Polyethylene glycol: A recyclable solvent system for the synthesis of benzimidazole derivatives using CAN as catalyst

Article abstract of DOI:10.1007/s12039-010-0095-7

Ceric ammonium nitrate (CAN) efficiently catalysed the synthesis of benzimidazole derivatives from o-phenylenediamine and aldehydes in PEG. This method provides a novel route for the synthesis of benzimidazoles in good yields with little catalyst loading.

Full text of DOI:10.1007/s12039-010-0095-7

J. Chem. Sci., Vol. 122, No. 4, July 2010, pp. 607–612. © Indian Academy of Sciences.
Polyethylene glycol: A recyclable solvent system for the synthesis of
benzimidazole derivatives using CAN as catalyst
MAZAAHIR KIDWAI*, ANWAR JAHAN and DIVYA BHATNAGAR
Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007
e-mail: kidwai.chemistry@gmail.com
MS received 27 November 2009; revised 26 April 2010; accepted 19 May 2010
Abstract. Ceric ammonium nitrate (CAN) efficiently catalysed the synthesis of benzimidazole deriva-
tives from o-phenylenediamine and aldehydes in PEG. This method provides a novel route for the syn-
thesis of benzimidazoles in good yields with little catalyst loading. The recovery and the successful
reutilization of the solvent system are also presented. Moreover, the easy set-up and purification tasks of
this sustainable method make it appealing for bulk industry applications.
Keywords. Green synthesis; ceric ammonium nitrate; PEG; OPD; benzimidazoles; recyclability.
1. Introduction
above usefulness, CAN became an effective catalyst
towards the synthesis of benzimidazole derivatives.
In performing the majority of organic transforma-
tion, solvents play a critical role in mixing the in-
Benzimidazole is a group of substances have found
1
practical applications in organic synthesis and a
21
significant structural element in medicinal chemistry
gredients to allow molecular interaction, like water
2,3
owing to its diverse biological activities. Benzimi-
22
and ionic-liquid as green solvent has also been
dazoles are also being developed as DNA minor
documented, but ionic liquids safety is still debated
and the reactions in water do not give good yields
because of the hydrophobic nature of the organic
reactants. Recently, polyethylene glycol is found to
be an interesting recyclable and eco-friendly solvent
system in synthetic chemistry for various organic
4
groove binding agents with antitumor activity.
These act as ligand to transition-metal for modelling
5
biological systems.
Benzimidazoles have been synthesized by a num-
ber of method and using a variety of starting mate-
6–9
rial. Literature survey revealed that the conden-
23
transformations with unique properties such as
sation of o-phenylenediamine with different
substituted aldehydes in the presence of various tran-
sition metal–triflate salts such as SC(OTf)3 or
thermal stability, commercial availability and
immiscibility with a number of organic solvents. In
general, PEG is an inexpensive, non-toxic, com-
pletely non-halogenated and possesses low validity.
Due to the low cost and easy handling of CAN and
10,11
12 13
sulphamic acid, H2O2–HCl, FeBr3,
14
Yb(OTf)3,
15
16
KHSO4 and HfCl4 afforded the title compound.
Although these methods suffer from many draw-
backs such as long reaction time, usage of expensive
and corrosive reagent, high temperature with lesser
yield products. In recent times ceric ammonium
24
the green nature of recyclable PEG encouraged us
to combine them together and used their utility for
the synthesis of benzimidazoles.
17
nitrate (CAN) has gained special attention and is
2. Experimental
extensively employed as a useful catalyst for C–C,
C–N, C–S and C–Se bond forming reaction in syn-
2.1 Materials and method
18,19
thetic organic chemistry
as it is economically
viable, water soluble with profound reactivity en-
All chemicals were purchased from sigma-Aldrich
and Lancaster and were used without further purifi-
cation. All reactions and purity of 2-aryl benzimida-
zole derivatives were monitored by thin layer
chromatography (TLC) using aluminium plates
20
dowed with the reduction potential. In view of the
*For correspondence
607

608
Mazaahir Kidwai et al
coated with silica gel (Merck) using 20% ethylace- hyde. These were stirred at ambient temperature in
tate, 80% pertroleum ether as an eluent. The isolated ethanol for 32 h and only 35% of the expected prod-
products were further purified by column-chroma- uct was obtained. The same reaction was then car-
tography using silica gel (100–200 mesh) purchased ried out using PEG as the reaction medium under
from Sisco Research Laboratories Pvt. Ltd. Mumbai, similar conditions. Surprisingly, a significant im-
1
India and purified products were recrystallized. H provement was observed and the yield of product
NMR spectra were recorded on a Bruker Avance was dramatically increased to 67% for 8 h. Further
Spectrospin 300 (300 MHz). All NMR samples were to improve the yield and also to explore the catalytic
run in CDCl3 and chemical shifts are expressed as δ activity of CAN the reaction was carried out with
relative to internal TMS. IR spectra were obtained same amount of reactants in PEG (5 mL) were
on Perkin Elmer FT–IR spectrometer spectrum-2000 stirred at 50°C in the presence of 2 mol% of CAN
using potassium bromide pellets. ESI–MS mass for 4 h, a good improvement was observed and the
spectra were recorded on a waters LCT Micromass. reaction yielded 95% benzimidazole (scheme 1).
The temperature of the reaction mixture was meas-
With this optimistic result in hand, we further
ured through a non-contact infrared thermometer investigated the best reaction condition by using dif-
(AZ, Mini Gun Type, Model 8868).
ferent amounts of CAN. An increase in the quantity
of CAN from 2 mol% to 5 mol%, not only decreased
the reaction time from 4 h to 2 h but also increased
the product yield from 95 to 98%. This showed that
the catalyst concentration plays a major role in op-
timization of the product yield. Although the use of
2.2 General procedure for the synthesis of
benzimidazoles
In a 50 ml round bottom flask, a mixture of o-
phenyldiamine (OPD) (1 mmol) and aldehydes
(1 mmol) in polyethylene glycol (5 ml) were mixed
and stirred in the presence of ceric ammonium ni-
trate (CAN) catalyst (5 mol%) at 50°C for 2 h. The
progress of reaction mixture was monitored by TLC.
On completion of reaction, the reaction mixture was
cooled in dry ice–acetone bath to precipitate the
PEG 400 and extracted with ether (PEG being
insoluble in ether). The reaction mixture was filtered
in order to recover the catalyst and filtrate was
washed with H2O and dried. The crude product was
purified by silica-gel column chromatography using
15% ethylacetate as an eluent to yield the 2-aryl
benzimidazoles. The recovered PEG can be reused
for further reactions. All the known compounds
were characterized by comparing their physical
Scheme 1.
25–28
1
and spectral data (IR, H NMR and
13
(MPs)
C
NMR) with those of reported compounds (see sup-
plementary information for details, www.ias.ac.in/
chemsci).
3. Results and discussion
In continuation of our efforts on developing green
methodologies for biologically active organic com-
29
pounds we report here a CAN catalysed procedure
for the synthesis of benzimidazole derivatives in
Figure 1. Catalytic activity evaluation for benzimidazoles.
Reaction conditions: o-phenylenediamine (1 mmol), ben-
zaldehyde (1 mmol); solvent PEG 400; temperature 50°C.
Isolated yields.
PEG at 50°C.
Initially, a blank reaction was carried out using 1
equiv. each of o-phenylenediamine and benzalde-

Polyethylene glycol: A recyclable solvent system for the synthesis of benzimidazole derivatives
609
a
Table 1. Synthesis of 2-phenyl benzimidazole derivatives by using CAN-PEG system.
b
Entry
Aldehyde
Product
Time (h)
Yield (%)
N
CHO
2
98
1
N
H
N
Cl
Cl
CHO
CHO
CHO
2
3
4
94
94
92
1⋅5
1⋅5
2⋅5
N
H
N
F
F
N
H
N
OH
HO
N
H
OH
HO
N
5
3
90
CHO
N
H
N
Me
Me
Me
N
N
CHO
6
7
2
2
92
90
Me
N
H
O
N
O
N
H
CHO
O
O
OCH
HO
3
OH
H CO
3
N
8
9
95
96
94
1⋅5
1⋅5
2
CHO
N
H
N
NO
2
CHO
O N
2
N
H
NO
2
O N
2
N
10
CHO
N
H
HO
OH
N
11
3
90
CHO
N
H
N
CH
3
H C
3
CHO
12
13
14
15
2
95
94
90
91
N
H
N
OCH
3
H CO
3
CHO
2
N
H
N
2⋅5
2⋅5
CHO
N
H
O
O
N
CHO
N
H
S
S
a
Reaction conditions: o-phenylenediamine (1 mmol), aldehydes (1 mmol), CAN (5 mol%); solvent
PEG 400; temperature 50°C
Isolated yields
b

610
Mazaahir Kidwai et al
10 mol% of CAN permitted the reaction time to be have been destroyed during the reaction when
decreased to 1h, the yield unexpectedly decreased to excess amount (10 mol%) of CAN was used in the
65%. A possible explanation for the low product reaction. It appears that a concentration of 5 mol%
yields is that the starting material or the product may of CAN is the suitable choice for an optimum yield
of benzimidazoles (figure 1).
In order to study the generality of this procedure,
the applicability of the PEG with CAN system was
then examined for the reaction of a series of aro-
matic aldehydes with o-phenylenediamine under the
optimized reaction conditions (table 1). As shown, a
variety of substituted aromatic aldehydes, bearing
either electron-donating or electron-withdrawing sub-
stituents, afforded the products in excellent yields
and high purities. In addition, heterocyclic alde-
hydes could also be used for efficient preparation of
various heterocyclic-benzimidazoles (table 1, entry
14 and 15). It was interesting to observe the remark-
able stability of a variety of functional groups such
as ether, nitro, hydroxyl, halides, and formyl under
the reaction conditions.
The nature of reaction media has an important
role in the synthesis of benzimidazoles in the
presence of CAN (5 mol%). Almost all solvents
afforded products in excellent yield with a variation
in reaction time. Therefore we used only PEG as a
Figure 2. CAN catalyze Benzimidazoles reaction in
solvent because it is recyclable, non-toxic and ther-
various solvents. Reaction conditions: o-phenylenedi-
mally stable (figure 2).
amine (1 mmol), benzaldehyde (1 mmol); solvent PEG
400; temperature 50°C. Isolated yields.
Figure 4. Recycling yields. Reaction conditions:
Figure 3. Effect of Temperature. Reaction conditions:
o-phenylenediamine (1 mmol), aldehyde (1 mmol), CAN
o-phenylenediamine (1 mmol), benzaldehyde (1 mmol),
(5 mol%); solvent PEG 400; temperature 50°C. Isolated
CAN (5 mol%); solvent PEG 400; temperature 50°C. Iso-
yields.
lated yields.

Polyethylene glycol: A recyclable solvent system for the synthesis of benzimidazole derivatives
611
Scheme 2.
The effect of temperature was also studied. Faster variety of aryl aldehydes using CAN as catalyst. In
reactions occurred on raising the temperature but the addition low cost, recyclable solvent system and
yield of product decreased at higher temperature ready availability of catalyst, an environmentally
possibly because one of the reactants (aldehydes) benign procedure makes this methodology a useful
oxidizes at high temperature in presence of CAN contribution to the existing procedures available for
(figure 3).
the synthesis of benzimidazole derivatives.
In order to prove that the use of polyethylene gly-
col as solvent is also practical, it was recycled with
minimum loss and decomposition. Since polyethyl-
ene glycol is immiscible with solvent ether, the
desired product may be extracted with it and remain-
ing PEG phase may be used. The solvent phase was
recycled with no change in reactivity for three
cycles but approximately 5% weight loss of PEG
was observed from cycle to cycle (figure 4).
A plausible mechanism as supported by the litera-
Acknowledgement
A J and D B thank University Grants Commission
(UGC), New Delhi for fellowship.
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