazepine ring therein, and obtained
various derivatives of 4 via modification at C4 and
hetero-fusion to the C4–N5 bond.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker Avance II spectrometer (Germany) at 400 and
100 MHz, respectively, using DMSO-d6 as solvent and
tetramethylsilane as internal standard. The melting
points were measured with a Boetius melting point
apparatus and are uncorrected. Commercially available
These findings may be rationalized assuming that
intermediate hydrazone derived from pentane-2,4-di-
one and hydrazine 12 exists as different tautomers in
Scheme 6.
Me
N
Me
Me
O
O
NH2
N
N
O
Me
N
N
HN
HN
Me
1,4-dioxane
Me
N
N
N
–H2O
N
N
N
N
N
N
N
N
N
N
O
O
Me
NH2
N
N
N
N
N
Me
Me
O
Me
EtOCH2CH2OH
NH
NH
–Me2CO
Me
N
N
N
N
N
N
N
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

KHARANEKO et al.
658
reagents of chemically pure and analytical grades
were used.
a small amount of methanol. Yield of 7 0.19 g (40%),
fine colorless crystals, mp 154–156°C. H NMR spec-
1
trum, δ, ppm: 3.02 s (3H, CH3), 4.52 d.d (1H, CH2, J =
13.4, 1.2 Hz), 4.80 d.d (1H, CH2, J = 13.4, 5.2 Hz),
5.15 q (1H, CH, J = 3.2 Hz), 7.14–7.20 m (3H, Ph,
CH), 7.25 t (2H, Ph, J = 6.8 Hz), 7.27–7.37 m (4H,
Ph), 7.77 d (2H, Ph, J = 7.6 Hz). 13C NMR spectrum,
δC, ppm: 33.0 (CH3), 52.6 (CH2), 60.7 (CH), 104.0,
125.5 (2C), 126.5 (2C), 128.8 (2C), 129.0, 129.2 (2C),
129.8, 132.7, 135.6, 138.5, 151.0, 157.6. Found, %:
C 75.26; H 5.68; N 13.88; O 5.18. C19H17N3O. Cal-
culated, %: C 75.23; H 5.65; N 13.85; O 5.27.
2,7-Diphenyl-5,8-dihydro-4H-pyrazolo[5,1-d]-
[1,2,5]triazepin-4-one (4). A mixture of 3.35 g
(11.63 mmol) of 2,6-diphenyl-4H-pyrazolo[5,1-c][1,4]-
oxazin-4-one (2) and 1.2 mL (24.0 mmol) of hydrazine
hydrate in 10 mL of 2-ethoxyethanol was refluxed for
4 h. Acetic acid, 1.5 mL, was added to the hot mixture,
and the mixture was refluxed for an additional 30 min.
After cooling, the mixture was diluted with 80 mL of
water under stirring, and the precipitate was filtered off
and washed with water. Yield 3.4 g (97%), colorless
crystals, mp 227–228°C; published data [2]: mp 230–
The mother liquor was evaporated to dryness under
reduced pressure, 10 mL of heptane was added to the
residue, and the mixture was heated to the boiling point
with stirring. The hot solution was separated from the
undissolved resin and was left overnight. The crystal-
line solid was filtered off and washed with heptane.
Yield of 6 0.14 g (30%), fine colorless crystals,
1
232°C. H NMR spectrum, δ, ppm: 5.53 s (2H, CH2),
7.27 s (1H, CH), 7.28 t (1H, Ph, J = 7.6 Hz), 7.37 t
(2H, Ph, J = 7.2 Hz), 7.40–7.48 m (3H, Ph), 7.81 d
(2H, Ph, J = 7.2 Hz), 7.90 d (1H, Ph, J = 6.8 Hz),
7.91 d (1H, Ph, J = 6.8 Hz), 11.44 s (1H, NH).
13C NMR spectrum, δC, ppm: 48.6 (CH2), 106.6 (CH),
125.2 (2C), 126.6 (2C), 127.7, 128.3 (2C), 128.5 (2C),
130.2, 132.0, 134.3, 137.1, 150.1, 154.4, 157.5 (CO).
Found, %: C 71.50; H 4.70; N 18.52; O 5.28.
C18H14N4O. Calculated, %: C 71.51; H 4.67; N 18.53;
O 5.29.
1
mp 106–108°C. H NMR spectrum, δ, ppm: 3.26 s
(3H, CH3), 7.38–7.44 m (4H, Ph), 7.46–7.55 m (6H,
Ph, CH), 7.93 d (2H, Ph, J = 6.8 Hz). 13C NMR spec-
trum, δC, ppm: 32.0 (CH3), 101.1, 109.3, 125.5 (2C),
127.9, 128.3 (2C), 128.4 (2C), 129.0, 129.2 (2C),
131.4, 131.7, 131.8, 133.0, 151.7, 154.8. Found, %:
C 75.78; H 5.05; N 13.97; O 5.50. C19H15N3O. Cal-
culated, %: C 75.73; H 5.02; N 13.94; O 5.31.
2,6-Diphenylpyrazolo[1,5-a]pyrazin-4-ol (5).
A mixture of 0.5 g (1.56 mmol) of compound 1 and
3 mL of formamide was refluxed for 1 h. The mixture
was cooled and diluted with 8 mL of water, and the
precipitate was filtered off and washed with water.
Yield 0.42 g (93%), fine colorless crystals, mp 242–
243°C. 1H NMR spectrum, δ, ppm: 7.33 t (1H, Ph, J =
6.8 Hz), 7.38 s (1H, CH), 7.40–7.49 m (5H, Ph), 7.73 d
(2H, Ph, J = 7.2 Hz), 7.91 s (1H, CH), 7.93 d (2H, Ph,
J = 7.6 Hz), 11.55 s (1H, OH). 13C NMR spectrum, δC,
ppm: 101.5 (CH), 107.9 (CH), 126.1 (2C), 126.7 (2C),
128.5, 128.9 (2C), 129.0 (3C), 129.2, 129.3, 131.7,
132.5, 134.2, 152.2, 156.12. Found, %: C 75.29;
H 4.60; N 14.59; O 5.52. C18H13N3O. Calculated, %:
C 75.25; H 4.56; N 14.62; O 5.57.
5-Amino-2,6-diphenylpyrazolo[1,5-a]pyrazin-
4(5H)-one (8). A mixture of 0.1 g (0.33 mmol) of 4 and
0.5 mL of 85% H3PO4 was heated with stirring to
140°C until complete dissolution. The mixture was
kept for 1 h at that temperature, cooled, diluted with
5 mL of water, and adjusted to pH ~9 with 30% aque-
ous ammonia. An oily material separated and crystal-
lized on grinding. The precipitate was filtered off,
dried, and recrystallized from toluene. Yield 0.096 g
(96%), fine colorless crystals, mp 138–139°C.
1H NMR spectrum, δ, ppm: 5.43 s (2H, NH2), 7.34 t
(1H, Ph, J = 6.8 Hz), 7.38–7.52 m (6H, Ph, CH), 7.57 s
(1H, CH), 7.62 t (2H, Ph, J = 3.6 Hz), 7.93 d (2H, Ph,
J = 7.2 Hz). 13C NMR spectrum, δC, ppm: 101.6, 109.3,
126.2 (3C), 128.1 (2C), 128.6, 128.9 (2C), 130.3 (2C),
132.2, 132.54, 133.0, 133.7, 152.5, 154.7. Found, %:
C 71.52; H 4.69; N 18.54; O 5.25. C18H14N4O. Cal-
culated, %: C 71.51; H 4.67; N 18.53; O 5.29.
5-Methyl-2,6-diphenylpyrazolo[1,5-a]pyrazin-
4(5H)-one (6) and 5-methyl-2,6-diphenyl-6,7-dihy-
dropyrazolo[1,5-a]pyrazin-4(5H)-one (7). A mixture
of 0.5 g (1.56 mmol) of compound 1 and 3 mL of
N-methylformamide was refluxed for 20 h. The mix-
ture was cooled and diluted with 10 mL of water, and
the resin-like material was separated by decanting. The
product was dissolved in 1 mL of methanol on heating
under reflux, and the solution was left overnight. The
crystalline solid was filtered off and washed with
2,7-Diphenyl-5,8-dihydro-4H-pyrazolo[5,1-d]-
[1,2,5]triazepine-4-thione (9). A mixture of 3.0 g
(9.97 mmol) of 4 and 3 g (7.48 mmol) of Lawessonʼs
reagent in 30 mL of anhydrous toluene was refluxed
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

SYNTHESIS AND MODIFICATION OF HETERO-FUSED PYRAZOLES
659
for 2 h. The solvent was completely removed under
reduced pressure, 30 mL of methanol was added to the
residue, and the mixture was refluxed for 2 h and left
overnight. The precipitate was filtered off and washed
with methanol. Yield 1.9 g (60%), fine yellow crystals,
O 4.30. C22H21N5O. Calculated, %: C 71.14; H 5.70;
N 18.85; O 4.31.
4-Hydrazinyl-2,7-diphenyl-8H-pyrazolo-
[5,1-d][1,2,5]triazepine (12). A mixture of 1.15 g
(3.63 mmol) of compound 9 and 3.63 mL (72.55 mmol)
of hydrazine hydrate in 19 mL of 2-ethoxyethanol was
refluxed with stirring. The mixture was cooled, 80 mL
of water and 3 g of sodium chloride were added, and
the precipitate was filtered off and washed with water.
Yield 1.03 g (90%), fine yellowish needles, mp 110–
1
mp 159–160°C. H NMR spectrum, δ, ppm: 5.55 s
(2H, CH2), 7.25–7.42 m (4H, Ph), 7.45–7.53 m (3H,
Ph, CH), 7.79 d (2H, Ph, J = 6.8 Hz), 7.97 d (2H, Ph,
J = 4.0 Hz), 13.13 s (1H, NH). 13C NMR spectrum, δC,
ppm: 49.4 (CH2), 110.5 (CH), 125.7 (2C), 127.7 (2C),
128.3, 128.8 (2C), 129.2 (2C), 131.6, 132.4, 133.8,
142.3, 150.8, 158.8, 180.5. Found, %: C 67.92; H 4.45;
N 17.57; S 10.06. C18H14N4S. Calculated, %: C 67.90;
H 4.43; N 17.60; S 10.07.
1
111°C. H NMR spectrum, δ, ppm: 5.40 s (2H, CH2),
5.67 br.s (2H, NH2), 6.78 s (1H, CH), 7.21 t (1H, Ph,
J = 7.2 Hz), 7.31 t (2H, Ph, J = 7.6 Hz), 7.34– 7.41 m
(3H, Ph, CH), 7.72 d (2H, Ph, J = 7.6 Hz), 7.81 d (2H,
Ph, J = 6.8 Hz), 9.28 br.s (1H, NH). 13C NMR spec-
trum, δC, ppm: 47.6 (CH2), 101.9 (CH), 125.1 (2C),
126.0 (2C), 127.2, 128.1, 128.4, 129.4, 132.6, 134.7,
135.2, 137.9, 149.3, 154.8. Found, %: C 68.37;
H 5.14; N 26.49. C18H16N6. Calculated, %: C 68.34;
H 5.10; N 26.56.
4-(Methylsulfanyl)-2,7-diphenyl-8H-pyrazolo-
[5,1-d][1,2,5]triazepine (10). Dimethyl sulfate,
0.19 mL (1.15 mmol), was added with vigorous stirring
to a mixture of 0.4 g (1.26 mmol) of compound 9 and
0.1 g (2.52 mmol) of sodium hydroxide in 10 mL of
acetone. The mixture was stirred for 1 h at room
temperature and diluted with 30 mL of water, and the
precipitate was filtered off and washed with water.
Yield 0.41 g (98%), fine pale yellow needles, mp 168–
3-Methyl-6,10-diphenyl-7H-pyrazolo[5,1-d]-
[1,2,4]triazolo[4,3-b][1,2,5]triazepine dihydro-
chloride (13a) and 3-(4-methoxyphenyl)-6,10-di-
phenyl-7H-pyrazolo[5,1-d][1,2,4]triazolo[4,3-b]-
[1,2,5]triazepine dihydrochloride (13b) (general
procedure). Acetyl chloride, 0.05 mL (0.633 mmol), or
4-methoxybenzoyl chloride, 0.11 mL (0.633 mmol),
was added to a solution of 0.1 g (0.316 mmol) of
compound 12 in 0.2 mL of anhydrous dioxane. The
mixture was refluxed for 5 min, saturated with gaseous
hydrogen chloride, and refluxed for an additional 2 h.
The mixture was cooled, diluted with 10 mL of diethyl
ether, and left to stand for 1 h. The resin-like material
was separated by decanting and treated with 0.3 mL
of propan-2-ol. The resin dissolved on heating with
grinding, and fine colorless crystals began to separate
from the solution. After 1 h, the precipitate was filtered
off and washed with propan-2-ol.
1
169°C. H NMR spectrum, δ, ppm: 2.64 s (3H, CH3),
3.13 s (2H, CH2), 7.00 s (1H, CH), 7.28 t (1H, Ph, J =
7.2 Hz), 7.37 t (2H, Ph, J = 7.6 Hz), 7.41–7.48 m (3H,
Ph), 7.79 d (2H, Ph, J = 7.2 Hz), 7.91–8.00 m (2H, Ph).
13C NMR spectrum, δC, ppm: 14.0 (CH3), 48.9 (CH2),
103.5 (CH), 125.8 (2C), 127.4 (2C), 128.2, 128.8
(2C), 129.0 (2C), 130.8, 132.5, 134.7, 135.7, 147.3,
151.0, 152.9. Found, %: C 68.67; H 4.88; N 16.86;
S 9.59. C19H16N4S. Calculated, %: C 68.65; H 4.85;
N 16.85; S 9.65.
4-(Morpholin-4-yl)-2,7-diphenyl-8H-pyrazolo-
[5,1-d][1,2,5]triazepine (11). A mixture of 0.12 g
(0.32 mmol) of compound 9 and 0.5 mL of morpholine
was refluxed for 1 h. The mixture was cooled, 1 mL of
water was added, an oily material separated and crys-
tallized on grinding, and the crystalline solid was
filtered off and washed with water. Yield 0.13 g (93%),
Compound 13a. Yield 0.056 g (43%), fine colorless
1
fine yellow crystals, mp 185–187°C. H NMR spec-
1
crystals, mp 194–195°C. H NMR spectrum, δ, ppm:
trum, δ, ppm: 3.49–3.56 m (4H, CH2), 3.64–3.73 m
(2H, CH2), 3.76–3.84 m (2H, CH2), 4.84 d (1H, CH2,
J = 14.4 Hz), 5.64 d (1H, CH2, J = 14.4 Hz), 6.91 s
(1H, CH), 7.27 t (2H, Ph, J = 7.2 Hz), 7.34 t (2H, Ph,
J = 7.6 Hz), 7.39–7.46 m (3H, Ph), 7.78 d (2H, Ph, J =
7.2 Hz), 7.89 d (2H, Ph, J = 8.0 Hz). 13C NMR spec-
trum, δC, ppm: 47.5 (2C, CH2), 47.8 (CH2), 65.9 (2C,
CH2), 103.1 (CH), 125.3 (2C), 126.4 (2C), 127.6, 128.2
(2C), 128.3 (2C), 129.6, 131.2, 132.3, 135.0, 145.6,
150.3, 153.4. Found, %: C 71.15; H 5.73; N 18.82;
2.69 s (3H, CH3), 5.76 s (2H, CH2), 7.30 t (1H, Ph, J =
7.2 Hz), 7.31–7.45 m (3H, Ph, CH), 7.50–7.62 m (3H,
Ph), 7.84 d (2H, Ph, J = 7.6 Hz), 8.13 d (2H, Ph, J =
7.2 Hz). 13C NMR spectrum, δC, ppm: 9.9 (CH3), 48.6
(CH2), 103.9 (CH), 125.3 (2C), 127.9, 128.0 (2C),
128.3 (2C), 128.8 (2C), 130.3, 131.8, 132.2, 133.0,
140.6, 151.4, 151.7, 161.3. Found, %: C 58.10; H 4.41;
Cl 17.13; N 20.36. C20H16N6·2HCl. Calculated, %:
C 58.12; H 4.39; Cl 17.16; N 20.33.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

KHARANEKO et al.
660
4-(3,5-Dimethyl-1H-pyrazol-1-yl)-2,7-diphenyl-
8H-pyrazolo[5,1-d][1,2,5]triazepine (15). A mixture
of 0.05 g (0.158 mmol) of compound 12 and 0.025 mL
(0.25 mmol) of pentane-2,4-dione in 0.25 mL of diox-
ane was refluxed for 4 h. The mixture was diluted with
0.5 mL of water, and the yellow resinous material was
separated by decanting and dissolved in 0.25 mL of
methanol on heating. After cooling, the precipitate was
filtered off and washed with methanol. Yield 0.031 g
(52%), fine colorless crystals, mp 170–172°C.
1H NMR spectrum, δ, ppm: 2.20 s (3H, CH3), 2.70 s
(3H, CH3), 4.94 br.s (1H, CH2), 5.93 br.s (1H, CH2),
6.12 s (1H, CH), 6.89 s (1H, CH), 7.28 t (1H, Ph, J =
7.2 Hz), 7.37 t (2H, Ph, J = 7.6 Hz), 7.47–7.50 m (3H,
Ph), 7.78 d (2H, Ph, J = 7.6 Hz), 7.95–8.12 m (2H, Ph).
13C NMR spectrum, δC, ppm: 13.4 (CH3), 13.6 (CH3),
48.8 (CH2), 105.6 (CH), 109.2 (CH), 125.3 (2C), 127.1
(2C), 127.6, 128.3 (2C), 128.5 (2C), 128.8, 130.5,
132.2, 133.7, 139.2, 142.2, 149.7, 150.3, 153.2.
Found, %: C 72.65; H 5.27; N 22.08. C23H20N6. Cal-
culated, %: C 72.61; H 5.30; N 22.09.
Compound 13b. Yield 0.062 g (39%), fine colorless
crystals, mp 205–206°C. H NMR spectrum, δ, ppm:
1
3.88 s (3H, CH3), 5.81 s (2H, CH2), 7.07 d (2H, Ph, J =
8.8 Hz), 7.30 t (1H, Ph, J = 7.6 Hz), 7.32–7.42 m (3H,
Ph, CH), 7.51–7.62 m (3H, Ph), 7.86 d (2H, Ph, J =
7.6 Hz), 7.97 d (2H, Ph, J = 8.8 Hz), 8.08 d (2H, Ph,
J = 6.8 Hz). 13C NMR spectrum, δC, ppm: 48.4 (CH2),
55.0 (CH3), 103.4 (CH), 113.7, 117.9, 125.3 (2C),
127.7, 127.8 (2C), 128.3 (2C), 128.8 (2C), 130.3 (2C),
131.0 (2C), 131.8, 132.0, 133.3, 141.5, 151.2, 152.8,
160.5, 160.9. Found, %: C 61.80; H 4.43; Cl 14.01;
N 16.67; O 3.09. C26H20N6O·2HCl. Calculated, %:
C 61.79; H 4.39; Cl 14.03; N 16.63; O 3.17.
3-Methyl-6,10-diphenyl-7H-pyrazolo[5,1-d]-
[1,2,4]triazolo[4,3-b][1,2,5]triazepine (13a) (alterna-
tive method). A mixture of 0.1 g (0.316 mmol) of
compound 12 and 0.06 mL (0.60 mmol) of pentane-
2,4-dione in 0.4 mL of 2-ethoxyethanol was refluxed
for 1 h. The solvent was distilled off under reduced
pressure, 0.1 mL of methanol was added to the residue,
and the mixture was heated to the boiling point. The
oily material crystallized on grinding, and the crystals
were filtered off and washed with methanol. Yield
0.053 g (49%), fine colorless crystals, mp 176–178°C.
1H NMR spectrum, δ, ppm: 2.59 s (3H, CH3), 5.68 s
(2H, CH2), 7.25–7.35 m (2H, Ph, CH), 7.39 t (2H, Ph,
J = 7.2 Hz), 7.53–7.62 m (3H, Ph), 7.85 d (2H, Ph, J =
7.2 Hz), 8.11 d (2H, Ph, J = 6.8 Hz). 13C NMR spec-
trum, δC, ppm: 10.1 (CH3), 48.4 (CH2), 103.0 (CH),
125.3 (2C), 127.8 (3C), 128.3 (2C), 128.8 (2C), 131.4,
131.8, 132.0, 133.4, 140.7, 151.1, 151.6, 159.4.
Found, %: C 70.59; H 4.73; N 24.68. C20H16N6. Cal-
culated, %: C 70.57; H 4.74; N 24.69.
4,4′-(Hydrazine-1,2-diyl)bis(2,7-diphenyl-8H-
pyrazolo[5,1-d][1,2,5]triazepine) (16). A mixture of
0.05 g (0.16 mmol) of compound 9 and 0.06 g
(0.19 mmol) of 12 in 0.2 mL of 2-ethoxyethanol was
refluxed for 4 h. The mixture was cooled and slowly
diluted with 2 mL of water while grinding the separat-
ing solid. The precipitate was filtered off and washed
with water. Yield 0.091 g (96%), fine yellow crystals,
1
mp 88–92°C. H NMR spectrum, δ, ppm: 5.56 s (4H,
CH2), 7.25–7.39 m (8H, Ph, CH), 7.48–7.55 m (6H,
Ph), 7.79 d (4H, Ph, J = 7.2 Hz), 7.98 d (4H, Ph, J =
5.6 Hz), 13.12 s (2H, NH). 13C NMR spectrum, δC,
ppm: 49.4 (2C, CH2), 110.5 (2C, CH), 125.7 (4C),
127.7 (4C), 128.3 (2C), 128.8 (4C), 129.2 (4C), 131.6
(2C). 132.4 (2C), 142.3 (2C), 150.8 (2C), 158.9 (2C),
180.5 (2C). Found, %: C 72.02; H 4.75; N 23.23.
C38H28N10. Calculated, %: C 71.98; H 4.70; N 23.32.
6,10-Diphenyl-7H-pyrazolo[5,1-d]tetrazolo-
[1,5-b][1,2,5]triazepine (14). Sodium nitrite, 0.03 g
(0.32 mmol), was added in one portion to a solution of
0.1 g (0.316 mmol) of compound 12 in 1 mL of acetic
acid, and the mixture was stirred for 1 h at room
temperature. The precipitate was filtered off and
washed with a small amount of acetic acid and with
water. Yield 0.059 g (57%), fine colorless crystals,
CONFLICT OF INTEREST
The authors declare the absence of conflict of interest.
REFERENCES
1
mp 206–207°C. H NMR spectrum, δ, ppm: 5.83 s
(2H, CH2), 7.30 t (1H, Ph, J = 7.2 Hz), 7.38 t (2H, Ph,
J = 7.6 Hz), 7.51–7.61 m (3H, Ph, CH), 7.64 t (1H, Ph,
J = 7.2 Hz), 7.85 d (2H, Ph, J = 7.2 Hz), 8.16 d (2H,
Ph, J = 7.2 Hz). 13C NMR spectrum, δC, ppm: 49.5
(CH2), 105.5 (CH), 125.9 (2C), 128.6, 128.9, 129.0
(4C), 129.5 (2C), 132.0, 133.0, 133.3, 141.7, 152.5,
162.0. Found, %: C 66.07; H 4.03; N 29.90. C18H13N7.
Calculated, %: C 66.05; H 4.00; N 29.95.
1. Zheng, L.-W., Zhao, B.-X., and Liu, Y.-R., J. Heterocycl.
Chem., 2012, vol. 49, p. 691.
https://doi.org/10.1002/jhet.833
2. Zheng, L.-W., Xuan, H.-Z., Liu, Y.-R., Zhao, B.-X.,
Liu, J.-T., and Miao, J.-Y., Helv. Chim. Acta, 2012,
vol. 95, p. 134.
https://doi.org/10.1002/hlca.201100249
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020

SYNTHESIS AND MODIFICATION OF HETERO-FUSED PYRAZOLES
661
3. Kharaneko, A.O. and Kharaneko, O.I., Russ. J. Org.
Chem., 2018, vol. 54, p. 742.
6. Menges, N., Sari, O., Abdullayev, Y., Erdem, S.S., and
Balci, M., J. Org. Chem., 2013, vol. 78, p. 5184.
https://doi.org/10.1021/jo4001228
https://doi.org/10.1134/S1070428018050111
4. Zheng, L.-W., Shao, J.-H., Zhao, B.-X., and Miao, J.-Y.,
Bioorg. Med. Chem. Lett., 2011, vol. 21, p. 3909.
https://doi.org/10.1016/j.bmcl.2011.05.035
5. Zaremba, O.V., Gorobets, N.Yu., Kovalenko, S.S.,
Drushlyak, O.G., Grevtsov, O.Yu., and Kovalenko, S.M.,
Chem. Heterocycl. Compd., 2013, vol. 49, p. 915.
https://doi.org/10.1007/s10593-013-1326-x
7. Kharaneko, O.I., Popov, V.Yu., and Bogza, S.L., Chem.
Heterocycl. Compd., 2013, vol. 49, p. 317.
https://doi.org/10.1007/s10593-013-1249-6
8. Kharaneko, A.O., Russ. J. Org. Chem., 2017, vol. 53,
p. 738.
https://doi.org/10.1134/S1070428017050153
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 4 2020