A simple and efficient one-pot synthesis of 2-substituted benzimidazoles

Article abstract of DOI:10.1055/s-2007-965878

A simple and efficient procedure for the synthesis of substituted benzimidazoles through a one-pot condensation of o-phenylenediamines with aryl aldehydes in the presence of H₂O₂/HCl system in acetonitrile at room temperature is described. Short reaction time, large-scale synthesis, easy and quick isolation of the products, and excellent yields are the main advantages of this procedure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965878

PAPER
547
A Simple and Efficient One-Pot Synthesis of 2-Substituted Benzimidazoles
O
ne-Pot Synthesis
i
of 2-S
umnzimidazoles ars Bahrami,* Mohammad Mehdi Khodaei,* Iman Kavianinia
Department of Chemistry, Razi University, Kermanshah 67149, Iran
Fax +98(831)4274559; E-mail: k2005bahrami@yahoo.com; E-mail: mmkhoda@razi.ac.ir
Received 9 October 2006; revised 13 November 2006
halic acid as a green halogenating agent for arenes
inspired us to explore the potential of this system for the
synthesis of 2-substituted benzimidazoles by the conden-
sation of o-phenylenediamine with aryl aldehydes. In this
Abstract: A simple and efficient procedure for the synthesis of sub-
stituted benzimidazoles through a one-pot condensation of o-phe-
nylenediamines with aryl aldehydes in the presence of H2O2/HCl
system in acetonitrile at room temperature is described. Short reac-
tion time, large-scale synthesis, easy and quick isolation of the paper, we wish to report a new and efficient method for
products, and excellent yields are the main advantages of this pro-
cedure.
the synthesis of 2-substituted benzimidazoles by the con-
densation of o-phenylenediamine with aldehydes using
Key words: o-phenylenediamines, benzimidazoles, aryl aldehydes,
hydrogen peroxide
aqueous HCl and H2O2 as efficient oxidant system in ace-
tonitrile at room temperature. The route for the synthesis
of 2-substituted benzimidazoles is shown in Scheme 1.
O
The development of simple, efficient and environmentally
benign chemical processes or methodologies for widely
used organic compounds from readily available reagents
is one of the major challenges for chemists in organic syn-
thesis. The benzimidazole ring is an important pharma-
cophore in modern drug discovery.1 Benzimidazole
derivatives exhibit significant activity against several vi-
ruses such as HIV,2 herpes (HSV-1),3 RNA,4 influenza,5
and human cytomegalovirus (HCMV).2a Bis-benzimid-
azoles are being developed as DNA minor-groove binding
agents with antitumor activity6 and can act as ligands to
transition metals for modeling biological systems.7 In ad-
dition, benzimidazoles are very important intermediates
in organic reactions.8 Therefore, the preparation of benz-
imidazoles has gained considerable attention in recent
years.9–12 Despite their importance from pharmacological,
industrial, and synthetic points of view, comparatively
few methods for the preparation of benzimidazoles have
been reported. These include the condensation of o-aryl-
diamines and aldehyde using air as the oxidant,13 the con-
densation of o-aryldiamines with carboxylic acids or their
derivatives in the presence of strong acids such as poly-
phosphoric acid14 or mineral acids,15 PS-PPh3/CCl3CN16
and thermal or acid promoted cyclization of N-(N-aryl-
R
R
NH2
NH2
N
H2O2/HCl
Ar
C H
Ar
+
MeCN, r.t.
– H2O
N
H
Scheme 1
Several solvents including acetonitrile, dichloromethane,
1,4-dioxane, and ethanol were investigated during the
course of this study. The best results were achieved using
acetonitrile. The applicability of the H2O2/HCl system
was then examined for the synthesis of 2-substituted benz-
imidazoles in acetonitrile at room temperature. A ratio of
1:1:7:3.5 of 1,2-phenylendiamine/aryl aldehyde/H2O2/
HCl was found to be optimum for the coupling of aryl al-
dehydes and phenylenediamines and the results are pre-
sented in Table 1. As shown, both aldehydes bearing
electron-donating (entries 2–5) and electron-withdrawing
(entries 6–10) substituents gave desired benzimidazoles
in excellent yields. This procedure is also applicable to
substituted o-phenylenediamines, which produced the
corresponding 2-arylbenzimidazoles smoothly in excel-
lent yields (entries 11–20). Finally, we have extended this
synthetic method for the preparation of additional extend-
ed bis-benzimidazoles in a 2:1:7:3.5 molar ratio of 1,2-
phenylenediamine/aryl dialdehyde/H2O2/HCl (Table 1,
entries 21–23).
benzimidoyl)-1,4-benzoquinoneimines.17 However,
a
number of these methods have some drawbacks such as
low yields, long reaction times, drastic reaction condi-
tions, tedious work-up procedures, and co-occurrence of
several side reactions. As a consequence, the introduction
of new methods and/or further work on technical im-
provements to overcome the limitations is still an impor-
tant experimental challenge.
To access the feasibility of applying this method on a pre-
parative scale, we carried out the coupling of 3,4-diamino-
toluene with benzaldehyde on a 50 mmol scale. As
expected, the reaction proceeded smoothly, similar to the
case in a smaller scale (entry 11, Table 1), and the desired
5-methyl-2-phenyl-1H-benzimidazole was obtained in
98% isolated yield.
A recent report by Neumann et al.18 on the use of a com-
bination of hydrogen peroxide and the respective hydro-
Regarding the mechanism of the oxidation step, the reac-
tion probably involves the formation of hypochlorous acid
by the reaction of aqueous hydrogen peroxide with hydro-
chloric acid,18 which then reacts with the cyclic hydroben-
SYNTHESIS 2007, No. 4, pp 0547–0550
Advanced online publication: 12.01.2007
DOI: 10.1055/s-2007-965878; Art ID: Z20006SS
x
x
.
x
x
.2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

548
K. Bahrami et al.
PAPER
NH2
O
N
H2O2, HCl
+
Ar
+
H
Ar
MeCN, r.t.
– H2O
N
H
NH2
H2O2
+
HCl
– H2O
HOCl
+
– HCl
Cl
N
..
N
H
NH2
N
Ar
H
Ar
Cl OH
– H2O
N
H
N
H
Ar
1
2
Scheme 2 Possible mechanism and tentative intermediates in the synthesis of benzimidazoles
zimidazoles 1 to afford intermediate 2 followed by the imidazoles has been explored. Short reaction time, large-
abstraction of hydrogen to yield the corresponding benz- scale synthesis, easy and quick isolation of the products,
imidazoles (Scheme 2).
and excellent yields are main advantages of this procedure
which make this method an attractive and useful contribu-
tion to the present methodologies.
In conclusion, a simple and efficient procedure for the
synthesis of 2-substituted benzimidazoles and bis-benz-
Table 1 Reaction of Aryl Aldehydes with o-Phenylenediamines
Entry
1
Substrates
Producta
Time (min)
35
Yield (%)b
97
N
NH2
OHC
N
H
NH2
NH2
2
3
4
5
30
35
40
40
98
98
99
99
N
OHC
OHC
OHC
OHC
OMe
Me
OMe
Me
N
H
NH2
NH2
N
N
H
NH2
NH2
N
NMe2
NMe2
N
H
NH2
NH2
N
N
H
NH2
NH2
HO
HO
6
7
8
40
35
40
98
96
97
N
OHC
OHC
OHC
Cl
F
Cl
F
N
H
NH2
NH2
N
N
H
NH2
NH2
N
N
H
NH2
NH2
Cl
Cl
9
43
47
99
98
N
OHC
OHC
N
H
NH2
NO2
NO2
10
NH2
NH2
N
NO2
NO2
N
H
Synthesis 2007, No. 4, 547–550 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 2-Substituted Benzimidazoles
549
Table 1 Reaction of Aryl Aldehydes with o-Phenylenediamines
Entry
11
Substrates
Producta
Time (min)
40
Yield (%)b
Me
N
98
Me
NH2
NH2
NH2
OHC
N
H
12
13
14
35
40
35
96
96
96
Me
Me
Me
N
Me
OHC
OHC
OHC
OMe
Me
OMe
Me
N
H
NH2
NH2
N
Me
Me
N
H
NH2
NH2
N
N
H
NH2
NH2
HO
HO
15
16
17
40
40
40
98
98
99
Me
Me
Me
N
Me
Me
Me
OHC
OHC
OHC
Cl
F
Cl
F
N
H
NH2
NH2
N
N
H
NH2
NH2
N
N
H
NH2
NH2
NH2
Cl
Cl
18
50
97
Me
N
Me
OHC
N
H
NO2
NO2
19
20
21
22
23
50
47
75
80
90
99
97
93
92
93
Me
N
Me
NH2
OHC
OHC
OHC
OHC
OHC
NO2
NO2
CHO
CHO
CHO
NO2
NO2
N
H
NH2
NH2
O2N
N
O2N
N
NH2
H
NH2
NH2
NH2
N
N
N
H
N
H
Me
Me
N
N
Me
N
H
N
NH2
NH2
H
NO2
O2N
O2N
N
N
NH2
N
H
N
H
a The products were characterized by comparison of their spectroscopic and physical data with those of samples synthesized by reported pro-
cedures.
b Yields refer to pure isolated products.
Benzimidazoles; General Procedure
(4 × 10 mL), and the combined extracts were dried (MgSO4). The
filtrate was evaporated and the corresponding benzimidazole was
obtained as the only product (Table 1). An identical procedure was
employed using o-phenylenediamine (2.0 mmol) and terephthalal-
dehyde (134.1 mg, 1.0 mmol) in the presence of aq 30% H2O2 (7.0
mmol) and aq 37% HCl (3.5 mmol) for the synthesis of bis-benzim-
idazoles (Table 1).
In a round-bottomed flask (50 mL) equipped with a magnetic stirrer,
a solution of o-phenylenediamine (1.0 mmol), and aryl aldehyde
(1.0 mmol) in MeCN (15 mL) was prepared. Aq 30% H2O2 (7.0
mmol) and aq 37% HCl (3.5 mmol) were added and the mixture was
stirred at r.t. for the time indicated in Table 1. The progress of the
reaction was monitored by TLC (eluent: n-hexane–EtOAc, 7:3).
When the starting materials had completely disappeared, the mix-
ture was quenched by adding H2O (10 mL), extracted with EtOAc
Selected characterization data for some benzimidazoles prepared
are given below.
Synthesis 2007, No. 4, 547–550 © Thieme Stuttgart · New York

550
K. Bahrami et al.
PAPER
2-Phenyl-1H-benzimidazole (Table 1, Entry 1)
Amorphous beige solid.
References
(1) Tebbe, M. J.; Spitzer, W. A.; Victor, F.; Miller, S. C.; Lee,
C. C.; Sattelberg, T. R.; Mckinney, E.; Tang, C. J. J. Med.
Chem. 1997, 40, 3937.
(2) (a) Porcari, A. R.; Devivar, R. V.; Kucera, L. S.; Drach, J. C.;
Townsend, L. B. J. Med. Chem. 1998, 41, 1251. (b) Roth,
M.; Morningstar, M. L.; Boyer, P. L.; Hughes, S. H.;
Bukheit, R. W.; Michejda, C. J. J. Med. Chem. 1997, 40,
4199.
(3) Migawa, M. T.; Giradet, J. L.; Walker, J. A.; Koszalka, G.
W.; Chamberlain, S. D.; Drach, J. C.; Townsend, L. B. J.
Med. Chem. 1998, 41, 1242.
(4) Tamm, I.; Seghal, P. B. Adv. Virus Res. 1978, 22, 187.
(5) Tamm, I. Science 1957, 126, 1235.
(6) Mann, J.; Baron, A.; Opoku-Boahen, Y.; Johansson, E.;
Parkinson, G.; Kelland, L. R.; Neidle, S. J. Med. Chem.
2001, 44, 138.
(7) (a) Bouwman, E.; Driessen, W. L.; Reedijk, J. Coord. Chem.
Rev. 1990, 104, 143. (b) Pujar, M. A.; Bharamgoudar, T. D.
Transition Met. Chem. 1988, 13, 423.
(8) (a) Bai, Y.; Lu, J.; Shi, Z.; Yang, B. Synlett 2001, 544.
(b) Hasegawa, E.; Yoneoka, A.; Suzuki, K.; Kato, T.;
Kitazume, T.; Yangi, K. Tetrahedron 1999, 55, 12957.
(9) Sazen, B.; Sames, D. Org. Lett. 2003, 5, 3607.
(10) Matsushita, H.; Lee, S. H.; Joung, M.; Clapham, B.; Janda,
K. D. Tetrahedron Lett. 2004, 45, 313.
IR (KBr): 3248, 1683, 1648, 1580, 1523, 1302 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 7.54 (m, 2 H), 7.75 (m, 3 H),
7.85 (m, 2 H), 8.3 (m, 2 H).
13C NMR (50 MHz, DMSO-d6): d = 114.2, 123.9, 125.7, 128.0,
129.8, 132.5, 133.0, 149.5.
4-(1H-Benzimidazol-2-yl)-N,N-dimethylaniline (Table 1, Entry
4)
Amorphous pale-yellow solid.
IR (KBr): 3380, 1618, 1590, 1484, 1456, 1420 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 3.1 (s, 3 H), 6.9 (d, J = 9.2 Hz,
2 H), 7.5 (m, 2 H), 7.2 (m, 2 H), 8.06 (d, J = 9.2 Hz, 2 H).
13C NMR (50 MHz, DMSO-d6): d = 39.5, 107.8, 111.8, 113.2,
125.1, 129.1, 131.5, 149.8, 153.2.
5-Methyl-2-phenyl-1H-benzimidazole (Table 1, Entry 11)
Amorphous pale-yellow solid.
IR (KBr): 3376, 1619, 1596, 1488, 1456, 1356, 1340 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.5 (s, 3 H), 7.4 (m, 1 H), 7.6
(s, 1 H), 7.75 (m, 4 H), 8.25 (m, 2 H).
13C NMR (50 MHz, DMSO-d6): d = 21.2, 113.4, 113.7, 123.5,
127.4, 127.8, 129.6, 130.3, 132.4, 133.0, 134.0, 148.7.
(11) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J.
A. Org. Lett. 2004, 6, 35.
5-Nitro-2-[4-(5-nitro-1H-benzimidazol-2-yl)phenyl]-1H-benz-
imidazole (Table 1, Entry 23)
Amorphous brown solid.
IR (KBr): 3250, 1630, 1513, 1342 cm–1.
1H NMR (200 MHz, DMSO-d6, TFA): d = 8.45 (s, 2 H), 8.2 (d, J =
8.4 Hz, 2 H), 8.1 (m, 2 H), 7.9 (m, 2 H), 7.7 (d, J = 8.4 Hz, 2 H).
(12) Pranjal, G.; Dilip, K. Tetrahedron Lett. 2006, 47, 79.
(13) Songnian, L.; Lihu, Y. Tetrahedron Lett. 2005, 46, 4315.
(14) Preston, P. N. Benzimidazoles, Congeneric Tricyclic
Compounds, In Chemistry of Heterocyclic Compounds, Part
1, Vol. 40; Weissberger, A.; Taylor, E. C., Eds.; Wiley: New
York, 1981, 6.
(15) Grimmet, M. R. Imidazoles and their Benzo Derivatives, In
Comprehensive Heterocyclic Chemistry, Vol. 5; Katritzky,
A. R.; Ress, C. W., Eds.; Pergamon: Oxford, 1984, 457.
(16) Wang, Y.; Sarris, K.; Sauer, D. R.; Djuric, S. W.
Tetrahedron Lett. 2006, 47, 4823.
13C NMR (50 MHz, DMSO-d6, TFA): d = 150.8, 111.4, 135.7,
122.1, 115.5, 146.5, 131.8, 122.6, 133.4, 134.6.
Acknowledgment
(17) Benincori, T.; Sannicolo, F. J. Heterocycl. Chem. 1998, 25,
1029.
(18) Daniel, R. B.; de Visser, S. P.; Shaik, S.; Neumann, R. J. Am.
Chem. Soc. 2003, 125, 12116.
We are thankful to the Razi University Research Council for partial
support of this work.
Synthesis 2007, No. 4, 547–550 © Thieme Stuttgart · New York