Reaction of chloro-substituted N-cyano-benzimidazoles with hydrazines. A route to 1H-[1,2,4]triazolo[4,3-a]benzimidazole and [1,2,4]triazino[4,5-a] benzimidazole

Full text of DOI:10.1007/s10593-013-1223-3

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
REACTION OF CHLORO-SUBSTITUTED N-CYANO-
BENZIMIDAZOLES WITH HYDRAZINES. A ROUTE
TO 1H-[1,2,4]TRIAZOLO[4,3-a]BENZIMIDAZOLE AND
[1,2,4]TRIAZINO[4,5-a]BENZIMIDAZOLE
A. S. Bunev1*, S. V. Naumov1, V. E. Statsyuk1, G. I. Ostapenko1, and P. P. Purygin2
Keywords: N-cyanoazoles, [1,2,4]triazino[4,5-a]benzimidazole, 1H-[1,2,4]triazolo[4,3-a]benzimidazole,
intramolecular cyclization.
Bicyclic compounds containing bridgehead nitrogen atoms in their structure are of both theoretical and
practical interest [1]. We have previously proposed [2] a synthesis of 1H-imidazo[5,1-c][1,2,4]triazole by the
intramolecular cyclization of 4,5-dichloro-1H-imidazol-1-ylcarboxamidrazone (prepared from the
corresponding N-cyanoimidazole and hydrazine). In this work, we have now studied transformations of the
corresponding benzimidazole derivatives in similar reactions. Treatment of the 2-chlorobenzimidazole (1a) with
cyanogen bromide in the presence of Et3N at low temperature gave the N-cyano derivative 2a in 80% yield. Due
to the highly active chlorine atom, the cyanation of compound 1b was achieved by refluxing with BrCN in
EtOAc, and the product 2b was obtained in 58% yield. Compound 2a was introduced in the reaction with
hydrazine hydrate or phenylhydrazine in EtOH solution at 0-5°C in the presence of Et3N and gave compounds
3a,b in 78 and 69% yield, respectively. The reaction of compound 2b with phenylhydrazine was carried out in
MeCN medium at 0ºC. Thanks to the high mobility of the chlorine atom, its intramolecular cyclization occurred
without the need for Et3N, and led to a six-membered heterocycle. After treatment of the reaction mixture with
NaHCO3, the product 4 was isolated as free base in 73% yield. The structures of all of the compounds were
1
determined using H and 13C NMR spectroscopy. In the case of compounds 3a,b and 4, the structure was
additionally confirmed using COSY and 13C HSQC 2D NMR experiments.
Hence, we have proposed a novel method for the synthesis of 1H-[1,2,4]triazolo[4,3-a]benzimidazole
derivatives [3] and for the novel [1,2,4]triazino[4,5-a]benzimidazole heterocyclic system.
1
IR spectra were recorded on an FSM-1201 instrument for KBr pellets. H and 13C NMR spectra were
recorded on a Bruker AM-400 instrument (400 and 100 MHz, respectively). The COSY and 13C HSQC experiments
1
were carried out on a Bruker Avance III spectrometer (600 MHz for H and 150 MHz for 13C). In all cases the
solvent was DMSO-d6 and the internal standard was TMS. Elemental analysis was performed on a vario EL cube
analyzer. Melting points were determined on a Boetius hot stage apparatus and were not corrected.
_______
*To whom correspondence should be addressed, e-mail: a.s.bunev@gmail.com.
1Institute of Chemistry and Environmental Engineering, Togliatti State University, 14 Belorusskaya St.,
Togliatti 445667, Russia.
2Samara State University, 1 Academika Pavlova St., Samara 443011, Russia; email: puryginpp2002@mail.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1997-1999, December, 2012.
Original article submitted December 3, 2012.
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0009-3122/13/4812-1874©2013 Springer Science+Business Media New York

R1NHNH2, EtOH, Et3N
N
N
N
0–5°C (for 3a)
BrCN
R
R
or PhNHNH2, MeCN
NaHCO3, 0°C (for 3b)
Et3N, Me2CO, 0–10°C
(for 2a)
or EtOAc,  (for 2b)
N
H
1a,b
CN
2a,b
9
8
6
5
N
N
7
6
7
8
R1
4
N1
N2
N3
N
N
+
Ph
4
9
10
5
3
N
1
2
3a,b
H2N
H2N
(from 2а)
4 (from 2b)
2-Chloro-1-cyanobenzimidazole (2a). Et3N (2.9 ml, 2.12 g, 21 mmol) was added to a solution of azole
1a (3.05 g, 20 mmol) in absolute acetone (40 ml) cooled to 0°C, and the reaction mixture was maintained below
10°C while a solution of cyanogen bromide (2.12 g, 20 mmol) in acetone (10 ml) was added. After 20 min, the
mixture was filtered, and the filtrate was evaporated. The dry residue after evaporation was then recrystallized
from hexane. Yield 2.84 g (80%). White crystalline powder. Mp 129-130°C (decomp.). IR spectrum, , cm-1:
1
2257, 1612, 1512, 1459, 1354, 1246, 1200, 756, 744. H NMR spectrum, , ppm: 7.56-7.54 (2H, m, H-6,7);
7.51-7.49 (2H, m, H-4,5). 13C NMR spectrum, , ppm: 102.1 (CN); 109.8 (C-7); 119.8 (C-4); 123.3 (C-5); 123.5
(C-6); 133.6 (C-7a); 140.2 (C-3a); 145.3 (C-2). Found, %: C 54.02; H 2.21; N 23.59. C8H4ClN3. Calculated, %
C 54.11; H 2.27; N 23.66.
2-(Chloromethyl)-1-cyanobenzimidazole (2b). A solution of cyanogen bromide (2.12 g, 20 mmol) in
EtOAc (10 ml) was added dropwise with vigorous stirring to a refluxing solution of azole 1b (6.66 g, 40 mmol)
in EtOAc (40 ml). The reaction mixture was refluxed for a further 30 min and cooled. The precipitated crystals
of 2-(chloromethyl)benzimidazole hydrobromide were filtered off and the filtrate was evaporated on a rotary
evaporator. The dry residue after evaporation was recrystallized from a mixture of hexane and EtOAc (9:1).
Yield 2.23 g (58%). White crystalline powder. Mp 122-124°C. IR spectrum, , cm-1: 2335, 1621, 1539, 1422,
1244, 1141, 806. 1H NMR spectrum, , ppm: 4.63 (2H, s, CH2Cl); 7.32-7.04 (2Н, m, H-5,6); 7.95-7.81 (2H, m,
H-4,7). 13C NMR spectrum, , ppm: 41.2 (CH2Cl); 99.7 (CN); 112.8 (C-7); 120.5 (C-4); 123.3 (C-6); 124.0
(C-5); 133.7 (C-7a); 139.4 (C-3a); 151.9 (C-2). Found, %: C 56.33; H 3.12; N 21.89. C9H6ClN3. Calculated, %:
C 56.41; H 3.16; N 21.93.
1H-[1,2,4]Triazolo[4,3-a]benzimidazol-3-amine (3a). A mixture of Et3N (0.84 ml, 0.607 g, 6.0 mmol)
and hydrazine hydrate (0.28 ml, 0.285 g, 5.7 mmol) in EtOH (5 ml) was added with stirring to a solution of
compound 2a (0.854 g, 5.6 mmol) in EtOH (10 ml) cooled to 0-5°C. The reaction mixture was heated to room
temperature and stirred for 1 h. The solution was evaporated on a rotary evaporator. The residue was dissolved
in acetone (5 ml), and Et3N·HCl was filtered off. The acetone solution was again evaporated and the dry residue
was recrystallized from EtOH. Yield 0.756 g (78%). White crystalline powder. Mp 203-205°C. IR spectrum, ,
1
cm-1: 3214-3125, 1659, 1557, 1471, 1278, 1242, 1005, 814. H NMR spectrum, , ppm: 11.40 (1Н, br. s, NН);
7.82-7.78 (2Н, m, Н-5,8); 7.32-7.27 (2Н, m, Н-6,7); 7.06 (2Н, br. s, NН2). 13C NMR spectrum, , ppm: 110.7
(С-5); 120.9 (С-6); 121.3 (С-8); 122.7 (С-7); 128.1 (С-4a); 139.1 (С-8a); 147.5 (С-9a); 152.0 (С-3). Found, %:
C 55.51; H 4.01; N 40.48. C8H7N5. Calculated, %: C 55.49; H 4.07; N 40.44.
1-Phenyl-1H-[1,2,4]triazolo[4,3-a]benzimidazol-3-amine (3b) was obtained similarly using
phenylhydrazine instead of hydrazine hydrate. Yield 0.963 g (69%). White crystalline powder. Mp 191-192°C.
1
IR spectrum, , cm-1: 3306-3126, 1632, 1474, 1443, 1339, 1292, 1027. H NMR spectrum, , ppm: 7.94-7.87
13
(1Н, m, Н-8); 7.51-7.34 (3Н, m, H-5, H Ph); 7.31-7.05 (5H, m, H-6,7, H Ph); 6.41 (1Н, br. s, NH2). C NMR
spectrum, , ppm: 110.6 (С-5); 119.9 (С Ph); 120.8 (C-6); 121.1 (C-8); 122.6 (C-7); 129.0 (C-4a); 129.1 (C Ph);
130.3 (C Ph); 136.1 (C Ph); 139.3 (C-8a); 151.6 (C-9a); 153.9 (C-3). Found, %: C 67.49; H 4.43; N 28.16.
C14H11N5. Calculated, %: C 67.46; H 4.45; N 28.09.
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3-Phenyl-3,4-dihydro[1,2,4]triazino[4,5-a]benzimidazol-1-amine (4). A solution of phenylhydrazine
(1.18 ml, 1.30 g, 12.0 mmol) in MeCN (5 ml) was added dropwise to a solution of compound 2b (2.01 g,
10.5 mmol) in MeCN (10 ml) cooled to 0°C, and the temperature was maintained at no higher than 0°C. After
addition of all of the phenylhydrazine, the reaction mixture was heated to room temperature, stirred for 1 h, and
dry NaHCO3 (1.00 g) was added. The mixture was stirred for a further 20 min, then filtered, and the filtrate
evaporated. The dry residue was crystallized from 2-PrOH. Yield 2.01 g (73%). Cream-colored crystalline
1
powder. Mp 192-194°C. IR spectrum, , cm-1: 3320-3178, 1632, 1522, 1458, 1420, 1373, 1279. H NMR
spectrum, , ppm: 7.95 (1Н, d, Н-6); 7.73 (1Н, d, Н-9); 7.48-7.26 (4H, m, H-7,8, H Ph); 7.23-6.90 (3H, m,
H Ph); 6.18 (2Н, br. s, NH2); 4.78 (2Н, s, 4-СН2). 13C NMR spectrum, , ppm: 47.0 (С-4); 112.1 (С Ph); 115.2
(C-9); 118.9 (C-6); 120.0 (С Ph); 121.5 (C-8); 123.9 (C-7); 129.6 (С Ph); 136.5 (C-9a); 138.2 (C-4a); 145.1
(С Ph); 147.2 (C-5a); 152.9 (C-1). Found, %: C 68.36; H 5.07; N 26.65. C15H13N5. Calculated, %: C 68.43;
H 4.98; N 26.60.
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