5-Amino-N-(2,2-dialkoxyethyl)pyrazole-4-carboxamides in the synthesis of 7-sulfanyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]diazepin-4-ones

Article abstract of DOI:10.1134/S107042801405011X

5-Amino-N-(2,2-dialkoxyethyl)pyrazole-4-carboxamides obtained by hydrolytic cleavage of 5-(2,2-diethoxyethyl)pyrazolo[3,4-d]pyrimidin-4-ones or by condensation of 3-(dimethylamino)-N-(2,2-dimethoxyethyl)-2-cyanoacrylamides with alkylhydrazines in formic a

Full text of DOI:10.1134/S107042801405011X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 5, pp. 685–690. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.V. Bol’but, S.V. Kemskii, M.V. Vovk, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 5, pp. 697–702.
5-Amino-N-(2,2-dialkoxyethyl)pyrazole-4-carboxamides
in the Synthesis of 7-Sulfanyl-5,6,7,8-tetrahydro-1Н-
pyrazolo[3,4-е][1,4]diazepin-4-ones
A. V. Bol’but, S. V. Kemskii, and M. V. Vovk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
Murmanskaya ul. 5, Kiev, 02660 Ukraine
e-mail: mvovk@i.com.ua
Received August 9, 2013
Abstract—5-Amino-N-(2,2-dialkoxyethyl)pyrazole-4-carboxamides obtained by hydrolytic cleavage of 5-(2,2-
diethoxyethyl)pyrazolo[3,4-d]pyrimidin-4-ones or by condensation of 3-(dimethylamino)-N-(2,2-dimethoxy-
ethyl)-2-cyanoacrylamides with alkylhydrazines in formic acid react with benzylthiol or thiophenols to afford
7-benzyl(aryl)sulfanyl-5,6,7,8-tetrahydro-1Н-pyrazolo[3,4-e][1,4]diazepin-4-ones.
DOI: 10.1134/S107042801405011X
Recently [1] by intramolecular cyclocondensation
of 5-amino-N-(2,2-diethoxyethyl)pyrazole-4-carboxa-
mides Іа–Id in acid medium we synthesized 7-
hydroxy-5,6,7,8-tetrahydro-1Н-pyrazolo[3,4-e][1,4]-
diazepin-4-ones ІIа–IId, singular polyfunctional
compounds containing in the diazepine ring fragments
convenient for further modification: carbamoyl and α-
aminohydroxy moieties.
Taking in consideration the data on the synthesis of
N-substituted 5-aminopyrazole-4-carboxamides by the
condensation of N-substituted 2-cyano-3-dimethyl-
aminoacrylamides with hydrazine hydrate [2–5] we
developed an efficient approach to new 5-amino-N-
(2,2-dimethoxyethyl)-pyrazole-4-carboxamides Ie–Il.
As the initial compound we used 2-cyano-N-(2,2-
dimethoxyethyl)-acetamide (ІІІ) easily obtained from
ethyl cyanoacetate and aminoacetaldehyde di-methyl-
acetal [6]. The subsequent heating of compound III
with dimethylform(acet)amide dimethylacetals ІVа
and IVb gave rise to 3-dimethylamino-N-(2,2-di-
methoxyethyl)-2-cyanoacryl(croton)amides Vа and Vb
whose condensation with hydrazine hydrate (VІа) or
alkylhydrazines Vb–Ve (unlike the reaction with
formerly used reagents [2–5]) was very sensitive to the
solvent nature. Amides Іe–Il are successfully obtained
in high yields only at heating the reagents in pyridine
for 3 h. Arylhydrazines do not enter in reaction of this
kind (Scheme 1).
O
O
H
N
N
H
CH(OEt)2
H+
N
N
N
H
NH2
OH
N
R
N
R
Ia_Id
IIa_IId
R = Me (а), PhCH2 (b), Ph (c), 4-FC6H4 (d).
The possibility to apply this cyclization to the
synthesis of the other 7-substituted pyrazolodiazepines
depends on the preparative accessibility of compounds
I. The described procedure of their preparation [1] by
the hydrolytic cleavage of 5-(2,2-diethoxyethyl)-
pyrazolo[3,4-d]pyrimidin-4-ones turned out to be
applicable only to the simplest 1-alkyl(aryl)-sub-
stituted compounds II. It was however impossible to
obtain by this method 1-unsubstituted or unstable in
alkaline media functionalized 1-R-analogs.
The structure of pyrazole derivatives Іe–Il was
confirmed by IR spectra that contained absorption
bands of С=О (1610–1625 cm–1) and N–H (3290–
1
3410 cm–1) bonds, and also by Н NMR spectra with
characteristic signals of protons (7.66–7.69 ppm) or
methyl groups (2.21–2.27 ppm) in the position 3, and
also of NH2 groups (5.38–6.31 ppm) in the position 5
of the pyrazole ring.
685

BOL’BUT et al.
686
Scheme 1.
O
O
O
R1
R1
N
Me2NC(R1)(OMe)2
R2NHNH2
VIa, VIe
N
H
CH(OMe)2
N
N
CH(OMe)2
CH(OMe)2
H
IVa, IVb
H
N
N
N
NH2
N
R2
III
Va, Vb
Ie-Il
І, R1 = Н, R2 = Me (e), PhCH2 (f), CH2CH2OH (g); R1 = Me, R2 = H (h), Me (i), PhCH2 (j), CH2CH2OH (k), СH2CH2CN (l); ІV and V,
R1 = H (а), Me (b); VI, R2 = H (а), Me (b), PhCH2 (c), CH2CH2OH (d), CH2CH2CN (e).
Taking into account that nowadays the modification
of versatile indole [7], 1,2,3-oxadizole [8, 9], 1,2,3-
triazole [10], benzothiazole 11], pyrimidine [12, 13]
compounds with sulfanyl groups has found wide
application to the rational design of scaffolds aiming at
the search for biologically active substances we regard
as an important task the introduction of sulfanyl
moieties in the structure of biophore pyrazolo[3,4-e]-
[1,4]diazepine system. Diazepines ІІа–IId are
convenient objects in this respect for their hydroxy
group can be utilized for the replacement by more
nucleophilic residues of thiols or thiophenols.
hydroxy derivatives II and provided the target
products in 72–97% yields (Scheme 2).
The treatment of compounds Іа–If, Ii, and Ij
solutions in formic acid with benzylthiol (ІХа) or with
thiophenols IXb and IXc led to the formation of 7-R-
sulfanyl derivatives VIIIа–VIIIj via the stage of
intermediate 7-hydroxy derivatives IIа–IIf. This
scheme is confirmed by the reaction of compound IIc
synthesized by procedure [1] with thiol ІХа in formic
acid to obtain compound VIIIf in 96% yield. The
conversion of compound II occurs most probably
through a cationic intermediate А that suffers the
attack of the HS-nucleophile.
In the model experiment of the conversion of amide
Ie into the corresponding pyrazolodiazepine ІІe in
boiling water in the presence of hydrochloric acid (cf.
[1]) an oily mixture was isolated which according to
GC-MS data contained 64% of compound ІІа and 20%
of the product of its intermolecular condensation VII.
The possibility of the formation of the latter is in
agreement with the description [14] of a similar
conversion in acid conditions of 4-amino-[N-(2,2-
diethoxyethyl)]-3-phenylisoxazole-5-carboxamide.
O
H
N
HO
H
N
N
HCl
N
Ie
+
IIa
N
N
H
HN
N
O
VII
The course of the cyclization followed by the
sulfanylation is essentially affected by the character of
the R2 substituent in the structure of amides I. From
compound Ih containing no substituent in the position
1 or from compounds Іg, Ik, and Il conaining a 2-
To prevent this unwanted reaction we developed a
one-pot procedure for the conversion of amides I into
7-R-sulfanylpyrazolodiazepinones VIII which exclu-
ded the necessity of isolation of the corresponding 7-
Scheme 2.
O
O
O
H
H
H
R1
N
N
R1
N
N
R1
N
R3SH
IXa_IXc
H+
HCO2H
Ia-If, Ii, Ij
_H2O
+
N
N
H
SR3
N
N
N
OH
N
N
H
H
R2
R2
R2
VIIIa_VIIIj
A
IIa-IIf
ІІ, R1 = H, R2 = Me (a), PhCH2 (b), Ph (c), 4-FC6H4 (d); R1 = Me, R2 = Me (e), PhCH2 (f); IX, R3 = PhCH2 (a), 4-ClC6H4 (b), 2-НОC6H4
(c); VIII, R1 = H: R2 = Me, R3 = PhCH2 (а), 4-ClC6H4 (b), 2-НОC6H4 (c); R2 = PhCH2, R3 = 4-ClC6H4 (d), 2-НОC6H4 (e); R2 = Ph, R3 =
PhCH2 (f), 4-ClC6H4 (g); R2 = 4-FC6H4, R3 = PhCH2 (h); R1 = Me: R2 = Me, R3 = PhCH2 (i); R2 = PhCH2, R3 = 2-НОC6H4 (j).
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5-AMINO-N-(2,2-DIALKOXYETHYL)PYRAZOLE-4-CARBOXAMIDES
687
hydroxyethyl or a 2-cyanoethyl substituents a dif-
ficultly separable mixture of substances formed where
along with 7-R-sulfanyl derivatives VIII (up to 50%)
the respective 7-hydroxy derivatives II (15–20%) are
present and the products of their condensation VII
(20–30%).
[M + 1]+ 242. C11H19N3O3. Calculated, %: C 54.76; H
7.94; N 17.41. M 241.29.
Compounds Ie–Il. To a solution of 0.11 mol of
hydrazine hydrate (VIа) or hydrazine VIb–VIe in 60 mL
of pyridine was added 0.10 mol of acryl(croton)amide
Vа and Vb, the mixture was boiled for 3 h, the solvent
was distilled off, the residue was crystallized from 2-
propanol.
The structure of 7-R-sulfanylpyrazolo[3,4-е][1,4]-
diazepines VIIIа–VIIIj is confirmed by their spectral
characteristics: in the IR spectra by the absorption
bands of С=О (1685–1695 cm–1) and N–H (3330–
5-Amino-1-methyl-N-(2,2-dimethoxyethyl)-1H-
pyrazole-4-carboxamide (Іe). Yield 97%, mp 66–67°С.
IR spectrum, ν, cm–1: 3400, 3300 (NH), 1625 (С=О).
1Н NMR spectrum, δ, ppm: 3.33–3.37 m (8Н, 2ОСН3,
СН2), 3.51 s (3Н, NСН3), 4.42 t [1Н, CH(ОСH3)2, J
5.4 Hz], 6.14 s (2Н, NН2), 7.66 s (1Н, Н3), 7.74 br.s
(1Н, NН). 13C NMR spectrum, δ, ppm: 33.87 (NCH3),
40.09 (NНCH2), 53.28 (2OCH3), 96.76 (C4), 102.44
[CH(ОСH3)2], 136.20 (C3), 159.33 (С5), 164.21
(CONH). Found, %: C 47.61; H 6.89; N 24.78. [M + 1]+
229. C9H16N4O3. Calculated, %: С 47.36; H 7.07; N
24.55. M 228.25.
1
3420 cm–1) groups, in the Н NMR spectra by the
proton signals of NH and substituents R1–R3, and also
by multiplets of H6 (3.37–3.65 ppm) and broadened
singlets of H7 (4.88–5.36 ppm). In 13С NMR spectra
the most characteristic signals are the resonances of the
carbon atoms of the diazepine ring: С6 (45–46 ppm),
С7 (60–62 ppm), С4 (165–166 ppm).
EXPERIMENTAL
IR spectra of compounds were recorded on a
1
spectrophotometer UR-20 from pellets with KBr. Н
5-Amino-1-benzyl-N-(2,2-dimethoxyethyl)-1H-
pyrazole-4-carboxamide (Іf). Yield 92%, mp 80–81°С.
IR spectrum, ν, cm–1: 3390, 3290 (NH), 1610 (С=О).
1Н NMR spectrum, δ, ppm: 3.28–3.31 m (8Н, 2ОСН3,
СН2), 4.49 t [1Н, CH(ОСH3)2, J 5.4 Hz], 4.91 s (2Н,
СН2Рh), 6.28 s (2Н, NН2), 7.14–7.37 m (5H, Harom),
7.64 s (1Н, Н3), 7.78 br.s (1Н, NН). 13C NMR spec-
trum, δ, ppm: 40.09 (NCH2), 48.97 (CH2Рh), 53.29
(2OCH3), 95.68 (C4), 102.29 [CH(ОСH3)2], 127.19
(C3', C5'), 127.29 (C4'), 128.30 (C2', C6'), 137.42 (C1'),
141.72 (C3), 153.61 (C5), 164.89 (CONH). Found, %:
C 59.01; H 6.97; N 18.26. [M + 1]+ 305. C15H20N4O3.
Calculated, %: С 59.20; H 6.62; N 18.41. M 304.35.
and 13С NMR spectra were registered on a spectro-
meter Bruker Advance DRX-500 (500.13, 125.75
MHz respectively) in DMSO-d6, internal reference
TMS. GC-MS measurements were carried out on an
instrument Aligent 1100\DAD\HSD\VLG 119562.
Compounds Vа and Vb. To a solution of 10 g
(0.1 mol) of acetamide in 100 mL of anhydrous
benzene was added 0.12 mol of acetal ІVа and IVb,
the mixture was boiled for 1 h, the solvent was
distilled off, the residue was crystallized from a mix-
ture benzene–hexane, 1 : 5.
3-(Dimethylamino)-N-(2,2-dimethoxyethyl)-2-
cyanoacrylamide (Va). Yield 94%, mp 57–58°С. IR
5-Amino-1-(2-hydroxyethyl)-N-(2,2-dimethoxy-
ethyl)-1H-pyrazole-4-carboxamide (Іg). Yield 77%,
mp 112–113°С. IR spectrum, ν, cm–1: 3400, 3310
1
spectrum, ν, cm–1: 3340 (NH), 1625 (С=О). Н NMR
1
spectrum, δ, ppm: 3.13–3.29 m (14Н, 2NСН3, 2ОСН3,
СН2), 3.90–4.47 m [1Н, CH(ОСH3)2], 6.91–7.01 m
(1Н, NН), 7.72 s (1Н, CН). Found, %: C 52.79; H
7.51; N 18.42. [M + 1]+ 228. C10H17N3O3. Calculated,
%: C 52.85; H 7.54; N 18.49. M 227.27.
(NH), 1625 (С=О). Н NMR spectrum, δ, ppm: 3.21–
3.31 m (8Н, 2ОСН3, СН2), 3.65–3.68 m (2Н, СН2),
3.91 t (2Н, СН2, J 5.7 Hz), 4.42 t [1Н, CH(ОСH3)2, J
5.4 Hz], 4.91 s (1Н, ОH), 6.07 s (2Н, NН2), 7.70 s
(1Н, Н3), 7.76 br.s (1Н, NН). 13C NMR spectrum, δ,
ppm: 40.13 (NНCH2), 49.02 (NCH2), 53.31 (2OCH3),
59.70 (CH2OH), 96.87 (C4), 102.24 [CH(ОСH3)2],
136.50 (C3), 149.63 (С5), 164.30 (CONH). Found, %:
C 46.27; H 6.75; N 21.50 [M + 1]+ 259. C10H18N4O4.
Calculated, %: С 46.50; H 7.02; N 21.69. M 258.28.
3-(Dimethylamino)-N-(2,2-dimethoxyethyl)-2-
cyanobut-2-enamide (Vb). Yield 91%, mp 106–107°С.
1
IR spectrum, ν, cm–1: 3290 (NH), 1650 (С=О). Н
NMR spectrum, δ, ppm: 2.23 s, 2.33 s (3Н, СН3), 2.94
s (3Н, NСН3), 3.18 s (3Н, NСН3), 3.22–3.36 m (8Н,
2ОСН3, СН2), 4.38–4.46 m [1Н, CH(ОСH3)2], 7.09
br.s (1Н, NН). Found, %: C 54.82; H 7.86; N 17.37.
5-Amino-3-methyl-N-(2,2-dimethoxyethyl)-1H-
pyrazole-4-carboxamide (Іh). Yield 98%, mp 66–67°С.
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BOL’BUT et al.
688
IR spectrum, ν, cm–1: 3395, 3320 (NH), 1620 (С=О).
1Н NMR spectrum, δ, ppm: 2.28 s (3Н, СН3), 3.17–
3.31 m (8Н, 2ОСН3, СН2), 4.47 t [1Н, CH(ОСH3)2, J
5.4 Hz], 5.38 s (2Н, NН2), 6.75 br.s (1Н, NН), 10.85–
11.29 br.s (1Н, NН). 13C NMR spectrum, δ, ppm:
12.95 (CH3), 40.10 (NCH2), 53.30 (2OCH3), 97.74
(C4), 102.29 [CH(ОСH3)2], 141.72 (C3), 153.61 (C5),
164.89 (CONH). Found, %: C 47.63; H 7.19; N 24.69.
[M + 1]+ 229. C9H16N4O3. Calculated, %: С 47.36; H
7.07; N 24.56. M 228.25.
5-Amino-3-methyl-N-(2,2-dimethoxyethyl)-1-(2-
cyanoethyl)-1H-pyrazole-4-carboxamide (Іl). Yield
81%, mp 140–141°С. IR spectrum, ν, cm–1: 3380,
1
3300 (NH), 1625 (С=О). Н NMR spectrum, δ, ppm:
2.24 s (3Н, СН3), 2.90 t (2Н, СН2, J 6.4 Hz), 3.28–3.36
m (8Н, 2ОСН3, СН2), 4.12 t (2Н, СН2, J 6.4 Hz), 4.48
t [1Н, CH(ОСH3)2, J 5.4 Hz], 6.31 s (2Н, NН2), 6.59
br.s (1Н, NН). 13C NMR spectrum, δ, ppm: 14.50
(CH3), 17.14 (NCH2), 40.22 (NНCH2), 41.47
(CH2CN), 53.28 (2OCH3), 95.53 (C4), 102.25
[CH(ОСH3)2], 118.50 (СN), 144.59 (C3), 150.29 (С5),
164.71 (CONH). Found, %: C 51.04; H 6.98; N 24.57.
[M + 1]+ 282. C12H19N4O3. Calculated, %: С 51.24; H
6.81; N 24.89. M 281.32.
5-Amino-1,3-dimethyl-N-(2,2-dimethoxyethyl)-
1H-pyrazole-4-carboxamide (Іi). Yield 97%, mp 72–
73°С. IR spectrum, ν, cm–1: 3410, 3320 (NH), 1625
1
(С=О). Н NMR spectrum, δ, ppm: 2.22 s (3Н, СН3),
3.27–3.35 m (8Н, 2ОСН3, СН2), 3.44 s (3Н, NСН3),
4.48 t [1Н, CH(ОСH3)2, J 5.4 Hz], 6.01 s (2Н, NН2),
6.50 br.s (1Н, NН). 13C NMR spectrum, δ, ppm: 14.36
(CH3), 33.47 (NCH3), 40.09 (NНCH2), 53.30 (2OCH3),
95.61 (C4), 102.29 [CH(ОСH3)2], 143.38 (C3), 150.22
(С5), 164.80 (CONH). Found, %: C 49.32; H 7.58; N
23.05. [M + 1]+ 243. C10H18N4O3. Calculated, %: С
49.56; H 7.49; N 23.12. M 242.12.
Compounds VIIIа–VIIIj. A solution of 4 mmol of
amide Iа–If, Ii, and Ij in 5 mL of formic acid was
stirred for 12 h, 4 mmol of thiol or thiophenol IXа–
IXc was added, and the mixture was stirred for 24 h at
room temperature. To the reaction mixture 20 mL of
water was added, the precipitate was filtered off and
washed with hot acetоnitrile.
7-Benzylsulfanyl-1-methyl-5,6,7,8-tetrahydro-
1Н-pyrazolo[3,4-e][1,4]diazepin-4-one (VІIІа).
Yield 92% (from Іа), 94% (from Іe), mp 127–128оС.
IR spectrum, ν, cm–1: 3460, 3200 (N–H), 1690 (C=O).
1Н NMR spectrum, δ, ppm: 3.37–3.40 m (2Н, CH2),
3.55 s (3Н, NCH3), 3.85 d (1Н, SCH2Ph, J 13.4 Hz),
3.92 d (1Н, SCH2Ph, J 13.4 Hz), 4.92 br.s (1Н, H7),
7.21–7.39 m (6H, Harom, NH), 7.50 с (1H, Н3), 7.70 d
(1H, NH, J 4.5 Hz). 13C NMR spectrum, δ, ppm: 33.14
(SCH2Ph), 34.94 (NCH3), 45.61 (C6), 60.39 (C7),
100.12 (C3a), 126.71 (C4''), 128.37 (C3'', C5''), 128.75
(C2'', C6''), 136.95 (C1''), 140.01 (С3), 143.37 (C8a),
165.47 (C4). Found, %: C 58.13; H 5.70; N 19.50.
[M + 1]+ 289.0. C14H16N4OS. Calculated, %: C 58.31;
H 5.59; N 19.43. M 288.37.
5-Amino-1-benzyl-3-methyl-N-(2,2-dimetho-
xyethyl)-1H-pyrazole-4-carboxamide (Іj). Yield
96%, mp 80–81°С. IR spectrum, ν, cm–1: 3390, 3300
1
(NH), 1620 (С=О). Н NMR spectrum, δ, ppm: 2.25 s
(3Н, СН3), 3.27–3.32 m (8Н, 2ОСН3, СН2), 4.50 t
[1Н, CH(ОСH3)2, J 5.4 Hz], 5.09 s (2Н, СН2Рh), 6.30
s (2Н, NН2), 6.57 br.s (1Н, NН), 7.14–7.39 m (5H,
H
arom). 13C NMR spectrum, δ, ppm: 14.49 (CH3), 40.09
(NCH2), 49.19 (CH2Рh), 53.34 (2OCH3), 95.44 (C4),
102.25 [CH(ОСH3)2], 127.17 (C3', C5'), 127.20 (C4'),
128.31 (C2', C6'), 137.41 (C1'), 144.20 (C3), 149.80
(C5), 164.80 (CONH). Found, %: C 60.14; H 7.18; N
17.74. [M + 1]+ 319. C16H22N4O3. Calculated, %: С
60.32; H 6.97; N 17.60. M 318.38.
5-Amino-1-(hydroxyethyl)-3-methyl-N-(2,2-
dimethoxyethyl)-1H-pyrazole-4-carboxamide (Іk).
Yield 77%, mp 107–108°С. IR spectrum, ν, cm–1:
7-(4-Chlorophenylsulfanyl)-1-methyl-5,6,7,8-
tetrahydro-1Н-pyrazolo[3,4-e][1,4]diazepin-4-one
(VІIІb). Yield 81% (from Іа), 85% (from Іe), mp
213–214оС. IR spectrum, ν, cm–1: 3400, 3360 (N–H),
1
3400, 3300 (NH), 1615 (С=О). Н NMR spectrum, δ,
1
ppm: 2.23 с (3Н, СН3), 3.23–3.35 m (8Н, 2ОСН3,
СН2), 3.63–3.67 m (2Н, СН2), 3.85 t (2Н, СН2, J 5.7 Hz),
4.46 t [Н, CH(ОСH3)2, J 5.4 Hz], 4.91 s (1Н, ОH),
6.02 s (2Н, NН2), 6.53 br.s (1Н, NН). 13C NMR
spectrum, δ, ppm: 14.51 (СH3), 40.09 (NНCH2), 48.63
(NCH2), 53.31 (2OCH3), 59.54 (CH2OH), 95.78 (C4),
102.29 [CH(ОСH3)2], 143.63 (C3), 150.46 (С5), 164.85
(CONH). Found, %: C 48.84; H 7.56; N 20.45. [M + 1]+
273. C11H20N4O4. Calculated, %: С 48.52; H 7.40; N
20.57. M 272.31.
1690 (C=O). Н NMR spectrum, δ, ppm: 3.40–3.47 m
(1Н, CH2), 3.48 s (3H, NCH3), 3.57–3.65 m (1Н,
CH2), 5.34 br.s (1Н, H7), 7.39–7.51 m (6H, 4Harom
,
NH, Н3), 7.76 d (1H, NH, J 4.7 Hz). 13C NMR
spectrum, δ, ppm: 34.69 (NCH3), 45.87 (C6), 64.78
(C7), 100.28 (C3a), 128.92 (C3'', C5''), 132.29 (C4''),
133.00 (C1''), 134.39 (C2'', C6''), 140.18 (С3), 142.92
(C8a), 165.34 (C4). Found, %: C 50.81; H 4.18; N
11.25. [M + 1]+ 309.1. C13H13ClN4OS. Calculated, %:
C 50.57; H 4.24; N 11.48. M 308.79.
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5-AMINO-N-(2,2-DIALKOXYETHYL)PYRAZOLE-4-CARBOXAMIDES
689
7-(2-Hydroxyphenylsulfanyl)-1-methyl-5,6,7,8-
tetrahydro-1Н-pyrazolo[3,4-e][1,4]diazepin-4-one
(VІIІc). Yield 72% (from Іа), 71% (from Іe), mp 197–
198оС. IR spectrum, ν, cm–1: 3400, 3360 (N–H), 1690
62.12; H 5.08; N 15.07. [M + 1]+ 367. C19H18N4OS.
Calculated, %: C 62.28; H 4.95; N 15.29. M 366.44.
7-Benzylsulfanyl-1-phenyl-5,6,7,8-tetrahydro-
1Н-pyrazolo[3,4-e][1,4]diazepin-4-one (VІIІf). Yield
94%, mp 207–208оС. IR spectrum, ν, cm–1: 3350, 3390
(N–H), 1685 (C=O). 1Н NMR spectrum, δ, ppm: 3.42–
3.46 m (2Н, CH2), 3.84 d (1Н, SCH2Ph, J 13.4 Hz),
3.90 d (1Н, SCH2Ph, J 13.4 Hz), 4.95 br.s (1Н, H7),
7.18–7.34 m (5H, Harom), 7.43–7.73 (7H, Harom, NH,
Н3), 7.93 br.s (1H, NH). 13C NMR spectrum, δ, ppm:
33.41 (SCH2Ph), 45.65 (C6), 60.96 (C7), 100.80 (C3a),
124.61 (C3', C5'), 126.69 (C4''), 127.79 (C4'), 128.36
(C3'', C5''), 128.67 (C2', C6'), 129.54 (C2'', C6''), 138.07
(C1''), 139.12 (C1'), 142.38 (С3), 143.02 (C8a), 165.31
(C4). Found, %: C 64.87; H 5.01; N 16.19. [M + 1]+
351.1. C19H18N4OS. Calculated, %: C 65.12; H 5.18; N
15.99. M 350.45.
1
(C=O). Н NMR spectrum, δ, ppm: 3.39–3.65 m (5Н,
CH2, NCH3), 5.31 br.s (1Н, H7), 6.78 t (1H, H5'', J
7.4 Hz), 6.92 d (1H, H3'', J 7.8 Hz), 7.16 t (1H, H4'', J
7.4 Hz), 7.27 d (1H, H6'', J 7.5 Hz), 7.40 d (1H, NH, J
5.4 Hz), 7.50 s (1H, H3'), 7.57 br.s (1H, NH), 9.81 br.s
(1H, OH). 13C NMR spectrum, δ, ppm: 34.87 (NCH3),
45.81 (C6), 61.89 (C7), 100.13 (C3a), 115.49 (C3''),
118.94 (C5''), 119.44 (C1''), 129.16 (C6''), 134.67 (C4''),
140.11 (С3), 143.37 (C8a), 157.52 (C2''), 165.40 (C4).
Found, %: C 54.02; H 5.02; N 19.39. [M + 1]+ 291.0.
C13H14N4O2S. Calculated, %: C 53.78; H 4.86; N
19.30. M 290.35.
1-Benzyl-7-(4-chlorophenylsulfanyl)-5,6,7,8-
tetrahydro-1Н-pyrazolo[3,4-e][1,4]diazepin-4-one
(VІIІd). Yield 95% (from Іb), 94% (from Іf), mp
194–195оС. IR spectrum, ν, cm–1: 3420, 3330 (N–H),
7-(4-Chlorophenylsulfanyl)-1-phenyl-5,6,7,8-
tetrahydro-1Н-pyrazolo[3,4-e][1,4]diazepin-4-one
(VІIІg). Yield 92%, mp 199–200оС. IR spectrum, ν,
cm–1: 3345, 3410 (N–H), 1690 (C=O). 1Н NMR
spectrum, δ, ppm: 3.50–3.53 m (1Н, CH2), 3.60–3.65
m (1Н, CH2), 5.33 br.s (1Н, H7), 7.27–7.34 m (2H,
H3'', H5''), 7.24–7.33 m (7H, Harom, NH, H3), 7.57–7.64
m (2H, H2'', H4''), 7.76 s (1H, NH). 13C NMR spectrum,
δ, ppm: 45.96 (C6), 64.89 (C7), 101.06 (C3a), 124.65
(C3', C5'), 127.86 (C4'), 128.84 (C3'', C5''), 129.30 (C2',
C6'), 132.28 (C4''), 132.73 (C1''), 134.49 (C2'', C6'')
137.91 (C1'), 142.44 (С3), 142.98 (C8a), 165.23 (C4).
Found, %: C 58.52; H 4.18; N 14.69. [M + 1]+ 371.0.
C18H15СlN4OS. Calculated, %: C 58.30; H 4.08; N
15.11. M 370.86.
1
1695 (C=O). Н NMR spectrum, δ, ppm: 3.44–3.48 m
(1Н, CH2), 3.60–3.69 m (1Н, CH2), 5.09 d (1Н,
CH2Ph, J 16.2 Hz), 5.16 d (1Н, CH2Ph, J 16.2 Hz),
5.36 br.s (1Н, H7), 7.02–7.08 m ( 2H, H3'', H5''), 7.24–
7.33 m (5H, Harom), 7.33–7.39 m (2H, H2'', H4''), 7.52 d
(1H, NH, J 5.4 Hz), 7.62 s (1H, Н3), 7.93 br.s (1H,
NH). 13C NMR spectrum, δ, ppm: 45.96 (C6), 50.23
(CH2Ph), 64.89 (C7), 100.36 (C3a), 126.89 (C3', C5'),
127.22 (C4'), 128.30 (C2', C6'), 128.75 (C3'', C5''),
132.19 (C4''), 132.76 (C1''), 134.39 (C2'', C6''), 137.00
(C1'), 141.12 (С3), 142.93 (C8a), 165.38 (C4). Found,
%: C 59.12; H 4.62; N 14.99. [M + 1]+ 385.0.
C19H17СlN4OS. Calculated, %: C 59.29; H 4.45; N
14.56. M 384.89.
7-Benzylsulfanyl-1-(4-fluorophenyl)-5,6,7,8-
tetrahydro-1Н-pyrazolo[3,4-e][1,4]diazepin-4-one
(VІIІh). Yield 86%, mp 204–205оС. IR spectrum, ν,
cm–1: 3415, 3335 (N–H), 1695 (C=O). 1Н NMR
spectrum, δ, ppm: 3.42–3.45 m (2Н, CH2), 3.83 d (1Н,
SCH2Ph, J 13.4 Hz), 3.90 d (1Н, SCH2Ph, J 13.4 Hz),
4.94 br.s (1Н, H7), 7.18–7.34 m (5H, Harom), 7.43–7.59
m (7H, Harom, NH, Н3), 7.92 s (1H, NH). 13C NMR
spectrum, δ, ppm: 33.43 (SCH2Ph), 45.65 (C6), 60.93
(C7), 100.60 (C3a), 116.33 (C3' C5'), 126.75 (C4'),
127.36 (C2', C6'), 128.42 (C3'', C5''), 128.73 (C2'', C6''),
134.40 (C1'), 139.11 (C1''), 142.37 (С3), 143.36 (C8a),
160.31 (C4', JCF 245.1 Hz), 165.31 (C4). Found, %: C
62.08; H 4.48; N 14.99. [M + 1]+ 369.0. C19H17FN4OS.
Calculated, %: C 61.94; H 4.65; N 15.21. M 368.44.
1-Benzyl-7-(2-hydroxyphenylsulfanyl)-5,6,7,8-
tetrahydro-1Н-pyrazolo[3,4-e][1,4]diazepin-4-one
(VІIІe). Yield 93% (from Іf), mp 192–193оС. IR
spectrum, ν, cm–1: 3430, 3340 (N–H), 1690 (C=O). 1Н
NMR spectrum, δ, ppm: 3.42–3.46 m (1Н, CH2), 3.56–
3.64 m (1Н, CH2), 5.03 d (1Н, CH2Ph, J 16.2 Hz), 5.14
d (1Н, CH2Ph, J 16.2 Hz), 5.36 br.s (1Н, H7), 6.69 t
(1H, H5'', J 7.4 Hz), 6.89 d (1H, H3'', J 7.8 Hz), 7.05–
7.20 m (4H, H3', H5', H6'', H4''), 7.23–7.34 m (3H, H1',
H2', H5'), 7.47 d (1H, NH, J 5.4 Hz), 7.58 s (1H, Н3),
7.82 br.s (1H, NH), 9.85 br.s (1H, OH). 13C NMR
spectrum, δ, ppm: 45.90 (C6), 50.18 (CH2Ph), 61.78
(C7), 99.76 (C3a), 115.42 (C3''), 118.66 (C5''), 119.44
(C1''), 127.07 (C3', C5'’), 127.18 (C4'), 128.31 (C2', C6'),
129.09 (C6''), 134.87 (C4''), 137.06 (C1'), 141.12 (С3),
143.47 (C8a), 157.57 (C2''), 165.48 (C4). Found, %: C
7-Benzylsulfanyl-1,3-dimethyl-5,6,7,8-tetra-
hydro-1Н-pyrazolo[3,4-e][1,4]diazepin-4-one
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 5 2014

BOL’BUT et al.
690
(VІIІi). Yield 97%, mp 172–173оС. IR spectrum, ν,
cm–1: 3420, 3370 (N–H), 1690 (C=O). 1Н NMR
spectrum, δ, ppm: 2.23 s (3Н, CH3), 3.35–3.35 m (2Н,
CH2), 3.46 s (3Н, NCH3), 3.85 d (1Н, SCH2Ph, J
13.4 Hz), 3.92 d (1Н, SCH2Ph, J 13.4 Hz), 4.88 br.s
(1Н, H7), 7.21–7.38 m (6H, Harom, NH), 7.53 br.s (1H,
NH). 13C NMR spectrum, δ, ppm: 14.70 (CH3), 33.17
(SCH2Ph), 39.52 (NCH3), 45.32 (C6), 60.70 (C7), 96.83
(C3a), 126.75 (C4''), 128.41 (C3'', C5''), 128.80 (C2'', C6''),
139.01 (C1''), 143.01 (С3), 148.71 (C8a) 165.31 (C4).
Found, %: C 59.82; H 6.18; N 18.64. [M + 1]+ 303.
C15H18N4OS. Calculated, %: C 59.58; H 6.00; N 18.53.
M 302.40.
2. Behdehani, H., Makhseed, S., Elnagdi, M., Ibrahim, H.M.,
and Mahmoud, H., Eur. J. Med. Chem., 2012,
vol. 52, p. 51.
3. Khalil, K.D., Al-Matar, H.M., Al-Dorri, D.M., and
Elnagdi, M., Tetrahedron, 2009, vol. 65, p. 7421.
4. Ibrahim, H.M., Makhseed, S., Abdel-Motoleb, R.M.,
Makhlout, A.M., and Elnagdi, M.H., Heterocycles,
2007, vol. 71, p. 1951.
5. Gouda, M.A., Berghot, M.A., Abdel-Ghani, G.E., and
Khalil, A.M., Eur. J. Med. Chem., 2010, vol. 45, p. 1338.
6. Wang, K., Kim, D., and Domling, A., J. Comb. Chem.,
2010, vol. 12, p. 111.
7. Mamedov, I.V., Lefrouc, F., Frolova, L.V., Banuls, L.M.Y.,
Peretti, A.S., Rogelj, S., Mathien, V., Kiss, R., and Kor-
nienko, A., Bioorg. Med. Chem. Lett., 2013, vol. 23,
p. 3277.
1-Benzyl-7-(2-hydroxyphenylsulfanyl)-3-methyl-
5,6,7,8-tetrahydro-1Н-pyrazolo[3,4-e][1,4]diazepin-
4-one (VІIІj). Yield 86%, mp 213–214оС. IR
spectrum, ν, cm–1: 3350, 3415 (N–H), 1685 (C=O). 1Н
NMR spectrum, δ, ppm: 2.24 s (3H, CH3), 3.54–3.58
m (1Н, CH2), 4.95 d (1Н, CH2Ph, J 16.2 Hz), 5.08 d
(1Н, CH2Ph, J 16.2 Hz), 5.32 s (1Н, H7), 6.64 t (1H,
H5'', J 7.4 Hz), 6.88 d (1H, H3'', J 7.8 Hz), 7.05–7.10 m
(2H, H3', H5'), 7.10–7.19 m (1H, H4'', H6''), 7.24–7.38 m
(4H, H4', H2', H6', NH), 7.65 d (1H, NH, J 4.7 Hz), 9.77
8. Lo Monte, F., Kramet, G.L., Brodrecht, M., Pilakowski, J.,
Fuertes, A., Dominques, J.M., Plotkin, B., Elder-
Finkelman, H., and Schmidl, B., Eur. J. Med. Chem.,
2013, vol. 61, p. 26.
9. Patel, N.B., Purohit, A.C., Rajani, O.P., Moo-Puc, R.,
and Rivera, G., Eur. J. Med. Chem., 2013, vol. 62, p. 677.
10. Handi, R., Zildan, N., Ali, S., El-Sadek, M., Lashin, E.,
Braucale, A., Jones, A.T., and Westwell, A.D., Bioorg.
Med. Chem. Lett., 2013, vol. 23, p. 2391.
13
c (1H, OH). C NMR spectrum, δ, ppm: 14.95 (CH3),
45.63 (C6), 49.75 (CH2Ph), 62.29 (C7), 96.87 (C3a),
115.42 (C3''), 118.78 (C5''), 119.38 (C1''), 127.04 (C3',
C5'), 127.13 (C4'), 128.31 (C2', C6'), 129.14 (C6''),
134.92 (C4''), 137.24 (C1'), 140.11 (С3), 149.65 (C8a),
157.47 (C2''), 166.32 (C4). Found, %: C 62.88; H 5.18;
N 14.99. [M + 1]+ 381. C20H20N4O2S. Calculated, %: C
63.14; H 5.30; N 14.73. M 380.43.
11. Zhaug, M., Zha, W., and Li, Y., Eur. J. Med. Chem.,
2013, vol. 61, p. 301.
12. Puig-de-la-Bellacosa, R., Gimeno, S., Petterson, S.,
Pascual, R., Gouralo, E., Este, J.A., Cloter, B., Borrell, J.Y.,
and Teixido, J., Eur. J. Med. Chem., 2012, vol. 54, p. 159.
13. Ynsuasty, B., Becerra, D., Quirogo, J., Alonia, R.,
Nogueras, S.M., and Cobo, J., Eur. J. Med. Chem.,
2013, vol. 61, p. 1.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 5 2014