Silphox [POCl3-n(SiO2)n] as a new, efficient, and heterogeneous reagent for the synthesis of benzimidazole derivatives under microwave irradiation

Article abstract of DOI:10.1080/10426500802080931

Silphox [POCl3-n(SiO2)n] efficiently catalyzes the condensation of benzene-1,2-diamine with mono and dicarboxylic acids under microwave irradiation to afford benzimidazole derivatives in high yields and short reaction times.

Full text of DOI:10.1080/10426500802080931

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Silphox [POCl3-n (SiO2) n ]
as a New, Efficient, and
Heterogeneous Reagent for
the Synthesis of Benzimidazole
Derivatives Under Microwave
Irradiation
Alireza Hasaninejad a , Khodabakhsh Niknam a
,
Abdolkarim Zare b , Ehsan Farsimadan b & Mohsen
Shekouhy a
a Department of Chemistry, Faculty of Sciences ,
Persian Gulf University , Bushehr , Iran
b Department of Chemistry , Payame Noor University
(PNU) , Bushehr , Iran
Published online: 19 Dec 2008.
To cite this article: Alireza Hasaninejad , Khodabakhsh Niknam , Abdolkarim Zare ,
Ehsan Farsimadan & Mohsen Shekouhy (2008) Silphox [POCl3-n (SiO2) n ] as a New,
Efficient, and Heterogeneous Reagent for the Synthesis of Benzimidazole Derivatives
Under Microwave Irradiation, Phosphorus, Sulfur, and Silicon and the Related
Elements, 184:1, 147-155, DOI: 10.1080/10426500802080931
To link to this article: http://dx.doi.org/10.1080/10426500802080931
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Phosphorus, Sulfur, and Silicon, 184:147–155, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802080931
Silphox [POCl3-n(SiO2)n] as a New, Efficient, and
Heterogeneous Reagent for the Synthesis of
Benzimidazole Derivatives Under Microwave Irradiation
Alireza Hasaninejad,1 Khodabakhsh Niknam,1
Abdolkarim Zare,2 Ehsan Farsimadan,2
and Mohsen Shekouhy1
1Department of Chemistry, Faculty of Sciences, Persian Gulf University,
Bushehr, Iran
2Department of Chemistry, Payame Noor University (PNU), Bushehr,
Iran
Silphox [POCl3 n(SiO2)n] efficiently catalyzes the condensation of benzene-1,2-
-
diamine with mono and dicarboxylic acids under microwave irradiation to afford
benzimidazole derivatives in high yields and short reaction times.
Keywords Benzene-1,2-diamine; benzimidazole derivatives; carboxylic acid; mi-
crowave; silphox.
INTRODUCTION
Benzo-fused heterocyclic systems such as benzimidazole are well-
known because they possess a wide range of biological proper-
ties and clinical applications.1 These heterocyclic ring systems are
present in numerous antiparasitic, fungicidal, anthelmintic, and anti-
inflammatory drugs.2 Antibacterial and antifungal activity has been
observed for benzimidazole derivatives.3 2-Aryl and 2-alkyl benzimida-
zoles exhibit activity against HIV4 and influenza viruses.5 Thus, the
synthesis of these compounds has received considerable attention in
diverse areas of chemistry. A number of synthetic methods have been
developed to uncover a variety of new reagents for the preparation
Received 5 January 2008; accepted 20 February 2008.
The authors thank Persian Gulf University and Payame Noor University Research
Councils for financial support of this work.
Address correspondence to Alireza Hasaninejad, Department of Chemistry, Fac-
ulty of Sciences, Persian Gulf University, Bushehr 75169, Iran. E-mail: ahassanine-
jad@yahoo.com or Abdolkarim Zare, Department of Chemistry, College of Sciences,
Payame Noor University (PNU), Bushehr 1698, Iran. E-mail: abdolkarimzare@yahoo.com
147

148
A. Hasaninejad et al.
NH2
NH2
X
X
N
Silphox, DMF (a few drops)
MW, 400, 7-8 min
+
HO2C
N
H
Y
Y
1
2a-j
3a-j
72-93%
X = H, N Y = H, Me, OMe, NO2, Cl, Br
SCHEME 1
of benzimidazoles.6−10 The most commonly used synthetic approaches
typically entail the condensation of o-arylenediamines with carbonyl
compounds, such as aldehydes, carboxylic acids, and their derivatives.7
In addition, there have been several reports on benzimidazole syn-
thesis via the reductive cyclization of o-nitroanilines with aldehydes,8
cyclization of o-nitroaniline derivatives with aryl isothiocyanates,9 and
Baker’s yeast reduction of 2,4-dinitroacyl anilines.10 Recently, Salehi
et al. reported that the reaction of benzene-1,2-diamine with aldehydes
in the presence of silica sulfuric acid produced 2-aryl-1-arylmethyl-1H-
1,3-benzimidazoles.11 However, many of the reported methods have
several drawbacks, including low yields, long reaction times, the use
of expensive reagents, tedious workup procedures involving more than
one step in their synthesis, and co-occurrence of several side reactions.
Microwave irradiation has been extensively used for the rapid syn-
thesis of a variety of heterocyclic compounds.12 The beneficial effects of
microwave irradiation are finding an increased role in process chem-
istry, especially when conventional methods require forcing conditions
or prolonged reaction times.12 Moreover, the possibilities offered by
this technology are particularly attractive where high-yielding proto-
cols and avoidance or ease of purification are highly desirable.12
On the basis of the above facts, and also along with our previous stud-
ies on the applications of phosphorus-containing reagents13 as well as
microwave technology in organic synthesis,14 herein, we wish to report
an efficient, rapid, and simple method for the preparation of benzim-
idazole derivatives from benzene-1,2-diamine, mono and dicarboxylic
acids in the presence of silphox [POCl3-n(SiO2)n, silica phosphinoxide]
and a few drops of N,N-dimethylformamide (DMF) under microwave
irradiation (Schemes 1 and 2).
RESULTS AND DISCUSSION
We have previously used phosphorus-containing reagents for several
organic transformations.13 One of these reagents is silphox, which is
easily prepared by the reaction of plate silica gel with POCl3.13a We have

Synthesis of Benzimidazoles
149
Z
N
N
NH2
NH2
Z
Silphox, DMF (a few drops)
+
NH HN
HO2C
CO2H
MW, 400, 15-17 min
1
4a-c
5a-c
82-87%
SCHEME 2
applied this reagent successfully for the condensation of sulfonamides
with carbonyl compounds to produce N-sulfonyl imines.13a As a part
of our studies on applications of phosphorus-containing reagents in
organic synthesis, we have decided to employ silphox for the synthesis
of benzimidazole derivatives via the reaction of benzene-1,2-diamine
with carboxylic acids. Thus, at first, the reaction of benzene-1,2-diamine
(1 mmol) with benzoic acid (1 mmol) in the presence of silphox (1 g) and
DMF (10 drops) as a model was examined at the range 70–130◦C. The
results are summarized in Table I. As it can be seen from Table I, the
respective benzimidazole 3a was obtained in 86% yield after 240 min
at 110◦C. The same reaction was also tested in the presence of plate
silica gel as well as POCl3 at 110◦C separately (Table II). The results
showed that these reagents alone were not efficient for the synthesis of
benzimidazoles. Furthermore, the reaction of benzene-1,2-diamine with
benzoic acid was examined using P2O5/SiO2 in the presence of a few
drops of DMF at 110◦C; however, compound 3a did not produce at all,
even by prolonging the reaction time and increasing the temperature
(Table II). In these conditions, the starting materials remained intact
plus two undesired products, the structures of which have not been
identified.
TABLE I The Condensation of Benzene-1,2-diamine
with Benzoic Acid in the Presence of Silphox at
Different Temperatures
Entry
Temperature (◦C)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
70
80
90
100
110
120
130
1000
720
540
360
240
210
150
26
40
63
74
86
81
73
aIsolated yield.

150
A. Hasaninejad et al.
TABLE II The Reaction of Benzene-1,2-diamine
with Benzoic Acid in the Presence of Several
Reagents at 110◦C
Entry
Reagent
Time (min)
Yielda (%)
1
2
3
4
5
Silphox
Silica gel
POCl3
P2O5/SiO2
P2O5/SiO2
240
720
240
360
720
86
–
32
–
–
aIsolated yield.
TABLE III The Reaction of Benzene-1,2-diamine
with Benzoic Acid in the Presence of Silphox
Promoted by Microwave Irradiation (MW)
Entry
Microwave Power
Time (min)
Yielda (%)
1
2
3
4
5
6
100
200
300
400
500
600
25
18
12
8
5
3
32
63
79
93
85
74
aIsolated yield.
As Tables I and II show, the reaction yield under conventional ther-
mal conditions was relatively high; however, the reaction time was long.
To improve the reaction time, the model reaction was checked under
microwave irradiation at the range 100–600 W of microwave power
(Table III). As it is shown in Table III (entry 4), microwave irradiation
significantly decreased the reaction time and also increased the yield.
Therefore, we selected the microwave conditions as our main method
for all reactions.
To realize the efficiency of silphox for the synthesis of benzimida-
zoles, benzene-1,2-diamine was condensed with structurally diverse
carboxylic and dicarboxylic acids under microwave irradiation. The re-
sults are displayed in Table IV. As is clear from Table IV, all reactions
proceeded efficiently, and the products were produced in good to high
yields and short reaction times. The effect of electron-releasing and
electron-withdrawing substituents on the aromatic ring of carboxylic
acids upon the reaction was investigated. It has been observed that
electron-releasing groups had no significant effect on the yields and
the reaction times (Table IV, entries 2–4). The electron-withdrawing

Synthesis of Benzimidazoles
151
TABLE IV Preparation of Benzimidazole Derivatives from
Benzene-1,2-diamine, Mono and Dicarboxylic Acids Under
Microwave Conditions (400 W)
Entry
1
Product
Time (min)
8
Yielda (%)
M.p. ◦C (Lit.)
93
288–290
(292–294)7a
2
3
4
8
8
8
90
87
89
265–267
(270)7b
223–225
(226)7b
203–205
(201–204)7a
5
6
7
8
7
7
7
7
78
72
90
92
260–263
(264–265)6a
207–209
(204–207)7a
233–235
(234)6b
236–239
(238)6b
(Continued on next page)

152
A. Hasaninejad et al.
TABLE IV Preparation of Benzimidazole Derivatives from
Benzene-1,2-diamine, Mono and Dicarboxylic Acids Under Microwave
Conditions (400 W) (Continued)
Entry
Product
Time (min) Yielda (%)
M.p. ◦C (Lit.)
9
7
89
245–247
(241–244)7a
10
8
89
87
84
216–218
(217–219)7d
11b
12b
15
17
[294–296 (dec.)]
[296–298 (dec.)]7d
[210–212 (dec.)]
[212 (dec.)]6c
13b
17
82
273–276
(>250)7d
aIsolated yield.
substituent did not affect on the reaction times while decreased the
yields (Table IV, entries 5 and 6). Moreover, the results showed that
the presence of a halogen on the aromatic ring of carboxylic acids
had negligible influence on the reaction results (Table IV, entries 7–
9). This method was also applied successfully for the condensation of
benzene-1,2-diamine (2 eq.) with dicarboxylic acids (1 eq.) to afford
bis-benzimidazoles in high yields and short reaction times (Table IV,
entries 11–13).
The efficiency and applicability of this new procedure was compared
with some reported methods for the preparation of 2-substituted ben-
zimidazoles (Table V). As Table V demonstrates, our method afforded
the better results.

Synthesis of Benzimidazoles
153
TABLE V The Comparative Synthesis of Compound 3a
Using the Reported Methods Versus the Present Method
Entry
Reagent
Time (min) Yielda (%) Ref.
1b
2
3
4
5
Silphox
Zeolite
Pyridine/SOCl2
In(OTf)3
Alumina-methanesulfonic acid
Air in capped tube
8
180
1080
30
8
960
93
81
92
95
87
85
–
7a
7b
7c
7d
7g
6
aIsolated yield.
bOur method.
In summary, we have introduced an efficient reagent for the conden-
sation of benzene-1,2-diamine with carboxylic acids under microwave
irradiation. The promising points for the presented methodology are
high conversion, ease of handling, and low cost of the reagent, and
cleaner reaction profile and short reaction times, which makes it a use-
ful and attractive process for the rapid synthesis of benzimidazoles and
bis-benzimidazoles as biologically interesting compounds.
EXPERIMENTAL
All chemicals were purchased from Merck or Fluka Chemical Com-
panies. Plate silica gel (Mesh 60, 15–40 µm) was used as support. All
known compounds were identified by comparison of their melting points
and 1H NMR data with those in the authentic samples.6a,6b,6c,7a,7b,7d All
reactions were carried out using a domestic microwave oven (MB 245,
1
Butan Industrial Co., Iran). The H NMR (250 MHz) and 13C NMR
(62.5 MHz) spectra were run on a Bruker Avance DPX-250, FT-NMR
spectrometer (δ in ppm). Melting points were recorded on a Stuart Sci-
entific Apparatus SMP3 (UK) in open capillary tubes.
Procedure for the Preparation of Silphox13a
Under nitrogen atmosphere, to a flask containing dry plate silica gel
(6.0 g, 0.1 mol), POCl3 (64 g, 0.5 mol) at room temperature was added
and stirred slowly with a mechanical stirrer for 30 min. The mixture
was then heated to 60◦C while it was stirring under pressure of nitrogen
for 3 h to remove all produced HCl. Afterward, the reaction mixture was
cooled to room temperature, filtered, and the resulting precipitate was
washed with dry CH2Cl2 (50 mL) to give silphox as a white solid (9.1–
9.3 g), which was stored in a capped bottle. The reagent can be kept
without any change for months.

154
A. Hasaninejad et al.
General Procedure for the Synthesis of Benzimidazoles via
Condensation of Benzene-1,2-diamine with Carboxylic Acids
Under Microwave Irradiation
To a well-ground mixture of benzene-1,2-diamine (0.11 g, 1 mmol),
carboxylic acid (1 mmol), and silphox (1 g) in a test tube, DMF (10
drops) was added and mixed carefully with a small rod. The resulting
mixture was irradiated in a microwave oven at 400 W for the times
reported in Table IV. Afterward, the reaction mixture was cooled to
room temperature, and warm EtOAc (50 mL) was added to the reaction
mixture, filtered, and the filtrate was washed with saturated NaHCO3
(2 × 50 mL) and H2O (2 × 50 mL). After evaporation of the solvent, the
resulting solid was recrystallized from EtOH to give the pure product.
Some Selected Spectral and Physical Data of Benzimidazole
Derivatives
2-Phenyl-1H-benzo[d]imidazole (3a)
1
White solid; m.p. 288–290◦C (Lit.7a 292–294◦C); H NMR (DMSO-
d6): δ 7.12–7.19 (m, 2H), 7.49–7.55 (m, 5H), 7.98 (m, 2H), 12.56 (s, 1H);
13C NMR (DMSO-d6): δ 114.2, 121.6, 125.3, 126.2, 130.6, 131.2, 134.7,
148.8.
2-[((1H-Benzo[d]imidazol-2-yl)methoxy)methyl]-1H-
benzo[d]imidazole (5a)
White solid; m.p. 294–296◦C (dec.) [Lit.7a 296–298◦C (dec.)]; 1H NMR
(DMSO-d6): δ 4.89 (s, 4H), 7.14–7.22 (m, 4H), 7.53–7.58 (m, 4H), 12.63
(s, 2H); 13C NMR (DMSO-d6): δ 65.9, 113.0, 119.4, 129.1, 149.2.
2-(6-(1H-Benzo[d]imidazol-2-yl)pyridin-2-yl)-1H-
benzo[d]imidazole (5c)
White solid; m.p. 273–276◦C (Lit.7d >250◦C); 1H NMR (DMSO-d6): δ
7.23–7.27 (m, 4H), 7.66–7.70 (m, 4H), 8.03 (m, 2H), 8.29 (d, 1H, J = 7.3
Hz), 12.55 (s, 2H); 13C NMR (DMSO-d6): δ 119.6, 123.9, 125.1, 138.1,
149.2, 151.2, 152.6.
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