Synthesis of 2-arylbenzimidazoles in water

Article abstract of DOI:10.1080/00397911003642682

A simple and efficient procedure for the synthesis of 2-arylbenzimidazoles through a one-pot condensation of o-phenylenediamines with aryl aldehydes in water is described. Short reaction time, large-scale synthesis, easy and quick isolation of the product

Full text of DOI:10.1080/00397911003642682

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Synthesis of 2-Arylbenzimidazoles in
Water
Siva S. Panda a & Subhash C. Jain a
a Department of Chemistry, University of Delhi, Delhi, India
Version of record first published: 31 Jan 2011
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Synthetic Communications1, 41: 729–735, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003642682
SYNTHESIS OF 2-ARYLBENZIMIDAZOLES IN WATER
Siva S. Panda and Subhash C. Jain
Department of Chemistry, University of Delhi, Delhi, India
Abstract A simple and efficient procedure for the synthesis of 2-arylbenzimidazoles through
a one-pot condensation of o-phenylenediamines with aryl aldehydes in water is described.
Short reaction time, large-scale synthesis, easy and quick isolation of the product, and
excellent yield are the main advantages of this procedure.
Keywords Benzimidazoles; excellent yields; green chemistry; o-phenylenediamine
INTRODUCTION
Benzimidazole is an important pharmacophore in modern drug discovery.[1]
Benzimidazole derivatives exhibit significant activity against several viruses such as
HIV,[2] herpes (HSV-1),[3] RNA,[4] influenza,[5] and human cytomegalovirus
(HCMV).[2a] Bis-benzimidazoles are being developed as DNA minor-groove binding
agents with antitumor activity[6] and can act as ligands to transition metals for mod-
eling biological systems.[7] In addition, benzimidazoles are also important intermedi-
ates in organic synthesis, which is why benzimidazoles have gained considerable
attention in recent years. Despite their importance, from pharmacological, indus-
trial, and synthetic points of view, unfortunately very few methods have been
reported for their preparation.
One such method involves coupling o-phenylenediamines and carboxylic
acids or their derivatives (nitriles, imidates, or orthoesters) using strong acids such
as polyphosphoric acid[8] or mineral acids[9] or high-temperature microwave
irradiation.[10] Another method involves a two-step procedure involving oxidative
cyclodehydrogenation of Schiff bases, which are often generated from the
Received October 6, 2009.
Address correspondence to Subhash C. Jain, Department of Chemistry, University of Delhi, Delhi,
India. E-mail: jainsc48@hotmail.com
729

730
S. S. PANDA AND S. C. JAIN
condensation of o-phenylenediamines and aldehydes. Various oxidative and catalytic
reagents such as sulfamic acid,[11] I2,[12] 2,3-dichloro-5,6-dicyanobenzoquinine
(DDQ),[13] In(OTf)3,[14] and Sc(OTf)3 have been employed. Because of the avail-
[15]
ability of a vast number of aldehydes, condensation of o-phenylenediamines and
aldehydes has been extensively used. Though these published methods are effective,
they suffer from one or more disadvantages such as (a) poor yields, (b) use of expens-
ive reagents, (c) multistage synthesis, (d) long reaction times, (e) tedious workup pro-
cedures, and (f) occurrence of several side reactions.
As a consequence, introduction of new methods and=or further work on tech-
nical improvements of procedures to overcome these limitations is still an important
experimental challenge.
Legislation to maintain environmental friendliness requires us to prevent the
generation of waste, avoid use of auxiliary substances (e.g., organic solvents,
additional reagent), and minimize the energy requirement in the development of
new procedures for the reaction.
Water is safe, nontoxic, environmentally friendly, and cheap. It has been
employed as a solvent in the past for the formation of CꢀS,[16] CꢀN,[17] and
CꢀC[18] bonds without using any catalyst. This inspired us to focus on the aspect
of ‘‘on water’’ heterocycle synthesis. In this communication, we present a highly
selective and efficient method for the synthesis of 2-arylbenzimidazole in water
without using any catalyst.
RESULTS AND DISCUSSION
We report herein an efficient synthesis of 2-arylbenzimidazoles in water in
the absence of any acid or base catalyst. The reaction of aryl aldehydes with
o-phenylenediamine afforded benzimidazoles in excellent yields (Table 1).
The effect of solvent was studied by reacting o-pehenylenediamine and
4-methoxybenzaldehyde in an equimolar ratio in different solvents at different tem-
perature as shown in Table 2. The yield of the product varied with the nature of the
solvent. From the table, it is clear that water stands out as the solvent of choice,
because it is nontoxic and results in good yield when the reaction is carried out
for the same time. Comparable results were obtained when a similar reaction was
carried out either in tap or distilled water, thereby saving the energy and effort
required to make distilled water.
The plausible mechanism for the formation of benzimidazole in such a reaction
is depicted in Schemes 1 and 2. Water plausibly exhibits ambiphilic dual activation
catalysis[19] by cooperative formation of hydrogen bonds with the carbonyl oxygen
and the hydrogen of the amine group of o-pehenylenediamine (TS-1), followed by
cyclocondensation to form benzimidazoline (path a), which, on dehydrogenation,
is converted into benzimidazole so that the heterocyclic moiety retains its aromatic
character. The conjugation effect of the 2-aryl group with the imine bond may also
play a significant role in the conversion of imidazoline to imidazole. The dissolved
oxygen in water may act as a hydrogen acceptor to facilitate the dehydrogenation,
corroborated by the faster rate of formation of imidazole by bubbling oxygen gas
into the reaction mixture. The role of the oxygen was also confirmed by carrying
out the reaction in degassed water.

SYNTHESIS OF 2-ARYLBENZIMIDAZOLES
731
Table 1. Condensation reaction of o-phenylenediamine (1.0 mmol) with different aldehydes (1.0 mmol)
using water as a solvent
Compound 3
Aldehyde
Time (h)
Yieldsa (%)
Melting pointsb
3a
3b
3c
3d
3e
3f
C6H5CHO
4-F C6H4CHO
2.0
2.5
2.0
2.0
3.0
2.0
2.5
3.0
3.5
2.0
2.0
2.5
3.0
3.0
3.5
4.5
4.0
85
92
90
94
98
96
92
94
91
95
96
98
94
96
92
88
84
295[14,20]
248[21]
4-Cl C6H4CHO
4-Br C6H4CHO
302[14,18,20]
300[21]
4-NO2 C6H4CHO
4-Me C6H4CHO
317[20]
275[20,14]
280[22]
3g
3h
3i
4-OH C6H4CHO
2-OH C6H4CHO
242[24]
3,4-DiOH C6H3CHO
4-MeO C6H4CHO
258[23]
3j
228[14,20]
231[24]
3k
3l
3,4-DiMeO C6H3CHO
3,4,5-TriMeO C6H2CHO
3-MeO-4-OH C6H3CHO
4-MeO-3-OH C6H3CHO
Indole-3-carboxaldehyde
Thiophene-2-carboxaldehyde
Furan-2-carboxaldehyde
259[24]
3m
3n
3o
3p
3q
220[24]
224[24]
221[25]
330[14]
296[20]
aIsolated product.
bResulting 2-arylbenzimidazole.
Table 2. Condensation reaction of o-phenylenediamine (1.0 mmol) with
4-methyl benzaldehyde (1.0 mmol) using different solvents
Entry
Solvent
Conditionsa
Yieldb (%)
1
2
3
4
5
6
7
CH2Cl2
THF
reflux
reflux
reflux
reflux
100 ꢁC
100 ꢁC
100 ꢁC
19
38
40
55
50
48
96
CH3OH
C2H5OH
DMSO
DMF
H2O
aReaction time 2 h.
bIsolated product.
Scheme 1. Condensation reaction of o-phenylaminediamine with aryl aldehyde in water.

732
S. S. PANDA AND S. C. JAIN
Scheme 2. Plausible mechanism for the formation of 2-arylbenzimidazole.
The faster rate of reaction in water as compared to the other solvents indicates
that water plays a specific role (probably through the TS-1) in promoting the con-
densation of o-pehenylenediamine with the aldehyde. The alternate path (part b),
involving formation of the imine followed by intramolecular nucleophilic attack
by the NH2 group and dehydrogenation of the resulting benzimidazoline, is also
suggested.
To test the general scope and versatility of this procedure, we repeated the
reaction with a number of different substituted arylaldehydes. We report here the
formation of benzimidazole in each case in good yields. The results are summarized
in Table 1. It clearly showed that aryl aldehydes bearing both electron-donating
and electron-withdrawing substituents gave the desired benzimidazoles in good
yields.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker Avance (400-MHz) spectrometer
using tetramethylsilane (TMS) as an internal standard and dimethylsulfoxide
(DMSO-d6) as a solvent. Turnover frequency (TOF) mass spectra (m=z) were
recorded on a Micromass Autospec LCTKC455. Fourier transform–infrared (FTIR)
spectra were determined on a Perkin-Elmer 2000 spectrophotometer. Thin-layer
chromatography (TLC) was done on GF254 plates using chloroform=methanol as
the developing solvent. Aldehydes and o-phenylenediamine were all commercial
products and procured from CDH, Spectrochem, Merck, and SRL and were used
without further purification. Melting points were determined on an electronic appar-
atus and are uncorrected.

SYNTHESIS OF 2-ARYLBENZIMIDAZOLES
733
Typical Procedure for the Synthesis of 2-Arylbenzimidazole
The magnetically stirred mixture of o-phenylenediamine (1 mmol) and alde-
hyde (1 mmol) in water (10 ml) was heated at 100 ꢁC in an oil bath. The progress
of the reaction was monitored by TLC. After completion of the reaction, the con-
tents were cooled to room temperature, the solvent was decanted, and the residue
was extracted with diethyl ether. The organic layer was dried over anhydrous
Na2SO4 and filtered, and the residue was purified by a silica-gel column. Elutions
with hexane–EtOAc (90:10) gave the desired product.
1
All products were characterized by H NMR, mass, and IR spectral data and
also by comparing their melting points with those from the literature. Selected char-
acterization data for some bezimidazoles prepared by this method are given.
Selected Data
2-(4-Fluorophenyl)-1H-1,3-benzimidazole (3b). White crystalline solid; mp
248 ꢁC. IR (KBr) 3052, 1602, 1498, 1435, 1228, 837, 746 cmꢀ1. 1H NMR (DMSO-d6,
400 MHz) d (ppm): 12.94 (s, 1H, D2O exchangable), 8.23 (d, 2H, J ¼ 8.2 Hz), 7.65
(m, 2H), 7.39 (d, 2H, J ¼ 8.2 Hz), 7.19 (m, 2H). Mass m=z (TOF): 213 (Mþ þ 1).
2-(4-Methylphenyl)-1H-1,3-benzimidazole (3f). Light yellow solid; mp
275 ꢁC. IR (KBr) 3052, 1618, 1500, 1447, 1274, 821, 745 cmꢀ1. 1H NMR (DMSO-d6,
400 MHz) d (ppm): 12.84 (s, 1H, D2O exchangable), 8.07 (d, 2H, J ¼ 8.4 Hz), 7.64
(m, 2H), 7.34 (d, 2H, J ¼ 8.4 Hz), 7.18 (m, 2H). Mass m=z (TOF): 209 (Mþ þ 1).
2-(3,4,5-Trimethoxyphenyl)-1H-1,3-benzimidazole (3l). White solid; mp
259 ꢁC. IR (KBr) 3056, 1590, 1500, 1463, 1243, 1015, 747 cmꢀ1. 1H NMR (DMSO-d6,
400 MHz) d (ppm): 12.86 (s, 1H, D2O exchangable), 7.65 (m, 4H), 7.19 (s, 2H), 3.89 (s,
6H, 2 ꢂ OCH3), 3.72 (s, 3H, OCH3). Mass m=z (TOF): 285 (Mþ þ 1).
CONCLUSION
A novel, simple, and efficient procedure for the synthesis of 2-arylsubstituted
benzimidazoles has been explored. Short reaction time, large-scale synthesis, easy
and quick isolation of the products, and excellent yields are the main advantages
of this procedure, which make this method more attractive. It is certainly a useful
contribution to the present methodologies.
ACKNOWLEDGMENT
The authors gratefully acknowledge financial support from the University
Grant Commission, New Delhi.
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