A practical and convenient method for the synthesis of some benzimidazoles

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Organic Preparations and Procedures
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A Practical and Convenient Method for
the Synthesis of Some Benzimidazoles
Babak Kaboudin a , Minoo Khodamorady a & Yaghoub Abedi a
a Department of Chemistry, Institute for Advanced Studies in Basic
Sciences, Gava Zang, Zanjan, 45137-66731, IRAN
Version of record first published: 20 Mar 2013.
To cite this article: Babak Kaboudin , Minoo Khodamorady & Yaghoub Abedi (2013): A Practical and
Convenient Method for the Synthesis of Some Benzimidazoles, Organic Preparations and Procedures
International: The New Journal for Organic Synthesis, 45:2, 162-167
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Organic Preparations and Procedures International, 45:162–167, 2013
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.765294
OPPI BRIEF
A Practical and Convenient Method
for the Synthesis of Some Benzimidazoles
Babak Kaboudin, Minoo Khodamorady, and Yaghoub Abedi
Department of Chemistry, Institute for Advanced Studies in Basic Sciences
Gava Zang, Zanjan 45137-66731, IRAN
Benzimidazole and its derivatives represent an important class of bioactive molecules.1
Some benzimidazoles are potent antiparasitic agents,2 topoisomerase I inhibitors,3 selective
neuropeptide Y Y1 receptor antagonists,4 angiotensin II (AII) inhibitors,5 inhibitors of
human cytomegalovirus (HCMV) replication,6 potential antitumour agents,7 antimicrobial
agents,8 and inhibitors of the hepatitis C virus RNA polymerase.9 They have also shown
significant activity against several viruses including HIV,10 herpes (HSV-1),11 RNA,12
and influenza.13 Benzimidazoles can also act as ligands to transition metals for modeling
biological systems14 and have been widely used as carbon skeletons for N-heterocyclic
carbenes.15
Many procedures have been reported for the synthesis of benzimidazoles16–20 and
some of these methods involve: 1) reaction of the appropriate o-phenylenediamines
with carboxylic acids in the presence of a strong protic acid21,22 or Lewis-acid
catalysts,23–25 2) reaction of o-phenylenediamines with nitriles,26 3) the reaction be-
tween N-ethoxycarbonylthioamides [RC(S)NHCO2Et] and aromatic 1,2-diamines,27 and
4) palladium-catalyzed intramolecular arylamination of o-bromoarylamidines.28 Recently
Wang and co-workers developed a new procedure for the preparation of these compounds
by the reaction of o-phenylenediamines with orthoesters in the presence of Lewis acids.29
Although these methods are suitable for the synthesis of benzimidazoles, they have draw-
backs, such as harsh reaction conditions, low yields, long reaction times, use of Lewis acids
and formation of side-products; in some cases, more than one step is required. Therefore, the
development of novel efficient, practical, economical, and environmentally benign methods
for the synthesis of important and biologically active benzimidazoles remains an active re-
search area.30–32 We now report a new method for the synthesis of some benzimidazoles by
the reaction of o-phenylenediamines with orthoesters under solvent-free conditions without
any additives such as base, acid or catalyst.
Submitted by 5, 2012.
Address correspondence to Babak Kaboudin, Department of Chemistry, Institute for Advanced
Studies in Basic Sciences, Gava Zang, Zanjan 45137-66731, IRAN. E-mail: kaboudin@iasbs.ac.ir
162

Synthesis of Some Benzimidazoles
163
Treatment of o-phenylenediamine (1a) with trimethyl orthoformate, as a model, was
studied under various conditions in several solvents (EtOH, EtOAc, dichloromethane,
chloroform, DMF, DMSO and water) and without any solvent. In water, the corresponding
adduct 2a was obtained in 30% yield after 24 hrs at ambient temperature while the yield in-
creased to only 35% at reflux temperature (Scheme 1). While treatment of 1a with trimethyl
orthoformate under solvent-free conditions at room temperature for 24 h gives 2a in only
35% yield, the same reaction proceeded smoothly under solvent-free conditions at 70◦C for
12 h to give 2a in 85% yield. The reaction with a number of o-phenylenediamines afforded
the corresponding benzimidazoles in 57–85% yields (Table 1). 2,3-Diaminonaphthalene
and 2,3-diaminopyridine gave the corresponding adducts 2e and 2f in 69% and 73% yield
respectively. However, under the same conditions cis-1,2-diaminocyclohexane, gave a com-
plex mixture of unknown products. The reaction of o-phenylenediamine with selected
NH2
N
HC(OR)3
+
N
H
NH2
2a
1a
R = OMe or OEt
Scheme 1
esters was also studied. Thus, similar treatment of 1a with tetraethyl orthocarbonate and
N,N-dimethylformamide dimethyl acetal (DMFDMA) afforded 2-ethoxy-H-benzimidazole
(4a) and 2a in 93% and 86% yields respectively. Treatment of 1a with trimethyl orthoben-
zoate under solvent-free conditions at 70◦C for 4h gives 5a in 90% yield but the same
reaction of 1a with trimethyl orthoacetate failed to give any product at 70◦C for 24 h; the
same reaction proceeded smoothly under solvent-free conditions at 90◦C for 18 h, gave 6a
in 87% (Scheme 2)
NH2
NH2
N
N
C(OEt)4
(MeO)2CHNMe2
OEt
70 °C, 12h
70 °C, 2h
N
H
N
H
4a
2a
1a
NH2
N
N
PhC(OMe)3
Ph
MeC(OMe)3
Me
70 °C, 4 h
90 °C, 18 h
N
H
N
H
NH2
1a
5a
6a
Scheme 2
In summary, we have developed a simple and practical process for the synthesis of
benzimidazoles in moderate to good yields under solvent- and catalyst-free conditions.

164
Kaboudin et al.
Table 1
Solvent- and catalyst-free synthesis of benzimidazoles (2)a
Time Yield
(hr) (%) mp. (◦C)
lit. mp.
(◦C)
Entry
1
Cmpd
Product (2)
12
85b 170–171 170–17231
N
NH2
N
H
NH2
NH2
2a
2
12
82c 170–171 170—17231
N
N
H
NH2
2a
3
4
5
6
7
8
24
24
18
14
18
14
66b 210–212 206–20832
68c 210–212 206–20832
50b 140–142 139–14133
80c 140–142 139–14133
NH2
N
N
H
O2N
O2N
O2N
NH2
NH2
2b
2b
N
N
H
O2N
NH2
N
NH2
N
H
MeO2C
MeO2C
NH2
NH2
2c
N
N
H
MeO2C
PhCO
NH2
NH2
MeO2C
PhCO
2c
51b
62c
98–100 124–12534
98–100 124–12534
N
N
H
NH2
NH2
2d
PhCO
Me
PhCO
Me
N
N
NH2
H
2d
9
14
83c 110–112 114–11727
NH2
N
N
H
NH2
NH2
2e
10
11
16
18
69c 193–195
22135
N
N
H
NH2
2f
73c
>300
>30036
NH2
N
N
H
N
N
NH2
2g
a) At 70◦C. b) Using HC(OMe)3. c) Using HC(OEt)3.

Synthesis of Some Benzimidazoles
165
Experimental Section
All chemicals were commercial products and were distilled or recrystallized before use.
NMR spectra were taken with a 400 MHz Brucker Avance instrument with the chemical
shifts being reported as δ and couplings expressed in Hertz. The chemical shift data for each
1
signal in H NMR are given in units of δ relative to CHCl3 (δ 7.26) for CDCl3 solution.
For 13C NMR spectra, the chemical shifts in CDCl3 are recorded relative to the CDCl3
resonance (δ = 77.0). Silica gel column chromatography was carried out with Silica gel
100 (Merck No. 10184). Merck Silica-gel 60 F254 plates (No. 5744) were used for the
preparative TLC.
Typical Procedure. Synthesis of Benzimidazole (2a)
A solution of o-phenylenediamine (5.40 g, 50 mmol) in trimethyl orthoformate (7.4 g,
70 mmol) (or orthocarbonate or DMFDMA) was stirred using magnetic stir bar for 12–24 h
at 70◦C (Table 1). The reaction mixture was then distilted under reduced pressure (to recover
excess reagent) and the oily residue was chromatographed on silica gel [EtOAc/n-hexane
(4:6)]; evaporation of the eluates (EtOAc and n-hexane) under reduced pressure gave pure
benzimidazole (5.90 g, 85%). All products gave spectral data in accord with the assigned
structures and literature data.33–41
2-Ethoxy-1H-benzimidazole (4a), mp.
165–167◦C lit.37 166–167◦C; 1H NMR (CDCl3, 400 MHz): δ1.49 (t, 3H, J = 7.2 Hz), 4.63
(q, 2H, J = 7.2 Hz), 7.10–7.20 (2H, m), 7.40–7.45 (2H, m), 8.50–9.50 (br, 1H); 13C-NMR
(CDCl3,100 MHz): δ 14.6, 66.1, 112.1–114.1 (br), 121.5, 158.1.
2-Phenyl-1H-benzimidazole (5a), mp.
1
293–295◦C lit.38 289–291◦C; H NMR (DMSO-d6–400 MHz): δ 7.15–7.28 (2H, m),
7.48–7.58 (4H, m), 7.60–7.75 (1H, m), 8.11 (2H, d, J = 7.2 Hz), 9.8–10.20 (br, 1H);
13C-NMR (DMSO-d 6-100 MHz): δ 111.7, 122.2, 126.9, 129.6, 130.5, 135.3, 144.2, 151.6.
2-Methyl-1H-benzimidazole (6a), mp.
179–180◦C lit.39 177–178◦C; 1H NMR (CDCl3-400 MHz): δ 2.67 (s, 3H), 7.15–7.28 (2H,
m), 7.48–7.68 (2H, m), 8.0–9.1 (br, 1H); 13C-NMR (CDCl3–100 MHz): δ 15.0, 114.5,
122.2, 139.6, 151.3.
Acknowledgement
The authors gratefully acknowledge support by the Institute for Advanced Studies in Basic
Sciences (IASBS) Research Council under grant No. G20109IASBS120.

166
Kaboudin et al.
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