5,7-Dihydropyrrolo[3,4-d][1,2]diazepin-1(2H)-ones. Synthesis and transformations

Article abstract of DOI:10.1134/S1070428016070228

A preparative procedure has been developed for the synthesis of substituted 5,7-dihydropyrrolo-[3,4-d][1,2]diazepines by recyclization of 6-phenylpyrano[3,4-c]pyrrol-4(2H)-one with hydrazine hydrate. The stability of the seven-membered ring in the products under acidic conditions, alkylation, and heteroring fusion to the diazepine ring have been studied.

Full text of DOI:10.1134/S1070428016070228

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 7, pp. 1043–1049. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © O.I. Kharaneko, S.L. Bogza, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 7, pp. 1049–1055.
5,7-Dihydropyrrolo[3,4-d][1,2]diazepin-1(2H)-ones.
Synthesis and Transformations
O. I. Kharanekoa* and S. L. Bogzab
a Litvinenko Institute of Physical Organic and Coal Chemistry, ul. R. Lyuksemburg 70, Donetsk, 83114 Ukraine
*e-mail: o_kharaneko@mail.ru
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 5, Kiev, 02660 Ukraine
Received March 29, 2016
Abstract—A preparative procedure has been developed for the synthesis of substituted 5,7-dihydropyrrolo-
[3,4-d][1,2]diazepines by recyclization of 6-phenylpyrano[3,4-c]pyrrol-4(2H)-one with hydrazine hydrate. The
stability of the seven-membered ring in the products under acidic conditions, alkylation, and heteroring fusion
to the diazepine ring have been studied.
DOI: 10.1134/S1070428016070228
Heterocyclic compounds containing a 1,2-diazepine
fragment exhibit a broad spectrum of biological
activity [1]. In particular, 2,3-benzodiazepines were
reported to possess tranquilizing [2], anxiolytic, and
anticonvulsant activity [3]. Drugs for the treatment of
Parkinson’s and Alzheimer’s diseases [4] and
amyotrophic lateral sclerosis [5] have been designed
on the basis of 2,3-benzodiazepines. Unlike 1,4-benzo-
diazepine drugs, 2,3-benzodiazepine derivatives are
characterized by not only selective action but also
the lack of side effects. Therefore, synthesis of
new 2,3-benzodiazepine compounds is an important
problem.
already existing benzene ring or heterocycle. Mutual
arrangement of the C=O groups in 1,5-dicarbonyl
compounds favors their cyclization to carbo- and
heterocyclic structures [14–16]. This ability of 1,5-di-
carbonyl compounds with a benzophenone fragment
[17] was successfully utilized previously in the syn-
thesis of 2,3-benzodiazepines by reactions with hydra-
zine hydrate and its derivatives.
We have developed a synthetic approach to 5,7-di-
hydropyrrolo[3,4-d][1,2]diazepines starting from
1,5-dicarbonyl compounds 3a–3c containing a pyrrole
fragment (Scheme 1). Initial compounds 3a–3c were
prepared by addition of enamines 1 derived from ethyl
acetoacetate and acetylacetone to dibenzoylethene 2,
which was accompanied by cyclization [18]. This
procedure ensured very good yields of pyrrole deriv-
atives 3a–3c, and it can be readily extended to other
related compounds.
1,2-Diazepines fused to a pyrrole ring are equally
interesting since the pyrrole ring is a structural unit of
many biologically active compounds which play
an important role in physiological processes. Currently
known pyrrolo[1,2-a][1,4]benzodiazepines affect cen-
tral nervous system [6‒11] due to their sedative, anti-
convulsant, myorelaxant, and other properties. Pyrrolo-
[2,3]diazepines still remain poorly studied. To the best
of our knowledge, only one procedure has been
reported for the synthesis of pyrrolo[2,3]diazepines by
cycloaddition of 4-methylbenzenesulfonyl thiocyanate
to 1,2-diazepines [12]. Depending on the substituent in
the diazepine ring, the yield of the target products
varied from 20 to 59%.
By heating compound 3c with hydrazine hydrate in
methanol we obtained 7-benzyl-1,8-dimethyl-4,6-
diphenyl-5,7-dihydropyrrolo[3,4-d][1,2]diazepine (5c)
1
which characteristically showed in the H NMR spec-
trum doublet signals at δ 2.91 and 3.79 ppm (J =
14 Hz) from nonequivalent methylene protons on C5,
indicating nonplanar structure of the diazepine ring.
Under analogous conditions, compound 3a afforded
exclusively the corresponding hydrazone 6 instead of
expected diazepinone 5a. Thus, the direction of the
reaction of pyrroles 3 with hydrazine hydrate is deter-
mined by the substituent on the nitrogen atom.
Analysis of published data revealed the possibility
of an alternative synthetic approach to fused diaze-
pines [13], which implies diazepine ring closure on
1043

KHARANEKO, BOGZA
1044
Scheme 1.
O
O
O
R2
Me
O
Ph
R1
Ph
+
Ph
N
R2
Me
Ph
H
O
O
N
R1
3a–3c
1a, 1b
2
O
Me
N
Me
N
NH
N2H4·H2O
TsOH
O
R1
R1
N
Ph
Ph
Ph
Ph
4a, 4b
NNH2
Ph
5a, 5b
Me
O
Me
N
EtO
N
N2H4·H2O
N2H4·H2O
3a
3c
PhCH2
N
Me
Ph
N
Ph
Ph
H
6
5c
1, 3, R1 = H, R2 = EtO (a); R1 = Me, R2 = EtO (b); R1 = PhCH2, R2 = Me (c); 4, 5, R = H (a), Me (b), PhCH2 (c).
In order to obtain pyrrolodiazepine derivatives from
procedures for the synthesis of 6-phenylpyrano[3,4-c]-
pyrrol-4(2H)-ones 4a and 4b and 4-phenyl-5,7-dihy-
dropyrrolo[3,4-d][1,2]diazepin-1(2H)-ones 5a and 5b
were described previously [19].
compounds 3a and 3b, the latter were preliminarily
converted to pyranopyrroles 4a and 4b by fusion with
a catalytic amount of p-toluenesulfonic acid. The
Scheme 2.
N2
N
1N
Me
N3
10
8
10b
HNO2
9
N
R
N5
O
Me
7
NH2·HCl
Ph
Ph
HCl
N
10a, 10b
R
N
Ph
NH2
N
N
N
HN
Ph
Me
N
Me
N
7a, 7b
N
N2H4·H2O
CH(OEt)3
5a, 5b
R
N
R
N
HS
Me
N
Ph
Ph
Ph
Ph
N
9a, 9b
11a, 11b
LR
R
N
Me
Ph
Ph
Ph
S
Me
N
Me
O
8a, 8b
PhC(O)CH2Br
N
Me
N
N
Ac2CH2
N
Me
N
N
R
N
Ph
Ph
Ph
Ph
13
12a, 12b
R = H (a), Me (b); LR stands for Lawesson’s reagent.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

5,7-DIHYDROPYRROLO[3,4-d][1,2]DIAZEPIN-1(2H)-ONES.
1045
δC, ppm
110
120
130
140
150
160
170
11
10
9
8
7
6
5
4
δ, ppm
Two-dimensional 1H–13C HMBC spectrum of 10-methyl-6,8-diphenyl-7,9-dihydropyrrolo[3,4-d][1,2,4]triazolo[4,3-b]diazepine (11a).
Scheme 2 illustrates main transformations of diaze-
pinones 5a and 5b.
tives 9a and 9b in 75% yield. Unlike diazepinones 5a
and 5b, thiols 8a and 8b and hydrazines 9a and 9b are
stable under acidic conditions, and no contraction of
the diazepine ring therein was observed on heating in
boiling aqueous HCl.
Heating of 5a and 5b with excess aqueous HCl
quantitatively afforded 5-amino-3-methyl-1,6-diphe-
nyl-2,5-dihydro-4H-pyrrolo[3,4-c]pyridin-4-one (7a)
and 5-amino-2,3-dimethyl-1,6-diphenyl-2,5-dihydro-
4H-pyrrolo[3,4-c]pyridin-4-one (7b), respectively.
Like 2,3-benzodiazepin-1-ylhydrazines reported
previously [20], compounds 9a and 9b may be
precursors to tricyclic structures with an additional
nitrogen heterocycle fused to the diazepine ring. The
reaction of pyrrolodiazepines 9a and 9b with nitrous
acid (NaNO2/AcOH) led to tetrazole ring fusion with
formation of 10-methyl-6,8-diphenyl-7,9-dihydropyr-
rolo[3,4-d]tetrazolo[1,5-b][1,2]diazepine (10a) and
9,10-dimethyl-6,8-diphenyl-7,9-dihydropyrrolo[3,4-d]-
tetrazolo[1,5-b][1,2]diazepine (10b). 10-Methyl-6,8-
diphenyl-7,9-dihydropyrrolo[3,4-d][1,2,4]triazolo-
[4,3-b]diazepine (11a) and 9,10-dimethyl-6,8-diphe-
nyl-7,9-dihydropyrrolo[3,4-d][1,2,4]triazolo[4,3-b]di-
azepine (11b) were obtained by heating compounds 9a
and 9b in triethyl orthoformate. The structure of 11a
was confirmed by 1H and 13C NMR spectra, as well as
by two-dimensional 1H–13C HMBC data (see figure).
1
Protons on C7 resonated in the H NMR spectra at
δ 6.48 (7a) and 6.10 ppm (7b), and the C7 signals were
observed in the 13C NMR spectra at δC 101.4 (7a) and
99.2 ppm (7b).
Treatment of 5a and 5b with Lawesson’s reagent
resulted in quantitative replacement of the carbonyl
oxygen atom by sulfur with formation of 8-methyl-4,6-
diphenyl-5,7-dihydropyrrolo[3,4-d][1,2]diazepine-1-
thiol (8a) and 7,8-dimethyl-4,6-diphenyl-5,7-dihydro-
pyrrolo[3,4-d][1,2]diazepine-1-thiol (8b). In the
13C NMR spectra of 8a and 8b, the C1 signal appeared
in a weaker field (δC 187.2 and 187.0 ppm, respec-
tively) relative to the C=O signal of 5 [12]. Com-
pounds 8a and 8b reacted with excess hydrazine
hydrate to give the corresponding 1-hydrazinyl deriva-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

KHARANEKO, BOGZA
The C10b signal was located in the 13C NMR spectra
1046
temperature. The resulting brown material was dis-
solved in 8 mL of methanol, and a crystalline solid
separated from the solution after a time. After 2‒3 h,
the precipitate was filtered off and washed with a small
amount of methanol. Yield 1.46 g (41%), colorless
crystals, mp 137–138°C. IR spectrum, ν, cm–1: 1660
of 10a and 10b at δC 146.1 and 145.7 ppm, respec-
tively, which is typical of tetrazole ring. Compounds
1
11a and 11b characteristically showed in the H NMR
spectra a signal at δ 8.60 and 8.60 ppm, respectively,
due to 3-H (triazole ring), and the C10b and C3 atoms
resonated in the 13C NMR spectra at δC 145.6 (11a) or
145.4 ppm (11b) and 142.6 ppm (11a, 11b) [21].
1
(C=O), 1600 (C=Carom). H NMR spectrum, δ, ppm:
2.34 s (3H, CH3CO), 2.46 s (3H, CH3), 4.16 s (2H,
CH2COPh), 5.10 s (2H, CH2Ph), 6.93 d (2H, Ph, J =
7.2 Hz), 7.15–7.36 m (8H, Ph), 7.47 t (2H, Ph, J =
7.6 Hz), 7.56 t (1H, Ph, J = 7.6 Hz), 7.95 d (2H, Ph,
J = 7.6 Hz). 13C NMR spectrum, δC, ppm: 12.8 (CH3),
30.4 (CH3CO), 36.2 (CH2COPh), 47.1 (CH2Ph), 115.1,
121.2, 125.2, 126.7, 127.6, 127.8, 128.0, 128.0, 128.3,
130.1, 130.7, 132.0, 133.2, 134.0, 137.2, 137.5, 192.7
(CO), 197.1 (CO). Found, %: C 83.51; H 6.19; N 3.45.
C28H25NO2. Calculated, %: C 83.53; H 6.18; N 3.44.
Like benzodiazepinethiol described in [13], com-
pound 8b was readily alkylated at the sulfur atom with
2-bromo-1-phenylethan-1-one to give 2-[(7,8-dimeth-
yl-4,6-diphenyl-5,7-dihydropyrrolo[3,4-d][1,2]diaze-
pin-1-yl)sulfanyl]-1-phenylethan-1-one (13). 1-Hydra-
zinylpyrrolodiazepines 9a and 9b reacted with acetyl-
acetone, yielding 1-(3,5-dimethyl-1H-pyrazol-1-yl)-
substituted derivatives 12a and 12b.
The 1H NMR spectra of 12a, 12b, and 13 displayed
doublet signals at δ 3.17 and 4.72 (J = 12.8 Hz) (12a),
3.04 and 4.02 (J = 13.6 Hz) (12b), and 2.94 and
3.79 ppm (J = 13.6 Hz) (13) from nonequivalent meth-
ylene protons on C5. The SCH2 protons in 13 were also
nonequivalent because of restricted rotation, and they
gave rise to two doublets at δ 4.71 and 4.82 ppm with
a coupling constant 2J of 12.8 Hz.
7-Benzyl-1,8-dimethyl-4,6-diphenyl-5,7-dihydro-
pyrrolo[3,4-d][1,2]diazepine (5c). A mixture of 1 g
(2.5 mmol) of compound 3c and 0.25 g (5.0 mmol) of
hydrazine hydrate in 5 mL of methanol was refluxed
for 4 h. The initial compound gradually dissolved, and
a solid separated. After cooling to room temperature,
the precipitate was filtered off and washed with a small
amount of methanol. Yield 0.8 g (81%), fine light
yellow crystals, mp 172–173°C. IR spectrum, ν, cm–1:
Thus, we have developed a preparative method for
the synthesis of 5,7-dihydropyrrolo[3,4-d][1,2]diaze-
pine derivatives from ethyl 4-(2-oxo-2-phenylethyl)-
1H-pyrrole-3-carboxylates, studied some their trans-
formations, and obtained new heterocyclic systems,
6-phenyl-7,9-dihydropyrrolo[3,4-d]tetrazolo[1,5-b]-
[1,2]diazepines and 6-phenyl-7,9-dihydropyrrolo-
[3,4-d][1,2,4]triazolo[4,3-b][1,2]diazepines.
1
1600, 1580 (C=Carom). H NMR spectrum, δ, ppm:
2.28 s (3H, CH3), 2.47 s (3H, CH3), 2.91 d and 3.79 d
(1H each, CH2, J = 14 Hz), 5.08 d.d (2H, CH2Ph, J =
16, 9.2 Hz), 6.80 d (2H, Ph, J = 7.2 Hz), 7.10–7.30 m
(8H, Ph), 7.35–7.41 m (3H, Ph), 7.45 d (2H, Ph, J =
7.6 Hz). 13C NMR spectrum, δC, ppm: 11.4 (CH3), 24.7
(CH3), 25.8 (CH2), 47.1 (CH2Ph), 116.0, 120.7, 125.1,
126.5, 126.6, 126.7, 126.7, 127.4, 127.7, 128.2, 128.3,
128.7, 129.9, 130.5, 136.1, 137.6, 149.9, 153.6. Found,
%: C 83.30; H 6.31; N 10.39. C28H25N3. Calculated, %:
C 83.34; H 6.24; N 10.41.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker Avance II spectrometer at 400 and 100 MHz,
respectively, using DMSO-d6 as solvent and tetra-
methylsilane as internal reference. The IR spectra were
measured in KBr on a Specord IR-75 spectrometer.
The melting points were determined on a Boetius hot
stage and are uncorrected. The elemental analyses
were obtained on a Vario EL Cube Elementar analyzer.
Ethyl 4-[(2Z)-2-hydrazinylidene-2-phenylethyl]-
2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (6).
A mixture of 1 g (2.8 mmol) of compound 3a and
0.14 g (2.8 mmol) of hydrazine hydrate in 5 mL of
2-ethoxyethanol was refluxed for 2 h. The solvent was
removed under reduced pressure, 5 mL of metanol was
added to the residue, and the viscous oily material was
crystallized on grinding and heating. After cooling, the
precipitate was filtered off and washed with methanol.
Yield 0.95 g (91%), colorless crystals, mp 141–142°C.
IR spectrum, ν, cm–1: 3360 (NH2), 3110 (NH), 1680
2-(4-Acetyl-1-benzyl-5-methyl-2-phenyl-1H-pyr-
rol-3-yl)-1-phenylethan-1-one (3c). A mixture of
0.85 g (8.5 mmol) of acetylacetone and 0.9 g
(8.5 mmol) of benzylamine was stirred for 5 min at
100°C, 8.5 mmol of 1,4-diphenylbut-2-ene-1,4-dione
was added, and the mixture was heated to 160°C, kept
for 5 min at that temperature, and cooled to room
1
(OC=O), 1640 (C=Carom), 1600 (C=Carom). H NMR
spectrum, δ, ppm: 1.28 t (3H, CH3, J = 7.2 Hz), 2.42 s
(3H, CH3), 4.08 s (2H, CH2), 4.13 q (2H, OCH2, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

5,7-DIHYDROPYRROLO[3,4-d][1,2]DIAZEPIN-1(2H)-ONES.
1047
6.8 Hz), 5.99 s (2H, NH2), 7.13 t (2H, Ph, J = 3.6 Hz),
7.21 t (1H, Ph, J = 7.2 Hz), 7.26–7.34 m (4H, Ph),
10.66 s (1H, NH). Found, %: C 72.84; H 6,52; N 11.5.
C22H23N3O2. Calculated, %: C 73.11; H 6.41; N 11.63.
mp 216–217°C. IR spectrum, ν, cm–1: 3040 (NH),
1600 (C=Carom). H NMR spectrum, δ, ppm: 2.62 s
1
(3H, CH3), 3.94 s (2H, CH2), 7.20–7.45 m (8H, Ph),
7.64 d (2H, Ph, J = 7.6 Hz), 11.5 s (1H, NH), 11.6 s
(1H, SH). 13C NMR spectrum, δC, ppm: 13.5 (CH3),
26.9 (CH2), 113.4, 120.2, 123.2, 126.2, 126.7, 126.8,
128.1, 128.3, 129.9, 131.4, 135.1, 136.4, 162.7,
187.2 (CS). Found, %: C 72.51; H 5.18; N 12.67;
S 9.63. C20H17N3S. Calculated, %: C 72.48; H 5.17;
N 12.68; S 9.67.
5-Amino-3-methyl-1,6-diphenyl-2,5-dihydro-4H-
pyrrolo[3,4-c]pyridin-4-one hydrochloride (7a).
A mixture of 1 g (3.18 mmol) of compound 5a and
10 mL of 1,4-dioxane was heated to the boiling point,
0.4 mL of 30% aqueous HCl was added, and the
mixture was refluxed for 5 min. A finely crystalline
solid began to separate from the solution in a few
seconds after addition of HCl. The mixture was cooled
to room temperature, and the precipitate was filtered
off and washed with a small amount of dioxane. If no
solid separated, the mixture was diluted with a small
amount of water. The oily material was ground with
a glass rod. Yield 1 g (90%), fine colorless crystals,
mp 204–205°C. IR spectrum, ν, cm–1: 3220 (NH2),
2810 (NH), 1660 (C=O), 1600 (C=Carom), 1570
7,8-Dimethyl-4,6-diphenyl-5,7-dihydropyrrolo-
[3,4-d][1,2]diazepine-1-thiol (8b) was synthesized in
a similar way from 1 g (3.04 mmol) of 5b. Yield 1 g
(95%), fine greenish–yellow crystals, mp 218–219°C.
1H NMR spectrum, δ, ppm: 2.69 s (3H, CH3), 3.44 s
(3H, CH3), 3.67 s (2H, CH2), 7.21 d (2H, Ph, J =
7.2 Hz), 7.28 t (2H, Ph, J = 7.2 Hz), 7.38 t (1H, Ph, J =
6.8 Hz), 7.40–7.50 m (3H, Ph), 7.52 d (2H, Ph, J =
8.0 Hz), 11.80 s (1H, SH). 13C NMR spectrum, δC,
ppm: 11.8 (CH3), 26.5 (CH2), 31.6 (CH3), 114.6, 119.2,
126.3, 126.7, 127.4, 127.9, 128.1, 129.7, 130.0, 130.1,
134.6, 136.1, 162.7, 187.0 (CS). Found, %: C 73.02;
H 5.57; N 12.15; S 9.26. C21H19N3S. Calculated, %:
C 73.01; H 5.54; N 12.16; S 9.28.
1
(C=Carom). H NMR spectrum, δ, ppm: 2.75 s (3H,
CH3), 4.55 br.s (3H, NH3+), 6.48 s (1H, 7-H), 7.14 t
(1H, Ph, J = 7.6 Hz), 7.32–7.43 m (5H, Ph), 7.59 t
(4H, Ph, J = 6.4 Hz), 12.19 s (1H, NH). 13C NMR
spectrum, δC, ppm: 11.84 (CH3), 101.4 (CH), 109.9,
118.6, 121.0, 125.0, 127.4, 127.5, 128.3, 129.2, 130.6,
132.3, 135.1, 138.4, 158.9, 162.5 (C=O). Found, %:
C 68.31; H 5.19; Cl 10.07; N 12.01. C20H18ClN3O.
Calculated, %: C 68.28; H 5.16; Cl 10.08; N 11.94.
1-Hydrazinyl-8-dimethyl-4,6-diphenyl-5,7-dihy-
dropyrrolo[3,4-d][1,2]diazepine (9a). A mixture of
1 g (2.9 mmol) of compound 8a and 10 g of hydrazine
hydrate was slowly heated to the boiling point with
stirring and was then refluxed for 1 h with stirring. The
mixture was cooled and diluted with 20 mL of water,
and the precipitate was filtered off, washed with water,
and recrystallized from methanol. Yield 0.75 g (75%),
fine colorless crystals, mp 134–136°C. IR spectrum,
ν, cm–1: 3370 (NH2), 3210 (NH), 1600 (C=Carom).
1H NMR spectrum, δ, ppm: 2.37 s (3H, CH3), 3.19 s
(1H, NH), 3.94 s (2H, CH2), 4.58 br.s (2H, NH2), 7.37–
7.40 m (4H, Ph), 7.38 m (4H, Ph), 7.51 d (2H, Ph, J =
7.2 Hz), 10.96 s (1H, NH). 13C NMR spectrum, δC,
ppm: 13.3 (CH3), 26.6 (CH2), 113.4, 115.4, 124.3,
126.6, 126.8, 127.1, 128.6, 129.0, 129.3, 129.7, 132.9,
137.5, 146.8, 160.9. Found, %: C 72.95; H 5.85;
N 21.20. C20H19N5. Calculated, %: C 72.93; H 5.81;
N 21.26.
5-Amino-2,3-dimethyl-1,6-diphenyl-2,5-dihydro-
4H-pyrrolo[3,4-c]pyridin-4-one hydrochloride (7b)
was synthesized in a similar way from 1 g (3.04 mmol)
of 5b. Yield 0.7 g (63%), fine colorless crystals,
1
mp 172–173°C. H NMR spectrum, δ, ppm: 2.82 s
(3H, CH3), 3.70 s (3H, CH3), 4.55 br.s (3H, NH3+),
6.10 s (1H, 7-H), 7.25–7.35 m (4H, Ph), 7.35–7.48 m
(6H, Ph). 13C NMR spectrum, δC, ppm: 10.8 (CH3),
31.7 (CH3), 99.2 (C7), 119.7, 123.4, 126.4, 126.8,
126,9, 128.2, 129.0, 129.1, 129.4, 131.1, 136.6, 139.9,
159.3, 165.1 (C=O). Found, %: C 68.96; H 5.54;
Cl 9.68; N 11.52. C21H20ClN3O. Calculated, %:
C 68.94; H 5.51; Cl 9.69; N 11.49.
8-Methyl-4,6-diphenyl-5,7-dihydropyrrolo-
[3,4-d][1,2]diazepine-1-thiol (8a). A solution of
0.91 g (2.25 mmol) of Lawesson’s reagent in 20 mL of
ethyl benzene (chlorobenzene or xylene can also be
used as solvent) was added to 1 g (3.18 mmol) of
compound 5a, and the mixture was refluxed for 1 h.
The mixture was cooled to room temperature, and the
yellow finely crystalline solid was filtered off and
washed with a small amount of anhydrous benzene.
Yield 1 g (95%), fine greenish–yellow crystals,
1-Hydrazinyl-7,8-dimethyl-4,6-diphenyl-5,7-di-
hydropyrrolo[3,4-d][1,2]diazepine (9b) was synthe-
sized in a similar way from 1 g (2.9 mmol) of 8b.
Yield 0.75 g (75%), fine colorless crystals, mp 182–
1
183°C. H NMR spectrum, δ, ppm: 2.47 s (3H, CH3),
3.41 s (3H, CH3), 3.69 s (2H, CH2), 7.30–7.15 m (5H,
Ph), 7.48–7.35 m (5H, Ph). 13C NMR spectrum, δC,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

KHARANEKO, BOGZA
1048
ppm: 11.9 (CH3), 26.4 (CH2), 31.9 (CH3), 112.3, 115.7,
126.5, 127.5, 127.9, 128.8, 129.0, 129.1, 129.7, 130.5,
131.5, 137.2, 146.3, 160.9. Found, %: C 73.43;
H 6.18; N 20.39. C21H21N5. Calculated, %; C 73.44;
H 6.16; N 20.39.
126.6, 127.5, 128.3, 128.4, 128.6, 130.7, 131.7, 135.2,
142.6 (C3), 145.6, 163.8 (C6). Found, %: C 74.35;
H 5.08; N 20.57. C21H17N5. Calculated, %: C 74.32;
H 5.05; N 20.63.
9,10-Dimethyl-6,8-diphenyl-7,9-dihydropyrrolo-
[3,4-d][1,2,4]triazolo[4,3-b]diazepine (11b) was syn-
thesized in a similar way from 0.5 g (1.46 mmol) of
9b. Yield 0.105 g (20%), fine yellow crystals, mp 198–
10-Methyl-6,8-diphenyl-7,9-dihydropyrrolo-
[3,4-d]tetrazolo[1,5-b][1,2]diazepine (10a). Sodium
nitrite, 0.21 g (3 mmol), was added with stirring to
a solution of 0.5 g (1.52 mmol) of compound 9a in
3 mL of acetic acid, and the mixture was stirred for
2 h. The finely crystalline solid was filtered off and
washed with a small amount of acetic acid and with
water. Yield 0.267 g (53%), fine colorless crystals,
mp 187‒188°C. IR spectrum, ν, cm–1: 3160 (NH),
1610 (C=Carom), 1580 (C=Carom). 1H NMR spectrum, δ,
ppm: 2.58 s (3H, CH3), 4.21 s (2H, CH2), 7.35 t (1H,
Ph, J = 6.8 Hz), 7.50–7.40 m (4H, Ph), 7.53 t (2H, Ph,
J = 7.2 Hz), 7.62 t (1H, Ph, J = 7.6 Hz), 7.93 d (2H,
Ph, J = 8.0 Hz), 12.02 s (1H, NH). 13C NMR spectrum,
δC, ppm: 11.9 (CH3), 27.5 (CH2), 104.9, 112.7, 126.6,
126,8, 127.1, 128.3, 129.0, 129.1, 130.5, 131.1, 132.2,
134.5, 146.1, 165.6 (C6). Found, %: C 70.59; H 4.75;
N 24.66. C20H16N6. Calculated, %: C 70.57; H 4.74;
N 24.69.
1
199°C. H NMR spectrum, δ, ppm: 2.62 s (3H, CH3),
3.50 s (3H, CH3), 3.78 s (2H, CH2), 7.22 d (2H, Ph, J =
7.6 Hz), 7.51–7.31 m (6H, Ph), 7.63 d (2H, Ph, J =
7.6 Hz), 8.58 s (1H, 3-H). 13C NMR spectrum, δC,
ppm: 10.8 (CH3), 26.7 (CH2), 31.5 (CH3), 106.7, 112.6,
127.3, 127.5, 128.2, 128.3, 128.5, 128.9, 129.9, 130.2,
130.8, 134.9, 142.6 (C3), 145.4, 163.6 (C6). Found, %:
C 74.75; H 5.45; N 19.80. C22H19N5. Calculated, %:
C 74.77; H 5.42; N 19.82.
1-(3,5-Dimethyl-1H-pyrazol-1-yl)-8-methyl-4,6-
diphenyl-5,7-dihydropyrrolo[3,4-d][1,2]diazepine
(12a). A solution of 0.5 g (1.52 mmol) of compound 9a
and 0.16 g (1.6 mmol) of acetylacetone in 3 mL of
2-ethoxyethanol was refluxed for 4 h. The mixture was
cooled, 5 mL of water was added, and the precipitate
was filtered off, washed with a small amount of water,
and recrystallized from methanol. Yield 0.23 g (38%),
fine light yellow crystals, mp 214–215°C. IR spec-
trum, ν, cm–1: 3380 (NH), 1600 (C=Carom), 1550
9,10-Dimethyl-6,8-diphenyl-7,9-dihydropyrrolo-
[3,4-d]tetrazolo[1,5-b][1,2]diazepine (10b) was syn-
thesized in a similar way from 0.5 g (1.46 mmol) of
9b. Yield 0.258 g (50%), fine colorless crystals,
1
(C=Carom). H NMR spectrum, δ, ppm: 1.80 s (3H,
1
mp 184–185°C. H NMR spectrum, δ, ppm: 7.75 d
CH3), 2.20 s (3H, CH3), 2.62 s (3H, CH3), 3.17 d and
4.42 d (1H each, 5-H, J = 12.8 Hz), 5.99 s (1H, 4′-H),
7.22–7.35 m (3H, Ph), 7.36–7.46 m (3H, Ph), 7.50 d
(2H, Ph, J = 7.2 Hz), 7.61 d (2H, Ph, J = 7.2 Hz),
11.55 s (1H, NH). 13C NMR spectrum, δC, ppm: 11.9
(CH3), 13.4 (CH3), 13.9 (CH3), 27.7 (CH2), 107.6,
112.6, 120.1, 124.0, 126.5, 126.8, 127.5, 128.6, 129.1,
129.7, 130.1, 132.6, 136.9, 141.5, 144.8, 149.0, 156.5
(C6). Found, %: C 76.30; H 5.92; N 17.78. C25H23N5.
Calculated, %: C 76.31; H 5.89; N 17.80.
(2H, Ph, J = 8.0 Hz), 2.64 s (3H, CH3), 3.53 s (3H,
CH3), 3.86 s (2H, CH2), 7.25 d (2H, Ph, J = 7.2 Hz),
7.56–7.38 m (6H, Ph). 13C NMR spectrum, δC, ppm:
10.9 (CH3), 26.9 (CH2), 31.8 (CH3), 103.7, 113.0,
127.8, 129.6, 129.9, 130.4, 131.5, 134.1, 145.7, 164.1
(C6). Found, %: C 71.20; H 5.15; N 23.65. C21H18N6.
Calculated, %: C 71.17; H 5.12; N 23.71.
10-Methyl-6,8-diphenyl-7,9-dihydropyrrolo-
[3,4-d][1,2,4]triazolo[4,3-b]diazepine (11a). A solu-
tion of 0.5 g (1.52 mmol) of compound 9a in 3 mL of
triethyl orthoformate was refluxed for 4 h. After
cooling, the precipitate was filtered off and washed
with a small amount of methanol. Yield 0.252 g (49%),
fine yellow crystals, mp 241–242°C. IR spectrum, ν,
cm–1: 3380 (NH), 1600 (C=Carom), 1550 (C=Carom).
1H NMR spectrum, δ, ppm: 2.57 s (3H, CH3), 4.05 s
(2H, CH2), 7.27 t (1H, Ph, J = 6.0 Hz), 7.40–7.35 m
(4H, Ph), 7.43 t (2H, Ph, J = 7.2 Hz), 7.50 t (1H, Ph,
J = 7.2 Hz), 7.81 d (2H, Ph, J = 7.6 Hz), 8.60 s (1H,
3-H), 11.49 s (1H, NH). 13C NMR spectrum, δC, ppm:
11.7 (CH3), 27.0 (CH2), 107.8, 111.8, 125.6, 126.1,
1-(3,5-Dimethyl-1H-pyrazol-1-yl)-7,8-dimethyl-
4,6-diphenyl-5,7-dihydropyrrolo[3,4-d][1,2]diaze-
pine (12b) was synthesized in a similar way from 0.5 g
(1.46 mmol) of 9b. Yield 210 mg (35%), fine light
yellow crystals, mp 200–201°C. 1H NMR spectrum, δ,
ppm: 1.77 s (3H, CH3), 2.21 s (3H, CH3), 2.63 s (3H,
CH3), 3.04 d (1H, 5-H, J = 13.6 Hz), 3.48 s (3H, CH3),
4.02 d (1H, 5-H, J = 13.6 Hz), 6.03 s (1H, 4′-H), 7.23 t
(2H, Ph, J = 7.2 Hz), 7.35–7.28 m (3H, Ph), 7.60–
7.40 m (5H, Ph). 13C NMR spectrum, δC, ppm: 9.4
(CH3), 11.6 (CH3), 12.0 (CH3), 25.3 (CH2), 30.4 (CH3),
105.9, 109.4, 118.5, 125.3, 125.5, 126.1, 126.6, 127.1,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

5,7-DIHYDROPYRROLO[3,4-d][1,2]DIAZEPIN-1(2H)-ONES.
1049
5. Howes, J.F. and Bell, C., Neurotherapeutics, 2007,
127.9, 128.1, 128.6, 129.2, 134.6, 139.6, 142.5, 147.3,
154.3 (C6). Found, %: C 76.60; H 6.21; N 17.19.
C26H25N5. Calculated, %: C 76.63; H 6.18; N 17.19.
vol. 4, p. 126.
6. Sorelli, F., Massa, S., Pantaleoni, G.C., Palumbo, G., and
Fanini, D., Farmaco, 1984, vol. 39, p. 707.
2-[(7,8-Dimethyl-4,6-diphenyl-5,7-dihydropyr-
rolo[3,4-d][1,2]diazepin-1-yl)sulfanyl]-1-phenyl-
ethan-1-one (13). A mixture of 0.5 g (1.45 mmol) of
compound 8b, 0.3 g (1.5 mmol) of 2-bromo-1-phenyl-
ethan-1-one, and 0.12 g (3.0 mmol) of finely powdered
sodium hydroxide in 10 mL of acetone was stirred for
4 h at room temperature. The mixture was diluted with
15 mL of water, and the precipitate was filtered off and
recrystallized from methanol. Yield 0.55 g (82%), fine
light yellow crystals, mp 138–139°C. IR spectrum, ν,
cm–1: 1690 (C=O), 1580 (C=Carom). 1H NMR spectrum,
δ, ppm: 2.56 s (3H, CH3), 2.94 d (1H, 5-H, J =
13.6 Hz), 3.47 s (3H, CH3), 3.79 d (1H, 5-H, J =
13.6 Hz), 4.71 d and 4.82 d (1H each, CH2S, J =
12.8 Hz), 7.17 t (2H, Ph, J = 7.6 Hz), 7.55–7.22 m
(11H, Ph), 7.61 t (1H, Ph, J = 7.2 Hz), 8.09 d (2H, Ph,
J = 7.6 Hz). 13C NMR spectrum, δC, ppm: 11.4 (CH3),
25.9 (CH3), 31.5 (CH2), 36.9 (CH2S), 113.0, 119.6,
126.5, 126.8, 127.3, 127.6, 128.0, 128.1, 128.2, 128.7,
129.8, 130.3, 132.6, 135.9, 143.6, 148.0, 155.3, 180.4,
193.0 (C=O). Found, %: C 75.10; H 6.48; N 9.10.
C29H25N3OS. Calculated, %: C 75.13; H 5.44; N 9.06.
7. Massa, S., Sorelli, F., Artico, M., Mai, A., Silvestri, R.,
Pantaleoni, G.C., Palumbo, G., Fanini, D., and
Giorgi, R., Farmaco, 1989, vol. 44, p. 109.
8. Sorelli, F., Massa, S., Stefancich, G., Ortenzi, G.,
Artico, M., Pantaleoni, G.C., Palumbo, G., Fanini, D.,
and Giorgi, R., Eur. J. Med. Chem. Chim. Ther., 1986,
vol. 21, p. 445.
9. Massa, S., Artico, M., Mai, A., Sorelli, F., Panta-
leoni, G.C., Giorgi, R., Ottaviani, D., and Cagnotto, A.,
Farmaco, 1990, vol. 45, p. 1265.
10. Massa, S., Artico, M., Mai, A., Sorelli, F., Botta, M.,
Tafi, A., Pantaleoni, G.C., Giorgi, R., Coppolino, M.F.,
Cagnotto, A., and Skorupska, M., J. Med. Chem., 1992,
vol. 35, p. 4533.
11. Mai, A., Di Santo, R., Massa, S., Artico, M., Panta-
leoni, G.C., Giorgi, R., Coppolino, M.F., and Bar-
racchini, A., Eur. J. Med. Chem., 1995, vol. 30, p. 593.
12. Harris, D., Syren, S., and Streith, J., Tetrahedron Lett.,
1978, vol. 42, p. 4093.
13. Tolkunov, A.S. and Bogza, S.L., Chem. Heterocycl.
Compd., 2010, vol. 46, no. 6, p. 711.
14. Baldwin, J.E. and Lusch, M.J., Tetrahedron, 1982,
vol. 38, p. 2939.
15. Overberger, C.G. and Monagle, J.J., J. Am. Chem. Soc.,
T h e a u t h o r s t h a n k s e n i o r r e s e a r c h e r
Dr. S.Yu. Suikov (Institute of Organic Chemistry,
National Academy of Sciences of Ukraine) for helpful
discussion of the NMR spectra.
1956, vol. 78, p. 4470.
16. Bisenieks, E.A., Bundule, M.F., Updrikis, Ya.R.,
Dubur, G.Ya., Mishnev, A.F., and Bleidedis, Ya.Ya.,
Chem. Heterocycl. Compd., 1987, vol. 23, no. 1, p. 88.
REFERENCES
17. Gatta, F., Piazza, D., Del Giudice, M.R., and Mas-
sotti, M., Farmaco, 1985, vol. 40, p. 942.
1. Pellow, S. and File, S.E., Pharmacol. Biochem. Behav.,
18. Kaup, G., Schmeyers, J., Kuse, A., and Atfeh, A.,
1986, vol. 24, p. 525.
Angew. Chem., Int. Ed., 1999, vol. 38, p. 2896.
2. Körösi, J. and Láng, T., Chem. Ber., 1974, vol. 107,
19. Kharaneko, O.I. and Bogza, S.L., Chem. Heterocycl.
Compd., 2012, vol. 48, no. 11, p. 1734.
20. Khabarov, K.M., Kharaneko, O.I., and Bogza, S.L.,
p. 3883.
3. Csuzdi, E., Migleczi, K., Hazai, I., Berzsenyi, P., and
Pallagi, I., Bioorg. Med. Chem. Lett., 2005, vol. 15,
p. 4662.
Chem. Heterocycl. Compd., 2009, vol. 45, no. 4, p. 468.
4. Zappala, M., Postorino, G., and Mikale, N., J. Med.
Chem., 2006, vol. 49, p. 575.
21. Kharaneko, O.I. and Bogza, S.L., Chem. Heterocycl.
Compd., 2013, vol. 49, no. 2, p. 317.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016