Microwave-assisted synthesis of 2-substituted 1h-benzo[d]imidazoles and their antifungal activities in vitro

Article abstract of DOI:10.3987/COM-13-12734

An efficient and novel microwave-assisted synthesis of 1H-benzo[d]imidazole derivatives via nitriles and o-phenyldiamines in the presence of polyphosphoric acid (PPA) and phosphoric acid is described. This method provides several advantages such as commercially high availabilities of starting materials, short reaction times, high yields and a simple workup procedure. Systematically antifungal biological tests showed 3f was most promising candidate against six phytopathogenic fungi.

Full text of DOI:10.3987/COM-13-12734

HETEROCYCLES, Vol. 87, No. 7, 2013, pp. - . © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 25th April, 2013, Accepted, 28th May, 2013, Published online, 4th June, 2013
DOI: 10.3987/COM-13-12734
MICROWAVE-ASSISTED
SYNTHESIS
OF
2-SUBSTITUTED
1H-BENZO[d]IMIDAZOLES AND THEIR ANTIFUNGAL ACTIVITIES IN
VITRO
Tao Zhang,1 Liang-Zhu Huang,1 Jia Wu,1 Dong Lu,1 Bo-Lin Ma,1 and
Zhen-Ting Du1,2*
1
College of Science, Northwest A&F University, Yangling 712100, Shaanxi
Province, P. R. China
2Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, Shanghai 20032, P. R.
China
Abstract – An efficient and novel microwave-assisted synthesis of
1H-benzo[d]imidazole derivatives via nitriles and o-phenyldiamines in the
presence of polyphosphoric acid (PPA) and phosphoric acid is described. This
method provides several advantages such as commercially high availabilities of
starting materials, short reaction times, high yields and a simple workup
procedure. Systematically antifungal biological tests showed 3f was most
promising candidate against six phytopathogenic fungi.
Microwave-assisted organic synthesis (MAOS) is a hot topic in which a large number of papers have
been published in last three decades.1 MAOS has significantly affected synthetic chemistry by providing a
new means of rapid, efficient, and scalable chemical operations. At the same time, MAOS can facilitate
the discovery of new reactions and reduce cycle time in the optimization of reactions.
1H-Benzo[d]imidazoles,2 which are also called benzimidazoles, play a key role in pharmacy and
agrochemicals, as these compounds possess a variety of biological activities including antiarrhythmic,
antiulcer, anthelmintic,3 inotropic, antihistamine,4 antifungal,5 and antiviral. Recent pharmaceutical
studies have revealed that some derivatives show promising biological activity as antiallergic agents,
factor Xa inhibitors,6 poly(ADP-ribose)polymerase inhibitors,7 and human cytomegalovirus inhibitors.8
Structurally, benzimidazole derivatives are isosteres of naturally occurring nucleotides, which allows
them to interact easily with the biopolymers of living systems. Moreover, polybenimidazoles (PBI) have

been developed as a kind of polymers that have applications as high temperature matrix resins,
non-flammable textile fibres, adhesives and foams.9
Generally, the synthesis of benzimidazoles is accomplished by utilizing the condensation reaction of
arylenediamines with carboxylic acids, carboxylic acid esters, lactones, anhydrides, and aldehydes under
different catalysts.10 Especially, hein discolsed only one example of thermal cyclization of benzonitrile
and o-phenyldiamine, however, it needed harsh condition such as high temperature 250-300 C.10f To the
best of our knowledge, there have been no reports on the condensation between nitriles and
arylenediamines under the microwave irradiation. We envisioned that microwave irradiation could
enhance the condensation of nitriles and arylenediamines and expand the scope this protocol. Compared
with other carboxyl equivalents, nitriles are structurally labile and ready intermediates because they can
be synthesized easily from alkyl halide and cyanide in large scale. Herein, we wish to report an efficient
and novel microwave-assisted synthesis of 1H-benzo[d]imidazole from readily available starting
materials and their antifungal activities to six phytopathogenic fungi in vitro.
H
NH2
NH2
N
MW, PPA
H3PO4
+
NC R
R
N
1
2
3
Scheme 1. Microwave-assisted synthesis of 1H-benzo[d]imidazole
Initially, a model reaction of o-phenyldiamine 1 (10 mmol) and benzonitrile 2 (10 mmol) in presence of a
kind of acid under microwave irradiation (275 W, 15 min) was planned (Scheme 1). When 6 M HCl, 12
M HCl, silica-supported sulfuric acids, and NH4Cl were tested, unfortunately, the cyclization of
benzo[d]imidazole did not occur and those acidic catalysts proved to be inappropriate. When the
H2SO4/DMSO system was used, an oily residue without any product was obtained. At last, when PPA
was used as the acid and solvent, 2-phenyl-1H-benzo[d]imidazole was provided in 75% yield. Because of
the high viscidity of PPA, some H3PO4 was added to buffer the heat of the microwave. To our satisfactory,
when 20 mL PPA and 10 mL H3PO4 were used, the yield of 2-phenyl-1H-benzo[d]imidazole increased to
92%. Therefore, we set up the optimized reaction conditions, 20 mL PPA and 10 mL H3PO4 used as the
co-solvent for per 10 mmol o-phenyldiamine and benzonitrile.
Under these optimized reaction conditions, we next examined the scope of PPA/H3PO4 catalyzed
cyclization of o-phenyldiamine 1 and nitrile 2 for the synthesis of substituted 1H-benzo[d]imidazoles.
The results are summarized in Table 1. A wide range of structurally diverse nitriles (Table 1), including
aryl (Table 1, entries 1-8, entries 11-13), aliphatic (Table 1, entries 9-10) cyclization with

o-phenyldiamine under this protocol to give the corresponding substituted 1H-benzo[d]imidazoles in
excellent yields. Among them, bromo (Table 1, entries 4-5), fluoro (Table 1, entry 6) and chloro (Table 1,
entries 2-3) groups can be tolerated. The bromo and chloro moieties could be functionalized to boric acid
or stannane easily, so our method effectively allows the preparation of halo 1H-benzo[d]imidazoles. It is
worth notice that if the equivalent of carboxylic acid was included in starting materials, the cyclization
occurred at both spots (Table entry 14). To our regret, the methoxy and nitro groups can not be tolerated
in such conditions, complicated results was obtained (Table entries 15-16). We suspected that these two
functional groups may react with PPA or H3PO4 under microwave irradiation. Thus, all the products in
our reactions listed in Table 1 were easily characterized on the basis of physical and spectral data and also
by comparison with authentic samples. All products (Table 1) were fully characterized by spectroscopic
methods, as well as by the comparison of the spectral data with reported values.
Table 1 Microwave-Assisted Synthesis of 1H-benzo[d]imidazoles
H
NH2
NH2
N
MW, PPA
H3PO4
+
NC R
R
N
1
2
3
Yield
(%)a
Yield
(%)a
Entry
1
Compd 2
Product 3
Entry
Compd 2
Product 3
H
N
H
N
Me
N
NC
92
84
86
75
86
9
N
NC Me
85
95
3a
3i
3j
Cl
H
H
N
N
Cl
2
3
4
5
10
11
12
13
N
NC
NC
N
NC
NC
3b
3c
Me
H
N
H
N
Me
Cl
Cl
90
89
86
N
N
3k
3l
Br
H
Me
H
Me
N
Br
N
N
N
NC
NC
NC
NC
3d
3e
H
N
H
N
Br
Br
N
N
N
N
3m

H
N
N
N
F
N
H
N
H
6
7
8
96
72
77
14
15
16
78b
NC
NC
F
NC
CO2H
OMe
N
3n
3f
H
N
complicated results
complicated results
-
-
NC
NC
N
3g
3h
H
N
NC
N
Br
NO2
Br
a isolated yield. b 2 equiv. of 1 are used.
The reaction presumably proceeds in four steps: nucleophilic addition of one amino group to
o-phenyldiamine 1 to acidified nitrile 2 to give the adduct 4. Then, 4 tautomerized to intermediate 5 via
proton exchange. Because of the high electrophilicity of the protonated imine, another amino group in
o-phenyldiamine would attack the carbon center to form intermediate 6. This could be transformed into
the final product 1H-benzo[d]imidazole after another proton exchange and deamination.
NH2
NH2
tautomerization,
proton exchange
NH2
NH2
N
NH
R
NH2
R
H+
H N
R
N
R
N
H2
H
4
5
H
N
HH
proton
exchange
+
NH2
R
NH3
R
-NH4
N
N
R
N
H
N
H
N
H
7
6
3
Scheme 2. Proposed mechanism of PPA/H3PO4 catalysed cyclization of o-phenyldiamines 1 and nitriles 2
Meanwhile, 13 products of 2-substituted 1H-benzo[d]imidazoles (3a-3m) against six phytopathogenic
fungi (Cytospora mandshurica, Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani,
Fusarium solani and Pyricularia oryzae) were investigated at the concentration of 100 g/mL in vitro by
poisoned food technique. While thiophanate-methyl, a commercially available agricultural fungicide, was
used as a positive control at 100 g/mL. As shown in the Table 2, we can see most of the 2-substituted

1H-benzo[d]imidazoles showed good to excellent antifungal activities. It should be note that the
compound 3f gave almost equal potential to thiophanate-methyl, but compound 3i and 3m give poor
antifungal activities, relatively. With regard to 3f, we suspected high penetrability of the fluoro atom
contributed to excellent activities as well as less aromatic moiety gave rise to low activities of 3i.
Table 2 Antifungal activities of 3a-3m to six phytopathogenic fungi
Antifungal activities (inhibition %)
Cytospora
Colletotrichum Botrytis Alternaria Fusarium
Pyricularia
grisea
Compound
mandshurica gloeosporioide cinerea solani
solani
3a
3b
3c
3d
3e
3f
86.85
69.09
84.87
78.95
44.09
90.79
61.19
44.09
30.28
27.65
85.53
68.43
2.66
85.16
84.42
74.04
81.44
61.06
92.21
55.87
32.50
14.33
76.64
92.21
74.04
27.31
64.31
59.22
57.67
58.48
60.12
79.08
78.43
71.24
69.93
49.02
75.73
64.08
53.89
59.23
44.67
92.23
47.10
40.79
15.07
58.75
82.04
62.14
24.77
65.17
52.92
68.40
38.73
45.82
89.68
54.85
28.41
12.93
45.18
76.78
79.36
14.86
100.00 88.24
3g
3h
3i
35.76
14.35
7.21
64.71
41.18
23.53
76.47
81.70
83.01
42.48
3j
32.19
57.17
78.59
10.78
3k
3l
3m
thiophanate-
methyl
86.85
76.99
78.59
54.25
94.18
30.99
In conclusion, a novel PPA/H3PO4 catalyzed cyclization of o-phenyldiamine and nitriles for the synthesis
of substituted 1H-benzo[d]imidazoles under microwave irradiation has been developed. This method
offers several advantages, such as high yields, short reaction times, clean reaction profiles, and simple
experimental and easy work-up procedures. 13 products of 2-substituted 1H-benzo[d]imidazoles were
tested again six phytopathogenic fungi.
EXPERIMENTAL
A mixture of nitrile (10 mmol), o-phenyldiamines (10 mmol) and PPA (20 mL) and H3PO4 (10 mL) was
vigorously stirred and irradiated in microwave reactor (Sineo MAS-II, Shanghai, China) at internal 150
C for 15 min (Table 1). Then the reaction mixture was poured into ice water and netrualized by 5 M
NaOH to pH = 8. The mixture was extracted by DCM (3×30 mL) and the combined organic layers were

washed with saturated aqueous NaHCO3 and brine, dried with anhydrous MgSO4. The solvent was
evaporated in vacuum and the residue was purified through column chromatography to give 3 (Table 1).
1
The H-NMR and 13C-NMR data were recorded in DMSO solution with Bruker-NMR spectrometers
(DRX 500, AM 400) if not noted otherwise. The chemical shifts are measured relative to TMS (= 0) or
chloroform (= 7.26) and the coupling J is expressed in Hertz.
2-Phenyl-1H-benzo[d]imidazole (3a)
1
Mp 290-292 C (lit.,11 292 C). H-NMR: 7.27 (dd, 2H, J = 3.0, J = 6.0), 7.49 (d, 1H, J = 7.4), 7.57 (d,
13
2H, J = 7.7), 7.73 (d, 2H, J =7.3), 8.34 (dd, 2H, J =1.1, J =7.9), 13.11 (s, 1H). C-NMR: 111.9, 119.4,
122.4, 122.9, 127.0, 129.4, 130.3, 130.8, 135.6, 144.5, 151.9.
2-(2-Chlorophenyl)-1H-benzo[d]imidazole (3b)
Mp 234-236 C (lit.,11 233-236 C). 1H-NMR: 7.26 (s, 2H), 7.51-7.56 (m, 2H), 7.60-7.72 (m, 3H), 7.93
(dd, 1H, J = 1.8, J = 7.1), 12.76 (s, 1H). 13C-NMR: 111.8, 119.2, 121.8, 122.9, 127.5, 130.1, 130.5, 131.3,
131.8, 132.2, 134.8, 143.4, 149.2.
2-(4-Chlorophenyl)-1H-benzo[d]imidazole (3c)
1
Mp 292-294 C (lit.,11 292-293 C). H-NMR: 7.23 (s, 2H), 7.55-7.67 (m, 4H), 8.19 (d, 2H, J = 8.4),
13.01 (s, 1H). 13C-NMR: 111.9, 119.4, 122.4, 123.3, 128.6, 129.4, 129.6, 135.0, 144.1, 150.5.
2-(2-Bromophenyl)-1H-benzo[d]imidazole (3d)
Mp 242-244 C (lit.,12 242 C). 1H-NMR: 7.23-7.28 (m, 2H), 7.48 (t, 1H, J = 7.7), 7.56 (t, 2H, J = 7.6),
7.70 (d, 1H, J = 7.7), 7.76 (d, 1H, J = 7.6), 7.83 (d, 1H, J = 8.0), 12.74 (s, 1H). 13C-NMR: 112.0, 119.6,
122.0, 122.1, 123.2, 128.3, 131.9, 132.7, 132.8, 133.9, 134.8, 143.6,150.8.
2-(4-Bromophenyl)-1H-benzo[d]imidazole (3e)
Mp 298-300 C (lit.,12 298 C). 1H-NMR: 7.24 (dd, 2H, J = 2.6, J = 5.4), 7.48-7.66 (m, 4H), 8.27(d, 2H, J
= 7.7), 13.01 (s, 1H).13C-NMR: 111.6, 119.1, 122.1, 122.8, 123.4, 128.5, 129.5, 132.1, 135.2, 143.8,
150.4.
2-(4-Fluorophenyl)-1H-benzo[d]imidazole (3f)
Mp 251-252 C (lit.,12 250-251 C). 1H-NMR: 7.22 (dd, 2H, J = 3.0, J = 5.8), 7.41 (t, 2H, J = 8.8), 7.63 (s,
13
2H), 8.27 (dt, 2H, J = 3.9, J = 7.0), 12.97 (s, 1H). C-NMR: 111.2, 116.0, 116.2, 122.3, 126.9, 127.0,
128.9, 129.0, 150.6, 162.3, 164.2.
2-Benzyl-1H-benzo[d]imidazole (3g)
Mp 195-196 C (lit.,13 195-196 C). 1H-NMR: 4.17 (s, 2H), 7.11-7.15 (m, 2H), 7.23 (t, 1H, J = 6.3),
13
7.30-7.34 (m, 4H), 7.41 (d, 1H, J = 7.3), 7.53 (d, 1H, J = 7.3), 12.29 (s, 1H). C-NMR: 35.4, 111.4,
118.7, 121.5, 122.2, 127.0, 129.0, 129.2, 134.7, 138.1, 143.8, 153.9.

2-(4-Bromobenzyl)-1H-benzo[d]imidazole (3h)
Mp 210-212-196 C (lit.,14 212-213 C). 1H-NMR: 4.16 (s, 2H), 7.13 (t, 2H, J = 6.8), 7.29 (d, 2H, J = 8.1),
13
7.42 (d, 1H, J = 7.4), 7.52 (t, 3H, J = 7.9), 12.29 (s, 1H). C-NMR: 34.6, 111.4, 118.8, 120.2, 121.5,
122.3, 131.5, 131.8, 134.7, 137.5, 143.7, 153.4.
2-Methyl-1H-benzo[d]imidazole (3i)
Mp 184-185 C (lit.,13 184-185 C). 1H-NMR: 2.55 (s, 3H), 7.14 (dd, 2H, J = 3.2, J = 9.2), 7.52 (dd, 2H, J
= 3.3, J = 5.8). 13C-NMR: 15.1, 114.6, 121.6, 139.5, 151.9.
2-Butyl-1H-benzo[d]imidazole (3j)
Mp 184-185 C (lit.,15 184-185 C). 1H-NMR: 0.91 (t, 3H, J = 7.4), 1.31-1.40 (m, 2H), 1.73-1.81 (m, 2H),
13
2.84 (t, 2H, J = 15.1), 7.10-7.14 (m, 2H), 7.49 (s, 2H), 12.29 (s, 1H). C-NMR: 14.1, 22.3, 28.7, 30.2,
114.6, 121.5, 138.6, 155.6.
2-(3-Methylphenyl)-1H-benzo[d]imidazole (3k)
1
Mp 221-222 C (lit.,13 222-223 C). H-NMR: 2.42 (s, 3H), 7.21 (dd, 2H, J = 2.8, J = 6.0), 7.31 (d, 1H,
J = 7.5), 7.44 (t, 1H, J = 7.6), 7.59-7.64 (m, 2H), 7.99 (d, 1H, J = 7.8), 8.05 (s, 1H), 12.90 (s, 1H).
13C-NMR: 21.5, 111.8, 119.2, 122.3, 122.9, 124.1, 127.5, 129.3, 130.6, 131.0, 133.9, 138.6, 144.3, 151.8.
2-(2-Methylphenyl)-1H-benzo[d]imidazole (3l)
Mp 239-240 C (lit.,13 239-240 C). 1H-NMR: 2.62 (s, 3H), 7.22 (t, 2H, J = 8.1), 7.35-7.41 (m, 3H), 7.54
13
(d, 1H, J = 7.4), 7.69 (d, 1H, J = 7.4), 7.75 (d, 1H, J = 7.0) , 12.64 (s, 1H). C-NMR (125 M, DMSO):
21.5, 111.7, 119.4, 121.9, 122.8, 126.4, 129.8, 129.9, 130.5, 131.7, 134.9, 137.5, 144.2, 152.4.
2-(Pyridin-3-yl)-1H-benzo[d]imidazole (3m)
1
Mp 218-219 C (lit.,11 218 C). H-NMR: 7.24-7.28 (m, 2H), 7.59-7.63 (m, 1H), 7.67 (s, 2H), 8.53 (dt,
1H, J = 2.2, J = 8.1), 8.70 (dd, 1H, J = 1.6, J = 4.8), 9.39 (dd, 1H, J = 0.6, J = 2.2), 13.15 (s, 1H).
13C-NMR: 111.7, 119.3, 122.3, 123.0, 124.5, 126.6, 134.2, 135.0, 143.9, 148.0, 149.3, 151.0.
1,4-Bis(1H-benzo[d]imidazol-2-yl)benzene (3n)
1
Mp >300 C (dec., lit.,16 >300 C). H-NMR (400 MHz, DMSO-d6): 7.19-7.26 (m, 4 H), 7.57 (d, J = 7.6
Hz, 2 H), 7.70 (d, J = 7.6 Hz, 2 H), 8.35 (s, 4 H), 13.05 (s, 2 H). 13C NMR (100MHz, DMSO-d6): 119.0,
121.9, 122.9, 126.9, 131.2, 143.9, 150.6.
ACKNOWLEDGEMENTS
Financial support from the open funding of Key Laboratory of Synthetic Chemistry of Natural Substances
of SIOC as well as the National Natural Science Foundation of China (31270388) is greatly appreciated.
We are grateful to Special Fund for Forestry Scientific Research in Public Interest (No. 200904004) for
partial support of this work.

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