Selective synthesis of 2-aryl-1-benzylated-1H-benzimidazoles

Article abstract of DOI:10.1002/cjoc.201180408

An efficient and simple procedure was developed for the green synthesis of various 2-aryl-1-ben-zylated-1H-benzimidazoles in high yields by condensation of o-phenylenediamine with aldehydes with P₂O₅/SiO ₂ as catalyst unde

Full text of DOI:10.1002/cjoc.201180408

FULL PAPER
Selective Synthesis of 2-Aryl-1-benzylated-1H-benzimidazoles
Shaterian, Hamid Reza
Fahimi, Nafiseh
Azizi, Kobra
Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan, PO Box 98135-674, Zahedan,
Iran
An efficient and simple procedure was developed for the green synthesis of various 2-aryl-1-ben-
zylated-1H-benzimidazoles in high yields by condensation of o-phenylenediamine with aldehydes with P2O5/SiO2
as catalyst under solvent-free and ambient conditions.
Keywords synthetic methods, aldehydes, one-pot, benzimidazoles, heterogeneous catalyst, solvent-free
Introduction
tion and simple work-up accompanied by removing it
from the reaction mixture by simple filtration.17 In con-
tinuation of our research on application of heterogene-
ous catalysts in organic reactions,18 we have employed
P2O5 supported on silica in preparation of benzimidaz-
oles. In our work, the reaction of o-phynelenediamine (1
equiv.) and benzaldehyde (1 equiv.) produced 2-aryl-
1-benzylated-1H-benzimidazoles instead of 2-aryl-1H-
benzimidazoles (1) and almost 50% of o-phynelene-
diamine was intact. Thus, we used 2 equiv. of benzal-
dehyde to complete the reaction.
The benzimidazole nucleus is of significant impor-
tance in medicinal chemistry and many benzimida-
zole-containing compounds exhibit important biological
activities such as selective neuropeptide YY1 receptor
ntagonists,1 angiotensin II inhibitors,2 5-HT3 antagonists
in isolated guinea pigileum,3 potential antitumor agents,4
antimicrobial agents,5 smooth muscle cell proliferation
inhibitors,6 a treatment for interstitial cystitis,7 as factor
Xa inhibitors,8 and in diverse areas of chemistry.9 In
addition, benzimidazoles are very important intermedi-
ates in organic reactions.10
Therefore, the preparation of benzimidazoles has
gained considerable attention in recent years.11-13 The
common synthesis of benzimidazoles includes the reac-
tion between an o-phenylendiamine and a carboxylic
acid or its derivatives (nitriles, amidates and orthoesters)
under harsh dehydrating conditions.14 Another method
for the synthesis of these compounds is the reaction of
o-phenylenediamine with aldehydes in the presence of
acidic catalysts under various reaction conditions.15a,15b
Phosphorus pentoxide is a white, flammable, dan-
gerous, corrosive to metal and extremely deliquescent
compound.16 It reacts vigorously with water and wa-
ter-containing substances, liberates much heat and may
even cause fire.16 There are many reports using phos-
phorus pentoxide as a reagent in organic reactions.16a
Phosphorus pentoxide-methanesulfonic acid was
used for the first time as a convenient alternative to
polyphosphoric acid by Eaton et al. to escape the diffi-
culties encountered with polyphosphoric acid (PPA).17a
P2O5 is difficult to handle due to its moisture sensitivity.
However, the preparation of P2O5 on silica (P2O5/SiO2)
is straight forward to escape from disadvantages of
P2O5.17b,17c
N
N
Ar
Ar
N
N
H
Ar
1
2
We found that the catalyst acted selectively for
preparation of 2-aryl-1-benzylated-1H-benzimidazoles
with molar ratio 2.0∶ 1.0 of aldehyde and o-phenyl-
enediamine (Eq. 1).
NH2
Catalyst (P2O5/SiO2)
Solvent-free (r.t.)
N
N
2 ArCHO
+
Ar
(1)
NH2
Ar
Literature survey showed that 2-aryl-1H-benzimid-
azoles (1) and their derivatives are prepared from the
reaction of o-phynelenediamine and aldehydes in the
presence of catalysts such as (SiO2-FeCl3),19a nanopor-
ous aluminosilicate,19b Dess-Martin-periodinane reagent
(DMP),19c ammonium metavanadate,19d tungstophos-
phoric acid impregnated zirconium phosphate,19e co-
balt(II) chloride hexahydrate.19f Whereas, 2-aryl-1-ben-
zylated-1H-benzimidazoles (2) are synthesized in the
presence of catalysts such as montmorillonite K-10,15a
acetic acid,15b L-proline.15c
P2O5/SiO2 as a heterogeneous catalyst shows several
advantages such as the easiness of handling, clean reac-
*
E-mail: hrshaterian@chem.usb.ac.ir; Tel.: 0098-541-2446565; Fax: 0098-541-2431067
Received April 29, 2011; revised June 13, 2011; accepted July 15, 2011.
Chin. J. Chem. 2011, 29, 2389— 2393
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Shaterian, Fahimi & Azizi
FULL PAPER
Experimental
2.0∶1.0) was performed in the presence of P2O5/SiO2
(0.5 g 7% w/w) as catalyst at room temperatures under
solvent-free conditions.
All reagents were purchased from Merck and
Sigma-Aldrich and used without further purification.
P2O5/SiO2 (7% w/w) was prepared according to the re-
ported procedure.20 All yields refer to isolated products
after purification. Products were characterized by com-
parison of physical data with authentic samples and
spectroscopic data (IR and NMR). The NMR spectra
were recorded on a Bruker Avance DPX 300 MHz in-
strument. The spectra were measured in DMSO relative
to TMS. IR spectra were recorded on a JASCO FT-IR
460 plus spectrophotometer. Melting points were deter-
mined in open capillaries with a BUCHI 510 melting
point apparatus. TLC was performed on Silica-gel poly-
gram SILG/UV 254 plates.
Next, to optimize the amount of the catalyst in the
mentioned reaction, we have carried out the reaction of
o-phenylenediamine, benzaldehyde (molar ratio 1.0∶
2.0) as model of our study with different amount of
P2O5/SiO2 as catalyst under solvent-free conditions at
room temperatures (Table 1). It was found that 0.05 g of
the catalyst showed maximum yield (95%) in minimum
reaction time (6 min).
Table 1 Optimization the amount of P2O5/SiO2 as the catalyst in
the reaction of o-phenylenediamine and benzaldehyde under sol-
vent-free conditions
Entry
Catalyst/mg
Time/min
Yielda/%
General procedure for the selective synthesis of
2-aryl-1-benzylated-1H-benzimidazoles derivatives
1
2
3
4
30
40
50
60
18
10
6
80
88
95
93
A stirred mixture of arylaldehydes (20 mmol),
o-phenylenediamine derivatives (10 mmol) and P2O5/
SiO2 (0.5 g, 7% w/w)20 was added and the reaction mix-
ture was stirred for the indicated time (Table 2) at room
temperatures. After the completion of reaction (moni-
tored by TLC), the reaction mixture was cooled, then 5
mL of ethanol was added to it and the total liquid was
filtered to remove P2O5/SiO2. The catalyst was washed
four times with ethylacetate (5 mL×4), and then that
recovered catalyst was dried in oven at 100 ℃ for 3 h.
Finally the crude product was recrystallized from etha-
nol.
5
a Yields refer to isolated pure product.
Using these optimized reaction conditions (0.05 g of
P2O5/SiO2 (7% w/w) at room temperatures and molar
ratio 2.0∶1.0 of aldehyde and o-phenylenediamine un-
der solvent-free conditions), the scope and efficiency of
the reaction were explored for the synthesis of a wide
variety of substituted 2-aryl-1-benzylated-1H-benzi-
midazoles. The results are summarized in Table 2.
The desired pure product(s) was characterized by
comparison of their physical data with those of known
compounds.15, 21-27
Table 2 Synthesis of 2-aryl-1-benzylated-1H-benzimidazole
derivatives through direct condensation of aldehyde and
o-phenylenediamine (molar ratio: 2.0/1.0) catalyzed by P2O5/SiO2
(0.05 g) under solvent free conditions at room temperature
2-(3,4-Dimethoxyphenyl)-1-(3,4-dimethoxyphen-
yl)methyl-1H-benzimidazole (Table 2, Entry 13) m.p.
1
170—172 ℃; H NMR (CDCl3, 300 MHz) δ: 7.71—
6.43 (m, 10H, Ar-H), 5.50 (s, 2H, CH2), 3.82, 3.71, 3.68,
3.64 (4s, 4OCH3); 13C NMR (CDCl3, 75 MHz) δ: 153.17,
149.98, 148.73, 148.58, 147.96, 142.55, 135.99, 129.31,
122.38, 122.35, 122.02, 121.55, 118.93, 117.91, 112.27,
111.74, 111.58, 110.92, 110.03, 55.52, 55.35, 55.31,
55.25, 47.19; IR (KBr) ν: 3050, 2999, 2963, 2838, 1611
Found m.p./℃
Entry
R
Time/min Yielda/%
[lit. m.p.]Ref
133—135
[134]21
1
2
3
4
5
6
7
8
C6H5
6
10
8
95
90
92
88
90
91
89
80
131—132
4-MeOC6H4
4-MeC6H4
4-ClC6H4
2-MeOC6H4
2-ClC6H4
4-O2NC6H4
4-NCC6H4
－
1
[131]15
cm ;
2-(2-Chlorophenyl)-1(2'-chlorophenylmethyl)-4-
methyl-1H-benzimidazole (Table 2, Entry 6) m.p.
129—130
[127—128]22
140—141
[137]15
1
152—154 ℃; H NMR (CDCl3, 300 MHz) δ: 7.52—
7.39 (m, 3H), 7.33 (d, J＝7.9 Hz, 1H), 7.27 (d, J＝7.7
Hz, 1H), 7.20—7.12 (m, 3H), 7.05 (t, J＝7.5 Hz, 2H),
6.63 (d, J＝7.5 Hz, 1H), 5.33 (s, 2H), 2.75 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ: 150.6, 142.3, 134.5, 134.4,
133.4, 132.3, 131.3, 130.0, 129.8, 129.5, 128.9, 127.8,
127.0, 126.9, 123.3, 123.1, 107.9, 45.7, 16.8; IR (KBr) ν:
3436, 3055, 2922, 2373, 1604, 1441, 1382, 1046, 755.
6
152—154
6
[151]15
158—159
[159]22
8
190—192
5
[192]15
Results and discussion
216—218
[216—219]27
7
In our initial experiments, we found that the conden-
sation of arylaldehyde, o-phenylenediamine (molar ratio
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 2389— 2393

Selective Synthesis of 2-Aryl-1-benzylated-1H-benzimidazoles
Continued
closure led to intermediate II. Finally, 1,3-hydride
transfer afforded 2-aryl-1-benzylated-1H-benzimidaz-
oles.
Found m.p./℃
[lit. m.p.]Ref
120—121
[120]22
Entry
9
R
Time/min Yielda/%
Scheme 1
2-O2NC6H4
4-(CH3)2NC6H4
4-BrC6H4
10
8
85
86
87
85
80
83
87
80
78
P2O5/SiO2
+O
255—257
P2O5/SiO2
10
[255]22
R
H
N
158—160
[157—158]24
113—115
[110—112]25
173—175
[170—172]24
190—192
[184—186]24
231—233
[229—231] 24
224—226
[222]23
Ar
H
+
11
8
N
NH2
Ar
I
12
4-FC6H4
5
NH2
P2O5/SiO2
13
10
12
10
8
Ar
H
N
N
N
N
3,4-(MeO)2C6H3
Ar
3-(MeO)-4-(HO)C6H3
14
Ar
Ar
P2O5/SiO2
II
15 4(MeO)-3-(HO)C6H3
Almost all substrates could give their corresponding
2-aryl-1-benzylated-1H-benzimidazoles exclusively as a
single product (without the formation of 2-aryl-1H-
benzimidazoles). The results are documented in Table 2.
It is noteworthy that 2,4-dichlorobenzaldehyde repre-
sents as a single exceptional example by furnishing
2-aryl-1H-benzimidazole exclusively instead of 2-aryl-
1-benzylated-1H-benzimidazole (Eq. 2). The formation
of 2-aryl-1H-benzimidazole from 2,4-dichlorobenzal-
dehyde also reported by other catalyst such as Amberlite
IR-120.24
16
17
4-HOC6H4
3-HOC6H4
255—257
10
[253]24
97
18
2-Furyl
8
75
[94—96]24
[94]26
176—178
[176]26
19
20
4-isoPropyl C6H4
2-Pyridyl
6
78
80
Cl
128—130
NH2
12
Catalyst (P2O5/SiO2)
[130]26
OHC
Cl
2
+
Solvent-free (r.t)
a
NH2
Yields refer to the isolated pure products. The desired pure
products were characterized by comparison of their physical data
(melting points, IR, 1H and 13C NMR) with those of known com-
pounds.15,21-27
Cl
N
Cl
(2)
N
H
As shown in Table 2, aromatic aldehydes react
without any significant difference in rate to give the
corresponding 2-aryl-1-benzylated-1H-benzimidazoles
in good yields. The method has the ability to tolerate
other functional groups such as methyl, methoxy, nitro
and halo groups. Consequently several aromatic alde-
hydes with different substituents on the aromatic ring
were subjected to the condensation reaction. We exam-
ined these reactions using aliphatic aldehydes, but no
appreciable amount of product was formed in the same
conditions.
In order to show the accessibility of the present work
in comparison with the reported results in the literature
such as LiCl or silica sulfuric acid,26 Dowex 50W (acid
form),27 L-proline,15c acetic acid15b and Amberlite
IR-120,24 we summarized some of the results for the
preparation of 2-aryl-1-benzylated-1H-benzimidazoles
in Table 3, which shows that P2O5/SiO2 (7% w/w) is the
most efficient catalyst with respect to the reaction time
and temperature and exhibits broad applicability in
terms of yield (Table 3).
We also investigated the recycling of the catalyst
under solvent-free conditions using a model reaction of
benzaldehyde, o-phenylenediamine (Table 2, Entry 1).
In this procedure, after completion of the reaction, the
As reported in literature,28 the proposed mechanism
for synthesis of 2-aryl-1-benzylated-1H-benzimidazoles
is shown in Scheme 1. P2O5/SiO2 activated the carbonyl
group of aldehydes for imine condensation to form the
dibenzylidene-o-phenylenediamine (I) and then ring
Chin. J. Chem. 2011, 29, 2389— 2393
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Shaterian, Fahimi & Azizi
FULL PAPER
Table 3 Comparison results of P2O5/SiO2 with LiCl or silica sulfuric acid, Dowex 50 W (acid form), L-proline, acetic acid and Amber-
lite IR-120 in the synthesis of 2-aryl-1-benzylated-1H-benzimidazolesa
Entry
Catalyst
LiCl
Amount of catalyst
0.02 g
Condition
In water (r.t.)
Time
2 h
Yield/%
71
1
Silica sulfuric acid
Dowex 50W (acid form)
L-Proline
0.11 g
In ethanol (r.t.)
1.5 h
8 h
75
2
3
4
5
6
10 mol%
10 mol%
10 mL
In water (70 ℃)
83
In CHCl3 (r.t.)
5 h
95
Acetic acid
MW (50 ℃) (heating in air)
EtOH/H2O (2∶1) (r.t.)
Solvent-free (r.t.)
25 min
1.45 h
6 min
97
Amberlite IR-120
0.1 g
95
P2O5/SiO2 (7% w/w)
0.05 g
95
a Based on the reaction of o-phenylenediamine, benzaldehyde.
mixture was cooled to room temperature, and the crude
solid product was dissolved in ethylacetate. The mixture
was filtered for separation of the catalyst. The catalyst
was washed four times with ethylacetate (5 mL×4),
and then recovered catalyst was dried in oven at 100 ℃
for 3 h. The recovered catalyst was used for the subse-
quent catalytic runs. It was observed that on five suc-
cessive runs with P2O5/SiO2 as the catalyst, the reactiv-
ity in all runs remained almost unchanged (Figure 1).
2
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Figure 1 Reusability of the catalyst.
Conclusions
We have developed a green and straightforward
protocol for the selective synthesis of 2-aryl-1-benzyl-
ated-1H-benzimidazoles in the presence of P2O5/SiO2 as
reusable and heterogeneous catalyst under solvent-free
conditions at ambient conditions. This procedure pro-
vides several advantages such as cleaner reactions, eas-
ier workup, reduced reaction times, reusable catalyst,
and eco-friendly promising strategy.
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