A clean method for the synthesis of 1,2-disubstituted benzimidazoles through a redox reaction of o-phenylenediamine and aldehydes

Article abstract of DOI:10.3184/174751912X13263910827245

The reactions of o-phenylenediamine with aromatic aldehydes gave 1,2-disubstituted benzimidazoles in good to excellent yields under mild reaction conditions by using water as the reaction medium in the presence of 20 mol% FeCl₃.

Full text of DOI:10.3184/174751912X13263910827245

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 61
FEBRUARY, 61–62
A clean method for the synthesis of 1,2-disubstituted benzimidazoles
through a redox reaction of o-phenylenediamine and aldehydes
Yunyun Liua* and Chunping Wanga
aCollege of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. China
The reactions of o-phenylenediamine with aromatic aldehydes gave 1,2-disubstituted benzimidazoles in good to excel-
lent yields under mild reaction conditions by using water as the reaction medium in the presence of 20 mol% FeCl3.
Keywords: benzimidazole, redox, green synthesis, iron(III) chloride, chemo-selective
Benzimidazoles have been shown to possess a range of
biological activities1 and have been used as lead compounds,2,3
pharmaceuticals,4 dyes5 as well as in material precursors.6
Thus, it is not surprising that the benzimidazole backbone has
been an important synthetic target. Among the known syn-
thetic procedures affording benzimidazoles, the condensation
reaction between o-phenylenediamine and carboxylic acids is
one of the earliest. However, a serious limitation of this method
is the harsh condition needed for the transformation.7 Numer-
ous efforts have been made to develop alternative routes
for benzimidazole synthesis. The synthesis using tandem
reactions initiated by C–N coupling reactions, is one widely
employed methodology.8 Despite the various approaches
available for benzimidazole synthesis, the reaction between
o-phenylenediamine and aldehyde furnishing 1,2-disubstituted
benzimidazoles 3 is the most straightforward and it possesses
the unique feature of high atom economy as a redox process is
involved as key transformation (Scheme 1).9,10 Even though the
formation of 2-substituted imidazoles 4 is possible, this chemo-
selective synthesis affording 3 has been efficiently performed
using a variety of different catalytic conditions.11–14 More inter-
estingly, it has been found that excellent chemo-selectivity in
this reaction could be achieved in an aqueous medium.15 Highly
useful as the water mediated organic transformations are,
developing new synthetic protocols catalysed by cheap and
abundant catalysts is equally important in terms of reducing
the environmental impact of chemistry.
Results and discussion
Initially, the reaction of o-phenylenediamine 1 and benzalde-
hyde 2a was selected as model reaction to optimise the reac-
tion conditions. As we wished to examine the catalyst activity
of iron on the reaction, we used the easily available FeCl3 as
a candidate catalyst and performed the model reaction with a
30 mol% catalyst loading. However, only a trace amount of
product was observed when the reaction was carried out at
room temperature (entry 1, Table 1). In further attempts, when
the reaction was heated at 80 °C, we were pleased to obtain an
excellent yield of 3a (entry 2, Table 1). Short experiments on
examining the effect of temperature and catalyst loading on the
reaction were then carried out. As indicated by the results in
entries 3–7 in Table 1, 60 °C and 20 mol% catalyst was found
to be the best conditions for the reaction.
On the basis of these optimisation experiments, the scope of
this clean catalyst system has been investigated by subjecting
various aryl aldehydes to reaction with o-phenylenediamine
under the standard conditions. As expected, this catalytic
system tolerated a broad range of aromatic aldehydes to fur-
nish the corresponding benzimidazoles 3 (Table 2). Aldehydes
possessing both electron donating and electron withdrawing
groups in the para- position gave good to excellent yields of
products with no evident effect caused by the electronic prop-
erties of the substituents (entries 1–7, Table). The reactions
using meta- or ortho- substituted benzaldehydes were found to
afford corresponding products with slightly lower yields,
which implied a possible influence of steric hindrance (entries
8–11, Table 2). Attempts to use an aliphatic aldehyde such as
propaldehyde were not successful under the present condi-
tions. The structures of all products from this section have
As one of the most typical metal species, iron catalysts have
recently been of interest due to their neutral abundance of iron,
its nontoxicity and easy recycling.16,17 To the best of our knowl-
edge, there is no report on the iron-catalysed redox reactions
between o-phenylenediamines and aldehydes providing
1,2-disubstituted benzimidazoles. We report here our results
on the FeCl3-catalysed, water mediated selective synthesis of
1,2-disubstituted benzimidazoles 3.
1
been unambiguously confirmed by comparing their H NMR
data with literature.
Scheme 1 Synthesis of benzimidazoles through redox process.
* Correspondent. E-mail: chemliuyunyun@gmail.com

62 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Examination on reaction conditionsa
Experimental
All chemicals were obtained from commercial sources and used with-
out further purification. Tap water was used as a reaction medium in
1
the experiments. H NMR were recorded in Bruker AVANCE II-400
MHz apparatus with CDCl3 as solvent (TMS as internal standard).
Melting points were determined using a X4-apparatus and were
uncorrected.
Synthesis of 1,2-disubstituted benzimidazoles in water; general
procedure
Entry
Temp./°C
Catalyst/%
Yield/%b
o-Phenylenediamine 1 (0.5 mmol) and water (2 mL) were placed in
a round bottomed flask equipped with condenser. The aldehyde
(1 mmol) and 20 mol% iron (III) chloride were then added with
stirring. The mixture was heated at 60 °C until starting materials were
fully consumed (TLC). The mixture was then extracted with ethyl
acetate (3 × 10 mL) and the combined organic phases were dried
over anhydrous Na2SO4. After removing the solvent, the residue was
subjected to silica gel chromatography to give pure benzimidazole
products.
1
2
3
4
5
6
7
RT
80
70
60
50
60
60
30
30
30
30
30
20
10
Trace
84
81
83
75
86
67
a All reaction were carried out in 0.5 mmol scale of diamine
(1 mmol aldehyde).
b Isolated yield.
The work is financially supported by a Doctoral Start-up
program from Jiangxi Normal Unversity.
Table 2 Synthesis of different benzimidazoles in watera
Received 29 December 2011; accepted 8 January 2012
Paper 1101069 doi: 10.3184/174751912X13263910827245
Published online: 23 February 2012
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In conclusion, a water mediated, iron-catalysed synthesis of
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