Efficient, rapid and one pot synthesis of 2-substituted benzimidazoles using the NaOH/I2 system as an oxidant under mild conditions

Article abstract of DOI:10.3184/174751913X13636014702351

A one-pot efficient synthesis of benzimidazole derivatives has been achieved from aryl aldehydes and o-phenylenediamine in the presence of the NaOH/I₂ system at room temperature in acetonitrile. The simplicity of the procedure and work-up, larg

Full text of DOI:10.3184/174751913X13636014702351

208 RESEARCH PAPER
APRIL, 208–209
JOURNAL OF CHEMICAL RESEARCH 2013
Efficient, rapid and one pot synthesis of 2-substituted benzimidazoles
using the NaOH/I2 system as an oxidant under mild conditions
Hossein Naeimi* and Nasrin Alishahi
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan 87317, Iran
A one-pot efficient synthesis of benzimidazole derivatives has been achieved from aryl aldehydes and o-phenylene-
diamine in the presence of the NaOH/I2 system at room temperature in acetonitrile. The simplicity of the procedure
and work-up, larger scale synthesis, high yields and short reaction times are the advantages of this method.
Keywords: o-phenylenediamine, benzimidazoles, aryl aldehydes, sodium hydroxide, iodine, acetonitrile
The benzimidazole scaffold is a useful structural motif for
displaying chemical functionality in biologically and pharma-
cologically active molecules. Optimisation of benzimidazole-
based structures has resulted in marketed medicines such as
Omeprazole1 and Pimobendan2 and lead compounds in a wide
range of therapeutic areas (e.g.,hepatitis C virus,3 casein kinas
2,4 factor Xa5). Medicinal chemists consider these heterocycles
privileged structures. Indeed, the development of new syn-
thetic methods, which could render accessible chemical space
currently not attainable by existing methods, would be of
considerable importance to the chemistry community.
Moreover, these fused heterocycles have been studied as
new non-nucleoside topoisomerase-I poisons, human immu-
nodeficiency virus-1 reverse transcriptase inhibitors, and/or
potent DNA gyrase inhibitors.6–8 They can act as ligands
to transition metals for modelling biological systems.9,10 In
addition, benzimidazoles are very important intermediates in
organic reactions.11,12
The most popular synthetic approaches generally include
the coupling of o-phenylenediamines and carboxylic acids or
various derivatives.13,14 Various catalysed syntheses of benz-
imidazole derivatives by condensation of o-phenylenediamine
with aldehydes in the presence of sodium hydrogen sulfite15
or oxone16 are known. Condensation of o-phenylenediamine
with orthoesters in the presence of various Lewis acid catalysts
are also known viz. ZrCl4, SnCl4.5H2O, TiCl4, BF3.Et2O,
ZrOCl2.8H2O and HfCl4.17,18 Phthalic acid attached to polyeth-
ylene glycol ether and polymer supported 4-fluoro-3-nitroben-
zoic acid in solid phase have been used as precursors for
2-substituted benzimidazoles.19,20 However, many of the syn-
thetic protocols reported so far suffer from disadvantages, such
as needing anhydrous conditions,21 harsh reaction conditions,
use of metals and expensive reagents,22 and prolonged reaction
times.23 Therefore, the development of a cost effective, safe
and inexpensive reagent system is desirable.
Firstly, in order to find the effect of solvent on this reaction,
several solvents including acetonitrile, dichloromethane, ace-
tone, and ethanol were investigated during the course of this
study. After screening different solvents, it was found that ace-
tonitrile was best (Table 1). A ratio of 5:2:1:1 of NaOH/I2/aryl
aldehyde/o-phenylendiamine was found to be optimum for the
reaction.
In order to ascertain of the limitation of this method, the
reaction of o-phenylenediamine with various aromatic alde-
hydes with the NaOH/I2 system under optimised conditions
in acetonitrile solvent were carried out. The results are
summarised in Table 2. In all entries, the benzimidazoles were
obtained as products in excellent yield after short reaction
times.
With regard to the mechanism of the oxidation step, the
reaction probably involves the formation of NaOI by the reac-
tion of sodium hydroxide with iodine which then reacts with
the initially formed hydrobenzimidazoles to afford intermedi-
ate 3 followed by the elimination of hydrogen iodide to yield
the corresponding benzimidazoles 2 (Scheme 2).
Table 1 Optimisation of solvent effect on the reactiona
Entry
Solvent
Time/min
Yield/%
1
2
3
4
Acetonitrile
Ethanol
33
58
45
60
93
39
32
28
Acetone
Dichloromethane
a Reaction of benzaldehyde with o-phenylenediamine in a vari-
ety of different solvents.
Table 2 Synthesis of 2-substituted benzimidazoles using
NaOH/I2
Results and discussion
Entry
Substrate
Producta Time/min Yield/%b M.p./°CRef.
We now report the results of our studies describing the devel-
opment of an efficient method for the synthesis of benzimid-
azoles in one step, whereby aryl aldehydes were condensed
with o-phenylenediamine using solid I2 and NaOH as an effi-
cient oxidant system in the presence of acetonitrile at room
temperature without the need for the preparation or isolation of
any intermediate agents (Scheme 1).
1
2
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
33
39
38
32
30
39
45
41
33
39
32
38
37
42
40
35
93
94
92
94
95
90
94
93
97
93
95
93
95
94
93
92
289–29024
200–20225
292–29325
290–29126
224–22627
231–23328
260–26128
238–24029
307–30930
254–25531
309–31032
293–29531
229–23031
197–19827
245–24727
212–21430
3-MeOC6H4
4-BrC6H4
3
4
4-ClC6H4
2,3-Cl2C6H3
2-ClC6H4
5
6
7
4-MeC6H4
2-HOC6H4
4-O2NC6H4
4-HOC6H4
3-O2NC6H4
4-Me2NC6H4
4-MeOC6H4
2,3-(MeO)2C6H3
3-HOC6H4
2-O2NC6H4
8
9
10
11
12
13
14
15
16
Scheme 1 Synthesis of 2-substituted benzimidazoles from
o-phenylenediamine and aryl aldehydes in the presence
NaOH/I2.
a All compounds are known and their physical and spectroscopic
data were in good agreement with those of authentic samples.
b Yields refer to pure isolated products.
* Correspondent. Email: naeimi@kashanu.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2013 209
ArH), 8.06 (2H, d, ArH, J = 8.0 Hz), 12.80 (1H, s, NH); 13C NMR
(DMSO-d6, 100 MHz) δ 21.4, 115.5, 122.4, 125.9, 127.9, 130, 139,
140.0, 151.9.
2-(4-Dimethylaminophenyl)benzimidazole (2l): Yellow solid; m.p.
293–295 °C (lit.31 294.2–296.3 °C); IR (KBr); νmax/cm−1; 3391 (NH),
1605 (C=N), 1518, 1459 (C = C, Ar); 1H NMR (DMSO-d6, 400 MHz)
δ 6.84 (2H, d, ArH, J = 7.8Hz), 7.43 (2H, m, ArH), 7.70 (2H, m, ArH),
8.21 (2H, d, ArH, J = 7.8 Hz), 15.20 (1H, s, NH); 13C NMR (DMSO-
d6, 100 MHz) δ 39.5, 107.8, 111.8, 113.2, 125.1, 129.1, 131.5, 149.8,
153.2.
Electronic Supplementary Information
IR and 1H NMR spectra of the compounds listed in Table 1 are
provided as electronic supplementary information available
through stl.publisher.ingentaconnect.com/content/stl/jcr/supp-
data.
Scheme 2 Proposed mechanism for synthesis of
2-substituted benzimidazole derivatives using the
NaOH/I2 system.
The authors are grateful to University of Kashan for support-
ing this work by Grant No. 159148/8.
The structure of the products has been confirmed by physi-
cal and spectroscopic data such as; IR, 1H NMR and 13C NMR.
In the 1H NMR spectra, the N-H proton has a chemical shift in
the range δ 7.10–15.20. The signals in the region δ 6.84–9.10
are assigned to the aromatic ring protons. In the 13C NMR
spectra, the benzimidazole C=N (C-2) carbon has a chemical
shift of 148.9–151 ppm.
Received 19 December 2012; accepted 11 February 2013
Paper 1201690 doi: 10.3184/174751913X13636014702351
Published online: 19 April 2013
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Experimental
All the materials were of commercial reagent grade. The aromatic
aldehydes, and o-phenylenediamine were purified by standard proce-
dures and their purity determined by TLC. IR spectra were recorded
as KBr pellets on a Perkin-Elmer 781 spectrophotometer and an
Impact 400 Nicolet FT-IR spectrophotometer. 1H NMR and 13C NMR
spectra were recorded for DMSO-d6 solutions on a Bruker DRX-400
spectrometer with tetramethylsilane as internal reference. Melting
points were obtained with a Yanagimoto micro melting point appara-
tus are uncorrected. The purity determination of the substrates
and reaction monitoring were accomplished by TLC on silica-gel
Polygram SILG/UV 254 plates.
Synthesis of benzimidazoles; general procedure
In a round-bottomed flask (50 mL) equipped with a magnetic stirrer,
a solution of o-phenylenediamine (1.0 mmol), and an aryl aldehyde
(1.0 mmol) in MeCN (4 mL) was prepared. NaOH (5.0 mmol) and
solid I2 (2.0 mmol) were added and the mixture was stirred at room
temperature for the time indicated in Table 1. The progress of the
reaction was monitored by TLC (eluent: ether–EtOAc, 7:3). When
the starting materials had completely disappeared, the mixture was
quenched with H2O (14 mL), extracted with CH2Cl2 (4 × 10 mL), and
the combined extracts were dried over MgSO4. The filtrate was evapo-
rated and the corresponding benzimidazole was obtained as the only
product (Table 1). Finally, the structure of the product was identified
and characterised by spectroscopic and physical data.
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Me) 7.18 (2H, m, ArH), 7.34 (2H, d, ArH, J = 8.0 Hz), 7.57 (2H, m,
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