Facile Synthesis of 1,2-Disubstituted Benzimidazoles Usingp-Toluenesulfonic Acid through Grinding Method

Article abstract of DOI:10.1134/S1070428020090201

Abstract: An efficient synthetic method for the highly selective synthesis ofpharmacologically active 1,2-disubstituted benzimidazole derivatives fromo-phenylenediamine and various aromaticaldehydes catalyzed by p-toluenesulfonic acidthrough grinding unde

Full text of DOI:10.1134/S1070428020090201

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 9, pp. 1628–1634. © Pleiades Publishing, Ltd., 2020.
Facile Synthesis of 1,2-Disubstituted Benzimidazoles
Using p-Toluenesulfonic Acid through Grinding Method
C. Kathinga, N. G. Singha, J. World Star Rania, R. Nongruma, and R. Nongkhlawa,*
a Centre for Advanced Studies in Chemistry, North-Eastern Hill University, Shillong, Meghalaya, 793022 India
*e-mail: rlnongkhlaw@nehu.ac.in
Received March 18, 2020; revised March 29, 2020; accepted March 31, 2020
Abstract—An efficient synthetic method for the highly selective synthesis of pharmacologically active 1,2-di-
substituted benzimidazole derivatives from o-phenylenediamine and various aromatic aldehydes catalyzed by
p-toluenesulfonic acid through grinding under solvent-free condition is described. The reaction requires the
catalyst only during the conversion of intermediate N,N′-dibenzylidene-o-phenylenediamine into the desired
product. The products were obtained within a short time with good yields by using only a mortar and pestle,
which makes the proposed method convenient and cost-effective.
Keywords: 1,2-disubstituted benzimidazole, p-toluenesulfonic acid, solvent-free reaction
DOI: 10.1134/S1070428020090201
INTRODUCTION
cyclization with o-nitroaniline and aldehydes [25, 26],
cyclocondensation of N-substituted o-aminoanilides
[27, 28], and condensation of N-substituted phenylene-
diamines with α-hydroxybenzylsulfonic acid sodium
salt [29].
In the field of medicine, compounds containing
a benzimidazole nucleus have been termed as “privi-
leged structures” for drug design owing to their broad
spectrum of biological activity [1]. Benzimidazole
derivatives exhibit diverse pharmacological properties
such as antihistamine [2, 3], antidiabetic [4], chemo-
therapeutic [5], antiparasitic [6, 7], antiproliferative
[8], anti-HIV [9, 10], anticonvulsant [11], antineoplastic
[12, 13], DNA binding agent [14], enzyme and receptor
agonists or antagonists [15]. In addition, they have
found applications in veterinary medicine as anthel-
mintic agents and have been used as organic ligands
[16, 17], fluorescent whitening agents [18] and func-
tional materials [19].
However, the most common method to access
1,2-disubstituted benzimidazoles is based on the direct
coupling of o-phenylenediamines with aromatic alde-
hydes in the presence of acid catalysts [30–36]. The
series of catalysts that have been used for the synthesis
of 1,2-disubstituted benzimidazoles includes trimethyl-
silyl chloride [37], ceric ammonium nitrate [38],
Dowex-50W [39], montmorillonite K-10 [40], SDS
micelles [41], SiO2/ZnCl2 [42], nano-indium oxide
[43], nano-ceria [44], iron(III) sulfate/silica [45],
amberlite IR-120 [46, 47], silica sulfuric acid [48],
glyoxalic acid [49], In(OTf)3 [50], Sm(OTf)3 [51],
HClO4-SiO2 [52], CuI/L-proline [53], AcOH/O2 [1],
SbCl3/Al2O3 [54], FePO4 [55], oxalic acid [56], and
Cu(NO3)2·3H2O [57].
The synthesis of 1,2-disubstituted benzimidazole
derivatives has been extensively studied, as evident
from the growing number of publications. Despite the
numerous records available it has been still explored
rapidly due to its high profile of biological applications.
General methods for the preparation of 2-substituted
benzimidazole derivatives involve the condensation of
o-phenylenediamines with carboxylic acids or their
derivatives (nitriles, imidates, or ortho esters) in the
presence of various acid catalysts [20–22]. The clas-
sical methods for the synthesis 1,2-disubstituted benz-
imidazole include N-alkylation of 2-substituted benz-
imidazole using a strong base [23, 24], reductive
Despite the satisfactory results obtained with vari-
ous catalysts, most of the described methods often led
to a mixture of products because of competitive forma-
tion of 1,2- and 2-substituted benzimidazoles. In addi-
tion, the reactions were carried out in drastic conditions
with the use of expensive reagents, they required a long
time, and the starting materials were poorly available.
Therefore, a direct synthetic method to furnish 1,2-di-
substituted benzimidazoles with a greener protocol and
1628

FACILE SYNTHESIS OF 1,2-DISUBSTITUTED BENZIMIDAZOLES
1629
Scheme 1.
No catalyst
solvent-free
r.t. grinding
R1
NH2
NH2
R1
N
N
R2
R2
R1
TsOH (2 mol %)
r.t. grinding
N
N
R2
+ R2CHO
R2
1
2a–2o
3a–3o
4a–4o
For R1, R2, see Table 1.
better selectivity remains the prime focus of re-
searchers. The interesting and diverse biological prop-
erties of benzimidazoles offers great utility in clinical
industries and prompted researchers to further develop
efficient methods of synthesis. As per exhaustive
literature survey, the production of benzimidazole com-
pounds with the simple use of bare mortar and pestle
has not been employed. In order to achieve the direct
synthesis of 1,2-disubstituted benzimidazole deriva-
tives, the reaction was carried out by grinding in the
presence of p-toluenesulfonic acid (TsOH) under
solvent-free conditions.
lytic amount of TsOH (Scheme 1). The method is quite
simple and convenient, and the desired products were
obtained within a short time using only mortar and
pestle.
The reaction was initially performed by grinding
the reactants, i.e., o-phenylenediamine 1 and aromatic
aldehyde 2 at a molar ratio of 1:2 without catalyst and
solvent. The reactants condensed rapidly to form a yel-
low solid intermediate, N,N′-dibenzylidene-o-pheny-
lenediamine (3). However, no cyclization occurred on
prolonged grinding. After addition of 2 mol % of
TsOH, the reaction mixture immediately changed from
yellow to brown, indicating the formation of 1,2-disub-
stituted benzimidazole 4, which was monitored by
TLC. Thus, a catalyst is required for ring closure
to construct the 5-membered ring moiety of benz-
imidazole.
RESULTS AND DISCUSSION
With the aim to develop a facile and convenient
protocol, our study focused on the synthesis of 1,2-di-
substituted benzimidazoles 4 by grinding with a cata-
Table 1. Synthesis of 1,2-disubstituted benzimidazoles 4a–4o
mp, °C
Comp. no.
R1
R2
Yield,a %
found
reported
132 [40]
4a
4b
4c
4d
4e
4f
H
Ph
97
94
95
93
92
94
93
91
90
92
93
90
88
85
82
130–132
130–131
127–128
136–138
154–156
200–201
119–120
206–208
192–194
168–170
170–171
96–98
H
4-MeOC6H4
4-MeC6H4
131 [40]
H
128–129 [37]
137 [40]
H
4-ClC6H4
H
2-ClC6H4
154–156 [58]
192–194 [59]
120–121 [60]
208–209 [61]
200–204 [62]
184–186 [63]
170–172 [38]
94–96 [63]
[37, 64–67]b
172–174 [68]
125 [69]
H
4-O2NC6H4
3-O2NC6H4
4-HOC6H4
2-HOC6H4
3-MeO-4-HOC6H3
3,4-(MeO)2C6H3
Furan-2-yl
(E)-PhCH=CH
Ph
4g
4h
4i
H
H
H
4j
H
4k
4l
H
H
4m
4n
4o
H
88–90
4-Cl
4-Cl
138–140
126–128
4-MeOC6H4
a
Isolated yield.
b
The nature of the compound does not match that reported in the literature, but its 1H and 13C NMR spectroscopic data are consistent with
the reported data.
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KATHING et al.
1630
Scheme 2.
O
Ts O–
Ts
H
H
N
H
R1
N
R2
R2
R1
R2
R2
R1
R2
N
TsOH
3
H
N
N
N
R2
A
B
R1
N
N
R2
1,3-Hydride shift
R2
4
Various catalysts like benzyl(triethyl)ammonium
chloride (BTEA), dodecylbenzenesulfonic acid
(DBSA), AlCl3, I2, and NaHSO4 were also investigated.
Despite their effective catalytic action, the selectivity
was poor, and a mixture of 2-mono- and 1,2-disub-
stituted products was formed. Thus, it was found that
TsOH exhibited the best catalytic effect for the selec-
tive formation of 1,2-disubstituted benzimidazole 4
as compared to other catalysts. A TsOH amount of
2 mol % was sufficient to facilitate the conversion of
intermediate 3 into the desired product; further increase
of the catalyst amount up to 20 mol % did not enhance
the yield.
The reaction pathway is consistent with the earlier
reported mechanism [30–36, 39, 42, 44] which is
initiated by the formation of N,N′-dibenzylidene-o-
phenylenediamine 3 via condensation of aldehyde 2
with diamine 1. Protonation of 3 with p-toluenesulfonic
acid, followed by cyclization, generated intermediate B
which underwent aromatization via deprotonation and
1,3-hydride shift resulting in final product 4.
All the compounds prepared were characterized and
1
authenticated by melting point data, FT-IR, H NMR,
1
13C NMR, and mass spectrometry. In the H NMR
spectrum of 4c (Fig. 1), the presence of a singlet at
δ 5.40 ppm confirmed the formation of 1,2-disubsti-
tuted benzimidazole. The signal at δC 48.19 ppm in the
13C NMR spectrum was assigned to the methylene
carbon. Protons of two methyl groups in the aromatic
rings resonated separately at δ 2.33 and 2.40 ppm.
Under the optimized conditions, a series of reactions
were performed to furnish 1,2-disubstituted benzimid-
azoles 4a–4o (Table 1). The effects of both electron-
donating and electron-withdrawing substituents in aro-
matic aldehydes do not hamper the selective formation
of compounds 4a–4o as evident from the excellent
yield of the products. The reaction also showed toler-
ance towards acid-sensitive aldehydes like furaldehyde
(3l) and α,β-unsaturated aldehydes like cinnamaldehyde
(3m), and the corresponding 1,2-disubstituted benz-
imidazole derivatives were formed in good yield.
The product structure was further confirmed by
X-ray analysis of a single crystal of 4c (Fig. 2), which
was obtained by slow evaporation of its solution in
ethanol.
In conclusion, a simple, efficient, and highly selec-
tive method has been developed for the synthesis of
1,2-disubstituted benzimidazoles by grinding at room
temperature in the presence of p-toluenesulfonic acid.
The method is quite economical compared to the other
existing methods, as it required catalyst only for the
conversion of intermediate into the desired product.
The experimental simplicity (i.e., the use of a mortar
and a pestle) makes the method convenient, environ-
mentally friendly, and cost-effective. Furthermore,
short reaction time, good yields, and the ease of isola-
tion and purification of the product by simple recrystal-
lization techniques are additional advantages of the
proposed protocol.
A plausible mechanism for the formation of 1,2-di-
substituted benzimidazoles 4 is shown in Scheme 2.
δ 2.33 s
δC 21.10
N
Me
N
δ 2.40 s
δC 21.44
Me
δ 5.40 s
δC 48.19
Fig. 1. Selected 1H and 13C NMR data of 4c.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 9 2020

FACILE SYNTHESIS OF 1,2-DISUBSTITUTED BENZIMIDAZOLES
1631
EXPERIMENTAL
The melting points were determined in open capil-
lary tubes with an Optics Technology melting point
apparatus and are uncorrected. The infrared spectra
were recorded in KBr on a Perkin Elmer Spectrum 400
1
FTIR instrument. The H NMR and 13C NMR spectra
were recorded on Bruker Avance II 400 and Bruker
Avance III HD 300 spectrometers using CDCl3 and
DMSO-d6 as solvents and tetramethylsilane as internal
standard. The mass spectra were obtained on a Waters
ZQ-4000/JMS-T100LC Accu TOF instrument. All
reactions were monitored by TLC using precoated
aluminum sheets (silica gel 60 F254, 0.2 mm thick-
ness); visualization was done by treatment with iodine
vapor or under a UVGL-15 lamp (λ 254 nm).
Fig. 2. ORTEP image of 4c (CCDC entry no. 1564165).
The X-ray diffraction data for compound 4c were
collected on an Agilent Xcalibur (Eos, Gemini) dif-
fractometer equipped with a graphite monochromator
(Mo Kα radiation, λ= 0.71073 Å) at 291.5(5) K. The
structure was solved by the direct method and was
refined by OLEX2. Figure 2 shows an ORTEP image
of molecule 4c. Crystal size 0.35×0.22×0.12 mm3;
C22H20N2, M 312.42; triclinic crystal system, space
group P-1; unit cell parameters: a = 9.6995(5), b =
10.4510(6), c = 17.8108(10) Å; α = 84.112(5), β =
81.452(4), γ = 75.822(4)°; V = 1726.92 Å3; Z = 4; μ =
0.071 mm–1; dcalc = 1.2015 g/cm3. Index ranges –12 ≤
h ≤ 12, –12 ≤ k ≤ 14, –23 ≤ l ≤ 23; 5.94 ≤ θ ≤ 57.5°.
Total of 13820 reflection intensities were measured,
including 7799 independent reflections (Rint = 0.0326);
goodness of fit (on F2) S = 0.942. Final divergence
factors: R1 = 0.0609, wR2 = 0.1470 [reflections with
I > 2σ(I)]; R1 = 0.1187, wR2 = 0.1918 (all independent
reflections); maximum/minimum residual electron
density peaks 0.30/–0.33 ē/Å3. The complete set of
X-ray diffraction data for compound 4c was deposited
to the Cambridge Crystallographic Data Centre (CCDC
entry no. 1564165).
on a rotary evaporator. The solid residue was almost
pure product 4; it was further purified by recrystal-
lization from hot ethanol.
Spectral data for some selected compounds are
given below.
1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-1H-
benzimidazole (4b) [40]. Light brown solid. IR spec-
trum, ν, cm–1: 1611 (C=N), 2961 (C–Haliph), 3055
1
(C–Harom). H NMR spectrum (300 MHz, CDCl3), δ,
ppm: 3.78 s (3H, OCH3), 3.85 s (3H, OCH3), 5.38 s
(2H, CH2), 6.82–7.82 m (12H, Harom). 13C NMR spec-
trum (75 MHz, CDCl3), δC, ppm: 48.09, 55.49, 55.57,
110.61, 114.40, 114.64, 119.92, 122.71, 122.93,
127.42, 128.70, 130.92, 136.30, 143.37, 154.31,
159.34, 161.12. Mass spectrum: m/z 345 [M + H]+.
1-(4-Methylbenzyl)-2-(4-methylphenyl)-1H-
benzimidazole (4c) [58]. Colorless solid. IR spectrum,
ν, cm–1: 1612 (C=N), 2918 (C–Haliph), 3024 (C–Harom).
1H NMR spectrum (300 MHz, CDCl3), δ, ppm: 2.33 s
(3H, CH3), 2.40 s (3H, CH3), 5.40 s (2H, CH2), 6.98–
7.86 m (12H, Harom). 13C NMR spectrum (100 MHz,
CDCl3), δC, ppm: 21.10, 21.40, 48.19, 110.52, 119.79,
122.57, 125.88, 127.10, 129.16, 129.45, 129.98,
133.42, 136.07, 137.44, 140.06, 143.07, 154.31. Mass
spectrum: m/z 313 [M + H]+.
General procedure for the preparation of 1,2-di-
substituted benzimidazoles 4a–4o. A mixture of
108 mg (1 mmol) of o-phenylenediamine and aromatic
aldehyde (2 mmol) was ground with a pestle in
a mortar for 5–10 min. A catalytic amount of p-toluene-
sulfonic acid (3.8 mg, 2 mol %) was then added, and
the mixture was ground until the reaction was complete
(TLC). The mixture was extracted with methylene
chloride (3×10 mL), and the combined extracts were
washed with water [(2–3)×15 mL], dried over anhy-
drous Na2SO4, and evaporated under reduced pressure
1-(4-Chlorobenzyl)-2-(4-chlorophenyl)-1H-benz-
imidazole (4d) [40]. Off-white solid. IR spectrum, ν,
cm–1: 1620 (C=N), 2920 (C–Haliph), 3040 (C–Harom).
1H NMR spectrum (400 MHz, CDCl3), δ, ppm: 5.40 s
(2H, CH2), 7.19–7.34 m (4H, Harom), 7.44 d (2H, Harom
,
J = 8.8 Hz,), 7.59 d (2H, Harom, J = 8.4 Hz,), 7.87 d
(2H, Harom, J = 8.0 Hz). 13C NMR spectrum (75 MHz,
CDCl3), δC, ppm: 47.97, 110.49, 120.37, 123.24,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 9 2020

KATHING et al.
1632
123.66, 127.43, 128.53, 129.34, 129.57, 130.62,
134.03, 136.10, 136.53, 143.26, 153.06. Mass spec-
trum: m/z 353 [M + H]+.
ACKNOWLEDGMENTS
The authors gratefully acknowledge SAIF, NEHU,
Shillong, and CDRI, Lucknow for the spectral analyses. We
also acknowledge the Department of Chemistry, NEHU,
Shillong, for the X-ray diffraction analysis.
1-(3-Nitrobenzyl)-2-(3-nitrophenyl)-1H-benz-
imidazole (4g) [61]. Off-white solid. IR spectrum
(KBr), ν, cm–1: 1613 (C=N), 2927 (C–Haliph), 3075
1
FUNDING
(C–Harom). H NMR spectrum (400 MHz, CDCl3), δ,
ppm: 5.52 s (2H, CH2), 7.21–8.29 m (12H, Harom).
13C NMR spectrum (100 MHz, CDCl3), δC, ppm:
47.84, 110.27, 120.70, 121.14, 123.36, 123.69, 123.92,
124.39, 124.80, 130.26, 130.58, 131.42, 131.79,
134.95, 135.85, 137.92, 143.02, 148.33, 148.77,
151.17. Mass spectrum: m/z 375 [M + H]+.
C. Kathing acknowledges the financial assistance
provided by UGC in the form of fellowship.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
SUPPLEMENTARY MATERIALS
4-[1-(4-Hydroxybenzyl)-1H-benzimidazol-2-yl]-
phenol (4h) [62]. Light yellow solid. IR spectrum
(KBr), ν, cm–1: 1611 (C=N), 2926 (C–Haliph), 3025
(C–Harom), 3305 (O–H). 1H NMR spectrum (400 MHz,
CDCl3), δ, ppm: 5.37 s (2H, CH2), 6.73–7.74 m (12H,
Supplementary materials are available for this article at
https://doi.org/10.1134/S1070428020090201 and are acces-
sible for authorized users.
H
arom), 9.13 s (1H, OH), 9.60 s (1H, OH). 13C NMR
spectrum (100 MHz, CDCl3), δC, ppm: 52.43, 115.86,
120.66, 123.89, 125.70, 127.01, 127.24, 131.91,
132.39, 140.87, 147.78, 158.92, 161.88, 164.09. Mass
spectrum: m/z 317 [M + H]+.
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