VOSO4catalyzed highly efficient synthesis of benzimidazoles, benzothiazoles, and quinoxalines

Article abstract of DOI:10.1016/j.tetlet.2016.06.074

Herein, we describe a highly efficient and eco-friendly protocol for the synthesis of benzimidazoles, benzothiazoles, and quinoxalines using VOSO₄as a catalyst in ethanol. Use of nontoxic and recyclable catalyst, clean reaction profile, high yi

Full text of DOI:10.1016/j.tetlet.2016.06.074

Accepted Manuscript
VOSO4 catalyzed highly efficient synthesis of benzimidazoles, benzothiazoles
and quinoxalines
Chander Singh Digwal, Upasana Yadav, Akash P. Sakla, P.V. Sri Ramya, Shams
Aaghaz, Ahmed Kamal
PII:
S0040-4039(16)30743-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.074
TETL 47801
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 May 2016
15 June 2016
16 June 2016
Please cite this article as: Digwal, C.S., Yadav, U., Sakla, A.P., Sri Ramya, P.V., Aaghaz, S., Kamal, A., VOSO4
catalyzed highly efficient synthesis of benzimidazoles, benzothiazoles and quinoxalines, Tetrahedron Letters
(2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.074
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Tetrahedron Letters
VOSO4 catalyzed highly efficient synthesis of benzimidazoles, benzothiazoles and
quinoxalines
Chander Singh Digwal, Upasana Yadav, Akash P. Sakla, P. V. Sri Ramya, Shams Aaghaz, Ahmed Kamal*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein, we describe a highly efficient and eco-friendly protocol for the synthesis of
benzimidazoles, benzothiazoles and quinoxalines using VOSO4 as a catalyst in ethanol. Use of
nontoxic and recyclable catalyst, clean reaction profile, high yields, scalability and broad
substrate scope are the important practical features of the present protocol.
Available online
© 2016 Elsevier Ltd. All rights reserved.
Keywords:
Benzimidazoles
Benzothiazoles
Quinoxalines
VOSO4
1. Introduction
Benzimidazole moiety can be accessed by direct C-N bond
activation,2 redox condensation of 2-nitro aniline with benzyl
Benzimidazole and its derivatives occupy an important place in
medicinal chemistry due to their synthetic utility and diversified
biological activities.1a-c It is considered to be privileged
component because many drugs such as albendazole
amine/benzyl alcohol3 and condensation of o-phenylenediamines
with carboxylic acids or its derivatives (nitriles, imidates or
orthoesters) requiring high temperatures and strong acidic
conditions.4 Moreover, the most commonly used method for the
synthesis of 2-substituted benzimidazoles is oxidative
cyclodehydrogenation of Schiff base obtained by reacting o-
phenylenediamines and aldehydes. In recent times, several
catalysts and reagents such as Na2S2O4,5 FeCl3·6H2O,6 Zn-
proline,7 CAN,8 NaHSO3,9 ZrCl4,10 PhI(OAc)2,11 Pb(OAc)4,12
sulfamic acid,13 HfCl4,14 DMP,15 nanoporous aluminosilicate,16
(anthelmintic),
astemizole
(antihistaminic),
telmisartan
(antihypertensive), omeprazole (antiulcer), etc. contain
benzimidazole as a core template (Figure 1).1d-f Owing to such a
wide range of biological activities, constant efforts have been
made by different research groups worldwide to develop efficient
strategies for the synthesis of various substituted benzimidazoles
and their derivatives.
CoCl2·6H2O,17
Co(OH)2/CoO(II),18
VO(acac)2-CeCl3,19
MgCl2·6H2O,20 Heuland natural zeolite,21 animal bone meal,22
sodium perborate,23 Sc(OTf)3,24 In(OTf)3,25 Cu(OTf)2,26
TiCl3OTf,27 and B(C6F5)328 have been reported for the synthesis
of benzimidazoles. Weinreb amide reagent has also been
successfully utilized as a substitute for aldehydes for the
synthesis of benzimidazoles and benzothiazoles in presence of
BF3·OEt2.29 However, some of the previously reported methods
have several limitations like harsh reaction conditions, longer
reaction times, high temperatures, low yields, generation of toxic
side products, use of expensive and/or toxic catalysts.
Vanadium is nontoxic, inexpensive and readily available.30a
Not only is it known to be present in various bacterial enzymes
such as bromoperoxidase,30b nitrogenase30c but also plays an
important role in redox chemistry in complex biological
systems.30d,e The role of vanadium based catalysts in
organometallic chemistry as well as in a number of organic
reactions has been well documented.31 However, vanadium
sulfate oxide (VOSO4), a commercially available nontoxic and
recyclable catalyst has not much been explored. Recently,
catalytic activity of VOSO4 was found prominent in the synthesis
Figure 1. Biologically active benzimidazole derivatives.
* Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189.
E-mail: ahmedkamal@iict.res.in

Tetrahedron Letters
of pyrazoles via C-N dehydrogenative cross coupling.32 Based on
Table 1
this knowledge and in view of the efforts towards development of
simple, mild, eco-friendly reaction protocol, we explored the
potential of VOSO4 as a catalyst for the synthesis of
benzimidazoles, benzothiazoles and quinoxalines (Scheme 1 &
2). To our delight, VOSO4 catalyzed reactions not only required
shorter reaction times but also provided the desired products in
good to excellent yields with low catalyst loading.
Optimization of the reaction conditions for the synthesis of
2-phenyl-1H-benzo[d]imidazole (3a)a
Entry
Catalyst (mol %)
Solvent
Time
Yieldb (%)
1
2
3
4
5
6
7
8
Nil
0.5
1
2
3
5
3
3
3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
CH2Cl2
CH3CN
DMF
24 h
6 h
5 h
2.5 h
60 min
60 min
60 min
60 min
60 min
60 min
60 min
23
75
83
89
92
93
82
56
63
70
52
2. Results and discussion
To standardize the reaction conditions, a model reaction of o-
phenylenediamine and benzaldehyde was carried out in the
presence of VOSO4 in ethanol at room temperature and the
results are summarized in Table 1. As evident from the results,
the reaction proceeds smoothly on addition of 0.5 mol % of
VOSO4 unlike in case of the reaction without the catalyst (entry
1, 2, Table 1). Further, to demonstrate the effect of catalyst
9
10
11
3
3
H2O
a Reaction conditions: o-phenylenediamine (1 mmol) and benzaldehyde (1
mmol) are used at room temperature.
b Isolated yield.
was investigated (entries 7-11, Table 1). However, ethanol
showed excellent yield (92%) in 60 min and was established to
be the best solvent for this transformation.
The generality and substrate scope for the described protocol
were
explored by using different substituted
o-
Scheme 1. Synthesis of 2-substituted benzimidazole derivatives.
phenylenediamines and aryl/heteroaryl aldehydes. The reaction
of o-phenylenediamine with a variety of arylaldehydes bearing
electron withdrawing as well as electron donating groups
provided the corresponding 2-arylbenzimidazoles in 84-92%
yield in short reaction times (entries 3a-3k, Table 2). Notably, the
present method is compatible with a wide range of functional
groups such as methoxy, halogens, cyano, hydroxyl, carboxyl
and functional group nature does not significantly affect the yield
of the reaction. Next, when the reaction was carried out using N-
loading, we carried out a series of reactions with increasing
amount of VOSO4. It was observed that increasing the catalyst
loading beyond 3 mol % showed no significant improvement in
terms of yield and reaction time (entry 5, 6, Table 1). Finally, we
could obtain the desired product in 92% yield at room
temperature with 3 mol % of VOSO4. With these optimized
reaction conditions, effect of different solvents such as methanol,
dichloromethane, acetonitrile, N,N-dimethylformamide and water
Table 2
Reaction of o-phenylenediamine or 2-aminothiophenol with aldehydes in ethanol at room temperaturea
Entry
Amine
Aldehydes
Product
Time
Yieldb (%)
92
Mp (°C)Refs.
291-2932b,29
60 min
3a
45 min
50 min
50 min
40 min
89
91
92
90
289-2912b
222-2242b,27
263-26527
248-25027
3b
3c
3d
3e
70 min
60 min
88
86
258-26013
205-208
3f
3g

Table 2 (Continued)
Entry
Amine
Aldehydes
Product
Time
Yieldb (%)
90
Mp (°C)Refs.
276-278
(lit.20 295-298)
50 min
3h
30 min
40 min
40 min
84
87
88
>300
3i
221-22320
265-267
3j
3k
263-265
8 h
4 h
78
85
3l
(lit.4c 270)
197-199
3m
5 h
4 h
82
86
212-214
239-241
3n
3o
3pc
24 h
74
220-222
3qc
24 h
78
238-240
45 min
40 min
50 min
40 min
92
87
89
90
110-11222
114-11622
117-11922
102-10422
3r
3s
3t
3u
a Reaction conditions: o-phenylenediamine/2-aminothiophenol (1 mmol), benzaldehyde (1 mmol), VOSO4 (3 mol %).
b Isolated yield.
c Reaction was carried out at 80 °C.

Tetrahedron Letters
substituted indole-3-carbaldehydes or 4-oxo-4H-chromene-3-
of 3a was carried out on gram scale with 5 g of o-
phenylenediamine and 4.91 g of benzaldehyde using 3 mol%
VOSO4 at room temperature in ethanol and the yield of product
3a obtained was 90% (8.1 g), that was found comparable to the
yield obtained in entry 3a, Table 2.
carbaldehyde, it was observed to proceed at room temperature in
good yields, although required longer reaction times (entries 3l-
3o, Table 2). Furthermore, the reaction of imidazo[1,2-a]pyridine
carbaldehydes with o-phenylenediamine proceeded only in
refluxing ethanol and afforded the desired product in moderate
yields after 24 h (entries 3p, 3q, Table 2). In order to study the
synthetic scope of this method, we carried out the reaction using
o-aminothiophenol and arylaldehydes. Gratifyingly, the reaction
furnished the corresponding benzothiazole derivatives in high
yields at room temperature (87-92%, entries 3r-3u, Table 2).
Encouraged by these results, the applicability of this protocol
was further extended for the synthesis of quinoxalines. The most
common strategy for the synthesis of 2,3-disubstituted
quinoxalines involves the condensation of an aryl 1,2-diamine
with a 1,2-dicarbonyl compound in ethanol or acetic acid which
often requires high reaction temperature and long reaction time.33
In recent years, synthesis of quinoxalines via condensation of o-
phenylenediamines with 1,2-dicarbonyl and/or α-hydroxy ketone
compounds in presence of several catalysts such as I2,34
Ga(OTf)3,35 CuSO4·5H2O,36 sulfamic acid,37 KF/alumina,38
Amberlite IR-120H,39 etc. have been well reported. To further
evaluate the catalytic ability of VOSO4, the present optimized
conditions were applied to the reaction of substituted o-
phenylenediamines and benzil, which underwent smooth
conversion to provide the corresponding 2,3-diphenyl
quinoxaline derivatives in excellent yields (91-96% yield after
20-40 min) (entries 5a-5e, Table 4).
In addition, we studied the reusability of the VOSO4 for the
synthesis of 3a. The catalyst was recovered as described in
experimental procedure after completion of the reaction and re-
used upto three times under the optimal reaction conditions. As
shown in Table 3, the recovered catalyst showed good reusability
with a slight decrease in yield over three runs. Also, the synthesis
Table 3
Reusability of VOSO4 (3 mol%) for the synthesis of 3a
Time
(min)
Yielda
(%)
Reaction
cycle
o-phenylene-
diamine
Entry
1
Benzaldehyde
491 mg
First
500 mg
60
92
(fresh
run)
2
3
4
Second
cycle
Third
cycle
Fourth
cycle
60
60
60
90
87
82
500 mg
500 mg
500 mg
491 mg
491 mg
491 mg
Scheme 2. Synthesis of 2,3-diphenylquinoxaline derivatives.
a Isolated yield.
Table 4
Reaction of substituted o-phenylenediamines with benzila
Entry
Amine
1,2-diketones
Product
Time (min)
20
Yieldb (%)
Mp (°C)Refs.
127-12935,39
96
5a
122-12439
20
35
30
40
95
94
94
91
5b
5c
5d
5e
125-12735
120-12235
102-10339
a Reaction conditions: o-phenylenediamines (1 mmol), benzil (1 mmol), VOSO4 (3 mol %).
b Isolated yield.

3. Conclusion
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In conclusion, we have developed an efficient and eco-friendly
method for the synthesis of 2-substituted benzimidazoles using
VOSO4 as a catalyst in ethanol. Wide applicability to various
substrates makes this method useful for the synthesis of
medicinally important benzimidazole, benzothiazole and
quinoxaline derivatives. The other key features of this protocol
include use of nontoxic and recyclable catalyst, scalability, high
functional group tolerance, high yields and easy work up
procedure.
Acknowledgement
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We are thankful to the Department of Pharmaceuticals (DoP),
Ministry of Chemical & Fertilizers, Govt. of India, for the award
of NIPER fellowship.
References and notes
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Graphical Abstract
VOSO4 catalyzed highly efficient synthesis of
benzimidazoles, benzothiazoles and
quinoxalines
Chander Singh Digwal, Upasana Yadav, Akash P. Sakla, P. V. Sri Ramya, Shams Aaghaz, Ahmed Kamal*

Tetrahedron Letters
Highlights





Synthesis of benzimidazoles, benzothiazoles and quinoxalines using VOSO4 as catalyst.
Environmentally benign protocol with mild reaction conditions and high yields.
Wide substrate scope shown by synthesis of structurally diverse benzimidazole derivatives.
Reusability of VOSO4 for at least three times.
The protocol is also useful in gram scale synthesis.