Highly selective synthesis of libraries of 1,2-disubstituted benzimidazoles using silica gel soaked with ferric sulfate

Article abstract of DOI:10.1016/j.tetlet.2012.05.129

An efficient and highly selective synthesis of functionalized 1,2-benzimidazoles has been developed under solvent-free conditions at ambient temperature using eco-friendly ferric sulfate soaked with silica [iron(III)sulfate-silica]. Recycling of the solid support up to six runs was investigated with appreciable yield and selectivity of the product.

Full text of DOI:10.1016/j.tetlet.2012.05.129

Tetrahedron Letters 53 (2012) 4130–4133
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly selective synthesis of libraries of 1,2-disubstituted benzimidazoles
using silica gel soaked with ferric sulfate
⇑
Susmita Paul, Basudeb Basu
Department of Chemistry, North Bengal University, Darjeeling, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and highly selective synthesis of functionalized 1,2-benzimidazoles has been developed
under solvent-free conditions at ambient temperature using eco-friendly ferric sulfate soaked with silica
[iron(III)sulfate–silica]. Recycling of the solid support up to six runs was investigated with appreciable
yield and selectivity of the product.
Received 27 April 2012
Revised 25 May 2012
Accepted 25 May 2012
Available online 1 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzimidazole
Selective synthesis
Iron(III)sulfate–silica
Supported catalysis
Solid-supported synthesis
Functionalized benzimidazoles represent an important class of
N-containing heterocyclic compounds and have received consider-
able attention in recent times because of their vast applications as
antiulcer, antihypertensive, antiviral, antifungal, anticancer, and
antihistamine activities.1 They are important intermediates in
many organic reactions,2 and also can act as ligands for complexa-
tion with transition metals, which are used for modeling biological
systems.3 Owing to broad range of biological and other technical
interest of the benzimidazole family of compounds, several syn-
thetic strategies have been developed for the preparation of func-
tionalized benzimidazoles.
The most popular strategy utilizes either direct condensation–
aromatization reaction of o-phenylenediamines (o-PDs) and alde-
hyde (Scheme 1) or reductive cyclization of o-nitroaniline with
aldehydes,4 for the synthesis of 2-substituted benzimidazole 4,5
and 1,2-disubstituted benzimidazole 3.6 Selective synthesis of
1,2-disubstituted benzimidazoles has been achieved by the direct
condensation–aromatization reaction of o-PD and aldehyde using
Zn-Proline,6e SDS micelle,6g TMSCl,6h Amberlite IR-120,6i glyoxalic
acid,6j 1-(4-sulfonicacid)butyl-3-methylimidazolium hydrogen
sulfate [(CH2)4SO3ÀHMIM][HSO4],6k nano indium oxide,6l in water
and refluxing in glycerol at 90 °C.6m Alternative approaches include
transition metal-catalyzed reactions such as Pd-catalyzed tandem
carbonylation–cyclization reaction of o-PDs,7a Pd-catalyzed tan-
dem dehydration-coupling reaction of o-bromoaniline,7b Rh-cata-
lyzed hydroformylation reaction of N-alkenyl phenylenediamines
etc.7c Solid-phase synthesis of benzimidazoles has also been devel-
oped.8 Although, a large body of protocols has been developed for
the synthesis of medicinally important benzimidazoles, primary
precincts that require attention of synthetic chemists are: (i)
strong acid-catalyzed conditions that limit functional group toler-
ance, (ii) transition metal-catalyzed methods pose a threat of con-
tamination of toxic metals with the product, and (iii) while a vast
methods are available for selective formation of 2-substituted
benzimidazole 4, synthetic methods for 1,2-disubstituted benz-
imidazole 3 often associate with co-occurrence of several side reac-
tions and by-products. Therefore, the search remains to be
continued for a better catalyst and greener protocol with greater
selectivity in the synthesis of benzimidazoles.
Among some approaches involving solid-phase acid catalysts,
Jacob et al. described silica-supported ZnCl2 as catalyst for the
selective preparation of 1,2-disubstituted benzimidazoles.9
Although their method did work effectively in several cases, poor
yields (35–40%) were reported in some examples. In contrast, iron
is not only ubiquitous but also one of the most versatile transition
metals,10 and important redox center for life and natural transfor-
mation processes.11 Although relatively underrepresented, the use
of iron salts in the synthesis of benzimidazoles has been reported
with limited success in terms of yield and selectivity.12 Since there
is no straightforward procedure involving iron-catalyzed
benzimidazole formation, we explored direct condensation–
aromatization reaction of o-PDs and aldehydes in the presence of
silica-supported iron salts as a general procedure. Herein, we re-
port an efficient, simple protocol for a highly selective synthesis
of 1,2-disubstituted benzimidazole 3, catalyzed by iron(III)sulfate
⇑
Corresponding author. Tel.: +91 353 2776381; fax: +91 353 2699001.
E-mail address: basu_nbu@hotmail.com (B. Basu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.129

S. Paul, B. Basu / Tetrahedron Letters 53 (2012) 4130–4133
4131
R2
R2
N
N
R2
N
NH2
NH2
CHO
N
R1
R1
R1
R1
N
N
H
R2
R2
4
3
5
1
2
R2
Scheme 1. Possible products for the direct condensation–aromatization reaction of o-PDs with aryl aldehydes.
Table 1
Reaction of o-PD and benzaldehyde using different catalyst systems
Entry
Catalyst system
o-PD/benzaldehyde
Time (h)
Temp. (°C)
% Yielda
1
2
3
4
5
6
7
8
9
1 mmol anhy. FeCl3 in 1 g silica
0.25 mmol anhy. FeCl3 in 1 g silica
1 mmol Fe(NO3)3Á9H2O in 1 g silica
0.25 mmol Fe(NO3)3Á9H2O in 1 g silica
1 mmol Fe2O3 in 1 g silica
1 mmol Fe2(SO4)3ÁxH2O in 1 g silica
0.5 mmol Fe2(SO4)3ÁxH2O in 1 g silica
0.25 mmol Fe2(SO4)3ÁxH2O in 1 g silica
0.25 mmol Fe2(SO4)3ÁxH2O in 1 g silica
0.5 mmol Fe2(SO4)3ÁxH2O in 1 g silica
Silica 1 g
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
2:4
2:4
1:2
1:2
2
2
2
2
8
2
2
2
2
2
2
6
30
30
30
30
30
30
30
30
30
30
30
60
3a (82); 4a (9)
3a (75); 4a (15)
3a (83); 4a (8)
3a (78); 4a (12)
3a (65); 4a (22)
3a (89)
3a (89)
3a (89)
3a (78); 4a (14)
3a (81); 4a (12)
3a (32); 4a (38); 5a (25)
3a (30); 4a (46); 5a (15)
10
11
12
Silica 1 g
a
Yields refer to pure product obtained by column chromatographic purification and characterized by 1H and 13C NMR spectral data.
Table 2
Reaction of different o-PDs with aldehydes
NH2
NH2
N
N
Iron(III)sulfate-silica
30 o
R2 CHO
R1
R2
R1
C
2
1
3
R2
Entry
R1
R2
Ph
Time (h)
Temp. (°C)
Product
% Yielda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16c
17
18
H
H
H
H
H
H
H
H
H
H
H
H
2
2
1.5
8
30
30
30
30
30
30
30
30
30
30
30
30
90
30
30
30
30
30
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
89
85
87
83
86
84
84
86
84
84
79
75
78
77b
75b
88
84
78
4-CH3OC6H4
4-ClC6H4
4-NO2C6H4
4-Me2NC6H4
4-Isopopyl C6H4
3-NO2C6H4
3-OHC6H4
3-OPhC6H4
1-Naphthyl
Furan-2-yl
5-Bromo-thiophene-2-yl
2-OHC6H4
5-Br-thiophene-2-yl
2-ClC6H4
2
1.5
24
5
3
6
4
6
15
8
5
H
3-CH3
3-CH3
3-COPh
H
Ph
14
4
12
Cyclohexyl
2-Methylpropyl
H
a
b
c
Yields refer to pure product obtained by column chromatographic purification and characterized by 1H and 13C NMR spectral data.
Mixture of regio-isomers, not separable by column chromatography, was obtained.
M.P. and NMR spectral data were found to be identical with one of the isomers reported in the literature6h and its structure is 1-benzyl-2-phenyl-1H-benzo[d]imidazol-5-yl)
(phenyl)methanone.
supported on silica at ambient temperature under solvent-free
conditions.
Initially o-PD and benzaldehyde were chosen as the model sub-
strates to optimize the catalyst and reaction conditions. The results
are presented in Table 1. Use of SiO2–FeCl3 or SiO2–Fe(NO3)3
showed some selectivity toward the formation of 1,2-disubstituted
benzimidazole over 2-substituted benzimidazole (entries 1–4).
Exploration with iron oxide (Fe2O3) also afforded a mixture of 3
and 4 in varying proportions (entry 5). In the search of more selec-
tivity, we further investigated the reaction with silica-supported

4132
S. Paul, B. Basu / Tetrahedron Letters 53 (2012) 4130–4133
NH2
NH2
Ph
2 PhCHO
N
H
Fe
Si
H
N
HO
OH
(6)
Ph
(5)
Fe
H
N
Ph
Ph
HO
OH
H
N
N
Si
Ph
N
Ph
(7)
Fe
(3a)
HO
OH
Si
Scheme 2. Plausible mechanism of the reaction furnishing 1,2-disubstituted
benzimidazole.
O
H
Fig. 1. The d position (ppm) of the OH of 8 at different concentrations: Solution 1
(100 mg), Solution 2 (50 mg), Solution 3 (20 mg), dissolved in 1.5 mL CDCl3.
N
NH2 OHC
Iron(III)sulfate-silica
30 o
(8)
C
Table 3
N
H
NH2
HO
Recycling of iron(III)sulfate–silica in catalyzing the reaction of o-PD and benzaldehyde
O
Entry
No. of cycle
% Yielda
Iron(III)sulfate-silica
90 oC, 15 h
Iron(III)sulfate-silica
90 oC, 15 h
1
2
3
4
5
6
0
1
2
3
4
5
89
86
88
89
86
88
N
C6H4 o-OH
N
C6H4 o-OH
3m
a
Yields refer to the pure product obtained by column chromatographic
Scheme 3. H-bonded Schiff base, undergoing cyclization and 1,3-H shift in
presence of iron(III)sulfate–silica at 90 °C.
purification.
ferric sulfate. Indeed, we were able to find that 1 mmol of ferric
sulfate adsorbed onto 1 g of silica can afford highly selective for-
mation of the 1,2-disubstituted benzimidazole 3 in excellent yield
(entry 6). Lowering of the catalyst loading per gram of the solid
support up to 0.25 mmol of ferric sulfate also showed complete
selectivity toward the formation of 1,2-disubstituted benzimid-
azole (entries 7, 8).13 Further lowering of the quantity of ferric sul-
fate per gram of silica gel with reference to reactant ratios resulted
in the loss of selectivity (entries 9, 10).
In order to check the role of silica, which is often used as dehy-
drating agent, similar reactions were carried out only on silica sur-
face, which led to a mixture of 3, 4, and 5 in varying proportions
(entries 12, 13). Thus we have the optimized reaction conditions
as follows: 0.25 mmol of the iron(III)sulfateÁxH2O adsorbed onto
silica gel (1 g) for the reaction of 1:2 mmol of o-PD and benzalde-
hyde, having stirred in neat at ambient temperature under open
atmosphere.14
Following identification of the optimal conditions, the scope
and limitations of the reaction were examined by subjecting differ-
ent 1,2-diamines and aldehydes. The results are shown in Table 2.
Aryl aldehydes bearing different functional groups as well as het-
eroaryl aldehydes reacted smoothly with o-PD leading to the for-
mation of corresponding 1,2-disubstituted benzimidazoles highly
selectively and in good to excellent yields (Table 2, entries 1–12).
No electronic or steric impact was found to be prominent in the
selective formation of 3a–l. However, In the case of o-salicylalde-
hyde, the reaction occurred at higher temperature (90 °C) (entry
13). The o-PDs possessing different substituents also afforded
similar reactions resulting in the formation of corresponding
benzimidazoles (3n–p) selectively in good yields (entries 14–16).
Further extension of the protocol to aliphatic aldehydes also affor-
ded selective formation of the corresponding 1,2-disubstituted
benzimidazoles (3q, 3r) at ambient temperature (entries 17, 18).
Although the exact mechanism is not clear, the Lewis acid-med-
iated mechanism is expected to play (Scheme 2). Adsorption of
iron(III)sulfate on the surface of silica is believed to make bond
with the silanol groups in a manner analogous to the formation
of OH-bridges in the polynuclear iron(III)hydroxyl complexes 6.15
Silica being a water adsorbent could facilitate formation of the
bis-Schiff base 5, which has been reported and indeed was isolated
when the reaction was stopped after 20 min. The Schiff base 5 may
undergo cyclization followed by 1,3-hydride shift,6e,6h (7), induced
by electrophilic catalyst, as shown in Scheme 2, resulting in the
formation of the 1,2-disubstituted benzimidazole 3. The 1,3-hy-
dride shift was tested previously by incorporating deuterium.6g
An indirect evidence in favor of 1,3-hydride shift may be proposed,
as we observed that the corresponding Schiff base 5, isolated from
o-PD and salicylaldehyde (8), showed reluctance to undergo cycli-
zation at room temperature. This is possibly because of intramolec-
ular H-bonding with o-OH group,16 making nitrogen less
nucleophilic, and thus required higher temperature (90 °C) for
the cyclization (Scheme 3). The existence of intramolecular hydro-
gen bonding in the Schiff base (8) was also checked by 1H NMR
studies at varying concentrations of the Schiff base in CDCl3. The
spectra (Fig. 1) show that the hydroxyl proton appears at d
13.09 0.01 ppm for compound 8 (solution 1: 100 mg in 1.5 mL
CDCl3), (solution 2: 50 mg in 1.5 mL CDCl3), and (solution 3:
20 mg in 1.5 mL CDCl3).

S. Paul, B. Basu / Tetrahedron Letters 53 (2012) 4130–4133
4133
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Finally, the advantage of using the silica-supported ferric sulfate
in this reaction was examined by its recovery and reuse after the
first run. Accordingly, after the reaction of o-PD and benzaldehyde,
the solid mixture was washed repeatedly with ethyl acetate and
filtered off. The solid was then washed with acetone followed by
drying in a hot air oven at 150 °C for 24 h and then dried under vac-
uum. The next batch of reaction was performed with the recovered
silica-supported ferric sulfate and found to be equally active in cat-
alyzing the process. Table 3 showed the results of six consecutive
recycle runs.
In conclusion, we have developed an efficient and highly selec-
tive procedure for the synthesis of 1,2-disubstituted benzimidaz-
oles via one-step condensation–aromatization reaction of o-PDs
with electronically divergent aldehydes under mild conditions pro-
moted over the surface of iron(III)sulfate–silica. The new method
requires only inexpensive eco-friendly reagents and the catalytic
system is recyclable. Further applications of iron(III)sulfateÀsilica
are currently underway in this laboratory.
7. (a) Perry, R. J.; Wilson, B. D. J. Org. Chem. 1993, 58, 7016–7021; (b) Brain, C. T.;
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people Need Iron & Animals Make Magnets; University Press: New Brunswick,
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13. Preparation of ferric sulfate adsorbed on silica: To a hot solution of iron(III)
sulfateÁxH2O (1 g, 2.5 mmol; x = 0) in water (20 mL) at 70 °C, silica gel (10 g,
particle size: À325 mesh, source. SRL, India) was added. This mixture was
stirred at 70 °C for 2 h. The solvent was evaporated under vacuo and the solid
mass was kept in a hot air oven at 150 °C for 24 h. This pale yellow solid mass
was further dried under vacuum (0.5 torr) for 2 h and the resulting free-
flowing iron(III)sulfate supported silica gel was used for the reaction and can
be kept under nitrogen for several weeks.
Acknowledgments
Financial support from the Department of Science and
Technology, New Delhi is acknowledged (Grant No. SR/S1/OC-86/
2010). S.P. thanks the CSIR, New Delhi for awarding senior research
fellowship.
14. Representative procedure for the synthesis of 1,2-disubstituted benzimidazole: To a
mixture of o-phenylenediamine (1 mmol) and iron(III)sulfate–silica (1 g) was
added benzaldehyde (2 mmol) and the resulting reaction mixture was
intimately mixed in a mortar pestle. Then the mixture was magnetically
stirred at 30 °C for 2 h under open atmosphere. After the completion of the
reaction (checked by tlc), the solid reaction mixture was washed repeatedly
with ethyl acetate (10 Â 3 mL) and the washings were combined and
evaporated under vacuum. The crude solid product, although pure enough
on tlc, was then passed through a short column of silica gel to afford pure
product 3a (mp 134–136 °C, lit.17 mp 134 °C). It was characterized by spectral
data (IR and 1H and 13C NMR). Characterization of other compounds was made
by spectral data and compared to those reported. Compound 3a: IR (KBr) mmax
cmÀ1: 3031, 2935, 1449, 1391, 1365, 1326, 1277, 1249, 1160. 1H NMR (DMSO-
d6, 300 MHz) d/ppm 7.75–7.23 (m, 3 H), 7.53–7.45 (m, 4 H), 7.29–7.21 (m, 5 H),
7.00 (d, 2 H, J = 7.5 Hz), 5.58 (s, 2 H); 13C NMR (DMSO-d6, 75 MHz) d/ppm 153.2,
142.6, 136.8, 135.8, 130.1, 129.7, 128.9, 128.7, 127.4, 125.9, 122.6, 122.1, 119.2,
111, 47.4.
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