Indian Journal of Chemistry

Vol. 52B, August 2013, pp 1152-1156

Note

A green synthesis of benzimidazoles
D Kathirvelan, P Yuvaraj, K Babu, Arasampattu S
Nagarajan & Boreddy S R Reddy*
Industrial Chemistry Laboratory, CSIR-Central Leather Research
Institute, Adyar, Chennai 600 020, India
E-mail: induchem2000@yahoo.com
Received 27 June 2011; accepted (revised) 31 May 2013
Various 2-substituted benzimidazole derivatives in moderate to
good yield have been prepared in a one-pot reaction by
condensation of o-phenylenediamine and an aldehyde in the
presence of ammonium chloride as a catalyst at 80-90C. The
reaction is green and economically viable.
Keywords: o-Phenylenediamine, economically viable,
green chemistry, benzimidazoles
Benzimidazole moieties are a very important class of
heterocyclic compounds that have many applications
in pharmaceutical chemistry
1
. Based on their broad
biological functions
2
, they are used in clinical
medicine
3
as anti-ulcer, anti-tumor and anti-viral
agents
4
. Also, these are being developed as DNA
minor groove binding agents that have significant anti
tumor activity
5
. In addition, these compounds also
seen as ligands for transition metals in model
biological systems
6
and they have potential use for
treatment of diseases such as ischemia-repersion
injury
7a
, hypertension
7b
and obesity
7c
.
Several synthetic methodologies are available for
the synthesis of benzimidazoles. Generally, the
condensation of o-phenylene diamine with carboxylic
acids and their nitrile, imidates and orthoester
8

derivatives have been widely used for benzimidazole
synthesis. Direct condensation of o-aryl diamine with
aldehyde is not a good synthetic route for these
molecules as it yields a complex mixture of 1,2-
disubstituted benzimidazole and bis dihydrobenzi-
midazole as side products
9
. But the use of transition
metal catalysts namely copper (II) acetate
10
and lead
tetra-acetate in these reactions afforded better results.
Ruthenium
11
, palladium
12
and rhodium
13
catalysts
have also been used.
An alternative synthetic approach using
[Fe(III)/Fe(II)] redox mediated
14
oxidation of Schiff
base intermediates derived from o-phenyllenediamine
and various aromatic hetrocyclic aldehydes gave the
desired products.The use of bismuth chloride and rare
earth metal triflates such as [Yb(OTf
3
)] and [Sc(Otf
3
)]
have also been reported
15
. But, syntheses of 2-
substituted benzimidazole using Ti (IV) isopropoxide
and cumene isoprpoxide were recently reported
16
.
Several of these reported procedures for the
preparation of 2-substituted benzimidazole derivatives
were neither versatile nor compatible with differently
substituted starting materials. They are associated
with many practical difficulties. For example, use of
high temperature for the polyphosphoric acid
mediated condensation reaction led to the formation
of by-products and benzimidazoles in low yield.
Though rare-earth metal catalysts give better yields,
the prohibitive cost of the catalysts make them
unsuitable for industrial application. The high boiling
point of nitrobenzene as solvent increases safety risks
at high temperature and difficulties in removal from
the product.
Results and Discussion
Benzimidazole derivatives were prepared by
refluxing o-phenylene diamine and various substituted
aldehydes using catalytic amount of NH
4
Cl in ethanol
at 80-90C to afford moderate to good yields
(Scheme I). The completion of the reaction was
monitored by TLC (2:1, v/v, hexane:ethylacetate) as
eluent. This methodology was applied to synthesize a
library of 2-substituted benzimidazole derivatives and
the results are summarized in Table I.
The electronic effects of the different substituted
aldehydes have been investigated and it was observed
that aldehydes having electron withdrawing groups
afford good yield with shorter reaction times
compared to aldehydes having electron donating
groups. At the same time, aliphatic aldehydes reacted
slowly with lower yields (10%). Aryl ketones such
as benzophenone, acetophenone and their derivatives
did not react with diamine. Furthermore, heteroaryl
carboxaldehyde afforded good yields compared to
substituted benzaldehyde derivatives. Products were
confirmed by comparing with authentic sample (IR,
NMR and MS). NH signal clearly appeared in the
region between 12.5 to 13.5 in
1
H NMR and
quarternary carbon appeared around 150-155 in
13
C
NMR as expected. The molecular ion peak appeared
at respective m/z values in ESI-MS spectrometry.
NOTES



1153


Scheme I Synthesis of benzimidazole derivatives



Table I Yield of benzimidazoles 3a-o with various R groups

Compd R Reaction time (h) Yield (%)
3a
N
H
N
OMe


3.0 78
3b


3.0 76
3c


3.0 65
3d
N
H
N


2.5 63
3e

3.0 67
3f


3.0 80
3g


2.5 78
3h


4.0 74
Contd

INDIAN J. CHEM., SEC B, AUGUST 2013



1154
Experimental Section

All chemicals were purchased from Aldrich and
SD Fine Chemical Company. Starting materials and
reagents were used without further purification. IR
spectra were recorded on Perkin Elmer 1700
spectrometer. The NMR spectra were recorded on
JEOL-500 or an ACF-500 Bruker instrument using
DMSO-d
6
as solvent and trimethylsilane as internal
standard. The chemical shifts were expressed in units
of parts per million (ppm) and the coupling constants
were in Hertz (Hz). Splitting patterns described
apparent multiplicities and were designated as s
(singlet), d (doublet), t (triplet), q (quartet), m
(multiple), or br s (broad singlet). Mass spectra (MS)
were recorded using ESI (Electrospray ionization)
technique on Mariner Mass Spectrum instrument.
Synthesis of benzimidazole derivative 3a
To a mixture of o-phenylenediamine (0.100 g, 0.92
mmol) and anisaldehyde (0.125 g, 0.92 mmol) in 4
mL of ethanol was added NH
4
Cl (0.15g, 30 mol%).
The resulting mixture was stirred for 2 h at 80C. The
completion of the reaction was confirmed by TLC
(ethylacetate: hexane, 1:2 v/v). The reaction mixture
was poured into ice cold water and the product was
precipitated as a pale yellow solid. The contents were
filtered and the product was washed with water twice
and it was dried and purified by recrystallization from
ethanol to give pure product 3a. The same procedure
was used for all other compounds.
Spectral data
2-(4-Methoxyphenyl)-1H-benzo[d]imidazole 3a:
Pale yellow solid. Yield 80%. m.p. 216-18C;

Table I Yield of benzimidazoles 3a-o with various R groups Contd

Compd R Reaction time (h) Yield (%)
3i

F
Cl

3.0 76
3j


2.5 84
3k


4.0 78
3l


4.0 68
3m


4.0 85
3n


4.0 81
3o

S

4.0 78

NOTES



1155
1
H NMR (500 MHz, DMSO-d
6
): 12.72 (s, 1H, NH),
8.08 (d, 2H), 7.13 (s, 2H), 7.07 (m, 4H), 3.80 (s, 3H);
13
C NMR (100 MHz, DMSO-d
6
): 55.85, 114.1,
122.0, 123.2, 128.5, 129.5, 151.8 and 161.1; ESI-MS:
Calcd m/z 224.25 and Obsd m/z 225.13.
2-(4-Chlorophenyl)-1H-benzo[d]imidazole 3b:
Colourless solid. Yield 82%. m.p. 290-92C. IR
(KBr): 3038, 1440, 1410, 1268, 950, 754 cm
-1
;
1
H
NMR (500 MHz, DMSO-d
6
): 12.9 (s, 1H, NH), 8.15
(d, 2H), 7.49-7.64(m, 4H), 7.20 (m, 2H);
13
C NMR
(100 MHz, DMSO-d
6
): 111.1, 118.6, 121.9, 126.2,
128.6, 129.5, 130.0, 134.8, 143.5, 151.0; ESI-MS:
Calcd m/z 194 and Obsd m/z 193.
2-(Isopropylphenyl)-1H-benzo[d]imidazole 3c:
White solid. Yield 73%. m.p. 230-32C. IR (KBr):
3046, 1444, 1410, 1275, 970, 745 cm
-1
;
1
H NMR (500
MHz, DMSO-d
6
): 12.85 (s, 1H, NH), 8.05(d, 2H),
7.65(d,1H), 7.52 (d, 1H); 7.42 (d, 2H), 7.1 (m, 2H).
2.9 (q, 1H), 1.23 (d, 6H);
13
C NMR (100 MHz,
DMSO-d
6
): 23.6, 33.3, 111.2, 118.6, 121.5, 122.3,
126.4, 126.8, 127.6, 134.8, 143.6, 150.4, 151.3; ESI-
MS: Calcd m/z 236.31 and Obsd m/z 237.13.
2-Phenyl -1H-benzo[d]imidazole 3d: White solid.
Yield 68%. m.p. 282-84C. IR (KBr): 3038, 1447,
1410, 1273, 970, 731 cm
-1
;
1
H NMR (500 MHz,
DMSO-d
6
): 12.88 (s, 1H, NH), 8.15 (m, 2H), 7.45-
7.53 (m, 5H) and 7.17 (m, 2H);
13
C NMR (100 MHz,
DMSO-d
6
): 111.85, 119.40, 122.2, 123.0, 126.9,
129.4, 130.3, 130.6, 135.5, 144.0, 151.7; ESI-MS:
Calcd m/z 194 and Obsd m/z 193.
2-(3, 5-Dimethoxyphenyl)-1H-benzo[d]imidazole
3e: White solid. Yield 84%. m.p. 228-30C. IR (KBr):
3039, 1442, 1410, 1265, 970, 736 cm
-1
;
1
H NMR (500
MHz, DMSO-d
6
): 12.9 (s, 1H, NH), 7.67 (d, 1H),
7.54 (d, 1H), 7.38 (m, 2H), 7.23 (m, 2H), 6.63 (s, 1H)
and 3.86 (s, 6H);
13
C NMR (100 MHz, DMSO-d
6
):
55.41, 111.2, 118.8, 121.6, 122.6, 131.9, 134.8, 143.5,
150.9; ESI-MS: Calcd m/z 254.28 and Obsd m/z
255.13.
2-(3-Nitrophenyl)-1H-benzo[d]imidazole 3f:
Dirty white solid. Yield 87%. m.p. 300-308C. IR
(KBr): 3040, 1441, 1370, 1262, 966, 734 cm
-1
;
1
H
NMR (500 MHz, DMSO-d
6
): 13.28 (s, 1H, NH), 9.0
(s, 1H), 8.55 (d, 1H), 8.34 (d, 1H), 8.3 (m, 1H), 7.5-
7.8 (dd, 2H), 7.24 (t, 2H);
13
C NMR (100 MHz,
DMSO-d
6
): 111.6, 119.1, 119.6, 120.7, 122.1,
123.2, 124.1, 130.6, 131.6, 135.2, 143.5, 148.3, 149.0;
ESI-MS: Calcd m/z 239.22 and Obsd m/z 240.07.
2-(2-Fluorophenyl)-1H-benzo[d]imidazole 3g:
Colourless solid. Yield 74%. m.p. 272-75C. IR
(KBr): 3030, 1428, 1380, 1275, 970, 754 cm
-1
;
1
H
NMR (500 MHz, DMSO-d
6
): 13.07 (s,1H, NH),
8.38 (S, 1H), 8.19 (d, 1H), 7.71(m, 2H), 7.5 (m, 2H
and 7.2 (s, 2H);
13
C NMR (100 MHz, DMSO-d
6
):
111.96, 119.5, 122.4, 123.3, 128.5, 128.6, 129.5,
129.6, 135.1, 135.5, 137.7, 144.2, 150.6; ESI-MS:
Calcd m/z 212.22 and Obsd m/z 212.88.
2-(4-Methylphenyl)-1H-benzo[d]imidazole 3h:
White solid. Yield 80%. m.p. 238-40C. IR (KBr):
3044, 1437, 1410, 1275, 727 cm
-1
;
1
H NMR (500
MHz, DMSO-d
6
): 12.9 (s, 1H, NH), 8.03 (d, 2H),
7.33-7.54 (m, 2H), 7.32 (d, 2H), 7.14 (m, 2H), 2.34 (s,
3H);
13
C NMR (100 MHz, DMSO-d
6
): 111.2, 116.6,
122.9, 126.9, 127.9, 129.4, 129.8, 130.0, 140.1, 151.8;
ESI-MS: Calcd m/z 208.25 and Obsd m/z 209.00.
2-(2-Chloro 6-fluorophenyl)-1H-benzo[d]imida-
zole 3i: White solid. Yield 80%. m.p. 235-43C. IR
(KBr): 3009, 1429, 1380, 1260, 970, 727 cm
-1
;
1
H
NMR (500 MHz, DMSO-d
6
): 12.96 (s, 1H, NH),
7.6-7.66 (m, 3H), 7.5 (d, 1H) and 7.23 (d, 2H);
13
C
NMR (100 MHz, DMSO-d
6
): 115.3, 115.5, 120.0,
120.3, 120.45, 122.8, 126.4, 133.2, 134.8, 140.0,
155.1, 160.2; ESI-MS: Calcd m/z 246.66 and Obsd
m/z 247.13.
2-(3-Bromophenyl)-1H-benzo[d]imidazole 3j:
White solid. Yield 80%. m.p. 294-96C. IR (KBr):
3037, 1441, 1390, 1272, 967, 690 cm
-1
;
1
H NMR (500
MHz, DMSO-d
6
): 13.0 (s, 1H, NH), 8.2 (s, 1H),
8.14 (d, 1H), 7.48-7.6 (m, 4H) and 7.2 (d, 2H);
13
C
NMR (100 MHz, DMSO-d
6
): 111.1,119.1, 120.4,
122.1, 123.2, 126.2, 130.6, 131.5, 132.0, 135.1, 143.5,
150.0; ESI-MS: Calcd m/z 273.12 and Obsd m/z
273.00.
2-Styryl-1H-benzo[d]imidazole 3k: Yellow solid.
Yield 80%. m.p. 216-18C. IR (KBr): 3044, 1330,
1388, 1225, 960 cm
-1
;
1
H NMR (500 MHz, DMSO-
d
6
): 12.6 (s, 1H, NH), 7.64 (m,2H), 7.4 (t,1H) 7.05
(m, 2H);
13
C NMR (100 MHz,DMSO-d
6
): 111.1,
118.6, 121.9, 126.2, 128.6, 129.5, 130.0, 134.8, 143.5,
151.0; ESI-MS: Calcd m/z 194 and Obsd m/z 193.
2-Cyclohexcyl-1H-benzo[d]imidazole 3l: White
solid. Yield 79%. m.p. 220-22C. IR (KBr): 3002,
1306, 1414, 1275, 944, 710 cm
-1
;
1
H NMR (500 MHz,
DMSO-d
6
): 12.4 (s, 1H, NH), 7.06 (d, 2H) 7.05 (d,
2H), 2.8 (m, 1H), 1.95 (t, 2H), 1.75 (t, 2H), 1.56 (t,
2H), 1.35 (m, 2H), 1.33 (t, 2H);
13
C NMR (100 MHz,
DMSO-d
6
): 111.1, 118.6, 121.9, 126.2, 128.6,
129.5, 130.0, 134.8, 143.5, 151.0; ESI-MS: Calcd m/z
200.27 and Obsd m/z 200.01.
3-(1H-Benzo[d]imidazol-2-yl) isoquinoline 3m:
Pale yellow solid. Yield 87%. m.p. 244-46C. IR
(KBr): 3046, 1444, 1410, 1275, 745 cm
-1
;
1
H NMR
INDIAN J. CHEM., SEC B, AUGUST 2013



1156
(500 MHz, DMSO-d
6
): 12.0 (s, 1H, NH), 8.18-8.20
(m, 9H) and 7.22-7.24 (s, 1H);
13
C NMR (100
MHz,DMSO-d
6
): 111.1, 118.6, 121.9, 126.2, 128.6,
129.5, 130.0, 134.8, 143.5, 151.0; ESI-MS: Calcd m/z
245.27 and Obsd m/z 246.00.
2-(Pyridin-3yl)-1H-benzo[d]imidazole 3n:
Yellow solid. Yield 83%. m.p. 240-42C. IR (KBr):
3041, 1444, 1410, 1275, 926 cm
-1
;
1
H NMR (500
MHz, DMSO-d
6
): 13.0 (s, 1H, NH), 9.3 (s, 2H),
8.63 (d, 1H), 8.45 (d, 1H), 7.57 (m, 4H), 7.2 (d, 2H);
13
C NMR (100 MHz, DMSO-d
6
): 112.3, 122.6,
124.6, 126.6, 134.3, 147.9, 149.3, 151.0; ESI-MS:
Calcd m/z 195.21 and Obsd m/z 194.5.
2-(Thiophen-2yl)-1H-benzo[d]imidazole 3o: Pale
yellow solid. Yield 70%. m.p. 246-48C. IR (KBr):
3046, 1444, 1410, 1275, 970, 745 cm
-1
;
1
H NMR (500
MHz, DMSO-d
6
): 12.7 (s, 1H, NH), 7.95 (m, 2H,
C2-H, C6-H), 7.25-7.35 (m,5H, C4-H, C7-H, C3-H,
C4-H, C5-H), 7.05 (m, 2H, C5-H, C6-H);
13
C NMR
(100 MHz, DMSO-d
6
): 111.1, 118.6, 121.9, 126.2,
128.6, 129.5, 130.0, 134.8, 143.5, 151.0; ESI-MS:
Calcd m/z 200.25, Obsd m/z 201.01.
Acknowledgements
DK and PY thank the Department of Science and
Technology, New Delhi (No. SR/S1/PC-33/2006) for
the Junior Research Fellowship and Project
Fellowship respectively.
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