Ultrasound promoted and SiO2/CCl3COOH mediated synthesis of 2-aryl-1-arylmethyl-1H-benzimidazole derivatives in aqueous media: An eco-friendly approach

Article abstract of DOI:10.1007/s12039-014-0662-4

Ultrasonic irradiation is an efficient and innocuous technique of reagent activation for synthesizing organic compounds. First one-pot synthesis of 2-aryl-1-arylmethyl-1H- benzimidazole derivatives from o- phenylenediamine and an aromatic aldehyde in the presence of silica gel supported trichloroacetic acid (SiTCA) was carried out with excellent yields at 50°C by sonication. This method provided several advantages such as green solvent, inexpensive catalyst, simple experimental methodology, shorter reaction time and higher yield.

Full text of DOI:10.1007/s12039-014-0662-4

J. Chem. Sci. Vol. 126, No. 6, November 2014, pp. 1831–1840. ꢀc Indian Academy of Sciences.
Ultrasound promoted and SiO /CCl COOH mediated synthesis
2
3
of 2-aryl-1-arylmethyl-1H-benzimidazole derivatives in aqueous media:
An eco-friendly approach
a,b,∗
b
c
b
BRAJESH KUMAR
, KUMARI SMITA , BRAJENDRA KUMAR and LUIS CUMBAL
a
Department of Chemistry, TATA College, Kolhan University, Chaibasa, Jharkhand, 833 202, India
Centro de Nanociencia y Nanotecnologia, Universidad de las Fuerzas Armadas -ESPE,
b
Av. Gral. Rumiñahui s/n, Sangolqui, P.O. BOX 171-5-231B, Ecuador
c
Department of Computer Science and Engineering, National Institute of Technology, Durgapur,
West Bengal, 713 209, India
e-mail: krmbraj@gmail.com
MS received 30 December 2013; revised 22 April 2014; accepted 25 April 2014
Abstract. Ultrasonic irradiation is an efficient and innocuous technique of reagent activation for synthesi-
zing organic compounds. First one-pot synthesis of 2-aryl-1-arylmethyl-1H- benzimidazole derivatives from
o- phenylenediamine and an aromatic aldehyde in the presence of silica gel supported trichloroacetic acid
◦
(
SiTCA) was carried out with excellent yields at 50 C by sonication. This method provided several advantages
such as green solvent, inexpensive catalyst, simple experimental methodology, shorter reaction time and higher
yield.
Keywords. 2-Aryl-1-arylmethyl-1H-benzimidazoles; silica gel supported trichloroacetic acid (SiTCA);
regioselective; one-pot synthesis; ultrasound irradiation.
6
7
1
. Introduction
antiallergic agents, factor Xa (FXa) inhibitors, poly
8
(
ADP-ribose) polymerase (PARP) inhibitors, human
cytomegalovirus (HCMV) inhibitors, xanthine oxi-
dase (XO) inhibitors and treatment of ulcers as
The preparation of small heterocyclic organic mole-
cules by using ultrasound has received considerable
attention in recent years. Use of ultrasound irradiation
is known to accelerate a wide range of synthetically
useful organic reactions. The use of ultrasonic waves
to promote chemical reactions is called sonochemistry
which also shares approach with the green chemistry.
It reduces the amount of any hazardous substance and
solvents, reduces energy consumption, and increases
9
10
11
antihistaminics.
This importance has led to the development of seve-
ral methods for the synthesis of benzimidazoles during
the last few years. Two protocols have been routinely
followed. One is the coupling of ring substituted
o-phenylenediamine derivatives with carboxylic acids
or their derivatives that usually required harsh conden-
sating conditions (170–180 C). The other method
involves condensation of o-phenylenediamine and aldeh-
ydes in the presence of acid catalysts under various
reaction conditions followed by oxidative cyclo dehy-
drogenation. The second approach became more po-
pular because of the ease of accessibility of a variety of
substituted aldehydes. The reported procedures for this
protocol involved wide spectrum of reagents, including
-Methyl-3-propylimidazolium tetrafluoroborate or
pmim]BF /1-Butyl imidazolium tetrafluoroborate or
1
2
1
◦
12
product selectivity. Nowadays the heterocyclic organic
molecules are important in several fields of science
including organic, inorganic, bioorganic, agricultural,
industrial, pharmaceutical, and medicinal chemistry, as
3
13
well in material science. The benzimidazole nucleus
plays an important role in medicinal chemistry as it is
present in pharmacophores showing biological activ-
ities against several viruses such as herpes (HSV-1),
HIV, RNA, influenza and human cytomegalovirus
1
4
(HCMV). In addition, benzimidazole derivatives have
[
[
[
4
14a
been used as selective neuropeptide YY1 receptor
antagonists, 5-lipoxygenase inhibitors for use as novel
Hbim]BF4, 1-Methylimidazolium triflouroacetate or
5
1
4b
14c
14d
Hmim]TFA/H O, Bi(OTf) /H O, L-proline/CHCl ,
2 3 2 3
14e
Trimethylsilyl chloride or TMSCl/H O, (bromodi-
methyl) sulfonium bromide/MeCN,
diacetate/1,4- dioxane,
2
1
4f
iodobenzene
H O /HCl in MeCN,
14g
14h
∗
For correspondence
2 2
1
831

1
832
Brajesh Kumar et al.
14i
chlorotrimethylsilane/DMF and silica sulphuric acid/ 2. Experimental
1
4j
H O. Some other important reagents reported are
2
15a
15b
2.1 General
I /KI/K CO /H O, air/dioxane, neat ytterbium tri-
2
2
3
2
15c
15d
flate,
p-TsOH/DMF,
Na S O in neat under
2 2 5
1
5e
All reagents were obtained from commercial sources
and used without further purification. Infrared spectra
were recorded on a Varian FT-IR spectrophotometer
(model: Varian-640 IR, CA, USA) fitted with Attenu-
microwave irradiation, [(NH )H PW O ] in dichlo-
roethane, H O /CAN, Graphite/PhNMe , ytter-
bium(III) perfluorooctanesulfonate,
20/EtOH-H O
4
2
12 14
15f
15g
15h
2
2
2
1
5i
amberlite IR
1
5j
15k
1
and Zn-proline/H O.
Although
2
2
1
13
ated Total Reflectance (ATR) accessories. H and
C
these methods are quite satisfactory, many of them
employed considerable amounts of hazardous organic
solvents (for example, chloroform, dichloromethane,
benzene, toluene, dimethyl formamide, etc.) either for
carrying out the reactions or for extraction and purifica-
tions (column chromatography) or for both which are
not environment friendly. Moreover, several reactions
were also carried out at higher temperatures, using
expensive reagents. However, one of the major limita-
tions of these methodologies is poor selectivity in terms
of N-1 substitution, which results in the formation of
two compounds, i.e., the formation of 2-substituted
benzimidazole along with 1, 2-disubstituted benzim-
idazole as a mixture. An attractive possible approach
is based on ultrasound-promoted 1, 2-disubstituted
benzimidazole heterocyclization reactions of suitably
functionalized substrates, which could allow the regios-
elective synthesis of highly functional heterocycles
using readily available starting materials under mild
and selective conditions.
NMR spectra of CDCl solutions were obtained with
3
an Avance 500 (Model: Bruker, 11.4 Tesla, 500 MHz)
spectrometer using tetramethylsilane (TMS) as the
internal standard. Chemical shifts (δ) are expressed in
ppm and coupling constants J are given in Hz. ESI-MS
were obtained on a Varian 91 500-LC ion trap mass
spectrometer. Sonication was performed in an ultra-
sonic processor, DAIGGER; model no. GE505 (with
a frequency of 20 kHz, amplitude (72%) and a nom-
inal power (500 W). Melting points determined on a
digital Stuart SMP 10 melting point apparatus (ST15,
OSA, UK) are uncorrected. The thin layer chromatog-
raphy (TLC) was performed using the aluminum sheets
coated with silica gel 60 (MERCK) containing fluores-
cent indicators, F254. The solvent for the development
of the TLC plate was hexane: ethyl acetate (7:3).
2.2 Preparation of silica supported trichloroacetic
acid (SiTCA)
In recent years, heterogeneous catalysts are gaining
16
In a 250 mL Pyrex conical flask 100 g silica (mesh size:
more importance due to enviro-economic factors. The
catalyst is generally of low cost with easy handling. Use
of these heterogeneous catalysts ensures less or no gen-
eration of an undesirable wastage as pollutant. Based
on these advantages, the experiments were designed for
synthesis of 1, 2-disubstituted benzimidazoles by con-
densation of o-phenylenediamine and aromatic alde-
1
20–230) and 10 mL CCl COOH were added together.
3
◦
The reaction mixture was stirred and sonicated at 60 C
for 30 min. Then it was dried under pressure and kept
for further use. TEM image of SiTCA (figure 2) shows
uniform particles of about 1 μm.
hydes using heterogeneous catalyst with sonication 2.3 General experimental procedure
figure 1). To the best of our knowledge, there is no pub-
(
lished report on the use of ultrasound mediated silica A suitable aromatic aldehyde (2.0 mmol) and o-
gel supported trichloroacetic acid (SiTCA) for synthesis phenylenediamine (1.0 mmol, 108.1 mg) was dissolved
of 1, 2-disubstituted benzimidazoles. The experimen- in 66% EtOH in H O (10 mL). To this solution
2
tal procedure to use this catalyst was proved to be very 100 mg SiTCA (6.5 mole%) catalyst was added and
◦
simple which could also be easily removed by simple the contents kept under sonication at 50 C until TLC
filtration.
indicated complete consumption of phenylenediamine
Figure 1. Scheme for synthesis of 1, 2-disubstituted benzimidazole derivatives.

Sonochemical synthesis of 1, 2-disubstituted benzimidazoles
1833
◦
−1
crystal; M.p. 227–228 C; FT-IR-ATR (ν , cm ):
1
max
1
465, 1558, 2935, 3039, 3260, 3355; H NMR
(
500 MHz, CDCl ):δ 5.63 (s, 2H, CH ), 6.78–7.97
3
2
(
2
m, 4H), 7.12–7.41 (m, 5H), 7.59 (d, J = 8.6 Hz,
13
H), 7.81 (d, J = 8. 0 Hz, 1H); C NMR (125 MHz,
CDCl ):δ 43.25, 110.8, 115.0, 116.1, 116.4, 118.7,
3
118.9, 122.0, 122.6, 126.6, 128.3, 130.2, 131.3. 135.1,
1
41.8, 152.0, 154.4, 156.3; MS (ESI, m/z): calcd for
+
C H N O (M +1) 317.12, found: 317.2 (100%).
20
16
2
2,
2.3c 1-(4-Chlorobenzyl)-2-(4-chlorophenyl)-1H-1, 3-
benzimidazole (3c): Isolated yield = 89.6; Light yel-
◦
−1
low crystal; M.p. 126–127 C; FT-IR-ATR (ν , cm ):
1
max
1
620, 2858, 2974, 3045, 3087; H NMR (500 MHz,
CDCl ): δ 5.40 (s, 1H), 7.19 (d, J = 7.1 Hz, 2H), 7.26
3
Figure 2. TEM images of SiTCA.
(
d, J = 8.7 Hz, 1H), 7.27–7.35 (m, 4H), 7.42–7.47 (m,
2H), 7.58–7.59 (m, 2H), 7.86 (d, J = 7.4 Hz, 1H);
(
6–18 min). Acoustic cavitation and mixing plays sig-
13
C NMR (125 MHz, CDCl ): δ 47.7, 110.3, 120.1,
3
nificant role in interaction of energy and matter. The ter-
mination of the reaction was monitored by TLC using
hexane: ethyl acetate (7:3) as eluent. After completion
of the reaction, the solution was filtered to remove the
catalyst. The filtrate was concentrated under reduced
pressure to furnish the crude product, which was
recrystallized from methanol to afford the pure product.
The catalyst could be reused thrice for fresh reactions
to slight loss of activity (2–10%). It is hypothesized
that, there is marginal loss of trichloroacetic acid atom
during the reaction and recycling process. So it can be
1
23.4, 127.2, 128.3, 129.1, 129.3, 130.4, 133.8, 134.6,
135.9, 136.3, 143.0, 152; MS (ESI, m/z): calcd for
+
C H N Cl (M +1) 353.05, found: 353.2 (100%).
20
14
2
2,
2.3d 1-(2-Methoxybenzyl)-2-(2-methoxyphenyl)-1H-
1
, 3-benzimidazole (3d): Yield = 93.2; Light yellow
◦
−1
powder; M.p. 152–154 C; FT-IR-ATR (ν , cm ):
max
1
1617, 2859, 2932, 3051, 3078; H NMR (500 MHz,
CDCl ):δ 3.58 (3H, s, CH ), 3.77 (3H, s, CH ), 5.23
3
3
3
(
s, 2H, CH ), 6.69 (m, 1H), 6.77 (t, J = 6.95 and
2
concluded that in SiTCA, CCl COOH moiety remains
3
7.15 Hz, 2H, Ar-H), 6.83 (d, J = 8.2 Hz, 2H, Ar-H),
immobilized on silica gel support.The product’s authen-
6
.96 (d, J = 8.35, 1H), 7.03–7.09 (m, 2H), 7.15–7.3
1
13
ticity was established by HNMR, C NMR, FTIR-
ATR, MS-ESI and their melting point compared with
that of in literatures.
(
8
m, 2H, Ar-H), 7.43 (m, 2H, Ar-H), 7.53 (dd, J =
13
.3 Hz, 1H, Ar-H), 7.82 (d, J = 8.0, 1H); C NMR
(125 MHz, CDCl ):δ 43.3, 55.0, 55.1, 109.8, 110.6,
3
1
19.7, 120.3, 121.8,122.3, 124.4, 127.6, 128.3, 131.3,
2
.3a 1-(2-Chlorobenzyl)-2-(2-chlorophenyl)-1H-1, 3- 132.2, 135.4, 143.2, 152.4, 156.3, 157.4; MS (ESI,
+
benzimidazole (3a): Isolated yield = 92.3; Pale yel- m/z): calcd for C H N O (M +1) 345.4, found:
22
20
2
2,
◦
−1
low crystal; M.p. 157–158 C; FT-IR-ATR (ν , cm ): 345.15 (100%).
max
1
1615, 2845, 2980, 3036, 3067; H NMR (500 MHz,
CDCl ):δ 5.38 (s, 2H, CH ), 6.65 (d, J = 8.0 Hz,
3
2
2
.3e 1-(4-Methylbenzyl)-2-(4-methylphenyl)-1H-1, 3-
1
H), 7.16 (t, J = 7.5 Hz, 2H), 7.24 (d, J = 7.5 Hz,
H), 7.29 (t, 2H), 7.37 (d, J = 8. 0 Hz, 1H), 7.42
benzimidazole (3e): Yield = 90.6; Yellowish white
1
◦
−1
crystal; M.p. 128–129 C; FT-IR-ATR (ν , cm ):
(
(
(
4
1
1
t, J = 7.5 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.55
max
1
1249, 1411, 2862, 2919, 3027; H NMR (500 MHz,
t, J = 7.5 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.76
1
3
CDCl ): δ 2.28 (s, 3H), 2.40 (s, 3H), 5.40 (s, 2H),
d, J = 8.5 Hz, 1H); C NMR (125 MHz, CDCl ):δ
3
3
6
1
7
.98 (d, J = 7.95 Hz,1H), 7.12 (d, J = 7.85 Hz,
H), 7.19–7.3 (m, 6H), 7.56 (d, J = 8.1 Hz, 2H),
.78 (d, J = 8 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H);
6.25, 112.4, 120.78, 123.44, 124.24, 128.5,128.59,
29.37, 130.54,130.58, 130.63, 130.85, 132.79, 133.02,
34.28, 136.07, 143.63, 151.93; MS (ESI, m/z): calcd
1
3
+
C NMR (125 MHz, CDCl ): δ 21.27, 21.61, 48.41,
for C H N Cl (M +1) 353.24, found: 353.2 (100%).
3
20
14
2
2,
5
1
8.02, 110.72, 119.94, 122.80, 123.08, 126.10, 126.72,
29.21, 129.36, 129.65, 129.90, 136.24, 137.67,
2
.3b 1-(2-Hydroxybenzyl)-2-(2-hydroxyphenyl)-1H-1, 140.30, 143.25, 154.57; MS (ESI, m/z): calcd for
+
3-benzimidazole (3b): Isolated yield = 80.2; Brown C H N ,(M +1) 313.1, found: 313.3 (100%).
22
20
2

1
834
Brajesh Kumar et al.
2
.3f 1-(4-Hydroxybenzyl)-2-(4-hydroxyphenyl)-1H-1, 129.42, 135.51, 135.84, 142.62, 149.82, 153.70; MS
+
3
-benzimidazole (3f): Isolated yield = 86.1; Dark (ESI, m/z): calcd for C H N (M +1) 285.13, found:
20
16 2,
◦
yellow powder; M.p. 208–209 C; FT-IR-ATR (ν
,
285.3.
max
−1
1
cm ): 1465, 2842, 2938, 3045; H NMR (500 MHz,
CDCl ): δ 5.28 (s, 2H, CH ), 6.88–6.91 (m, 3H), 7.03–
3
2
7
2
3
.1 (m, 3H), 7.19–7.27 (m, 4H), 7.78 (d, J = 8.0 Hz, 2.3k 1-((Pyridin-2-yl) methyl)-1H-1,3-benzimidazole
+
H); MS (ESI, m/z): calcd for C H N O ,(M +1) (3k): Yield = 88.7; Light yellow powder; M.p. 129–
20
16
2
2
◦
−1
17.3, found: 317.2 (100%).
130 C; FT-IR-ATR (ν , cm ):1356, 1446, 1675,
max
1
2
2
7
991, 3055; H NMR (500 MHz, CDCl ): δ 6.29 (s,
H, CH ), 7.03–7.10 (m, 2H), 7.25–7.35 (m, 5H), 7.45–
.53 (m, 3H, Ar-H), 7.82–7.88 (m, 2H, Ar-H); MS (ESI,
3
2
2.3g 1-(3-Nitrobenzyl)-2-(3-nitrophenyl)-1H-1,3-ben-
zimidazole (3g): Isolated yield = 82.5; yellow crystal;
+
m/z): calcd for C H N (M +1) 287.12, found: 287.3
◦
−1
18 14 4,
M.p. 154–155 C; FT-IR-ATR (ν , cm ): 1348,
max
(
100 %).
1
1532, 2842, 3178; H NMR (500 MHz, CDCl ):δ 5.40
3
(
7
1
s, 2H, CH ), 7.12–7.20 (m, 2H), 7.27 (d, 1H, J =
2
2
.3l 1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-1H-1,
.6 Hz), 7.29–7.34 (m, 2H), 7.64–7.70 (m, 2H), 7.81 (s,
3
-benzimidazole (3l): Isolated yield = 98%; Pale
H), 7.80–7.82 (m, 2H), 8.22 (d, 2H, J = 8.22 Hz), 8.48
◦
13
yellow crystal; M.p. = 126–127 C; FTIR-ATR
(s, 1H); C NMR (125 MHz, CDCl ): δ 46.7, 111.1,
3
−1
1
(neat): 1619, 2856, 2965, 3026, 3077 cm ; H NMR
1
1
1
3
19.8, 121.3, 122.5, 122.8, 123.6, 123.7, 124.4, 130.7,
(
500 MHz, CDCl ): δ = 3.78 (s, 3H,CH ), 3.85 (s,
3
3
31.2, 132.7, 135.2, 136.0, 139.0, 142.4, 147.8, 150.9,
+
3H, CH
3
), 5.38 (s, 2H, CH
2
), 6.84 (d, J = 8.70 Hz,
56.0; MS (ESI, m/z): calcd for C H N O (M +1)
20
14
2
4,
2
8
7
1
5
H), 6.96 (d, J = 8.85 Hz, 2H, Ar-H), 7.02 (d, J =
75.1, found: 375.2 (100%).
.75 Hz, 2H, Ar-H), 7.21 (m, 2H), 7.27(m, 1H, Ar-H),
.62 (d, J = 8.85 Hz, 2H, Ar-H), 7.83 (d, J = 8.0 Hz,
13
2
.3h 1-(3-Chlorobenzyl)-2-(2-chlorophenyl)-1H-1, 3-
H, Ar-H); C NMR (125 MHz, CDCl ): δ = 48.10,
3
benzimidazole (3h): Isolated yield = 84.2; Pale yel-
5.52, 55.58, 110.61, 114.40, 114.64, 119.93, 122.68,
◦
−1
low crystal; M.p. 166-167 C; FT-IR-ATR (ν , cm ):
max
122.94, 127.43, 128.71, 130.92, 136.30, 143.38,
1
+
1
635, 2857, 2983, 3041, 3071; H NMR (500 MHz,
1
54.33, 159.33, 161.11; MS-ESI: m/z [M+H] calcd
CDCl ): δ 5.36 (s, 2H, CH ), 6.93 (d, J = 7.2 Hz,
3
2
for C H N O : 345.41; found: 345.15.
22 20 2 2
1
2
7
H), 7.12 (s, 1H), 7.22–7.39 (m, 4H), 7.45–7.5 (m,
H), 7.64 (m, 1H), 7.70 (m, 1H), 7.88 (d, J =
.95 Hz, 1H), 7.98 (m, 1H); MS (ESI, m/z): calcd
3. Results and Discussion
+
for C H N Cl (M +1) 353.24, found: 353.2
20
14
2
2,
(100%).
In order to access the effect of ultrasound, the reac-
tion of o-phenylenediamine 1a with aromatic aldehyde
2
a in the presence of different catalysts (amberlite IR
2
.3i 1-(4-Fluorobenzyl)-2-(2-fluorophenyl)-1H-1, 3-
120, SiTCA, HClO , TFA and FeCl ) and organic sol-
4
3
benzimidazole (3i): Isolated yield = 90.0; Pale yel-
vents were carried out under sonication (table 1). The
yield of product slightly increased with an increase in
the quantity of catalyst and ratio of both expected prod-
ucts (table 1, 3a and 4a) based on the nature of the
solvent. Interestingly, lowest yield was observed in the
presence of acetone due to its volatilization and highest
yield in the ethanol/water (2/1) mixture. The amount of
◦
−1
low powder; M.p. 98–99 C; FT-IR-ATR (ν , cm ):
max
1
1
5
7
465, 2842, 2938, 3045; H NMR (500 MHz, CDCl ):δ
.40 (s, 1H), 7.0–7.07 (m, 4H), 7.13–7.33 (m, 5H),
.62–7.65 (m, 2H, ArH), 7.84 (d, J = 7.95.1H); MS
3
+
(ESI, m/z): calcd for C H N F , (M +1) 321.11,
20
14
2 2
found: 321.2 (100%).
4a, was formed in minor amount (12%, 15% and 25%)
2
.3j 1-Benzyl-2-phenyl-1H-1,3-benzimidazole (3j): when the reaction was carried out in ethanol, methanol
◦
Yield = 91.4; Light brown powder; M.p. 139–141 C; and water. The isolated yield of the desired product 3a
−1
FT-IR-ATR (ν , cm ): 1358, 1457, 2949, 3035; was less in all the solvents than in ethanol/water (2/1)
max
1
H NMR (500 MHz, CDCl ): δ 5.45 (s, 2H, CH ), mixture. So, ethanol/water mixture came out as the best
3
2
7
7
2
.08–7.12 (m, 3H, Ar-H), 7.22–7.31 (m, 5H, Ar-H), choice of the solvents as the reaction medium. It can be
.35–7.46 (m, 3H, Ar-H), 7.63 (dd, J = 8.0 and explained that, when sound passes through a liquid, the
1
3
.0 Hz, 2H, Ar-H), 7.86 (d, J = 7.7 Hz, 1H);
C
formation, growth and implosive collapse of bubbles
NMR (125 MHz, CDCl ):δ 47.80, 110.32, 119.41, can occur. This process is called acoustic cavitation.1
3
122.23, 125.72, 127.31, 128.46, 128.78, 128.80, An acoustic wave is a pressure wave that has the ability

Sonochemical synthesis of 1, 2-disubstituted benzimidazoles
Table 1. Optimization of reaction conditions by using o-phenylenediamine and o-chlorobenzaldehyde at 50 C.
1835
◦
Cl
Cl
N
N
N
NH2
NH2
CHO
Cl
+
+
2
N
H
Cl
3a
4a
1a
2a
Catalyst
load (g)
Ultrasound irradiation
time (min)
a
a
Entry
Catalyst
SiTCA
Solvent (10 mL)
H2O
Yield (3a) (%) Yield (4a) (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
.
-
18
25
12
12
12
12
12
12
17
12
12
12
12
09
12
12
12
12
12
12
12
12
1 2
12
12
12
12
12
72
56
84
83
89
90
70
22
58
60
85
88
75
96
18
77
65
75
78
16
40
38
70
64
66
50
52
72
28
44
16
17
11
10
30
78
42
40
15
12
25
04
82
23
35
25
22
84
60
62
30
36
34
50
48
28
.
.
.
.
.
.
.
.
0.
1.
2.
3.
4.
5.
6.
7.
8.
9.
0.
1.
2.
3.
4.
5.
6.
7.
8.
Amberlite IR 120
Amberlite IR 120
Amberlite IR 120
Amberlite IR 120
SiTCA
Amberlite IR 120
Amberlite IR 120
SiTCA
SiTCA
SiTCA
SiTCA
SiTCA
SiTCA
SiTCA
SiTCA
HClO4
HClO4
HClO4
HClO4
Silica
-
H2O
EtOH
MeOH
EtOH/H2O(2/1)
EtOH
THF
Acetone
Toluene
DCM
MeOH
EtOH
H2O
EtOH/ H2O (2/1)
Acetone
THF
H2O
EtOH
EtOH/ H2O (2/1)
Acetone
EtOH/ H2O (2/1)
EtOH
EtOH/ H2O (2/1)
EtOH/ H2O (2/1)
EtOH/ H2O (2/1)
-
EtOH/ H2O
EtOH/ H2O (2/1)
0.1
0.1
0.1
0.15
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
b
b
b
b
Silica
SiTCA
Amberlite IR 120
TFA
TFA
FeCl3
TCA
c
c
b
b
0.1
0.1
a
Isolated yield based on the aromatic aldehyde
Quantity of catalyst in mL
b
c
5
mL solvent
to break the intermolecular van der Waals forces main- the product with higher reaction time as compared to
taining the cohesion of the liquid. The cavitational col- the sonochemical reaction. In the presence of a widely
lapse in a liquid produces intense local heating, high distributed roughness of the solid acid catalyst surface,
pressures, with very short lifetimes, i.e., an extraordi- sonication provides a unique interaction of energy and
10
17
nary heating and cooling rate (>10 K/s). These tran- matter, and causes high energy chemical reactions to
sient, localized hotspots can cause the reaction to take occur.
place rapidly, and the hotspot has an equivalent tem-
To study the effect of substituents on the reaction,
◦
perature of roughly 5000 C, a pressure of about 2000 the reaction was carried out with o-phenylenediamine
17
atmospheres. Thus, catalyst (SiTCA) was more selec- and a wide range of structurally diverse aldehydes
tive towards the formation of 3a, 96% as compared to using SiTCA as a catalyst in the presence of ultra-
4a, 60% for 9 min as shown in entry 14, table 1. It sonic irradiation under frequency of 20 kHz (72%
could affect the reaction, but it gave a lower yield of amplitude) (table 2). All the reactions were carried out

1
836
Brajesh Kumar et al.
Table 2. SiTCA catalyzed selective synthesis of 2-aryl-1-arylmethyl-1H-benzimidazole from o-phenylenediamine and
◦
various aldehydes at 50 C. The literature melting points is given in parentheses.
◦
Entry
Aldehyde (2)
Product (3)
Ultrasonic
irradiation time (min)
Yield
(%)
M.p. C
(Obs.)
a
1
09
96
157-158
2
3
12
12
88
91
227-228
126-127
4
12
95
153-154
5
6
06
09
93
89
128-129
208-209
7
17
84
154-155

Sonochemical synthesis of 1, 2-disubstituted benzimidazoles
1837
Table 2. (continued)
◦
Entry
Aldehyde (2)
Product (3)
Ultrasonic
irradiation time (min)
Yield
(%)
M.p. C
a
(Obs.)
8
9
12
87
166-167
09
12
12
92
93
89
98-99
1
1
0
1
139-141
129-130
N
N
OCH3
CHO
1
2
08
98
126-127
H CO
3
3l
H CO
3
aIsolated yield based on the aromatic aldehyde
◦
at 50 C and drastic reduction in time was observed powder, which provided greater surface area with
in contrast to the reported methods, due to the syn- proper chemical polarization towards the substrates to
ergestic effect of sonication under the temperature of accomplish facile bimolecular condensation. Herein,
◦
5
0 C. These results are consistence with the literature, we wish to report the ultrasonically catalyzed two
because as the ultrasonic frequency is increased, the components N-alkylation-cyclization of aldehyde and
production of cavitation in liquids decreases.1 Reac- o-phenylenediamine (figure 1).
8
tions with o-phenylenediamine, SiTCA and formalde-
o-Chlorobenzaldehyde and o-phenylenediamine was
hyde failed to give the expected 1, 2-disubstituted ben- used as standard substrates to search for a suitable sol-
zimidazole. It was observed that SiTCA could cat- vent in favour of the SiTCA, amberlite IR 120, HClO4,
alyze the reaction efficiently than amberlite IR 120 and TFA and FeCl catalyzed 1, 2 disubstituted benzimida-
3
HClO in presence of ultrasonic waves. To rational- zole synthesis. Among the solvent tested, EtOH/H O
4
2
ize the result, it was speculated that the SiTCA pow- (2/1, v/v) was best reaction medium for this ultrasound
der was more selective due to the catalytic activities mediated one-pot synthesis. At the completion of the
of trichloroacetic acid on the rough surface of silica reaction, the use of EtOH/H O influenced the reaction
2

1
838
Brajesh Kumar et al.
of aldehyde and o-phenylenediamine with better yield. irradiation has several additional enhancement effects,
Slight lower yields were obtained while using methanol and this is especially useful when the solid acts as
19
and ethanol as solvent (table 1, entries 11, 12). Toluene, a catalyst. No significant difference was observed
dichloromethane, water and tetrahydrofuran afford the while slightly increasing the catalyst loading in solvent
product in only low or moderate yields (table 1, entries (table 1, entry 6). When silica and trichloroacetic acid
9
, 10, 13, 16). Undesired product was detected by were used separately, no good results were found
NMR when the reaction was carried out in acetone (table 1, entries 21, 28). It was surprising that the
table 1, entry 8, 15). It was also observed that yield reaction proceeded to give 1, 2-disubstituted benzimi-
of product in a 0.1 M solution was more than 0.2 M dazole as a single product, when we employed 1:1 or
table 1, entries 14, 23) because at lower concen- 1:2 or 1:3 mol o-phenylenediamine and benzaldehyde
(
(
tration, two molecules of benzaldehyde approaches for reaction. The optimized reaction condition under so-
to o-phenylenediamine more efficiently than higher nication includes 1.0 equiv mol of o-phenylenediamine,
concentrations. The chemical effects of ultrasounds 2.0 equiv. mol of aromatic aldehyde and 0.1 g of SiTCA
have been attributed to the implosive collapse of the (6.5 mole %) in 10 mL EtOH/ H O (2/1) solvents at
2
1
◦
cavitation bubbles and associated shock waves. The 50 C. It is found that ultrasonic mediated reaction is
bubbles are generated at localized sites in the liquid more selective.
mixture that contain small amounts of dissolved gases. To explore the scope of ultrasound in the synthesis
20
When these bubbles burst, it results in high temperature of 1, 2-disubstituted benzimidazoles, various aldehy-
and high pressure which facilitate the intermolecular des were used as a substrates under the optimized
reaction. When one of the phases is a solid, the ultrasonic reaction conditions and the results are summarized
Figure 3. The proposed mechanism for SiTCA catalyzed 1, 2- disubstituted
and monosubstituted benzimidazole synthesis.

Sonochemical synthesis of 1, 2-disubstituted benzimidazoles
1839
in table 2. All the known products were character- In addition, the SiTCA as a heterogeneous catalyst
1
ized by comparing their physical and spectral ( H could be reused thrice for fresh reactions to slight loss
13
NMR, C NMR, ESI-MS and IR) data with those of activity.
14,15
of the authentic samples reported in the literature.
As mentioned method, the undesired mono substi-
tuted benzimidazoles products were found to be 2–15%
respectively.
Supplementary Information
The electronic supplementary information can be seen
in www.ias.ac.in/chemsci.
In general, aromatic aldehydes underwent the addi-
tion reaction smoothly to provide the desired product
in good (table 2, entry 7) to excellent yield (table 2,
entries 4, 12). However, SiTCA catalyzed N-alkylation
cyclization reaction was found to be strongly influ-
enced by the nature of aldehyde. As shown in table 2,
o, p- chlorobenzaldehydes in entry 1 and 3 are more
efficient than m-chlorobenzaldehyde in entry 8. Sali-
cylaldehyde gave lower yields under the standard con-
dition than p-hydroxy benzaldehyde (table 2, entries
Acknowledgements
This scientific work has been partially funded by
the Prometeo Project of the National Secretariat of
Higher Education, Science, Technology and Innovation
(SENESCYT), Ecuador. The authors are also grateful
to the TATA College research fund (2013–2014) for the
financial support.
2, 6) due to the existence of intramolecular hydrogen
bond, which prevents cyclization. In a similar fashion,
heteroaromatic aldehyde also reacted well with
o-phenylenediamine to furnish the corresponding prod-
uct in good yields (table 2, entry 11). The present
protocol is equally effective for aromatic aldehydes
bearing either electron donating (such as alkyl, or
alkoxyl group) or electron withdrawing substituent
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