1,4-Diphenyl-5H-[1,2,5]triazepino[5,4-a]benzimidazole—A New Heterocyclic System. Synthesis and Properties

Article abstract of DOI:10.1134/S1070428019010147

The first representative of a new heterocyclic system, 1,4-diphenyl-5H-[1,2,5]triazepino[5,4-a]-benzimidazole, has been synthesized by condensation of ethyl (2-benzoyl-1H-benzimidazol-1-yl)acetate with hydrazine hydrate, followed by thermal heterocyclization of intermediate bis-hydrazone.

Full text of DOI:10.1134/S1070428019010147

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 1, pp. 115–117. © Pleiades Publishing, Ltd., 2019.
Russian Text © A.O. Kharaneko, 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 1, pp. 123–126.
SHORT
COMMUNICATIONS
1,4-Diphenyl-5H-[1,2,5]triazepino[5,4-a]benzimidazole—A New
Heterocyclic System. Synthesis and Properties
A. O. Kharanekoa
a Litvinenko Institute of Physical Organic and Coal Chemistry, ul. R. Lyuksemburg 70, Donetsk, 83114 Ukraine
e-mail: antonhar08@rambler.ru
Received June 26, 2018; revised July 2, 2018; accepted July 6, 2018
Abstract—The first representative of a new heterocyclic system, 1,4-diphenyl-5H-[1,2,5]triazepino[5,4-a]-
benzimidazole, has been synthesized by condensation of ethyl (2-benzoyl-1H-benzimidazol-1-yl)acetate with
hydrazine hydrate, followed by thermal heterocyclization of intermediate bis-hydrazone.
Keywords: 5H-[1,2,5]triazepino[5,4-a]benzimidazole, synthesis, thermal heterocyclization, hydrazine hydrate,
ethyl (2-benzoyl-1H-benzimidazol-1-yl)acetate.
DOI: 10.1134/S1070428019010147
Seven-membered nitrogen-containing heterocycles,
as well as benzimidazole derivatives, exhibit a broad
spectrum of pharmacological activity [1–4]. These
heterocycles are structural units of a number of com-
mercial drugs such as phenazepam, tofisopam, omep-
razole, esomeprazole, mebendazole, etc. The concept
of combining pharmacophoric groups in a single mole-
cule underlies an important line in the design of new
medicinal agents. For example, fused benzimidazo-
1,4-diazepin-2-ones [5] are considered to be potential
antitumor agents, while 4,5-dihydro[1,2,4]triazepino-
[3,5-a]benzimidazole derivatives possess bacteriostatic
and fungicidal properties [6].
hydrate was expected to produce the corresponding
hydrazone. However, the reaction of 2a with hydrazine
hydrate in boiling methanol involved elimination of
the benzoyl group with the formation of 2-(1H-benz-
imidazol-1-yl)acetohydrazide and benzohydrazide.
The alkylation of 1 with α-bromoacetophenone
under similar conditions afforded 2-(2-benzoyl-1H-
benzimidazol-1-yl)-1-phenylethanone (2b). Compound
2b reacted with hydrazine hydrate in methanol to give
a mixture of several products (according to the
1H NMR data), one of which was 1,4-diphenyl-5H-
[1,2,5]triazepino[5,4-a]benzimidazole (3b); the frac-
tion of 3b in the product mixture did not exceed 5–7%.
After heating the product mixture for 2 h at 150°C,
triazepinobenzimidazole 3b was isolated in 50% yield.
On the other hand, triazepinobenzimidazoles
belong to a poorly explored heterocyclic system.
Several examples of synthesis of 1,2,4- [6‒8] and
1,3,5-triazepinobenzimidazoles have been reported [9],
whereas no published data are available on 1,2,5-tri-
azepinobenzimidazoles.
Compound 3b underwent prototropic isomerization
to 1,4-diphenyl-3H-[1,2,5]triazepino[5,4-a]benzimida-
zole (4b) on heating in boiling acetic acid. The reduc-
tion of 3b with sodium tetrahydridoborate afforded
(4RS)-1,4-diphenyl-4,5-dihydro-3H-[1,2,5]triazepino-
[5,4-a]benzimidazole (5b). Attempted oxidation of 3b
with selenium dioxide in acetic acid led to the forma-
tion of initial compound 2b. A similar result was
obtained previously [12] in the oxidation of 4-methyl-
5H-pyrrolo[2,1-d][1,2,5]triazepine with selenium di-
oxide in dioxane.
The present communication reports a synthetic ap-
proach to the first representative of a new heterocyclic
system, 1,4-diphenyl-5H-[1,2,5]triazepino[5,4-a]benz-
imidazole, starting from 1H-benzimidazol-2-yl-
(phenyl)methanone (1). The alkylation of 1 with ethyl
iodoacetate in DMF in the presence of potassium
carbonate gave ethyl (2-benzoyl-1H-benzimidazol-1-
yl)acetate (2a) in a good yield. Compound 1 failed to
react with ethyl chloroacetate. By analogy with the
data of [10, 11], treatment of 2a with hydrazine
Ethyl (2-benzoyl-1H-benzimidazol-1-yl)acetate
(2a) and 2-(2-benzoyl-1H-benzimidazol-1-yl)-1-
phenylethanone (2b) (general procedure). Compound
115

KHARANEKO
116
Ph
N
N
N
N
Ph
O
N
N2H4·H2O
XCH2COR, K2CO3
+
NH2NHCOPh
O
R = OEt
N
H
O
O
NHNH2
R
2a, 2b
1
N2H4·H2O
R = Ph
Ph
Ph
O
N
N
N
N
Ph
N
N
Ph
N
N
Ph
N
N
+
+
+
+
N
N
N
N
N
H2N
H2N
NH
O
N
N
H2N
Ph
H2N
Ph
NH NH2
Ph
Ph
Ph
3b
150°C
Ph
Ph
N
N
N
N
AcOH
NaBH4
3b
N
N
NH
NH
Ph
Ph
4b
5b
X = I, R = OEt (a); X = Br, R = Ph (b).
1
1, 15.95 g (71.85 mmol), was dissolved in 160 mL of (C=O), 1600 s (C=Carom). H NMR spectrum, δ, ppm:
DMF, 107.8 mmol of ethyl iodoacetate (in the syn-
thesis of 2a) or α-bromoacetophenone (in the synthesis
of 2b) and 39.66 g (278.4 mmol) of finely powdered
potassium carbonate were added, and the resulting
suspension was stirred for 4 h on heating on a boiling
water bath. The mixture was poured into 600 mL of
water, and the precipitate was filtered off, dried, and
recrystallized from methanol.
6.27 s (2H, CH2), 7.35–7.47 m (2H, Harom), 7.53–
7.63 m (4H, Harom), 7.65–7.77 m (3H, Harom), 7.88 d
(1H, Harom, J = 8.0 Hz), 8.14 d (2H, Harom, J = 7.6 Hz),
8.37 d (2H, Harom, J = 7.6 Hz). 13C NMR spectrum, δC,
ppm: 53.6 (CH2), 113.2, 123.3, 125.2, 127.4, 129.8,
130.2, 130.6, 133.0, 135.1, 135.6, 136.5, 138.2, 138.4,
143.4, 148.2, 187.2 (C=O), 194.3 (C=O). Found, %:
C 77.62; H 4.76; N 8.21. C22H16N2O2. Calculated, %:
C 77.63; H 4.74; N 8.23.
Compound 2a. Yield 75%, white crystals, mp 68–
69°C. 1H NMR spectrum, δ, ppm: 1.29 t (3H, CH3, J =
7.2 Hz), 4.21 q (2H, CH2, J = 7.2 Hz), 5.44 s (2H,
1,4-Diphenyl-5H-[1,2,5]triazepino[5,4-a]benz-
imidazole (3b). A mixture of 5.8 g (17.06 mmol)
of compound 2a, 70 mL of methanol, and 1.11 mL
(22.18 mmol) of hydrazine hydrate was refluxed for
7 h. The solution was cooled to room temperature and
poured into 500 mL of brine. The precipitate was
filtered off, dried, and heated for 2 h at 150°C. The
melt was cooled to room temperature, 10 mL of
methanol was added, and the mixture was stirred until
complete dissolution, maintaining it slightly boiling.
The solution was cooled to room temperature, and the
precipitate was filtered off and washed with methanol.
CH2), 7.38 t (1H, Harom, J = 7.6 Hz), 7.46 t (1H, Harom
,
J = 7.6 Hz), 7.57 t (2H, Harom, J = 7.2 Hz), 7.66–
7.74 m (2H, Harom), 7.86 d (1H, Harom, J = 8.0 Hz),
8.40 d (2H, Harom, J = 8.0 Hz). 13C NMR spectrum, δC,
ppm: 16.0 (CH3), 48.5 (CH2), 63.0 (CH2), 113.0,
123.4, 125.4, 127.6, 129.9, 133.0, 135.1, 138.0, 138.1,
143.2, 147.8, 169.7 (C=O), 187.1 (C=O). Found, %:
C 70.11; H 5.25; N 9.08. C18H16N2O3. Calculated, %:
C 70.12; H 5.23; N 9.09.
Compound 2b. Yield 83%, white crystals, mp 186–
187°C. IR spectrum, ν, cm–1: 1680 s (C=O), 1640 s Yield 2.85 g (50%), bright yellow crystals, mp 221–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 1 2019

1,4-DIPHENYL-5H-[1,2,5]TRIAZEPINO[5,4-a]BENZIMIDAZOLE
117
222°C. IR spectrum, ν, cm–1: 1620 m (C=Carom), 1450 s
(C=N–N=C). H NMR spectrum, δ, ppm: 4.74 d and
142.3, 144.2, 149.1. Found, %: C 78.06; H 5.37;
N 16.57. C22H18N4. Calculated, %: C 78.08; H 5.36;
N 16.56.
1
6.22 d (1H each, CH2, J = 14.0 Hz), 7.31 t (1H, Harom
,
The H and 13C NMR spectra were recorded on
1
J = 7.6 Hz), 7.42 t (1H, Harom, J = 8.0 Hz), 7.46–
7.54 m (6H, Harom), 7.77 d (1H, Harom, J = 8.0 Hz),
8.09 d (2H, Harom, J = 6.8 Hz), 8.13 d (2H, Harom, J =
7.6 Hz). 13C NMR spectrum, δC, ppm: 42.5 (CH2),
112.4, 122.4, 124.9, 126.0, 129.3, 130.0, 130.7, 131.0,
132.5, 132.6, 134.5, 135.4, 137.2, 144.7, 145.5, 149.2,
154.3. Found, %: C 78.54; H 4.81; N 16.64. C22H16N4.
Calculated, %: C 78.55; H 4.79; N 16.65.
a Bruker Avance II spectrometer at 400 and 100 MHz,
respectively, using DMSO-d6 as solvent and tetra-
methylsilane as internal standard. The IR spectra were
recorded in KBr on a Specord IR-75 spectrometer. The
melting points were measured on a Boetius type
melting point apparatus and are uncorrected. The
elemental analyses were obtained with a Vario EL
Cube Elementar analyzer.
1,4-Diphenyl-3H-[1,2,5]triazepino[5,4-a]benz-
imidazole (4b). A mixture of 0.4 g (1.19 mmol) of
compound 3b and 5 mL of glacial acetic acid was
refluxed for 10 h. After cooling, the precipitate was
filtered off and washed with methanol. Yield 0.12 g
CONFLICT OF INTERESTS
The author declares the absence of conflict of
interests.
1
(30%), dark yellow needles, mp 223–224°C. H NMR
spectrum, δ, ppm: 7.38 t (1H, Harom, J = 6.8 Hz), 7.45–
7.66 m (8H, Harom,), 7.98 d (1H, Harom, J = 8.0 Hz),
8.29 d (2H, Harom, J = 7.6 Hz), 8.52 d (1H, Harom, J =
8.4 Hz), 9.06 d (2H, Harom, J = 7.6 Hz), 9.63 s
(1H, NH). 13C NMR spectrum, δC, ppm: 115.7, 117.1,
121.3, 125.3, 127.9, 129.7, 130.2, 130.3, 130.5, 130.7,
131.4, 132.5, 137.4, 137.9, 138.7, 140.4, 143.4, 149.2.
Found, %: C 78.54; H 4.81; N 16.64; C22H16N4. Cal-
culated, %: C 78.55; H 4.79; N 16.65.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 1 2019