Tosic acid-on-silica gel: A cheap and eco-friendly catalyst for a convenient one-pot synthesis of substituted benzimidazoles

Article abstract of DOI:10.1007/s00706-007-0714-2

2-Substituted and 1,2-disubstited benzimidazoles were prepared efficiently from o-phenylenediamines and aryl aldehydes using p-toluenesulphonic acid (5∈mol%)-on-silica gel as a cheap and environmentally benign catalyst.

Full text of DOI:10.1007/s00706-007-0714-2

Monatshefte fu¨r Chemie 138, 1279–1282 (2007)
DOI 10.1007/s00706-007-0714-2
Printed in The Netherlands
Tosic Acid-on-Silica Gel: A Cheap and Eco-friendly Catalyst
for a Convenient One-pot Synthesis of Substituted Benzimidazoles
Manas Chakrabarty1;ꢀ, Ratna Mukherjee1, Sulakshana Karmakar1, and Yoshihiro Harigaya2
1
Department of Chemistry, Bose Institute, Kolkata, India
2
Department of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan
Received April 30, 2007; accepted May 14, 2007; published online September 24, 2007
# Springer-Verlag 2007
Summary. 2-Substituted and 1,2-disubstited benzimidazoles
were prepared efficiently from o-phenylenediamines and aryl
aldehydes using p-toluenesulphonic acid (5mol%)-on-silica
gel as a cheap and environmentally benign catalyst.
useful heterocyclic molecules [7], we found that
TLC-grade silica gel doped with a catalytic amount
(5mol%) of p-toluenesulphonic acid (TsOH-SiO2),
can act as an efficient catalyst. Our findings, since im-
Keywords. Benzimidazoles; Synthesis; o-Phenylenedia-
portant, are presented briefly in this paper.
mines; Aryl aldehydes; Tosic acid-on-silica gel.
Introduction
Results and Discussion
1,3-Azoles are known to be useful pharmacophores.
Of them, benzimidazoles are especially important
because of their use as anthelmintics in veterinary
medicine [1] and their potential as anticancer, anti-
viral, antiallergic, antiulcer, and anticoagulant com-
pounds in human therapeutics [2]. The commonest
route to substituted benzimidazoles is the condensa-
tion of o-phenylenediamines (o-PDs) with carboxyl-
ic acids, nitriles, amidates, or orthoesters [3], which
usually require strongly acidic reagents under harsh
conditions. In recent years, the preferred route has,
therefore, been the oxidative cyclisation of o-PDs with
aryl aldehydes employing a variety of catalysts [4].
But practically all the catalysts used for this pur-
pose have their drawbacks. Accordingly, new cata-
lysts continue to be developed [5, 6]. In view of this
need for more suitable catalysts for the synthesis of
substituted benzimidazoles by this route and in con-
tinuation of our interest in the newer applications of
environmentally benign catalysts in the synthesis of
In order to ascertain a suitable condition, o-PD (1a)
was treated with benzaldehyde (2a) (2 equivalents)
by adsorbing them uniformly on TsOH-SiO2 (i) at
room temperature, (ii) by heating at 60–70ꢁC in an
oven, (iii) in acetonitrile solution, both at room tem-
perature and under reflux, and (iv) in methanol so-
lution, also at room temperature as well as under
reflux. These experiments furnished in each case
the same mixture of two differently substituted ben-
zimidazoles (see later) in respective overall yields of
93% (1.25 h), 91% (0.25 h), 84=77% (3.5=1.75 h),
and 89=85% (2.0=0.75 h). These results demonstrat-
ed that heating at 60–70ꢁC (condition ii) was the
best of the conditions used in terms of both the re-
action time and the overall yields of benzimidazoles.
Accordingly, o-PD (1a) was treated separately with
each of the aryl aldehydes (2a–2h, 2k) and two het-
eroaryl aldehydes (2i, 2j) on TsOH-SiO2 at 60–70ꢁC
(oven). Two products were formed (TLC) from each
of the aldehydes (2a–2c, 2g–2i, 2k), whereas each of
the other aldehydes furnished a single product. The
products, identified by physical and spectroscopic
ꢀ
Corresponding author. E-mail: chakmanas@yahoo.co.in

1280
M. Chakrabarty et al.
Scheme 1
Table 1. Formation of substituted benzimidazoles from o-PD (1a) and (hetero)aryl aldehydes 2a–2k
Entry
Ar
Time=min
Yield=%
mp=ꢁC found (reported)
3
4
Total
3
4
1
2
3
4
5
6
7
8
9
2a ¼ C6H5
2b ¼ 4-OCH3-C6H4
2c ¼ 4-BrC6H4
15
30
25
10
5
10
5
20
20
15
30
32
22
56
–
87
–
42
39
35
–
59
75
35
84
–
78
46
60
62
76
63
91
97
91
84
87
78
88
99
97
76
89
292–293 (292)a
227–228 (226)a
291–292 (291–294)c
–
132 (132)b
130–131 (131)b
159 (158)d
2d ¼ 4-CNC6H4
2e ¼ 4-NO2C6H4
2f ¼ 3-NO2C6H4
2g ¼ 2-NO2C6H4
2h ¼ 1-Naphthyl
2i ¼ 2-Thienyl
218–219 (–)e
–
311–312 (316)a
–
167–168 (170)f
132–133 (120)d
158–159 (160)d
145–146 (146–148)g
256–257 (–)e
170–171 (171–172)g
262–263 (260)g
264–265 (266)h
324–325 (326)g
–
10
11
2j ¼ 3-Indolyl
2k ¼ 3,4-OCH2OC6H3
26
244–245 (246)g
a
b
Ref. [9]; Ref. [8a]; Ref. [10]; Ref. [11]; new compound; Ref. [12]; Ref. [7d]; Ref. [13]
c
d
e
f
g
h
Scheme 2
means (vide Experimental), were either the 2-aryl-
benzimidazoles (3), the 1-arylmethyl-2-arylbenzimi-
dazoles (4), or both. The reactions are shown in
Scheme 1 and the results in Table 1.
Table 2. Formation of N-Me-2-arylbenzimidazoles from N-
Me-o-PD 1b and (hetero)aryl aldehydes
Entry
2
Time= Yield=% mp=ꢁC found (reported)
min
of 5
Clearly, the aldehydes bearing electron-donat-
ing groups (2a–2c, 2k), furnished both 3 and 4,
whereas the aldehydes bearing electron-withdrawing
groups (2d–2f) behaved otherwise. Thus, 2d and 2f
furnished only the respective 1,2-disubstituted benz-
imidazoles (4d, 4f), whereas 2e gave only the corre-
sponding 2-arylbenzimidazole (3e).
As an extension, N-methyl-o-PD (1b) was sepa-
rately treated with three aryl aldehydes (2b, 2e, 2j),
which furnished, as expected, only the respective
1-methyl-2-arylbenzimidazoles (5b, 5e, 5j) efficient-
ly and expeditiously. The reactions are shown in
Scheme 2 and the results in Table 2.
1
2
3
2b
2e
2j
10
5
10
82
77
81
118–119 (118.5–119.5)a
210–211 (208–209)b
302–303 (–)c
a
b
Ref. [14]; Ref. [15]; new compound
c
For a comparative evaluation of the efficacy of
TsOH-SiO2 with those of other catalysts reported
recently for the preparation of substituted benz-
imidazoles via this route, two points require to be
highlighted. Firstly, in all the cases, including those
claimed to be a ‘‘green’’ procedure [6a], ‘‘eco-
friendly’’ methods [5d–f], and ‘‘solvent-free’’ proto-

Tosic Acid-on-Silica Gel
1281
was purified by preparative TLC (except for 4d, 3e, 4f, and
4j). The latter, each a single product, were purified by direct
crystallisation to afford the pure benzimidazoles.
cols [8], the final products were invariably extracted
with volatile organic solvents – ethyl acetate in most
cases. Secondly, since the present catalyst contains
TsOH, the purification of the products necessitated
the washing of the solvent extracts with dilute aqu.
sodium bicarbonate, which does not pose any hazard
to the environment and consequently does not affect
the eco-friendliness of the catalyst. In view of the
aforesaid, TsOH-SiO2 is definitely eco-friendly and
undoubtedly cheap too. Additionally, the present
method is indeed more expeditious than the rest of
the methods except those mediated by iodobenzene
diacetate [5a] and montmorillonite K-10 clay-micro-
wave [8a]. Consequently, our method can certainly
be considered as a convenient alternative to the other
eco-friendly catalysts used for the one-pot synthesis
of substituted benzimidazoles via this route.
1-(4-Cyanophenyl)methyl-2-(4-cyanophenyl)benzimidazole
(4d, C22H14N4)
Off-white crystals, mp 218–219ꢁC; IR (nujol): ꢀꢀ¼ 2223,
1
1606, 1288, 1162, 1023, 850, 744 cmꢃ1; H NMR (500 MHz,
CDCl3): ꢁ ¼ 7.90 (d, J ¼ 8 Hz, H-4), 7.76–7.72 (m, H-200, 600,
H-300, 500), 7.65 (d, J ¼ 8.5 Hz, H-30, 50), 7.38 (dt, J ¼ 1, 7.5Hz,
H-5), 7.32 (dt, J ¼ 1, 7.5 Hz, H-6), 7.19 (d, J ¼ 8 Hz, H-20, 60),
7.18 (d, J ¼ 8 Hz, H-7), 5.51 (s, CH2) ppm; 13C NMR
(125MHz): ꢁ ¼ 152.1 (C-2), 143.5 (C-3a), 141.4 (C-10),
136.3 (C-7a), 134.5 (C-100), 133.5 (CH-30, 50), 133.0, 130.0
(CH-200, 600, ꢃ300, 500), 126.9 (CH-20, 60), 124.7 (CH-6), 124.0
(CH-5), 121.1 (CH-4), 118.49, 118.40 (C-40, C-400-CN), 114.2
(C-400), 112.8 (C-40), 110.6 (CH-7), 48.5 (CH2) ppm; LR
EI-MS: m=z (%) ¼ 334 (Mþ, 100), 219 (38), 116 (90); HR
ESI-MS TOF (þve) calcd for C22H14N4Na, 357.1116
(Mþ Na)þ, found 357.1113.
1-(Indol-3-yl)methyl-2-(indol-3-yl)benzimidazole
(4j, C24H18N4)
Experimental
Pale yellow crystals, mp 256–257ꢁC; IR (nujol): ꢀꢀ¼ 3397,
Melting points were recorded on a Toshniwal apparatus. The
IR spectra were recorded on a Nicolet Impact 410 FT-IR
spectrophotometer, the 1H (500MHz) and 13C (125 MHz)
NMR spectra, both 1D and 2D, including DEPT-135, HMQC
and HMBC spectra, on a BRUKER DRX-500 NMR spectro-
meter and the LR EI-MS, the HR EI=FAB-MS, and the HR
ESI-MS spectra on a JEOL JMS-AX505HA, JEOL JMS-
700M Station, and a Q-TOF MICRO YA263 mass spectro-
1619, 1573, 1242, 1122, 1016, 937, 746 cmꢃ1 1H NMR
;
(500MHz, DMSO-d6): ꢁ ¼ 11.69 (s, 1H), 11.01 (s, 1H), 8.33
(d, J ¼ 8 Hz, 1H), 7.86 (s, 1H), 7.68 (d, J ¼ 7.5 Hz, 1H), 7.54
(d, J ¼ 7.5 Hz, 1H), 7.49 (d, J ¼ 8 Hz, 1H), 7.32 (d, J ¼ 8 Hz,
1H), 7.26 (d, J ¼ 8 Hz, 1H), 7.22 (t, J ¼ 7 Hz, 1H), 7.18 (t,
J ¼ 7.5Hz, 2H), 7.14 (t, J ¼ 7.5 Hz, 1H), 7.03 (t, J ¼ 7.5 Hz,
1H), 7.03 (s, 1H), 6.84 (t, J ¼ 7.5 Hz, 1H), 5.82 (s, 2H) ppm;
13C NMR (125 MHz): ꢁ ¼ 150.5, 144.2, 137.2, 136.9, 136.5,
127.4, 126.4, 111.2, 106.0 (all C), 127.2, 124.3, 123.1, 122.27,
122.26, 122.25, 122.23, 121.1, 119.6, 119.2, 119.0, 112.6,
112.5, 111.3 (all CH), 41.5 (CH2) ppm; LR EI-MS: m=z
(%) ¼ 362 (Mþ, 11), 233 (100), 205 (24), 129 (51); HR
FAB-MS (m-NBA) calcd for C24H19N4, 363.1610 (Mþ H)þ,
found 363.1614.
1
meter. Individual H and 13C NMR spectral assignments of
4d were ascertained additionally from its HMQC and HMBC
spectra. The three new compounds (4d, 4j, 5j) were subjected
to elemental analysis in a Perkin Elmer 2400 Series II C, H, N
Analyser and the results were found to be in good agreement
with the calculated values. The thin layer chromatographies
(TLCs), both analytical and preparative, were carried out on
silica gel G (Merck, India) plates. p-Toluenesulphonic acid
(Pure) was procured from Riedel, Germany.
1-Methyl-2-(indol-3-yl)benzimidazole (5j, C16H13N3)
Brown crystals, mp 302–303ꢁC; IR (nujol): ꢀꢀ¼ 3383, 1558,
1281, 1239, 1145, 1008, 746 cmꢃ1 1H NMR (500 MHz,
;
Preparation of the Catalyst (TsOH-SiO2)
DMSO-d6): ꢁ ¼ 11.77 (s, 1H), 8.36 (d, J ¼ 7.5 Hz, 1H), 8.07
(d, J ¼ 2.5 Hz, 1H), 7.65 (d, J ¼ 7 Hz, 1H), 7.56 (d, J ¼ 7 Hz,
1H), 7.50 (d, J ¼ 7.5 Hz, 1H), 7.22 (t, J ¼ 7.5 Hz, 1H), 7.20
(t, J ¼ 7.5 Hz, 1H), 7.20–7.17 (m, 1H), 7.16 (t, J ¼ 7 Hz,
1H), 3.96 (s, 3H) ppm; 13C NMR (125MHz): ꢁ ¼ 150.7,
143.8, 136.9, 136.8, 127.2, 105.9 (all C), 127.7, 123.1,
122.3, 122.2 (ꢂ2), 121.0, 119.0, 112.6, 110.5 (all CH),
32.3 (N-CH3) ppm; LR EI-MS: m=z (%) ¼ 247 (Mþ, 70),
246 (100); HR EI-MS calcd for C16H13N3, 247.1110 (M)þ,
found 247.1107.
A solution of 5 mg TsOH (5mol% with respect to o-PD) in
0.5 cm3 dry MeOH was uniformly adsorbed on 0.5 g silica gel
G, the solvent was allowed to evaporate at rt inside a hood.
Within few minutes, it led to a free-flowing solid to be used as
the catalyst.
Preparation of Benzimidazoles 3 and 4
A solution of 54mg o-PD (0.5mmol) and 1 mmol aldehyde in
0.5 cm3 of ca. 10% MeOH in EtOAc was adsorbed on 0.5 g
freshly prepared TsOH-SiO2. After a few minutes at rt, when
the reactants-on-SiO2 did not smell of solvent, it was heated at
60–70ꢁC in an oven. When the starting materials were con-
sumed (TLC), silica gel was leached with EtOAc (3ꢂ10cm3),
and the pooled extracts were freed from acid by washing with
2% aqu. NaHCO3, washed free of alkali with water, dried
(Na2SO4), and the solvent removed. The resulting residue
Acknowledgements
We sincerely thank Professor S. Raha, the Director, Bose
Institute for laboratory facilities, the C.S.I.R., Govt. of India
for providing a Fellowship (R.M.), Mr. B. Majumder, NMR

1282
M. Chakrabarty et al.: Tosic Acid-on-Silica Gel
Facilities and Mr. P. Dey, Microanalytical Laboratory, both of
the Bose Institute, for recording the spectra.
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