Catalyst-free one-pot synthesis of benzimidazoles from 1,2-diaminoarenes and alcohols

Article abstract of DOI:10.1016/j.tetlet.2014.09.081

A new and efficient protocol is described for the one-pot synthesis of benzimidazoles from a variety of aryl alcohols and 1,2-diaminoarenes. The yields were ranging from moderate to excellent. Moreover, the present method is utilizing alcohols instead of aldehydes and the reactions are carried out under solvent- and catalyst-free conditions, offering an environmentally benign process.

Full text of DOI:10.1016/j.tetlet.2014.09.081

Accepted Manuscript
Catalyst-free one-pot synthesis of benzimidazoles from 1,2-diaminoarenes and
alcohols
Mahender Reddy Marri, Swamy Peraka, Arun Kumar Macharla, Naresh
Mameda, Srujana Kodumuri, Narender Nama
PII:
S0040-4039(14)01596-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.09.081
TETL 45175
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 August 2014
16 September 2014
16 September 2014
Please cite this article as: Marri, M.R., Peraka, S., Macharla, A.K., Mameda, N., Kodumuri, S., Nama, N., Catalyst-
free one-pot synthesis of benzimidazoles from 1,2-diaminoarenes and alcohols, Tetrahedron Letters (2014), doi:
http://dx.doi.org/10.1016/j.tetlet.2014.09.081
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Graphical Abstract
Catalyst-free one-pot synthesis of
benzimidazoles from 1,2-diaminoarenes and
alcohols
Leave this area blank for abstract info.
Mahender Reddy Marri, Swamy Peraka, Arun Kumar Macharla, Naresh Mameda, Srujana Kodumuri, Narender
Nama

1
Tetrahedron Letters
journal homepage: www.els evier.com
Catalyst-free one-pot synthesis of benzimidazoles from 1,2-diaminoarenes and
alcohols
Mahender Reddy Marri, Swamy Peraka, Arun Kumar Macharla, Naresh Mameda, Srujana Kodumuri,
Narender Nama∗
I&PC Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A new and efficient protocol is described for the one-pot synthesis of benzimidazoles from a
variety of aryl alcohols and 1,2-diaminoarenes. The yields ranging from moderate to excellent.
Moreover, the present method is utilizing alcohols instead of aldehydes and the reactions are
carried out under solvent- and catalyst-free conditions, offering an environmentally benign
process.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Aryl alcohols
Amines
Benzimidazoles
Environmentally-benign
Atom economy
The development of new strategies that present high synthetic
efficiency and atom economy has been an important task for
synthetic organic chemists. Tandem reactions are good
candidates for this target and are a rapidly growing area.1
Tandem reactions complete several chemical transformations in a
single step and offer a powerful approach for rapidly increasing
molecular complexity from simple starting materials. The main
advantages of tandem reactions are reduction of overall steps by
avoiding isolation of often highly reactive intermediates,
minimization of waste compared to stepwise reactions, the
amount of solvents, reagents, adsorbents and energy can be
dramatically decreased.
unstable aldehydes as reactants. Recently, Nguyen et al.8 reported
the formation of benzimidazoles from amines and 1,2-
diaminoarenes under oxidative conditions.
An alternative environmentally-benign approach to the
synthesis of benzimidazole is a one-pot multi-step process using
inexpensive and readily available alcohols and 1,2-diaminoarenes
as starting materials. Until now, many transitional metal
complexes/salts/supported catalysts such as, iron,9 ruthenium,10
platinum-titanium,11 manganese12 and aurum-cerium13 have been
reported for the synthesis of benzimidazoles from alcohols. A
couple of transition metal-free14 (I2 and IBX mediated) protocols
have also been reported using alcohols. However, many of these
methods have several limitations such as low yields, tedious
work-up procedures, use of expensive catalysts and reagents.
Benzazoles, such as benzimidazoles are studied as privileged
motifs in the field of medicinal chemistry.2 Benzimidazole
derivatives have been found to possess enormous therapeutic
applications including antiviral, antihypertensive, antiulcer,
antifungal, antihistaminic, anticancer activities3 and are also very
useful intermediates in organic synthesis.4 Moreover,
benzimidazole derivatives exhibit significant activity against
several viruses such as HIV, herpes (HSV-1) and influenza.5 Due
to their interesting properties and applications, various synthetic
methods have been developed for the synthesis of
benzimidazoles. Among these methods, the most common
method being the heterocyclization of 1,2-diaminoarenes with
carboxylic acids or their derivatives,6 which requires strong
acidic conditions and sometimes combines high temperatures or
use of microwave. The other method is condensation of 1,2-
diaminoarenes and aldehydes followed by oxidation to give
Today the world is facing major problems from global
pollution. To overcome this issue, chemical waste should be
reduced. This would be especially significant on the industrial
scale. In this context, metal-free reactions appear to be greatly
desirable to maximize atom-economy and to avoid chemical
waste. Herein, we report a novel straightforward method for the
preparation of benzimidazoles from aryl alcohols and 1,2-
diaminoarenes without employing any oxidant/catalyst.
Initially, we studied the reaction of 1,2-phenylenediamine (1
equiv.) with benzyl alcohol (1.5 equiv.) as a model reaction to
optimize the best reaction conditions (Table 1). The reaction was
remarkably accelerated by varying the reaction temperature from
100 to 135 °C (Table 1, entries 1-4) and yield gradually improved
benzimidazoles.7 This process needs oxidizing agents and
———
∗ Corresponding author. Tel.: (+91)–40-27191703; fax: +(+91)-40-27160387/27160757; e-mail: narendern33@yahoo.co.in

2
Tetrahedron
N
Table 1
Optimization of reaction conditions for the synthesis of
benzimidazolea
OH
Bu-t
N
H
5
6
76
74
61
81
60
71
72
82
91
89
85
t-Bu
N
OH
OMe
N
H
MeO
N
OH
Yieldb (%)
OMe
7
Entry
Temperature (°C)
Time (h)
N
H
MeO
1
2
100
110
120
135
135
24
24
24
24
24
31
39
55
78
61
N
OH
8
N
H
Br
Br
3
N
OH
Br
9
4
N
H
Br
5c
N
OH
a
10
11
12
13
14
N
H
Reaction conditions: Benzyl alcohol (3 mmol), 1,2-
Phenylenediamine (2 mmol), open atmosphere.
Cl
Cl
N
OH
b
Products were characterized by NMR, Mass spectra and
isolated yields calculated based on 1,2-Phenylenediamine.
c Benzyl alcohol (2 mmol), 1,2-Phenylenediamine (2 mmol).
N
H
Cl
Cl
N
Cl
OH
N
H
Cl
from 31 to 78%. The effect of mole ratio of amine to alcohol was
then investigated at 135 °C. When decreasing the mole ratio of
amine to alcohol (1:1.5 to 1:1.0), the yield of the desired product
was decreased from 78% to 61% (Table 1, entries 4 and 5). The
above results revealed that 1:1.5 mole ratio of 1,2-
phenylenediamine and benzyl alcohol at 135 °C showed to be the
optimum reaction conditions for synthesis of 2-phenyl-1H-
benzimidazole (Table 1, entry 4).
N
OH
F
N
H
F
F
F
N
OH
N
H
CF3
CF3
N
OH
N
H
15c
16c
17d
18d
19d
CF3
CF3
N
OH
CF3
78
78
91
55
N
H
CF3
N
OH
N
H
Scheme 1. Synthesis of benzimidazoles from 1,2-
diaminoarenes and alcohols.
NO2
NO2
N
NO2
Under the optimized conditions, next we explored the scope
and generality of the reaction with various combinations of
substrates (aryl alcohols and 1,2-diaminoarenes) and results are
summarized in Table 2 and 3 (Scheme 1). As shown in Table 2,
various aryl alcohols successfully reacted with 1,2-
phenylenediamine to afford moderate to excellent yields of the
corresponding benzimidazoles.
OH
N
H
O2N
N
OH
OH
N
H
OH
OH
N
20d
21
70
89
−
Table 2
Synthesis of benzimidazole derivatives from aryl alcohols and
1,2-phenylenediaminea
N
H
N
OH
N
N
H
N
N
OH
22
N
H
N
OH
Entry
Alcohol
Product
Yieldb (%)
4
N
H
23
24
−
−
4
N
OH
N
OH
Ph
1
2
3
4
78
82
72
71
Ph
N
H
N
H
a
N
Reaction conditions: Alcohol (3 mmol), 1,2-
Phenylenediamine (2 mmol), 135 °C, 24 h, open atmosphere.
OH
OH
N
H
Me
Me
b
Products were characterized by NMR, Mass spectra and
isolated yields calculated based on 1,2-Phenylenediamine.
N
N
H
Me
c 12 h.
Me
N
OH
Me
d Reaction temperature 150 °C.
N
H
Me

3
(Table 2, entries 17 and 18) under slightly higher temperature
(150 °C). Moreover, 1,2-benzenedimethanol and polyaromatic
alcohol i.e. 1-naphthalenemethanol reacted with 1,2-
phenylenediamine to give the respective benzimidazoles
selectively in 55% and 70% yields, respectively, at higher
temperature (150 °C) (Table 2, entries 19 and 20). Also, the
reaction with 2-pyridinemethanol did not reduce the yield of the
corresponding product (Table 2, entry 21). However, the reaction
of 2-phenylethylalcohol and aliphatic alcohols with 1,2-
phenylenediamine was not quite successful (Table 2, entries 22-
24). This method can be well tolerated by many valuable
functional groups such as methyl, methoxy, bromo, chloro,
fluoro, trifluoromethyl and nitro groups in the present reaction
conditions.
In order to determine the influence of substitution on the
aromatic ring of benzyl alcohol on the reaction path we carried
out the reaction of different substituted benzyl alcohols with 1,2-
phenylenediamine under optimized conditions. It was noticed
that there is not much difference in reactivity between the
electron-donating and electron-withdrawing groups and the
reaction proceeded well to give the corresponding products in
moderate to excellent yields (Table 2, entries 2-18). The position
of substitution on the phenyl ring of benzyl alcohol affects the
reaction yield. Interestingly, methyl (Table 2, entries 2 and 4),
methoxy (Table 2, entries 6 and 7), bromo (Table 2, entries 8 and
9) and trifluoromethyl (Table 2, entries 14 and 16) groups at
ortho position furnished higher yield compared to para position.
To further examine the scope of this reaction, various
substituted 1,2-diaminoarenes were employed to react with
benzyl alcohol under the optimized conditions to provide the
corresponding benzimidazole products in moderate to excellent
yields (Table 3). 1,2-Phenylenediamine bearing electron-donating
groups were successfully converted into the respective
benzimidazole derivatives in excellent yields (Table 3, entries 1
and 2). However, strongly electron-withdrawing groups such as
cyano and nitro groups present on 1,2-phenylenediamine yielded
the respective benzimidazole derivatives in 58% and 71% yields,
respectively (Table 3, entries 3 and 4) at 150 °C. It is noteworthy
that, 1,2-diaminoanthraquinone furnished the corresponding
benzimidazole in 83% yield (Table 3, entry 5) at 150 °C, which is
used as colorimetric and ratiometric fluorescent chemosensors for
fluoride.15 The heterocyclic 1,2-diamines such as 2,3-
diaminopyridine and 3,4-diaminopyridine were also shown to be
effective (at 150 °C) in this reaction conditions and afforded
corresponding benzimidazole derivatives in 70% and 88% yields,
respectively (Table 3, entries 6 and 7). Unfortunately, 2-
aminophenol, 2-aminothiophenol and 1,2-diaminocyclohexane
failed to give any product under similar conditions (Table 3,
entries 8-10).
Table 3
Synthesis of benzimidazole derivatives from different 1,2-
diaminoarenes and benzyl alcohola
Entry
1,2-Diaminoarene
Product
Yieldb (%)
Me
Me
NH2
N
1c
2
75
73
58
71
Ph
N
H
NH2
Me
NH2
Me
N
Ph
N
H
NH2
NC
NH2
NH2
NC
3d
N
Ph
N
H
4d
O2
N
NH2
NH2
O2
N
N
Ph
N
H
Ph
O
NH2
O
HN
5d
83
NH
N
2
O
O
NH2
NH2
N
6d
70
88
Ph
N
N
H
N
Ph
N
NH
2
HN
7d
NH2
N
N
N
NH2
Ph
−
−
−
8
N
H
Scheme 2. Plausible reaction mechanism for the synthesis of
benzimidazole.
NH2
NH2
N
Ph
Ph
To obtain an insight into the reaction mechanism for the
formation of benzimidazoles from 1,2-diaminoarenes and aryl
alcohols, a couple of experiments were carried out using our
standard reaction conditions. The reaction of benzyl alcohol with
1,2-phenylenediamine under inert atmosphere also provided the
respective benzimidazole in excellent yield. To confirm the N-
benzylated product A as an intermediate, we performed the
reaction with A in benzyl alcohol at 135 °C to give the
corresponding benzimidazole. Based on above experimental
observations, we propose a possible reaction mechanism for the
formation of benzimidazoles from amines and alcohols are
illustrated in Scheme 2.
O
N
9
OH
NH2
10
S
SH
a
Reaction conditions: Benzyl alcohol (3 mmol), 1,2-
Diaminoarene (2 mmol), 135 °C, 24 h, open atmosphere.
b
Products were characterized by NMR, Mass spectra and
isolated yields calculated based on 1,2-Diaminoarene.
c mixture of tautomers.
d Reaction temperature 150 °C.
It is assumed that, the reaction of amine with benzyl alcohol
gave the corresponding N-benzylated product A. This then
dehydrogenated to imine B, which remain in equilibrium with the
However chloro group at ortho position provided lesser yield
than para position (Table 2, entries 10 and 12). Notably, the
reaction was also effective with nitro substituted benzyl alcohols

4
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using catalyst or additive under solvent-free conditions. Notable
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Acknowledgments
We thank the CSIR Network project CSC-0123 for financial
support. M.M.R, M.A.K and M.N acknowledge the financial
support from CSIR, India in the form of fellowship. P.S and K.S
acknowledge the financial support from UGC, India in the form
of fellowship.
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Supplementary data
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at
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