Facile route for the synthesis of benzothiazoles and benzimidazoles in the presence of tungstophosphoric acid impregnated zirconium phosphate under solvent-free conditions

Article abstract of DOI:10.1002/hc.20534

Rapid and efficient condensation reactions of o-phenylenediamine and o-aminothiophenol with various aldehydes were carried out using tungstophosphoric acid impregnated zirconium phosphate in solvent-free conditions to afford the corresponding 2-substituted arylbenzimidazole and arylbenzothiazole derivatives in good to excellent yields. This procedure constitutes a simple and practical green synthetic method for 2-arylbenzimidazoles and 2-arylbenzothiazoles and their structural analogs. Furthermore, the catalyst can be reused for several times but it will be less active.

Full text of DOI:10.1002/hc.20534

Heteroatom Chemistry
Volume 20, Number 4, 2009
Facile Route for the Synthesis of
Benzothiazoles and Benzimidazoles in the
Presence of Tungstophosphoric Acid
Impregnated Zirconium Phosphate under
Solvent-Free Conditions
Hamid Aliyan, Razieh Fazaeli, Nahid Fazaeli, Ahmad Reza Mssah,
Hamid Javaherian Naghash, Mohammad Alizadeh,
and Ginous Emami
Department of Chemistry, Islamic Azad University, Shahreza Branch, 86145-311, Iran
Received 15 December 2008; revised 8 March 2009
have many applications in both pharmaceutical
ABSTRACT: Rapid and efficient condensation reac-
and industrial research. They are widely used in
tions of o-phenylenediamine and o-aminothiophenol
bio-organic and medicinal chemistry with wide
with various aldehydes were carried out using
applications in drug discovery such as antiviral,
tungstophosphoric acid impregnated zirconium phos-
anticonvulsant, antiulcer, anti-inflammatory, an-
phate in solvent-free conditions to afford the corre-
tiparasitic, antihelmintic, antiallergic, anticoagu-
sponding 2-substituted arylbenzimidazole and aryl-
lant, and antitumor applications [1]. For example,
benzothiazole derivatives in good to excellent yields.
2-(4-aminophenyl)benzothiazoles exhibit nanomo-
This procedure constitutes a simple and practical
lar inhibitory activity against a range of human
green synthetic method for 2-arylbenzimidazoles and
breast, ovarian, colon, and renal cell lines in vitro
2-arylbenzothiazoles and their structural analogs. Fur-
[2]. They are also used in industry as antioxi-
thermore, the catalyst can be reused for several times
dants, vulcanization accelerators, as a dopant in
ꢀ
C
but it will be less active.
2009 Wiley Periodicals,
a light-emitting organic electroluminescent device
[3]. They are also applied in agriculture as strobil-
urin derivatives (agricultural fungicides) [4]. Several
methods have been developed for the prepara-
tion of these heterocycles including the conden-
sation of carboxylic acids [5], acid chlorides [6],
nitriles [7], orthoesters [8], amides [9], esters [10],
or aldehydes [11] with o-aminothiophenols, and o-
phenylenediamine (OPD). In another method, 2-
mercapto and 2-chlorobenzothiazoles have been
prepared by classical cyclization of the correspond-
ing ortho-haloanlines with potassium/sodium O-
ethyl dithiocarbonate [12].
Inc. Heteroatom Chem 20:202–207, 2009; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20534
INTRODUCTION
Benzimidazoles and benzothiazoles are very im-
portant groups of heterocyclic compounds that
Correspondence to: Hamid Aliyan; e-mail: aliyan@iaush.ac.ir;
Razieh Fazaeli; e-mail: fazaeli@iaush.ac.ir.
Contract grant sponsor: Islamic Azad University, Shahreza
However, most of these methods have following
drawbacks: high thermal conditions, long reaction
Branch.
c
ꢀ
2009 Wiley Periodicals, Inc.
202

Facile Route for the Synthesis of Benzothiazoles and Benzimidazoles 203
NH2
NH2
NH2
N
N
SH
RCHO
R
R
HTP/ZrP
HTP/ZrP
N
H
S
2
1
3
SCHEME 1 Synthesis of benzimidazoles (2) and benzothiazoles (3).
times, low yields of the products, harsh reaction con-
ditions, and the use of toxic metallic compounds that
result in waste streams.
that the impregnated products are crystalline. Some
peaks of HTP overlapped with that of zirconium
phosphate. This may be due to the interaction of
HPA with that of the support.
In recent decades, the use of heteropolyacids
(HPAs) as catalysts for fine organic synthetic pro-
cesses has been developed and is important for in-
dustries related to fine chemicals [13], including fla-
vors, pharmaceuticals, and food industries [14,15].
Solid heteropolyacids have attracted much attention
in organic synthesis owing to easy workup proce-
dures, easy filtration, and minimization of cost and
waste generation due to reuse and recycling of the
catalysts [16]. For heterogeneous systems, it is possi-
ble to control solid strength by supporting HPAs on
different carriers [17]. An immobilization of HPAs
on a number of porous supports such as silica, ac-
tive carbon, montmorillonite K-10, zeolite, zirco-
nium phosphate and so on [17–22] was, therefore,
extensively studied.
In continuation of our previously reported cat-
alytic properties of heteropolyacids [23], herein, we
wish to report a suitable method for the use of zir-
conium phosphate (ZrP) as inorganic support with
the Keggin-type polyoxometalate (POM), H3PW12O40
(denoted as HTP hereafter) as heterogeneous cata-
lyst for the synthesis of 2-arylbenzimidazole (2) and
2-arylbenzothiazole (3) derivatives (Scheme 1).
Synthesis of 2-Arylbenzothiazoles and
2-Arylbenzimidazoles in the Presence of
Catalytic Amounts of Polyoxometalate under
Solvent-Free Conditions
At first, for optimization of the reaction conditions,
the reaction of 4-methoxybenzaldehyde (1 mmol)
with OPD (1.5 mmol) in CH3CN at room tem-
perature in the presence of a catalytic amount of
HTP (5 mol%) was studied. The analysis of the re-
action mixture showed the desired product 2-(4-
methoxyphenyl)-1H-benzimidazole was produced
only in 55% yield after 15 min plus unreacted
starting materials (Table 1, entry 2). Then, we de-
cided to study the catalytic ability of the sup-
ported HTP on ZrP. We observed that the reac-
tion of 4-methoxybenzaldehyde (1 mmol) with OPD
(1.5 mmol) in CH3CN in the presence of the sup-
ported catalyst (40% HTP/ZrP, 5 mol%) was per-
formed smoothly and the desired product 2-(4-
methoxyphenyl)-1H-benzimidazole was obtained in
78% yield after 15 min (Table 1, entry 4). We
have also studied the above-mentioned reaction in
the presence of pure ZrP (Table 1, entry 1). Al-
though this catalyst (ZrP) was active for the con-
densation reactions, but the yields were insignifi-
cant when compared to those with the supported
catalysts. These results show the strong synergistic
effects of ZrP upon the catalytic activity of HTP in
the reaction of 4-methoxybenzaldehyde with OPD
(Table 1). In addition, because of the current chal-
lenge for developing solvent-free and environmen-
tally benign protocols [15], we studied the reac-
tion of 4-methoxybenzaldehyde (1 mmol) with OPD
(1.5 mmol) under solvent-free conditions in the pres-
ence of HTP/ZrP (Table 1, entry 9). We found that
the solvent-free condition was more suitable and ef-
ficient to complete the reaction within 15 min. The
results of this study are presented in Table 1.
RESULTS AND DISCUSSION
Physicochemical Characterization
Figure 1 shows the FT-IR spectra of the 40 wt% sam-
ples of HTP-impregnated ZrP. From the FT-IR spec-
tra, it was found that at 110◦C-dried samples the Keg-
gin bands are observed at 1064, 815, and 607 cm−1
for HTP/ZrP. The FT-IR spectra of HTP/ZrP indicate
that most of characteristic bands of the parent Keg-
gin structure, could be found in the HPA fingerprint
region (1250–500 cm−1), are not shown or appeared
in the same assignable position of the bands corre-
spond to ZrP host material. The observed band at
516 cm−1 may be attributed to the δ(P O) vibration.
Moreover, the band located at 1633 cm−1 may be
characteristic of the O H stretching vibration [18].
Figure 2b shows the XRD pattern of 40 wt% of HTP-
impregnated ZrP dried at 110◦C. It can be observed
From the results presented in Table 1, the reac-
tion conditions we chose were o-phenylenediamine
Heteroatom Chemistry DOI 10.1002/hc

204 Aliyan et al.
FIGURE 1 FTIR spectra of 40 wt% HTP/ZrP, dried at 110◦C.
TABLE 1 Synthesis of 2-Arylbenzimidazolesa in different
(1.5 mmol), aldehydes (1 mmol), and 50% HTP/ZrP
(0.1 g, 3 mol%). Under these reaction conditions,
we performed a series of experiments for reac-
tions of OPD and o-aminothiophenol with differ-
ent aldehydes under solvent-free conditions. The
results are summarized in Table 2, and both alde-
hydes bearing electron-donating (Table 2, entries
b–e) and electron-withdrawing (Table 2, entries f,
g) substituents gave desired benzimidazoles in ex-
cellent yields. Heteroaryl aldehydes, such as 2-furyl
and 2-pyridyl (Table 2, entries h, i), were well tol-
erated under these conditions. Aliphatic aldehy-
des also reacted with OPD and o-aminothiophenol
under similar conditions to give the correspond-
ing 2-arylbenzimidazoles and 2-alkylbenzothiazoles.
However, the yields were lower than that of the aro-
matic aldehydes (Table 2, entry j).
conditions after 15 min
Entry
Catalyst
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
ZrP (0.2 g)
HTP (5 mol%)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
MeOH
21
55
68
78
78
45
60
43
95
HTP/ZrP (3 mol%)b
HTP/ZrP (5 mol%)
HTP/ZrP (7 mol%)
HTP/ZrP (5 mol%)
HTP/ZrP (5 mol%)
HTP/ZrP (5 mol%)
HTP/ZrP (5 mol%)
EtOH
Solvent-free
aReaction conditions: 1 mmol of 4-methoxybenzaldehyde with OPD
(1.5 mmol) at room temperature was used.
bHTP/ZrP (40% w/w).
substrate in the presence of HTP/ZrP under solvent-
free conditions. In typical reactions, catalyst was
simply filtered from the reaction mixture, washed
with ethanol, dried and calcinated at 350◦C for 4 h,
and reused for five runs (Table 3). On the basis of
observations made from different experiments, one
Recovery
The feasibility of reusability of the catalyst was also
examined with 4-methoxybenzaldehyde as a model
Heteroatom Chemistry DOI 10.1002/hc

Facile Route for the Synthesis of Benzothiazoles and Benzimidazoles 205
FIGURE 2 XRD patterns of (a) ZrP and (b) 40 wt% HTP/ZrP, dried at 110◦C.
rate of 2◦ min−1. The products were purified by col-
umn or thick layer chromatography techniques. FT-
IR spectra were obtained as potassium bromide pel-
lets in the range 400–4000 cm−1 with Nicolet Impact
400 D. 1H NMR spectra were recorded with a Bruker-
Avance AQS 300 MHz.
can conclude whether the recovered catalyst is cal-
cinated after drying; the activity of the catalyst will
increase. Supposedly, adsorbed water in the reaction
will decrease the activity of the catalyst. The reaction
proceeded smoothly with a yield of 95%–82%, and
this result indicates that the catalyst can be reused
but it will be less active.
Preparation of Zirconium Phosphate
EXPERIMENTAL
Zirconium phosphate was prepared by taking 1 M
aqueous solution of ZrOCl2·8H2O and it was slowly
added to ten time excess of 1 M H3PO4. The precipi-
tate was washed several times with de-ionized water,
dried 2 h at 368 K, and stored at 100% relative hu-
midity and room temperature [24].
All solvents and reagents were purchased from Fluka
or Merck. The X-ray powdered diffraction patterns
were recorded on a Philips PW 1710 diffractome-
ter with automatic control. The patterns were run
with monochromatic Cu Kα radiation with a scan
Heteroatom Chemistry DOI 10.1002/hc

206 Aliyan et al.
were calcined
were dried
assembly
H2O, r.t.
ZrPO (ZrP)
+ H3PW12O40 (HTP)
HTP/ZrP
4
for 4 h at 350oC
for 4 h at 110oC
SCHEME 2 Representation of HTP/ZrP preparation.
TABLE 2 Synthesis of Benzothiazoles and Benzimidazolesa
together in a mortar with a pestle at room temper-
ature for 15 min. The progress of the reaction was
monitored by TLC. At the end of the reaction, the
reaction mixture was washed with cold diethyl ether
and filtered to remove HTP/ZrP. Then, the organic
solution was purified on a silica gel plate or a silica
gel column (20% ethyl acetate in hexane). The prod-
ucts were identified by comparison of their physi-
cal data with those prepared in accordance with the
literature procedures.
Catalyzed by HTP/ZrP after 15 min
Yield (%)b
Entry
R
2c
3
a
b
c
d
e
f
g
h
i
Ph
85
85
95
98
90
92
80
80
80
78
92
98
95
92
85
95
87
85
80
78
2-MeO-C6H4
4-MeO-C6H4
2-OH-C6H4
4-OH-C6H4
3-NO2-C6H4
4-NO2-C6H4
2-Furyl
2-Pyridyl
C5H11
CONCLUSIONS
j
In summary, we developed a fast, simple procedure,
and convenient method for the synthesis of benz-
imidazoles and benzothiazoles using HTP/ZrP, as
an eco-friendly, inexpensive, and efficient catalyst
without using a solvent. The salient features of this
method include the simple reaction setups, mild re-
action conditions, and short reaction time. These ad-
vantages render the synthesis of benzimidazoles and
benzothiazoles and the related compounds more ef-
ficient and environmental friendly.
ao-Phenylenediamine (1.5 mmol), or o-aminothiophenol (1.5 mmol),
aldehyde (1 mmol), and 40% HTP/ZrP (5 mol%).
bIsolated yield.
cSpectroscopic data for 2-(4-methoxyphenyl)-1H-benzimidazole
(2c): Mp 165–167◦C. 1H NMR (DMSO-d6): δ (ppm) = 3.82 (s, 3H,
OCH3), 7.25–7.73 (m, 8H, aromatic), 12.99 (bs, NH).
TABLE 3 Recycling of HTP/ZrPa
Run
Yield (%)
1
2
3
4
5
95
94
93
94
82
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Heteroatom Chemistry DOI 10.1002/hc