Synthesis of benzo[b]thieno[3,2-e]benzimidazoles, first representatives of a new heterocyclic system

Full text of DOI:10.1007/s10593-008-0148-8

Chemistry of Heterocyclic Compounds, Vol. 44, No. 8, 2008
SYNTHESIS OF BENZO[b]THIENO-
[3,2-e]BENZIMIDAZOLES, FIRST
REPRESENTATIVES OF A NEW
HETEROCYCLIC SYSTEM
T. E. Khoshtariya, L. N. Kurkovskaya,
T. Z. Gakhokidze, and M. G. Maisuradze
Keywords: 2-acetylbenzo[b]thieno[3,2-e]benzimidazole, 1H-benzo[b]thieno[3,2-e]benzimidazole,
2-methylbenzo[b]thieno[3,2-e]benzimidazole.
In the present work, we have prepared a tetracyclic condensed system containing bicyclic
benzo[b]thiophene and benzimidazole fragments, each of which separately has high pharmacological activity.
The idea to combine these fragments was based on the high activity of imidazole derivatives, of which dibasol,
antibiotic azomycin (2-nitroimidazole) [2, 3], and histidine (an amino acid) [4] form an incomplete list of
pharmaceuticals used in medicine. We have synthesized unsubstituted benzo[b]thieno[3,2-e]benzimidazole (1),
which is first representative of a new heterocyclic system.
NO2
H
1
H
9
1
9
9
1
2
N
COMe
N
COMe
2
NH2
2
8
7
8
7
8
7
3
3
3
S
S
S
4
6
4
6
4
6
5
5
5
2
1
N
NH2
2
NH2
H
9
6
1
9
10
1
N
COMe
2
NH2
2
NH
8
7
9
8
8
7
3
3
3
4
S
4
S
S
5
5
4
6
7
5
6
4
3
1
2-Aminodibenzothiophene (2) [1] was selected as the starting compound. A series of transformations
converted this compound into 1,2-diaminodibenzothiophene 3, which gives unsubstituted 1H-benzo[b]thieno-
[3,2-e]benz-imidazole (1) by the action of formic acid in the presence of a catalytic amount of concentrated
hydrochloric acid.
__________________________________________________________________________________________
Georgian Technological University, Tbilisi 380075, Georgia; e-mail: t_khoshtaria@yaahoo.com.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1267-1270, August, 2008. Original article
submitted February 17, 2008, submitted after revision June 20, 2008.
1024
0009-3122/08/4408-1024©2008 Springer Science+Business Media, Inc.

The cyclization of 2-acetylamino derivative 4 gave 2-substituted benzothieno-benzimidazoles 5 and 6,
which will permit study of the biological activity of 1H-benzo[b]thieno-[3,2-e]benzimidazole derivatives.
Carrying out the cyclization in formic or acetic acid in the presence of ethyl orthoformate and a catalytic amount
of hydrochloric acid gives 2-acetylbenzo[b]thieno[3,2-e]benzimidazole (6). The cyclization in acetic acid
catalyzed by hydrochloric acid without ethyl orthoformate leads to 2-methylbenzo[b]thieno-
[3,2-e]benzimidazole (5). The structures of these compounds were established by 1H NMR and IR spectroscopy.
4
1
N
1
COMe
Me
2
N
2
b
b
c
a
10
7
c a
10
7
NH
NH
9
8
3
9
8
3
d
d
e
e
4
4
S
S
5
5
6
6
5
6
The course of the reactions and purity of the products were monitored on Silufol UV-254 plates using
1:3:5 benzene–ethyl acetate–ether as the eluent. The IR spectra were taken on a UR-20 spectrometer with NaCl
1
and LiF prisms for vaseline mulls. The H NMR spectra were taken on a Bruker WP 20SY spectrometer at
200 MHz in DMSO–d6 with TMS as the internal standard.
Benzo[b]thieno[3,2-e]benzimidazole (1). A mixture of 1,2-diaminodibenzothiophene (10.7 g,
0.05 mol), formic acid (3.48 ml), and concentrated hydrochloric acid (1 ml) was heated at reflux for 1.5-2 h in a
100 ml three-necked flask. Then, activated charcoal (1 g) was added and the mixture was heated at reflux for an
additional 15-20 min. The charcoal was filtered off. The filtrate was carefully made basic with vigorous stirring
and cooling by adding dilute ammonium hydroxide until a slight odor of ammonia was detected. The precipitate
formed was filtered off, thoroughly washed with four portions of glacial acetic acid (25 ml), and dried to give
compound 1 in 80% yield; mp 236-238°C. IR spectrum, ν, cm-1: 1670 (C=O), 3360 (NH), 1560 (imidazole
ring). 1H NMR spectrum, δ, ppm: 12.80 (1H, br. s, NH); 9.01 (1H, m, CH); 8.39 (1H, s, CH); 8.04 (1H, m, CH);
7.75 (2H, s, CH); 7.60 (2H, m, CH). Found, %: C 69.5; H 3.6; N 12.7; S 14.5. C13H8N2S. Calculated, %:
C 69.65; H 3.57; N 12.50; S 14.28.
1H-2-Methylbenzo[b]thieno[3,2-e]benzimidazole (5). A mixture of 2-acetylamino-1-aminodibenzo-
thiophene (4) (0.5 g, 1.9 mmol), acetic acid or formic acid (7 ml), and concentrated hydrochloric acid (1-2 ml)
was stirred for 40 min at 60°C. At the end of the reaction, the flask contents were cooled to room temperature
and made basic by adding dilute ammonium hydroxide. The crystalline precipitate was filtered off and washed
with water until the wash water was neutral. A white powder was formed in quantitative yield. Recrystallization
from benzene gave compound 5 in 80% yield, mp 248-250°C, Rf 0.21. IR spectrum, ν, cm-1: 3300 (NH); 1550
1
(imidazole ring). H NMR spectrum, δ, ppm (J, Hz): 12.60 (1H, br. s, NH); 8.97 (1H, m, CH); 8.01 (1H, m,
CH); 7.71 (1H, d, Jo = 8.1, CH); 7.62 (1H, d, Jo = 8.1, CH); 7.50 (2H, m, CH); 2.64 (3H, s, CH3). Found, %:
C 79.7; H 4.5; N 11.7; S 13.0. C14H10N2S. Calculated, %: C 70.58; H 4.20; N 11.76; S 13.44.
2-Acetyl-1H-benzo[b]thieno[3,2-e]benzimidazole (6). A mixture of compound 4 (0.5 g, 1.7 mmol),
ethyl orthoformate (1.5 ml), and formic acid (5 ml) with two drops of hydrochloric acid was stirred for
30-35 min at 60°C. After cooling, dilute ammonium hydroxide was added until the mixture was basic. The
1025

crystalline precipitate was filtered off, washed with water, and dried to give compound 6 in quantitative yield.
Recrystallization from benzene gave 2.8 g (85%) compound 6; mp 243-245°C, Rf 0.18. IR spectrum, ν, cm-1:
1
1670 (C=O); 3360 (NH); 1560 (imidazole ring). H NMR spectrum, δ, ppm (J, Hz): 12.60 (1H, s, NH); 9.17
(1H, m, CH); 8.14 (1H, m, CH); 8.11 (1H, d, Jo = 8.8, CH); 7.86 (1H, d, Jo = 8.8, CH); 7.60 (2H, m, CH); 2.96
(3H, s, COCH3). Found, %: C 70.5; H 4.6; N 11.9; S 13.7. C14H10N2S. Calculated, %: C 70.58; H 4.20; N 11.76;
S 13.44.
REFERENCES
1.
2.
3.
H. Gilman and G. R. Wilder, J. Am. Chem. Soc., 76, 2906 (1954).
A. F. Pozharskii, Yu. D. Garnovskii, and A. M. Simonov, Usp. Khim., 45, 269 (1966).
R. Elderfield, Heterocyclic Compounds [Russian translation], vol. 5, Izd. Inos. Lit., Moscow
(1961), p. 161.
4.
M. D. Mashkovskii, Drugs [in Russian], Meditsina, Moscow, part 2 (1993), p. 114.
1026