A mild, one-pot synthesis of disubstituted benzimidazoles from 2-nitroanilines

Article abstract of DOI:10.1016/j.tetlet.2006.05.111

A one-pot synthesis of disubstituted benzimidazoles from 2-nitroanilines is described. Hydrogenation of N-substituted 2-nitroanilines with palladium on carbon as catalyst in the presence of trimethyl orthoformate and catalytic pyridinium p-toluenesulfonate (PPTS) at room temperature provided good to excellent yields of the corresponding disubstituted benzimidazoles.

Full text of DOI:10.1016/j.tetlet.2006.05.111

Tetrahedron Letters 47 (2006) 5359–5361
A mild, one-pot synthesis of disubstituted benzimidazoles
from 2-nitroanilines
Keith R. Hornberger,* George M. Adjabeng, Hamilton D. Dickson
and Ronda G. Davis-Ward
Department of Chemistry, Microbial, Musculoskeletal, and Proliferative Diseases Center of Excellence for Drug Discovery,
GlaxoSmithKline, Research Triangle Park, NC 27709, USA
Received 10 April 2006; revised 15 May 2006; accepted 17 May 2006
Available online 12 June 2006
Abstract—A one-pot synthesis of disubstituted benzimidazoles from 2-nitroanilines is described. Hydrogenation of N-substituted 2-
nitroanilines with palladium on carbon as catalyst in the presence of trimethyl orthoformate and catalytic pyridinium p-toluenesulf-
onate (PPTS) at room temperature provided good to excellent yields of the corresponding disubstituted benzimidazoles.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Benzimidazoles have a ubiquitous presence in pharma-
ceuticals,1 such as in entire classes of anthelmintics2
and proton pump inhibitors.3 Classically, benzimid-
azoles are prepared from 1,2-dianilines by acid-pro-
moted dehydrative cyclocondensation with a carbonyl
derivative, often at elevated temperatures.4 The requisite
1,2-dianilines are most often produced by reduction of
the corresponding 2-nitroaniline compounds.
azole 2a (Table 1). Simply, hydrogenation of 1a with a
suitable heterogeneous catalyst at room temperature in
the presence of trimethyl orthoformate, either as solvent
or a co-solvent with ethyl acetate, and a mild acid co-
catalyst directly afforded 2a.
A variety of heterogeneous catalysts may be used (Table
1, entries 1–6), with the exception of rhodium on alumina.
Further optimization was conducted with palladium on
carbon as the catalyst. It was not necessary to use tri-
methyl orthoformate as the solvent; a 10-fold excess
was sufficient to provide good yields, although using less
than 10 equiv resulted in a reduction in yield (entries 7 and
8). The optimal catalyst loading was determined to be
5 mol %; further reduction in catalyst loading resulted
in prolonged reaction times and diminished yields (entries
9 and 10). Both pyridinium p-toluenesulfonate (PPTS)
and formic acid were suitable acid co-catalysts (entries 7
and 12). Ultimately, it was determined for this particular
substrate that an acid co-catalyst was not necessary at all
(entries 11 and 13). This phenomenon was not general
when extended to other substrates, however. Therefore,
the preferred conditions were hydrogenation at 50 psi
with 5 mol % palladium on carbon, using ethyl acetate
as solvent, in the presence of 10 equiv of trimethyl ortho-
formate and 10 mol % PPTS.11 The ability to employ a
number of different catalysts, however, can provide a
wider scope of functional group tolerance (vide infra).
This common sequence of events suggested to us and
other groups that these transformations could be conve-
niently combined into one pot. Indeed, others have
recently reported methods for preparing benzimidazoles
directly from 2-nitroanilines.5–9 These methods, how-
ever, use stoichiometric amounts of toxic metals or
require forcing conditions such as strong protic acids
and/or elevated temperatures. We now report a simple
and mild one-pot method for the synthesis of benzimid-
azoles from 2-nitroanilines by hydrogenation with a
suitable heterogeneous catalyst at room temperature in
the presence of trimethyl orthoformate,10 either as sol-
vent or a co-solvent, and a mild acid co-catalyst (pyrid-
inium p-toluenesulfonate or formic acid).
The general process is outlined in the reaction optimiza-
tion for the conversion of nitroaniline 1a to benzimid-
Keywords: Benzimidazoles; Hydrogenation; Cyclocondensation.
The substrate scope of this method is outlined in Table 2.
A variety of functionality can be placed on the aniline
*
Corresponding author. Tel.: +1 919 483 6206; fax: +1 919 483
6053; e-mail: keith.r.hornberger@gsk.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.111

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K. R. Hornberger et al. / Tetrahedron Letters 47 (2006) 5359–5361
Table 1. Optimization of one-pot hydrogenation/cyclization conditions for substrate 1aa
NO2
H
N
N
N
conditions
1a
2a
Cl
Cl
Entry
Catalyst (mol %)
Co-catalyst (mol %)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd/C (5)
Pt/C (5)
PPTS (10)
PPTS (10)
PPTS (10)
PPTS (10)
PPTS (10)
PPTS (20)
PPTS (10)
PPTS (10)
PPTS (10)
PPTS (10)
PPTS (1)
HCO2H (10)
None
HC(OMe)3
HC(OMe)3
HC(OMe)3
HC(OMe)3
HC(OMe)3
HC(OMe)3
EtOAc + 10 equiv HC(OMe)3
EtOAc + 1.5 equiv HC(OMe)3
EtOAc + 1.5 equiv HC(OMe)3
EtOAc + 10 equiv HC(OMe)3
EtOAc + 10 equiv HC(OMe)3
EtOAc + 10 equiv HC(OMe)3
EtOAc + 10 equiv HC(OMe)3
2.5
4
5
6
5
17
7
3
24
6
8
92
95
92
98
0
85d
100
74d
<10
74d
100
100
90d
Sulfided Pt/C (5)
Pd(OH)2/C (5)
Rh/Al2O3 (5)
Pd/C (10)c
Pd/C (5)
Pd/C (5)
Pd/C (1)
Pd/C (2.5)
Pd/C (5)
Pd/C (5)
5
3
Pd/C (5)
a All reactions were conducted in a Fischer–Porter hydrogenation apparatus at 50 psi of H2 unless otherwise indicated.
b Yields refer to yields of pure (by LC/MS) product following aqueous work-up. Column chromatography was not required unless otherwise
indicated.
c Reaction was conducted under a balloon (ꢀ1 atm) of H2.
d Isolated yield following column chromatography.
Table 2. Substrate scope of one-pot reduction–cyclization of 2-nitroanilines
R3
NO2
H2 (50 psi), 5 mol% Pd/C
10 mol% PPTS
H
N
N
R1
3
R1
N
10 equiv R3C(OMe)3
EtOAc (0.1 M), RT
4
R2
6
5
R2
1
2
Entry
Nitroaniline
R1
R2
R3
Time (h)
Product
Yielda (%)
1
2
3
4
5
6e
7f
8
1a
1b
1c
1d
1e
1f
Ph
H
H
5-Cl
5-Cl
4-OMe
5-OMe
5-Cl
H
H
H
H
H
H
H
H
H
3
23
12
5
6
6
2a
2b
2c
2d
2e
2f
100b
0c
0d
H
0c
Me
i-Pr
Bn
88
73
82
95
1g
1h
H
H
6
3
2g
2h
p-MeOC6H4
9e
1i
1j
H
H
H
H
6
2i
2j
94
80
N Boc
10
OTBDPS
16
11f
12e
13
1k
1l
Ph
i-Pr
Ph
6-Br
5-OMOM
5-Cl
H
H
Me
16
22
72
2k
2l
75
60
0d
1m
2m
a Yield refers to isolated yield of analytically pure (by LC/MS) product following column chromatography, unless otherwise stated.
b Product was analytically pure by LC/MS without column chromatography.
c Starting material was recovered unchanged.
d Starting material was reduced to the dianiline (by LC/MS), but the cyclized product was not observed.
e Reaction was performed using the orthoformate as solvent.
f Sulfided Pt/C used as catalyst.
nitrogen, such as alkyl, branched alkyl, aryl, and benzyl
(entries 1 and 5–10). Both electron-donating and elec-
tron-withdrawing substituents are tolerated on the aryl
ring (entries 1, 5, and 11–12). A preliminary experiment
using trimethyl orthoacetate to obtain a 2-methyl benz-
imidazole (entry 13) was unsuccessful. In some cases
(entries 7 and 11), sulfided platinum on carbon was suc-
cessfully employed as the catalyst to prevent debenzyla-
tion or dehalogenation, respectively, of the substrate.
Interestingly, the only class of substrates for which the
method failed was when the aniline nitrogen was unsub-

K. R. Hornberger et al. / Tetrahedron Letters 47 (2006) 5359–5361
5361
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9871–9874.
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Commun. 2004, 34, 4265–4272; (b) Hashtroudi, M. S.;
Nia, S. S.; Asadollahi, H.; Balalaie, S. Ind. J. Heterocycl.
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stituted (entries 2–4). In some cases, only starting 2-nit-
roaniline was observed. In other cases, we have deter-
mined by mass spectroscopy and 1H NMR that the
nitro group was rapidly reduced to provide the 1,2-dian-
iline, but no cyclized products were observed. One
hypothesis for this latter result is that the cyclization
event is not kinetically favorable for unsubstituted
dianilines at room temperature. For example, hydro-
genating 1c to the dianiline in neat trimethyl orthoformate
(6 h reaction time), removing the reaction mixture from
the hydrogenator, filtering to remove the catalyst, and
then heating the filtered solution to 100 ꢁC for 3 h af-
fected complete conversion (by LC/MS) to benzimid-
azole 2c. Further experiments are planned to
understand the nature of this differential reactivity.
11. Typical experimental procedure: Benzimidazole 2a (6-
chloro-1-phenyl-1H-benzimidazole). To a stirred solution
of nitroaniline 1a (497 mg, 2.00 mmol) and pyridinium p-
toluenesulfonate (50 mg, 0.20 mmol) in ethyl acetate
(20 mL) and trimethyl orthoformate (2.2 mL, 20 mmol)
was added palladium on carbon (10 wt %, 106 mg,
0.10 mmol Pd). The reaction mixture was hydrogenated
in a Fischer–Porter apparatus under 50 psi of H2 for 6 h.
At the end of the reaction, H2 was removed and the
apparatus was purged with nitrogen. The reaction mixture
was filtered to remove the catalyst, and the filter cake was
washed with dichloromethane (25 mL). The combined
filtrates were concentrated, then redissolved in dichloro-
methane (25 mL) and washed with 0.1 N aqueous HCl
(1 · 25 mL), saturated aqueous NaHCO3 (1 · 25 mL), and
brine (1 · 25 mL). The organic fraction was dried over
Na2SO4, filtered, and concentrated to afford 457 mg
(100%) of benzimidazole 2a as a light gray solid. The
product was judged to be >95% pure by HPLC analysis.
1H NMR (300 MHz, CDCl3): d 8.10 (s, 1H), 7.78 (d, 1H,
J = 8.7 Hz), 7.63–7.57 (m, 2H), 7.52–7.47 (m, 4H), 7.31
(dd, 1H, J = 2.0, 8.7 Hz). 13C NMR (100 MHz, CDCl3): d
143.0, 142.7, 135.8, 134.4, 130.2, 129.6, 128.4, 124.1, 123.5,
121.5, 110.6. HRMS (ESI): calcd for C13H10ClN2 [M+H]+
229.0533, found 229.0540. All products in Table 2 gave
satisfactory analytical data (1H NMR, HRMS, and LC/
MS).
In summary, we have developed a simple and mild one-
pot method for the conversion of 2-nitroanilines to
benzimidazoles. This method is notable for its mild con-
ditions, requiring only an acid co-catalyst, and may be
readily performed at room temperature to prepare a
variety of functionalized benzimidazoles.
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