Zn2+-K10-clay (clayzic) as an efficient water-tolerant, solid acid catalyst for the synthesis of benzimidazoles and quinoxalines at room temperature

Article abstract of DOI:10.1016/j.tetlet.2010.10.146

A very simple, green and efficient protocol is developed in which zinc chloride-exchanged K10-montmorillonite (clayzic) is employed as a Lewis acid catalyst in aqueous media at room temperature for the synthesis of various benzimidazoles and quinoxalines from carbonyl compounds and o-phenylenediamine. Among the various catalysts (including claycop and Zn²⁺-Y) studied, clayzic produces benzimidazoles and quinoxalines in higher yield, and with a flexible diamine such as ethylenediamine only the bis-Schiff base is formed. Other salient features of this protocol include milder conditions, atom-economy, absence of coupling agents, and no wastes.

Full text of DOI:10.1016/j.tetlet.2010.10.146

Tetrahedron Letters 52 (2011) 69–73
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Tetrahedron Letters
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Zn2+-K10-clay (clayzic) as an efficient water-tolerant, solid acid catalyst for
the synthesis of benzimidazoles and quinoxalines at room temperature
⇑
Amarajothi Dhakshinamoorthy, Kuppusamy Kanagaraj, Kasi Pitchumani
School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A very simple, green and efficient protocol is developed in which zinc chloride-exchanged K10-
montmorillonite (clayzic) is employed as a Lewis acid catalyst in aqueous media at room temperature
for the synthesis of various benzimidazoles and quinoxalines from carbonyl compounds and
o-phenylenediamine. Among the various catalysts (including claycop and Zn2+–Y) studied, clayzic
produces benzimidazoles and quinoxalines in higher yield, and with a flexible diamine such as
ethylenediamine only the bis-Schiff base is formed. Other salient features of this protocol include milder
conditions, atom-economy, absence of coupling agents, and no wastes.
Received 31 August 2010
Revised 26 October 2010
Accepted 28 October 2010
Available online 31 October 2010
Keywords:
Benzimidazoles
Quinoxalines
K10-Montmorillonite
Clayzic
Ó 2010 Elsevier Ltd. All rights reserved.
Lewis acids
Benzimidazoles are very useful intermediates for the
development of molecules of pharmaceutical and biological inter-
est. Substituted benzimidazole derivatives have found applications
in diverse therapeutic areas including antiulcers, antihyperten-
sives, antivirals, antifungals, anticancers, and antihistaminics.1–3
The widespread interest in benzimidazole-containing structures
has prompted extensive studies for their synthesis. There are two
general methods for the synthesis of 2-substituted benzimidazoles.
One is the coupling of o-phenylenediamines and carboxylic acids4
or their derivatives (nitriles, imidates, or orthoesters),5 which often
require strong acidic conditions and sometimes combines with
very high temperatures (i.e., PPA, 180 °C) or the use of microwave
irradiation.6 The other way involves a two-step procedure that
includes the oxidative cyclodehydrogenation of aniline Schiff’s
bases, which are often generated in situ from the condensation of
o-phenylenediamines and aldehydes. Various oxidative reagents
such as nitrobenzene (high-boiling point oxidant/solvent),7 1,4-
benzoquinone,8 DDQ,9 tetracyanoethylene,10 benzofuroxan,11
widespread importance25 and catalytic systems26–28 have been
developed for their synthesis. Ranu and co-workers have reported
the synthesis of 2-substituted benzimidazoles in the presence of
1-methyl-3-pentylimidazolium tetrafluoroborate as solvent and
catalyst.29 An environmentally benign tandem procedure has
also been reported for the synthesis of quinoxaline derivatives
with manganese oxide octahedral molecular sieves as reusable
catalysts.30
Lewis acid catalysis has attracted considerable attention in het-
erogeneous catalysis.31 Although various kinds of Lewis acids have
been developed, many of them must be used only under strictly
anhydrous conditions. In addition, all these processes require stoi-
chiometric or excess amount of catalyst/reagents and most of them
employ considerable amounts of hazardous organic solvents which
are not environmentally friendly. Also, several of these reactions
are carried out at higher temperatures.
Recently, with an objective to develop environmentally benign
reaction conditions and media for organic reactions with excellent
efficiency and selectivity, water has been shown to be a useful sol-
vent.32 In this context, in the present study, we report here the use
clayzic as an eco-friendly water tolerant Lewis acid catalyst for the
synthesis of substituted benzimidazoles and quinoxalines, as
shown in Scheme 1. Clayzic has been extensively used as an eco-
friendly catalyst ‘Envirocat’, in Lewis acid-catalyzed reactions,
including benzylations, olefinations, and Fridel–Crafts alkylation
of benzenoid compounds, a reaction that is facile even at room
temperature.33 Recently, Varala et al. have used zinc montmoril-
lonite as a reusable catalyst for the synthesis of benzodiazepine
derivatives.34
16
MnO2,12 Pb(OAc)4,13 Oxone,14 NaHSO3,15 and Na2S2O5 have been
employed.
Recently, a variety of catalysts such as homogeneous Lewis
acids,17
pyridinium-p-toluenesulfonate,18
sulfur/ultrasonic,19
I2/KI/K2CO3/H2O,20 ionic liquids,21 (bromodimethyl)sulfonium
bromide,22 polyaniline-sulfate,23 and a tandem oxidation process24
have been used for the synthesis of benzimidazoles. Quinoxaline
derivatives are nitrogen containing heterocyclic compounds with
⇑
Corresponding author. Tel.: +91 452 2456614; fax: +91 452 2459181.
E-mail address: pit12399@yahoo.com (K. Pitchumani).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.146

70
A. Dhakshinamoorthy et al. / Tetrahedron Letters 52 (2011) 69–73
Ph
O
O
CHO
Ph
Ph
NH2
NH2
N
N
N
Ph
K10- Zn2+
+
H2O: CH3OH
H2O: CH3CN
N
H
Scheme 1. Synthesis of benzimidazoles and quinoxalines.
Table 1
To minimize the formation of byproducts and to achieve a good
yield of the desired product, the reaction is optimized by varying
the amount of catalyst (25 and 50 mg), time of the reaction, and
using various solvents. Equimolar amounts of benzaldehyde and
diamine are dissolved in various solvents and the mixture is stirred
for the required time. Significant amounts of 2-phenylbenzimida-
zole (Table 1) are produced under these mild conditions when
clayzic is used instead of other Lewis acid catalysts. Also, among
the different solvents tried to optimize the reaction conditions,
alcoholic solvents seemed to be a better choice in terms of yield
of the isolated product. The same trend is also observed when
equal amount of water is used along with methanol. Though vari-
ous catalytic systems have been developed for the synthesis of
quinoxaline derivatives, use of aqueous medium is more relevant
from the context of green chemistry. Hence, it is proposed to syn-
thesize those heterocyclic compounds in aqueous medium with
clayzic as the water tolerant Lewis acid catalyst.
Optimization of reaction conditions for the synthesis of 2-phenylbenzimidazolea
Run
Catalyst
Solvent
Time (h)
Percentage
conversionb
1
2
3
4
5
6
7
9
10
11
12
13
14
15
None
H2O/CH3OHc
H2O/CH3OHc
Hexane
H2O
CH3OH
24
24
24
24
24
24
24
24
12
24
24
24
24
24
—
K10-clay
Clayzic
Clayzic
Clayzic
Clayzic
Clayzic
Clayzic
Clayzic
Clayzicd
Clayzice
K10-Cu2+
K10-Pb2+
Zn2+–Y
26
19
32
89
91
84
98
64
15
32
84
30
26
EtOH
ACN
H2O/CH3OHc
H2O/CH3OHc
H2O/CH3OHc
H2O/CH3OHc
H2O/CH3OHc
H2O/CH3OHc
H2O/CH3OHc
a
Catalyst (100 mg), o-phenylenediamine (0.9 mmol), benzaldehyde (0.9 mmol),
solvent (3 mL), rt.
To generalize the scope and versatility of this protocol, different
substituted arylaldehydes are used for the synthesis of substituted
benzimidazoles.36 Equimolar amounts of o-phenylenediamine and
aryl aldehydes are stirred at room temperature in water–methanol
b
Determined by GC.
1:1 ratio.
25 mg of clayzic.
c
d
e
50 mg of clayzic.
Table 2
Synthesis of benzimidazoles and quinoxaline derivativesa
Entry
1
Amine
Carbonyl compound
Product
Isolated yieldb
NH2
N
CHO
94 (89, 88, 84, 83)c (78)d
N
H
NH2
NH2
N
H3C
CH3O
Cl
CHO
CH3
OCH3
Cl
2
3
4
5
6
7
8e
81
69
92
88
78
72
89
N
H
NH2
NH2
N
CHO
N
H
NH2
NH2
N
CHO
N
H
N
NH2
NH2
F
CHO
F
N
H
NH2
NH2
N
O2N
CHO
NO2
N
H
NH2
NH2
N
CHO
O
O
N
H
NH2
NH2
Ph
O
O
N
Ph
Ph
NH2
N
Ph

A. Dhakshinamoorthy et al. / Tetrahedron Letters 52 (2011) 69–73
71
Table 2 (continued)
Entry
Amine
Carbonyl compound
Product
Isolated yieldb
NH2
NH2
O
N
N
9e
89
O
O
N
O
N
NH2
NH2
N
N
N
N
10e
84
NH2
NH2
Ph
Ph
O
O
N
N
Ph
11e
81f
Ph
a
Aldehyde (0.9 mmol), diamine (0.9 mmol), clayzic (100 mg), water–methanol (1.5:1.5 mL), rt for 24 h.
b
c
d
e
f
Isolated yield.
Yields in successive reused runs 1–4.
Scale up reaction: benzaldehyde (10 mmol), o-phenylenediamine (10 mmol), clayzic (1 g), water–methanol (15:15 mL), rt for 24 h.
Ketone (0.4 mmol), diamine (0.4 mmol), clayzic (50 mg), water–acetonitrile (1.5:1.5 mL), rt for 2.5 h.
Isolated as cis/trans mixture.
Table 3
Synthesis of bis-Schiff base from the reaction between ethylenediamine and aldehydes in the presence of clayzic at room temperaturea
Entry
12
Aldehyde
Bis-Schiff base
Isolated yield
N
N
CHO
85
90
N
N
OHC
CH3
13
14
H3C
CH3
N
N
OH C
OCH3
89
82
80
H3CO
OCH3
OCH3
OCH3
N
N
OHC
OHC
15
16
H3CO
OCH3
OCH3
OCH3
N
N
F
F
F
a
Aldehyde (0.9 mmol), diamine (0.9 mmol), clayzic (100 mg), water–methanol (1.5:1.5 mL), rt for 24 h.
(1:1) mixture and the observed results are given in Table 2.
Aldehydes bearing both electron-donating, electron-withdrawing
substituents (Table 2, entries 1–4) and heteroaromatic aldehydes
(Table 2, entry 7) resulted in the corresponding benzimidazoles in
good to excellent yields. In addition, the synthesis of 2-phenylbenz-
imidazole was also performed in 10 mmol scale of benzaldehyde as
mentioned in Table 2. Seventy-eight percent of the desired product
was isolated, indicating that this method could also be used for the
large scale synthesis without any undesired products. The applica-
bility of the present methodology is further extended to synthesis
of quinoxaline derivatives (Table 2, entries 8–11) by performing
the reaction in (1:1) water–acetonitrile mixture. The feasibility of
the reaction is tested on various 1,2-dicarbonyl compounds with
o-phenylenediamine in good yield. Also the present protocol works
for aliphatic 1,2-diamine with 1,2-dicarbonyl compounds to give
the corresponding quinoxaline derivatives in good to moderate
yield. This process is thus green, environmental friendly,17 clean,
and can be performed easily at room temperature with no undesir-
able side reactions. Water displayed a specific functionality in reg-
ulating the selectivity, and hence can be considered as a remarkable
medium over organic solvents in terms of yields as well as in the
work-up procedure of the reactions. In all the cases, the products
are isolated and are characterized by their 1H NMR and GC–MS data
(Supplementary data).
Another advantage of the present methodology is the
reusability of the catalyst. After completion of the reaction, the
catalyst is removed by simple filtration. The catalyst is again
treated with dichloromethane followed by filtration. The catalyst
is then dried at 80 °C for 2 h and can be reused for another
reaction. The recycled catalyst is used for four consecutive

72
A. Dhakshinamoorthy et al. / Tetrahedron Letters 52 (2011) 69–73
H
scribed in Table 1 and the formation of 2-phenylbenzimidazole
decreases to <2%. This clearly demonstrates the role of oxygen as
an oxidant in the present study.
δ
Ph
δ
O
O
Ph
H2N
H2N
NH3
NH3
H+
Zn2+
2
H
In a similar fashion, clayzic facilitates the formation of quinox-
aline derivatives as outlined in the following mechanism (Scheme
3). 1,2-Diketone stabilized in the interlayer of clay via interaction
with Zn2+ by partial polarization of carbonyl group reacts readily
with o-phenylenediamine. The resultant amino-1,2-diol undergoes
base-induced dehydration to give quinoxaline as the end product.
In summary, a very simple, green, energy-efficient, and atom-
economical protocol has been developed for the synthesis of bio-
logically active benzimidazoles and quinoxaline derivatives with
a cheap, benign water tolerant Lewis acid catalyst namely clayzic
in water–methanol mixture at room temperature. An attempt to
prepare imidazoline by a similar methodology is unsuccessful
and has resulted in a bis-Schiff base. The advantage of the present
protocol is the elimination of corrosive liquid acids, conventional
organic solvents, and toxic reagents. The reaction is also character-
ized by its operational simplicity, high yield of products, and above
all the catalyst can be reused for more runs without any loss in its
activity. The observed results are rationalized by proposing suit-
able mechanisms involving Lewis acidic sites (Zn2+) of clay.
- H2O
NH2
Zn2+
N
C
H
Ph
clayzic
Zn2+
I
H
N
N
air oxidation
Ph
Ph
N
H
N
H
H
II
Scheme 2. Proposed mechanism for the synthesis of benzimidazoles.
Zn2+
NH3
NH3
NH2
NH2
2H+
Acknowledgments
δ
O
δ
Ph
Ph
K.P. thanks the Department of Science and Technology, New
Delhi, for financial assistance. A.D.M. thanks the Council of
Scientific and Industrial Research, New Delhi, for the award of
Senior Research Fellowship.
δ
O
δ
Zn2+
Zn2+
Zn2+
H
N
Supplementary data
OH
Ph
Ph
clayzic
Complete experimental procedures are provided, including
preparation of catalyst, general procedure for the synthesis of benz-
imidazoles and quinoxalines, 1H NMR and MS (EI) spectra of all
compounds are available in Supplementary data. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2010.10.146.
N
H
OH
Zn2+
N
N
Ph
Ph
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give the desired benzimidazole as the final product. A control exper-
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A. Dhakshinamoorthy et al. / Tetrahedron Letters 52 (2011) 69–73
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