One-pot sequential synthesis of 1,2-disubstituted benzimidazoles under metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2013.07.083

An easy and inexpensive method has been developed to access 1,2-disubstituted benzimidazoles following a one-pot sequential coupling/reduction/cyclization process under metal-free neutral conditions.

Full text of DOI:10.1016/j.tetlet.2013.07.083

Tetrahedron Letters 54 (2013) 5243–5245
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot sequential synthesis of 1,2-disubstituted benzimidazoles
under metal-free conditions
⇑
Priyabrata Roy, Animesh Pramanik
Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An easy and inexpensive method has been developed to access 1,2-disubstituted benzimidazoles follow-
ing a one-pot sequential coupling/reduction/cyclization process under metal-free neutral conditions.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 7 June 2013
Revised 11 July 2013
Accepted 12 July 2013
Available online 20 July 2013
Keywords:
Benzimidazole
1-Fluoro-2-nitrobenzene
Nucleophilic aromatic substitution
Sodium dithionite reduction
Cyclization
One-pot synthesis
Benzimidazole and its derivatives are a very important class of
compounds due to their pharmacological and biological activities.1
1,2-Disubstituted benzimidazoles represent an important branch
of this family. These structures are valuable bioactive structures
and have been reported as specific angiotensin II receptor type 1
selective antagonists,2 or hepatitis C virus NS5B polymerase inhib-
itors.3 Furthermore, they exhibit several other pharmacological
activities4 and have been used in antidiabetic, antihistamine, anal-
gesic, antiviral, antifungal, and antiparasitic applications.
Although a number of methods for the synthesis of 1- or 2-mon-
osubstituted benzimidazoles have been reported,5 the assembly of
1,2-disubstituted benzimidazoles still encounters challenges in
controlling regioisomeric selectivity, increasing efficiency, and
improving generality.6,7 Most of the methods toward 1,2-disubsti-
tuted benzimidazoles such as the condensation of carboxylic acids
with N-substituted 1,2-diaminoarenes and N-arylation/alkylation
reactions of 1H-benzimidazoles have often suffered from a limited
scope7g and led to a mixture of two regioisomers because of the
difficulty of differentiating the two N-atoms.6 Alternatively, the
palladium-,8 copper-,9 indium-,10 ruthenium-,11 and cobalt-5e,12
catalyzed intramolecular N-arylation starting from o-haloani-
lines/o-halonitrobenzene has been used. However, most of these
protocols involve multistep synthetic transformations and engage
a complex isolation process leading to a high cost and/or they
suffer from poor availability of starting materials. In some cases
the use of strong acid-catalyzed conditions also limits the func-
tional group tolerance. In addition, the employed metals are not
environmentally friendly and are not attractive for commercial
adoption due to a low catalyst activity and the generation of corro-
sive waste. These drawbacks prompted us to investigate a more
practical access to the 1,2-disubstituted benzimidazole scaffold.
Herein, we wish to describe a simple one-pot multicomponent
reaction sequence to access these ring systems under metal-free
neutral conditions (Scheme 1). The synthetic approach involves
(i) coupling of a primary amine 2 with 1-fluoro-2-nitrobenzene 1,
by nucleophilic aromatic substitution, (ii) reduction of the coupled
nitroarene 3 by sodium dithionite, and (iii) cyclization of the corre-
sponding diamine 4 using an aldehyde 5.
R1NH2(2)
DMSO, 130
NO2
F
NO2
°
C
NH
R1
1
3
Na2S2O4
DMSO, 130°C
R2CHO(5)
DMSO, 130
NH2
N
R2
°C
N
NH
R1
⇑
Corresponding author. Tel.: +91 33 24841647; fax: +91 33 23519755.
E-mail address: animesh_in2001@yahoo.co.in (A. Pramanik).
R1
6
4
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.083
Scheme 1. Strategy toward synthesis of 1,2-disubstituted benzimidazoles.

5244
P. Roy, A. Pramanik / Tetrahedron Letters 54 (2013) 5243–5245
To test the viability of the proposed pentannulation reaction,
another 1 h gave benzimidazole derivative 6a in only 41% yield
along with starting material 1 and 2a (Table 1, entry 1). A higher
yield of product 6a was obtained when the reaction was performed
at higher temperature using DMSO as the solvent (entry 2). Reac-
tion temperature and solvents were found to have dramatic effects
on the reaction, and DMSO was found to be the best solvent in our
study as the use of other solvents, for example DMF, CH3CN, DCM,
and toluene decreased the product yield (entries 3–7). The reaction
was carried out for 6 h and increase of reaction time did not im-
prove the product yield (entry 8). The yield of the product was con-
siderably lower in dilute solution (entry 9).
Having prepared benzimidazole 6a successfully, we decided to
explore the scope and generality of this reaction in the synthesis
of other analogues varying the substituent at N-1 and C-2. Accord-
ingly, a variety of commercially available primary amines 2 and
aldehydes 5 were reacted with 1-fluoro-2-nitrobenzene 1 (Table 2)
under the optimized conditions (Table 1, entry 2). As evident from
Table 2, all the primary amines and aldehydes participated well in
this substitution/reduction/cyclization reaction affording the de-
sired products in good yields. In case of entry e the corresponding
diamine intermediate 4e was isolated in 5% yield with desired
benzimidazole derivative 6e in 81% yield. All the structures of
the cyclized products were determined by a detailed study of the
spectroscopic data. Furthermore, the formation of products 6a
and 6k was unambiguously confirmed through X-ray crystallo-
graphic analysis (Figs. 1 and 2).
we first considered the coupling of 1-fluoro-2-nitrobenzene 1 with
p-chloroaniline 2a and p-dimethylaminobenzaldehyde 5a (Table 1).
Thus, exposure of amine 2a to 1-fluoro-2-nitrobenzene 1 in DMSO
at 90 °C for 2 h followed by treatment with p-dimethylaminobenz-
aldehyde and sodium dithionite at the same temperature for
Table 1
Optimization of reaction conditionsa
NH2
CHO
N
N
NO2
F
N
Na2S2O4
+
+
Cl
N
1
2a
5a
6a
Cl
Entry
Solvent
Timeb (h)
Concnc (M)
T (°C)
Yieldd (%)
1
2
3
4
5
6
7
8
9
DMSO
DMSO
DMF
DMF
CH3CN
DCM
Toluene
DMSO
DMSO
3
3
3
6
3
3
3
6
3
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
90
41
130
100
150
—
—
—
91e
13
19
4f
15f
Tracef
90
130
130
78
a
The reaction was carried out using a 1:1:1.2:1.5 ratio of 1-fluoro-2-nitroben-
zene–amine–aldehyde–sodium dithionite.
b
Typical reaction time (see the Supplementary data).
Concentration of 1-fluoro-2-nitrobenzene and amine in respective solvents.
Isolated yields.
For a representative procedure see, Ref. 13.
In conclusion, a straightforward, efficient, and more sustainable
metal-free one-pot sequential synthesis of 1,2-disubstituted benz-
imidazoles has been described. The protocol involves coupling of a
primary amine with 1-fluoro-2-nitrobenzene, reduction of the
c
d
e
f
Reactions were conducted at the reflux temperature.
Table 2
Synthesis of 1,2-disubstituted benzimidazoles 6a
NO2
N
Na2S2O4
DMSO, 130°C, 2 h
+
R2
R2CHO
+
R1NH2
N
F
R1
1
2
5
81-92%
6
Entry
R1
R2
Product
Yieldb (%)
Mp (°C)
Ref. Mp (°C)
a
b
c
d
e
f
Cl
Cl
N
6a
6b
6c
6d
6e
6f
91
87
89
90
81
87
164–166
144–145
118–120
>300
–
–
O
Cl
Cl
Cl
119–12012
HO
O
–
–
–
169–170
166–168
F
F
g
6g
6h
85
88
100–101
124–125
–
h
123–1247c
Br
i
6i
92
85
85
91
90
132–133
119–121
160–162
92–94
130–1317c
j
F
6j
–
NC
k
l
6k
6l
–
95–9714
–
m
O
F
6m
118–120
O
n
o
6n
6o
85
87
189–190
110–112
–
NH2
109–11012
a
The reaction was carried out using a 1:1:1.2:1.5 ratio of 1-fluoro-2-nitrobenzene–amine–ldehyde–sodium dithionite. Reaction time was typically 3 h (see the Supple-
mentary data).
b
Isolated yields.

P. Roy, A. Pramanik / Tetrahedron Letters 54 (2013) 5243–5245
5245
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coupled nitroarene by sodium dithionite, and cyclization of the
corresponding diamine using an aldehyde.
13. Representative procedure. Synthesis of benzimidazole derivative 6a: A mixture
of 1-fluoro-2-nitrobenzene
1 (141 mg, 1.0 mmol) and p-chloroaniline 2a
Acknowledgments
(127 mg, 1.0 mmol) in DMSO (2 mL) was stirred for 2 h at 130 °C
temperature. Sodium dithionite (261 mg, 1.5 mmol) and p-dimethyl amino
benzaldehyde 5a (179 mg, 1.2 mmol) were then added and heating was
continued for 1 h. Water (10 mL) was added to the mixture and extracted with
EtOAc (3 Â 15 mL). The combined organic layer was washed with brine (5 mL)
and dried over anhydrous Na2SO4. The solvent was removed on rotary
evaporator and the residue was purified by column chromatography (silica
gel, ethylacetate/petroleum ether,1:2) to yield the benzimidazole derivative 6a
(316 mg, 91%) as a white solid. Mp: 164–166 °C; IR (KBr, cmÀ1): 1610; 1H NMR
(300 MHz, CDCl3): d 7.85 (dd, 1H, J = 7.8, 0.6 Hz), 7.47 (ddd, 4H, J = 15.3, 8.4,
1.2 Hz), 7.35–7.13 (m, 5H), 6.62 (d, 2H, J = 7.8 Hz), 3.00 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 152.7, 150.5, 142.5, 136.5, 135.6, 133.7, 130.1, 129.6, 128.4,
122.5, 122.3, 118.8, 116.0, 111.0, 109.3, 39.6; Anal. Calcd for C21H18ClN3: C,
72.51; H, 5.22; N, 12.08. Found: C, 72.37; H, 5.14; N, 12.01.
P.R. thanks the University Grants Commission (UGC), New Del-
hi, India for the award of Dr. D.S. Kothari Postdoctoral Fellowship
[No.F.4-2/2006(BSR)/13-755/2012(BSR)].
Supplementary data
Supplementary data (detailed experimental procedures and
spectral data (IR, 1H, 13C) for all new compounds (PDF) and X-ray
structural data of 6a and 6k (CCDC 939808 and CCDC 939807))
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2013.07.083.
9
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