Facile synthesis of benzimidazole, benzoxazole, and benzothiazole derivatives catalyzed by sulfonated rice husk ash (RHA-SO3H) as an efficient solid acid catalyst

Article abstract of DOI:10.1007/s11164-014-1685-7

A mild, simple, and efficient solvent-free method, with sulfonated rice husk ash as solid acid catalyst, has been developed for preparation of benzimidazole, benzoxazole, and benzothiazole derivatives. The products are obtained in good to high yields after very short reaction times, and the catalyst can be reused five times without loss of its catalytic activity.

Full text of DOI:10.1007/s11164-014-1685-7

Res Chem Intermed
DOI 10.1007/s11164-014-1685-7
Facile synthesis of benzimidazole, benzoxazole,
and benzothiazole derivatives catalyzed by sulfonated
rice husk ash (RHA-SO3H) as an efficient solid acid
catalyst
•
Farhad Shirini Manouchehr Mamaghani
Mohadeseh Seddighi
•
Received: 5 February 2014 / Accepted: 22 April 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract A mild, simple, and efficient solvent-free method, with sulfonated rice
husk ash as solid acid catalyst, has been developed for preparation of benzimid-
azole, benzoxazole, and benzothiazole derivatives. The products are obtained in
good to high yields after very short reaction times, and the catalyst can be reused
five times without loss of its catalytic activity.
Keywords Rice husk ash Á Sulfonated rice husk ash Á ortho esters Á
Benzimidazole
Introduction
Benzimidazole, benzoxazole, benzothiazole, and their derivatives are among the
most important classes of heterocyclic compound occurring widely in natural
products. They have a wide range of biological activity, for example anticancer [1,
2], anti-inflammatory [3], anti-HBV [4], antimicrobial [5, 6], antitumor [7], and
antiviral [8]. They are, therefore, used as important intermediates for synthesis of a
variety of potent commercial drugs, for example albendazole (inhibitor of
Encephalitozoon intestinalis infection in AIDS patients), omeprazole (proton pump
inhibitor), pimobendan (ionodilator), mebendazole (anthelmintic), and phortress [3,
7] (Scheme 1). These compounds can also act as ligands for transition metals [9,
10].
A range of methods is available for synthesis of these heterocycles, including
condensation of o-aminobenzenethiol, o-aminophenol, or o-phenylenediamine with
acid chlorides [11], carboxylic acids [12, 13], esters [14], aldehydes [15–19], nitrile
F. Shirini (&) Á M. Mamaghani Á M. Seddighi
Department of Chemistry, College of Science, University of Guilan, Post Box 1914, 41335 Rasht,
Islamic Republic of Iran
e-mail: shirini@guilan.ac.ir
123

F. Shirini et al.
O
O
O
H
N
H
N
O
N
OCH3
S
F
OCH3
N
S
NH
NH
N
H
H
N
(CH2)4NH2
Albendazole
Mebendazole
Phortress
H
N
O
N
S
N
OCH3
N
N
H3CO
H
N
O
N
OCH3
H
Pimobendan
Omeprazole
Scheme 1 Pharmaceutically active compounds containing the benzimidazole and benzothiazole
structures
oxide [20], dibromomethylarenes [21], and ortho esters [22–29] in the presence of a
strong acid. Copper or palladium-catalyzed cyclization of ortho halobenzanilides
[30, 31] and radical cyclization of substituted thioformanilides with manganese
triacetate [32] have also been reported. Although these procedures are an
improvement, many of these catalysts or activators suffer from such disadvantages
as long reaction time, harsh reaction conditions, need for excess amounts of the
reagents, use of organic solvents, use of toxic reagents, and non-recoverability of
the catalyst. Furthermore, use of homogeneous catalysts has several serious
problems, for example difficulty of separation and recovery of the catalyst, and
corrosion problems. Therefore, introduction of simple, efficient, and mild proce-
dures with easily separable and reusable solid catalysts to overcome these problems
is still in demand.
Replacement of conventional, toxic and polluting Brønsted and Lewis acid
catalysts with eco-friendly reusable heterogeneous catalysts is a topic of current
interest. In this context, there has been renewed interest in the synthesis of solid acid
catalysts for organic reactions. Solid acid catalysts have many advantages compared
with traditional liquid acids, for example efficiency, operational simplicity, easy
recyclability and recoverability, non-corrosive nature, and benign effect on the
environment, all of which are important in industry. Solid acid catalysts might,
therefore, be extremely important in the development of clean technology. In this
work sulfonated rice husk ash (RHA-SO3H) was used as an efficient solid acid
catalyst.
Experimental
Chemicals were purchased from Fluka, Merck, and Aldrich. All yields refer to
isolated products. Products were characterized by comparison of their physical
properties and their IR and NMR spectra with those of authentic samples and with
data reported in the literature. Determination of purity and monitoring of reactions
were performed by TLC on Polygram SILG/UV 254 silica gel plates.
123

Benzimidazole, benzoxazole, and benzothiazole derivatives
1,2-Phenylenediamine, 2-aminophenol, or 2-aminothiophenol) (1 mmol) was
added to a mixture of RHA-SO3H (30 mg) and the ortho ester (trimethyl
orthoformate, triethyl orthoformate, or triethyl orthoacetate) (1.5 mmol), and the
resulting mixture was stirred at 65 °C for the appropriate time (Table 2). After
completion of the reaction, monitored by TLC (EtOAc–n-hexane 1:1), ethyl acetate
(20 mL) was added and the catalyst was separated by filtration. The organic phase
was washed with brine and dried over Na2SO4. The solvent was removed under
reduced pressure. If necessary the products were purified by recrystallization from
n-hexane to afford the desire product in good to high yield.
Selected spectral data
1
Benzimidazole (Table 2, entry 1): m.p. 171–173; H NMR (CDCl3, 400 MHz,):
d = 7.33 (2H, dd, J1 = 6.0 Hz, J2 = 3.2 Hz), 7.71 (2H, dd, J1 = 6.2 Hz,
J2 = 3.2 Hz), 8.10 (s, 1H); 13C NMR (CDCl3, 100 MHz): d = 115.3, 121.3,
137.1, 140.5.
2-Methyl-5-nitrobenzimidazole (Table 2, entry 6): m.p. 225–226; 1H NMR
(CDCl3, 400 MHz,): d = 2.72 (3H, s, CH3), 7.60 (1H, d, J = 8.8 Hz), 8.21 (1H, dd,
J1 = 8.8, J2 = 2 Hz), 8.50 (1H, s).
1
2-Methylbenzothiazole (Table 2, entry 13): Oil; H NMR (CDCl3, 400 MHz,):
d = 2.83 (3H, s, CH3), 7.34 (1H, td, J1 = 7.4 Hz, J2 = 1.2 Hz), 7.44 (1H, td,
J1 = 7.8 Hz, J2 = 1.2 Hz), 7.81 (1H, d, J = 8.0 Hz), 7.96 (1H, d, J = 8.0 Hz); 13
C
NMR (CDCl3, 100 MHz): d = 20.1, 121.4, 122.4, 124.7, 125.9, 135.6, 153.3,
167.0.
Results and discussion
Very recently we reported the preparation and characterization of sulfonated rice
husk ash (RHA-SO3H) as a new solid acid catalyst and its suitability for
chemoselective preparation and deprotection of 1,1-diacetates [33] and for synthesis
some of bis-heterocyclic compounds [34].
On the basis of information obtained from studies on RHA-SO3H, we expected it
to be an efficient solid acid catalyst and were interested in investigating its use for
promotion of the synthesis of benzoxazoles, benzothiazoles, and benzimidazoles.
For optimization of the reaction conditions, the reaction between 1,2-phenyl-
enediamine and triethyl orthoformate to give the corresponding benzimidazole was
chosen as model reaction and different conditions, including temperature and
amount of catalyst, were examined (Table 1). The best result was obtained by use of
30 mg RHA-SO3H and 1.5 mmol triethyl orthoformate at 60 °C under solvent-free
conditions. Any further increase in the amount of catalyst or of temperature did not
improve the reaction time or yield. To illustrate the efficiency of RHA-SO3H in
these reactions, the model reaction was also conducted in the absence of catalyst;
under these conditions the reaction proceeded slowly (Table 1, entry 7). Moreover,
the long reaction time observed for the same reaction when RHA was used as
123

F. Shirini et al.
Table 1 Optimization of the
reaction conditions for catalysis
by RHA-SO3H
Entry
Amount of
catalyst (mg)
Temperature
(°C)
Time
(min)
Conversion
(%)
1
2
3
4
5
6
7
8a
100
50
50
50
30
30
0
r.t.b
r.t.
50
15
30
6
100
100
100
100
100
100
20
60
3
60
3
80
3
60
120
180
a
RHA was used as catalyst
30
60s
90
b
Room temperature
catalyst confirms the importance of the catalyst’s -SO3H groups in promotion of the
reaction (Table 1, entry 8).
After optimization of the reaction conditions, to establish the effectiveness and
acceptability of the method we investigated the procedure with a variety of simple,
readily available substrates under the optimum conditions (Scheme 2). As presented
in Table 2, several ortho esters (including trimethyl orthoformate, triethyl
orthoformate, and triethyl orthoacetate) were used, and afforded a variety of
benzimidazole, benzoxazole and benzothiazole derivatives in good to excellent
yields without the formation of any by-products A series of o-phenylenediamine
derivatives reacted with these ortho esters and afforded the respective benzimidaz-
oles in good to excellent yields (Table 2, entries 1–8). It is apparent that o-
phenylene diamines with electron-donating groups gave the desired products in
excellent yields in very short times (Table 2, entries 7, 8) whereas o-phenylene
diamines with electron-withdrawing groups required heating at 80 °C (Table 2,
entries 4–6). Reaction of o-aminophenol with ortho esters was also investigated.
These reactions were conducted at higher temperature (80 °C) because of the low
nucleophilicity of the OH group, and the corresponding benzoxazoles were obtained
(Table 2, entries 9, 10). The method was also found to be useful for synthesis of
benzothiazole derivatives, in very short reaction times, by reaction of o-
aminothiophenol and ortho esters (Table 2, entries 11–13).
The mechanism proposed for synthesis of benzimidazole in the presence of
RHA-SO3H as catalyst is shown in Scheme 3. On the basis of this mechanism,
RHA-SO3H acts as a Brønsted acid and activates the ortho ester against the
nucleophilic attack.
NH2
N
X
RHA-SO3H (30 mg)
Neat, 60 oC
R1C(OR2)3
R1
+
R
XH
R
Scheme 2 Synthesis of benzimidazole, benzoxazole, and benzothiazole derivatives catalyzed by RHA-
SO3H solid acid
123

Benzimidazole, benzoxazole, and benzothiazole derivatives
Table 2 Synthesis of benzimidazole, benzoxazole, and benzothiazole derivatives catalyzed by RHA-
SO3H solid acid
Entry Substrate
ortho Ester
CH(OEt)3
Product
Time
(min)
Yield m.p. (°C)
(%)
Found
Reported
1
3
3
2
4
3
94
92
90
91
88
171–173 173 [27]
N
NH2
NH2
NH2
NH2
NH2
NH2
N
H
2
CH(OCH3)3
CH3C(OEt)3
CH(OEt)3
–
–
N
N
H
3
175–177 176–177
[26]
N
N
H
4a
205–207 206–208
[36]
N
NH2
N
H
O2N
O2N
O2N
NH2
5a
CH(OCH3)3
–
–
N
NH2
NH2
NH2
NH2
N
H
O2N
6a
CH3C(OEt)3
CH(OEt)3
4
7
4
4
1
1
1
1
87
95
89
92
91
95
92
93
225–226 225–227
[36]
N
N
O2N
O2N
H
7
109–111 108–110
[31]
NH2
NH2
N
N
H
3C
H
3C
3C
H
8
CH3C(OEt)3
CH(OEt)3
198–200 198–200
[36]
NH2
NH2
N
N
H
3C
H
H
9a
Oil
Oil
Oil
–
Oil [35]
Oil [35]
Oil [36]
–
H
O
O
N
NH2
10a
11
12
13
CH3C(OEt)3
CH(OEt)3
O
H
O
N
NH2
H
S
S
N
NH2
CH(OCH3)3
CH3C(OEt)3
H
S
S
N
NH2
Oil
Oil [35]
H
S
S
N
NH2
Reaction conditions: substrate (1 mmol), triethyl orthoformate (1.5 mmol), RHA-SO3H (30 mg) under
solvent-free conditions at 60 °C
a
Reaction performed at 80 °C
123

F. Shirini et al.
H
N
N
-EtOH
EtO
N
H
N
H
Product
(VII)
O
S
RHA
O
N
N
O
EtO
O
S
OEt
RHA
OH
H
H
Et
O
H
(VI)
O
H
OEt
H
N
EtO
(I)
EtO
H2N
(V)
H
Et
O
S
O
RHA
OH
H
O
OEt
EtO
EtO
EtO
H
N
H2N
H
2N
(IV)
H
H
H2N
EtO
EtO
(II)
N
O
H2N
RHA
O
S
O
O
RHA
O
S
(III)
O
Scheme 3 Proposed mechanism for reaction of o-phenylenediamine with triethyl orthoformate using
RHA-SO3H as catalyst
To check the reusability of the catalyst, reaction of o-phenylenediamine and
triethyl orthoformate under the optimized reaction conditions was studied again.
When the reaction completed, ethyl acetate was added and the catalyst was
separated by filtration. The recovered catalyst was washed with dichloromethane,
dried, and reused for the same reaction. This process was repeated five times and all
the reactions led to the desired products without any changes in reaction time or
yield, which clearly demonstrates the practical recyclability of RHA-SO3H. pH
analysis of the recovered catalyst revealed the proton loading was 2.4 mmol H?/g,
suggesting that the nature of the catalyst remains intact after each run and leaching
of the acid species does not occur during the course of the reaction.
To show the efficiency of the method, we compared our result obtained from
reaction of 1,2-phenylenediamine, 5-nitro-1,2-phenylenediamine, or 1,2-aminothio-
phenol with triethyl orthoformate in the presence of RHA-SO3H with other results
reported in the literature. As is apparent from Table 3, this method avoids the
disadvantages of other procedures, for example long reaction times, excess reagents,
high temperature, and organic solvents.
123

Benzimidazole, benzoxazole, and benzothiazole derivatives
123

F. Shirini et al.
Conclusion
In conclusion, we have used RHA-SO3H as a highly powerful solid acid catalyst for
simple and efficient synthesis of benzimidazole, benzoxazole, and benzothiazole,
and their derivatives. The procedure has several advantages, for example high rates
of reaction, ease of preparation and handling of the catalyst, simple experimental
procedure, and use of an inexpensive and reusable catalyst. Furthermore, this
process avoids problems associated with organic solvents and use of liquid acids;
these economic and environmental advantages make it a useful and attractive
strategy. The effectiveness of this convenient technique is comparable with that of
existing methods for synthesis of benzimidazole and its derivatives. Studies of
practical applications of RHA-SO3H as catalyst in other organic reactions are
currently in progress in our laboratory.
Acknowledgments We are thankful to the University of Guilan Research Council for partial support of
this work.
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