The synthesis of benzimidazole derivatives in the absence of solvent and catalyst

Article abstract of DOI:10.3184/030823409X447763

Differently substituted benzimidazoles have been synthesised from o-phenylenediamine and arylaldehydes or arylmethylene-malononitriles absorbed on silica gel. The reaction was carried out by intermittent grinding or by a microwave-assisted technique under solvent- and catalyst-free conditions giving good yields of the products.

Full text of DOI:10.3184/030823409X447763

JOURNAL OF CHEMICAL RESEARCH 2009
MAy, 333–336
RESEARCH PAPER 333
The synthesis of benzimidazole derivatives in the absence of solvent
and catalyst
Chuanming Yu, Peng Guo, Can Jin and Weike Su*
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University
of Technology, Hangzhou 310014, P.R. China
Differently substituted benzimidazoles have been synthesised from o-phenylenediamine and arylaldehydes or
arylmethylene-malononitriles absorbed on silica gel. The reaction was carried out by intermittent grinding or by a
microwave-assisted technique under solvent- and catalyst-free conditions giving good yields of the products.
Keywords: benzimidazole, o-phenylenediamine, solventless, silica gel, arylmethylene-malononitriles
Benzimidazole and its derivatives are of significance in
medicinal chemistry, because of their biological activity.1
Activity has been reported against viruses such as HIV,2 herpes
(HSV-1),3 RNA,4 influenza,5 and human cytomegalovirus
(HCMV).6 Substituted benzimidazole derivatives have also
found application as anti-ulcer, anti-hypertensive, anti-
viral, anti-fungal, anti-cancer, and anti-histamine agents.7-12
Therefore, the discovery of mild and practical routes for the
synthesis of 2-substituted benzimidazoles continues to attract
attention.
The traditional synthesis of 2-substituted benzimidazoles
usually started from o-phenylenediamine. There are two
general routes. The first is the condensation of o-phenylene-
diamine with a carboxylic acid13 or a derivative (nitriles,
amidates or orthoester)14-16 which often requires strong acidic
conditions. The second is the oxidative cyclodehydration of
o-phenylenediamine with aldehydes using various oxidative
reagents such as nitrobenzene,17 DDQ,18 MnO2,19 NaHSO3,20
Na2S2O5,21 IBD,22 I223 and air.24 In addition, other methods
from o-dibromobenzene,25 N-aryl amidoxime26 and N-
benzyl-2-nitrobenzenamines27 have also been reported
recently. However, many of these methods have drawbacks
including low yields, prolonged reaction times, harsh reaction
conditions, tedious work-up procedures, use of toxic solvents,
and the use of metals and expensive reagents. We report here a
convenient, inexpensive and green method for the preparation
of benzimidazoles in the solid state using o-phenylenediamine
and aromatic aldehydes which were supported on silica gel
under solvent- and catalyst-free conditions.
Table 1 Effects of temperature and time in the synthesis of
benzimidazole under intermittent grinding
Entry
Temp/°C
Time/min
Yield/%a
1
2
25°C
25 °C
25 °C
50°C
50°C
50°C
90°C
90°C
90°C
90°C
5
15
30
5
15
30
5
15
30
60
45
50
51
65
70
73
70
86
93
93
3
4
5
6
7
8
9b
10
aIsolated yield based on 1.
bThe optimum condition of using grinding.
the reaction temperature. Finally, we established the optimum
temperature of about 90°C. The effect of reaction time was
also examined. Although air plays an important role in this
reaction as an oxidant and long reaction time was of benefit
to the reaction, 0.5 h was enough to produce excellent
conversions (by TLC).
To test the generality of this procedure for the synthesis
of 2-substituted benzimidazoles 4a–m, a series of aldehydes
were investigated (Table 2, entries 1–13) using the optimised
reaction conditions (90°C, 0.5–1 h). As shown in Table 2
(Method A), we found that both aldehydes bearing electron-
withdrawing (entries 2–7) and electron-donating (entries
8–11) substituents gave the corresponding benzimidazoles
in good yields. Surprisingly halogenated aldehydes (entries
2–4) gave high yields. When the phenyl ring was replaced
with thiophene, the corresponding product was obtained in
moderate yield (Table 2, entry 12, 74% yield). As expected, the
reactions were generally complete within 0.5 h, except for the
cases of 4-nitrobenzaldeyde and 2-thiophenecarboxaldehyde
which required 1 h or longer to obtain an acceptable yields.
Initially, in order to optimise the reaction conditions,
o-phenylenediamine (1a) and 4-chlorobenzaldehyde (2b)
were used in a model reaction in order to examine the reaction
time and temperature.
As shown in Table 1, the reaction gave low yield at room
temperature for 30 min. The yield was improved by increasing
NH2
NH2
Silica-supported
conditions
N
CHO
Cl
+
N
H
Cl
1
2b
4b
Scheme 1
O
NH2
NH2
N
Silica-supported
90oC, 0.5-1h
Ar
+
H
Ar
N
H
1
2
4
Scheme 2
* Correspondent. E-mail: suweike@zjut.edu.cn

334 JOURNAL OF CHEMICAL RESEARCH 2009
Table 2 The synthesis of benzimidazole under different methodsa.b.c
Entry
Aldehyde (Ar = )
Method Aa
Method Bb
Product
Time/h (Yield/%)a
Time/min (Yield/%)b
1
2
Ph
0.5 (80),(7)c
0.5 (93)
0.5 (92)
0.5 (94)
0.5 (88)
1.0 (80)
0.5 (89)
0.5 (88)
0.5 (87)
0.5 (85)
0.5 (84)
1.0 (74),(9)c
0.5 (85)
7 (83),(7)c
7 (93)
4a
4b
4c
4d
4e
4f
4-ClC6H4
3
4-FC6H4
3-BrC6H4
7 (93)
4
7 (95)
7 (89)
5
2-Cl-6FC6H3
3-NO2C6H4
4-CNC6H4
4-OHC6H4
4-CH3C6H4
3-CH3OC6H4
3,4-(CH3) 2C6H3
2-Thiophene
6
10 (82)
7 (90)
7
4g
4h
4i
8
7 (90)
9
7 (89)
10
11
12
13
7 (88)
4j
7 (86)
4k
4l
7 (77),(9)c
7 (88)
N
Cl
4m
CHO
Reaction conditions:
a1 (1.0 mmol), 2 (1.1 mmol), the reactions were carried out at 90°C for 0.5–1 h.
b1 (1.0 mmol), 2 (1.1 mmol), the reactions were carried out at microwave irradiation(320 W) for 7–10 min.
cIn parentheses, isolated yields of product 5.
dThe reaction was monitored by TLC.
As a novel, effective and universal technique in organic
synthesis, microwave irradiation (Method B) was used to
promote the reaction. As shown in Table 2 (Method B),
microwave irradiation of the reactions were achieved at 320 W,
and in all cases, the reaction was complete in about 7–10
minutes. Compared with method A, the reaction time was
significantly shortened.
Under the optimised reaction conditions, in most cases
the yields were high and product 4 was formed exclusively
as shown in Table 2. Nevertheless, in two cases (entries
1 and 12), not only was product 4 detected, but also an
unexpected by-product 5 was obtained (Scheme 3, 4).
A possible mechanism for the formation of this 1,2-disubstituted
benzimidazole is shown in Scheme 5. There are three steps:
(1) condensation of benzaldehyde with o-phenylenediamine
to form the dibenzylidene-derivative; (2) protonation of this
and ring closure leading to a five-membered ring either in a
sequential or concerted manner; and (3) 1,3-hydride transfer
and deprotonation. Based on this mechanism, a reaction using
a 1:2 of o-phenylenediamine and 4-chlorobenzaldehydes
was examined. It was found that 4b was the major product,
whereas very little of product 5b was detected by TLC.
The result indicated that this procedure have high selectivity
for the synthesis of 2-substituted benzimidazoles.
CHO
NH2
N
N
Silica-supported
+
+
N
NH2
N
H
conditions
1
2a
4a
5a
minor
major
Scheme 3
N
N
N
NH2
NH2
Silica-supported
conditions
+
+
S
CHO
S
N
H
S
S
4l
5l
minor
1
2l
major
Scheme 4
H+
N
Ph
H
H
O
N
Ph
N
N
H
Ph
Ph
H2N
H2N
H
N
2 equiv.
2
Ph
H
N
+
5
1
Ph
Scheme 5 Proposed mechanism for the formation of 1,2-disubstituted benzimidazoles.

JOURNAL OF CHEMICAL RESEARCH 2009 335
NH2
NH2
N
Silica-supported
conditions
N
N
CN
CN
Ar
+
Ar
Ar
Ar
+
N
H
1
4
5
3
single
none
Scheme 6
Silica-supported
90oC 0.5-1h
NH2
NH2
N
COOH
+
N
H
4
1
6
Scheme 7
Surprisingly we found that the o-phenylenediamine reacted
with arylmethylene-malononitriles (Scheme 6) using the
grinding technique to give excellent yields of a single desired
product with a 1:1 mol ratio of reactions. With two equivalents
of arylmethylene-malononitriles, an extra reductive product
was formed.28 It was interesting that most of the 2-substituted
benzimidazoles were obtained in slightly higher yields
(e.g. 4a, 4h, 4k and 4l Table 3). This is presumably due to
the better stability of aryl-methylenemalononitriles compared
to some aldehydes. This reaction had excellent selectivity
and no product 5 was detected. Benzoic acid was also used to
investigate the scope of this method, but no desired product
was obtained either by the grinding or microwave-assisted
technique (Scheme 7).
In summary, we have reported alternative and highly efficient
methods for the synthesis of benzimidazoles under solvent-
and catalyst-free conditions. The desired benzimidazoles were
obtained in good to excellent yields. The notable advantages
of this procedure include the substrates being loaded onto
silica gel without any other catalyst (using atmospheric air as
the oxidant). No toxic reagent(s) were involved, and there was
a simple work-up procedure. The method is environmentally
friendly, and possesses high generality. The study of the
potential bioactivities of these benzimidazole derivatives are
in progress in our laboratory.
Table 3 The synthesis of benzimidazole using arylmethylene-
malononitrilesa,b
Entry
Ar =
Time/h
Yield/%
Product
1
2
3
4
5
6
7
8
9
10
Ph
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
92
95
90
87
94
91
90
88
88
86
4a
4b
4e
4f
4g
4h
4i
4j
4k
4l
4-ClC6H4
2-Cl-,6-FC6H3
3-NO2C6H4
4-CNC6H4
4-OHC6H4
4-CH3C6H4
3-CH3OC6H4
3,4-(CH3) 2C6H3
2-Thiophene
aReaction conditions: 1 (1.0 mmol), 3 (1.0 mmol), the reactions
were carried out under intermittent grinding at 90°C for 0.5 h.
bThe reaction was monitored by TLC.
directly purified by column chromatography with EtOAc–petroleum
ether (1:5) to afford compounds 4a–m.
2-Phenylbenzimidazole (4a): Colourless solid; m.p. 295–296°C
1
(Lit.23 295°C). H NMR d: 7.21 (d, 2H, J = 4.8 Hz), 7.48–7.58 (m,
4H), 7.66 (s, 1H), 8.18 (d, 2H, J = 8.0 Hz), 12.91 (s, 1H). 13C NMR
d: 122.1, 126.4, 128.4, 128.9, 129.2, 129.8, 130.1, 151.2. MS (ESI):
m/z = 195 (M+ + 1).
2-(4-Chlorophenyl)benzimidazole (4b): White solid; m.p. 292–
294°C (Lit.22 292–294°C). 1H NMR d: 7.22 (d, 2H, J = 6.2 Hz),
7.63–7.70 (m, 4H), 8.19 (d, 2H, J = 9.2 Hz), 12.99 (s, 1H). 13C NMR
d: 111.4, 118.9, 121.9, 122.5, 128.1, 129.0, 134.5, 150.1. MS (ESI):
m/z = 231 ([M+ + 2], 33), 229 ([M+ + 1], 100).
Experimental
2-(4-Fluorophenyl)benzimidazole (4c): White solid; m.p. 250–
252°C (Lit.22 250–251°C). 1H NMR d: 7.21 (dd, 2H, J1 = 7.2,
J2 = 9.2 Hz), 7.39–7.43 (m, 2H), 7.54 (d, 1H, J = 7.2 Hz), 7.67 (d,
1H, J = 7.6 Hz), 8.21–8.25 (m, 2H), 12.92 (s, 1H). 13C NMR d: 111.3,
115.9, 116.1, 118.8, 121.7, 122.5, 126.8, 128.7, 128.8, 135.0, 143.8,
150.4, 163.1 (d, J = 246.5 Hz). MS (EI): m/z (%) = 212 (M+, 100).
2-(3-Bromophenyl)benzimidazole (4d): White solid; m.p. 250–
251°C. 1H NMR d: 7.20–7.27 (m, 2H), 7.51–7.56 (m, 2H), 7.69 (t, 1H,
J = 6.4 Hz), 8.19 (d, 1H, J = 8.0 Hz), 8.38 (s, 1H), 13.05 (s, 1H). 13C NMR
d: 111.4, 119.0, 121.9, 122.2, 122.9, 125.3, 128.8, 131.1, 132.4, 134.9,
143.6, 149.6. MS (EI): m/z (%) = 274 ([M+ + 2], 90), 272 (M+,100).
2-(2-Chloro-6-fluorophenyl)benzimidazole (4e): Pale yellow
The NMR spectra were measured with a Bruker Advance III 500
or Varian Mercury Plus-400 instrument using TMS as an internal
standard and DMSO as the solvent. Mass spectra were measured
with a Finnigan Trace DSQ spectrometer, HRMS analysis was
measured on an Agilent 6210. Melting points (m.p.) were recorded
on digital melting point apparatus WRS-1B and uncorrected. Flash
column chromatography was carried out on 200–300 mesh silica gel.
Microwave assisted reactions were carried out in an APEX reactor.
General experimental procedure for the synthesis of 4a–m:
(arylaldehydes as the reagents)
o-Phenylenediamine (1.0 mmol) and benzaldehyde 2a (1.1 mmol)
were ground in a mortar with 0.4 g silica gel (200–300 mesh) each
to give a homogeneous mixture. The two mixtures were combined
and ground intermittently at 90°C or reacted under microwave-
irradiation for an appropriate time given in Table 2 in the presence
of air. The reaction was monitored by TLC. After completion of the
reaction and cooling to room temperature, the residue was directly
purified by column chromatography with EtOAc–petroleum ether
(1:5) to afford compounds 4a and 5a.
1
solid; m.p. 217–219°C. H NMR d: 7.22–7.30 (m, 2H), 7.46 (t, 1H,
J = 8.4 Hz), 7.54–7.57 (m, 2H), 7.62–7.68 (m, 1H), 7.72 (d, 1H,
J = 8.0 Hz), 12.90 (s, 1H). 13C NMR d: 111.5, 114.7, 114.9, 119.2,
119.7, 119.9, 121.6, 122.8, 125.8 (d, J = 2.3 Hz), 132.5 (d, J = 9.1 Hz),
134.2 (d, J = 5.3 Hz), 143.4 (d, J = 24.2 Hz), 160.7 (d, J = 248.7 Hz).
MS (EI): m/z (%) = 248 ([M+ + 2], 33), 246 (M+, 100). HRMS (ESI):
Calcd for (C13H8ClFN2 + H) 247.0438. Found 247.0433.
2-(3-Nitrophenyl)benzimidazole (4f): Yellow solid; m.p. 203–
1
205°C (Lit.30 202–203°C). H NMR d: 7.26 (s, 2H), 7.60 (s, 1H),
General experimental procedure for the synthesis of 4a–m:
(arylmethylene–malononitriles as the reagents)
7.72 (s, 1H), 7.87 (t, 1H, J = 8.0 Hz), 8.34 (d, 1H, J = 8.4 Hz), 8.62
(d, 1H, J = 8.0 Hz), 9.02 (s, 1H), 13.30 (s, 1H). 13C NMR d: 111.7,
119.2, 120.8, 122.1, 123.2, 124.2, 130.6, 131.7, 132.5, 148.3, 149.0.
MS (ESI): m/z = 240 (M+ + 1).
2-(4-Cyanophenyl)benzimidazole (4g): White solid; m.p. 262–
263°C (Lit.30 262°C). 1H NMR d: 7.26 (s, 2H), 7.65 (s, 2H), 8.04 (d,
2H, J = 8.4 Hz), 8.35 (d, 2H, J = 8.8 Hz), 13.20 (s, 1H). 13C NMR d:
o-Phenylenediamine (1.0 mmol) and aryl-methylenemalononitriles
3a (1.0 mmol) were ground in a mortar with 0.4 g silica gel (200–
300 mesh) each to give a homogeneous mixture. The two mixtures
were combined and ground intermittently for 0.5 h at 90°C in the
presence of air. The reaction was monitored by TLC. After completion
of the reaction and cooling to room temperature, the residue was

336 JOURNAL OF CHEMICAL RESEARCH 2009
111.9, 118.6, 119.3, 122.2, 123.2, 126.4, 127.0, 132.9, 134.2, 149.3.
MS (EI): m/z (%) = 219 (M+, 100).
2-(4-Hydroxyphenyl)benzimidazole (4h): Pale yellow solid; m.p.
294–296°C (Lit.29 294–296°C). 1H NMR d: 6.92 (d, 2H, J = 8.4 Hz),
7.15 (d, 2H, J = 5.6 Hz), 7.48–7.59 (m, 2H), 8.01 (d, 2H, J = 8.0 Hz),
9.97 (s, 1H), 12.66 (s, 1H). 13C NMR d: 115.7, 121.1, 121.6, 128.2,
151.8, 159.1. MS (ESI): m/z = 211 (M+ + 1).
Received 16 January 2009; accepted 19 March 2009
Paper 09/0396 doi: 10.3184/030823409X447763
Published online: 20 May 2009
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3-(1H-benzimidazol-2-yl)-2-chloro-6-methyl-Quinoline
(4m):
1
White solid; m.p. 273–275°C. H NMR d: 2.55 (s, 3H), 7.28 (t, 2H,
J = 8.4 Hz), 7.63 (d, 1H, J = 7.6 Hz), 7.74–7.79 (m, 2H), 7.95–7.98
(m, 2H), 8.87 (s, 1H), 12.93 (s, 1H). 13C NMR d: 21.1, 111.8, 119.1,
121.9, 123.0, 124.4, 126.3, 127.1, 127.4, 134.2, 134.8, 137.8, 140.6,
143.3, 145.5, 146.2, 147.8. MS (EI): m/z (%) = 295 ([M+ + 2], 33),
293 (M+, 100).
1-Benzyl-2-phenylbenzimidazole(5a):Whitesolid;m.p.132–133°C
1
(Lit.30 132°C). H NMR d: 5.48 (s, 2H), 7.11 (d, 2H, J = 6.4 Hz),
7.23–7.26 (m, 2H), 7.31–7.35 (m, 4H), 7.46–7.49 (m, 3H), 7.70 (dd,
2H, J1 = 1.6, J2 = 8.0 Hz), 7.90 (d, 1H, J = 7.6 Hz). 13C NMR d: 48.4,
110.5, 119.9, 122.7, 123.0, 125.9, 127.7, 128.7, 129.0, 129.2, 129.9,
136.0, 136.4, 143.1, 154.1. MS (ESI): m/z = 285 (M+ + 1).
1-(2-Thienylmethyl)-2-(2-thienyl)benzimidazole (5l): Pale yellow
solid; m.p. 146–147°C (Lit.32 146–148°C). 1H NMR d: 5.71 (s,
2H), 6.87 (d, 1H, J = 2.4 Hz), 6.95 (t, 1H, J = 4.4 Hz), 7.15 (t, 1H,
J = 4.4 Hz), 7.24–7.33 (m, 3H), 7.38 (dd, 1H, J1 = 2.4, J2 = 6.8 Hz),
7.48 (d, 1H, J = 2.8 Hz), 7.52 (d, 1H, J = 4.8 Hz), 7.84 (dd, 1H,
J1 = 2.4, J2 = 7.2 Hz). 13C NMR d: 44.1, 109.9, 119.9, 123.0, 123.3,
125.4, 125.5, 127.2, 127.8, 128.1, 128.8, 131.8, 135.9, 138.8, 143.0,
147.6. MS (ESI): m/z = 297 (M+ + 1).
We are grateful to the National Natural Science Foundation
of China (No. 20676123 and 20876147) and for financial
support.