A new method for the synthesis of 2-aryl-1H-benzimidazoles: Selenium-catalyzed reductive N-heterocyclization of benzylidene(2-nitroaryl) amines with carbon monoxide

Article abstract of DOI:10.1055/s-2005-922771

The treatment of benzylidene(2-nitroaryl)amines, prepared by the reaction of o-nitro aniline and benzaldehydes, with carbon monoxide in the presence of a catalytic amount of selenium under basic conditions, afforded 2-aryl-1H-benzimidazoles in moderate to good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922771

LETTER
109
A New Method for the Synthesis of 2-Aryl-1H-benzimidazoles: Selenium-
Catalyzed Reductive N-Heterocyclization of Benzylidene(2-nitroaryl)amines
with Carbon Monoxide
S
ynthesis of 2-Ary
u
l-1
H
-benzim
t
idazole
a
s
ka Nishiyama,* Mayu Fujimoto, Noboru Sonoda*
Department of Applied Chemistry, Faculty of Engineering, Kansai University, Suita, Osaka 564-8680, Japan
Fax +81(6)63394026; E-mail: nishiya@pcku.kansai-u.ac.jp
Received 8 August 2005
1H-benzimidazole (2a) in 64% yield (entry 5). The use of
Abstract: The treatment of benzylidene(2-nitroaryl)amines, pre-
pared by the reaction of o-nitro aniline and benzaldehydes, with car-
bon monoxide in the presence of a catalytic amount of selenium
under basic conditions, afforded 2-aryl-1H-benzimidazoles in
moderate to good yields.
MS 3 Å as an additive gave 2a almost quantitatively
(entry 4). Although 1a was reductively N-heterocyclized
with carbon monoxide, even using acetonitrile, toluene,
DMF, and THF instead of 1,4-dioxane as the solvent, the
best yield of 2a was observed when 1,4-dioxane was the
solvent (entries 4 and 6–9). A similar reductive N-hetero-
cyclization of 1a proceeded in the presence of DBN, N-
methylpyrrolidine and triethylamine to give 2a, albeit in
significantly lower yields (entries 1–4). Higher and lower
reaction temperatures or a lower carbon monoxide
pressure reduced the yields of 2a (entries 10–13).
Key words: selenium, carbon monoxide, 2-aryl-1H-benzimida-
zole, benzylidene(2-nitroaryl)amine
Since N-heterocyclic compounds, such as benzimida-
zoles, are known as useful medicines and herbicides,
many methods for their synthesis have already been
reported.1 As one approach, the reductive N-hetero-
cyclization of benzylidene(2-nitroaryl)amines with car-
bon monoxide has attracted considerable attention in
organic and medical chemistry. It has been shown that
transition metal complexes act as a catalyst for the reac-
tion.2,3 However, there are some disadvantages for these
methods: (i) the requirement of harsh reaction conditions
(CO: 50 atm, reaction temperature: 220 °C) and (ii) low or
moderate product yields.
The synthesis of the 2-aryl-1H-benzimidazoles by the
treatment of the benzylidene(2-nitroaryl)amines and
carbon monoxide in the presence of a catalytic amount of
selenium (20 mol%) was next examined. These results,
summarized in Table 2, showed that the reaction was
amenable to the synthesis of various 2-aryl-1H-benzoim-
idazoles.8 When the 2-methyl-, 3-methyl-, and 4-methyl-
benzylidene(2-nitrophenyl)amines were allowed to react
with carbon monoxide, the 2-aryl-1H-benzimidazoles
were obtained in 79–89% yields (entries 1–3). Similarly,
the 4-cyano-, 4-chloro-, and 4-methoxy-benzylidene(2-
nitrophenyl)amines were reductively N-heterocyclized
with carbon monoxide to give the 2-aryl-1H-imidazoles
in 99%, 76%, and 85% yields, respectively (entries 4–6).
2-Phenyl-1H-naphtho[2,3-d]imidazole was also obtained
by the reaction of naphthalen-2-ylmethylene(2-nitrophen-
yl)amine with carbon monoxide in 82% yield (entry 7).
For the reaction of butylidene(2-nitrophenyl)amine, the
yield of 2-propyl-1H-benzimidazole was low due to the
preparation of various by-products (Scheme 2).
In this paper, we have shown a new synthetic method for
2-aryl-1H-benzimidazoles by the selenium-catalyzed
reductive N-heterocyclization of benzylidene(2-nitro-
aryl)amines with carbon monoxide (Scheme 1).4
N
Ar
N
cat. Se
+ CO
Ar
N
H
NO2
Scheme 1
Se (0.1 mmol)
N
C3H7
+ CO
N
To determine the optimized reaction conditions, benzyl-
idene(2-nitrophenyl)amine (1a) was allowed to react with
carbon monoxide in the presence of a catalytic amount of
selenium under various reaction conditions and the results
are shown in Table 1. The reaction of 1a with carbon
monoxide (30 atm) in the presence of DBU (400 mol%)
and a catalytic amount of selenium (20 mol%) in 1,4-di-
oxane solvent at 120 °C for 3 hours afforded 2-phenyl-
MS3Å (0.3 g)
C3H7
1,4-dioxane
(5 mL)
N
H
NO2
(0.5 mmol)
(30 atm)
38%
Scheme 2
We have previously reported a method for the preparation
of carbonyl selenide (SeCO) via the acidolysis of second-
ary amine salts of the selenocarbamates generated by the
reaction of elemental selenium with carbon monoxide and
a secondary amine under mild conditions.9 It was then
proposed that the generation of the nitrenoid (or nitrene)
SYNLETT 2006, No. 1, pp 0109–0111
0
5.
0
1.
2
0
0
6
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922771; Art ID: U26605ST
© Georg Thieme Verlag Stuttgart · New York

110
Y. Nishiyama et al.
LETTER
Table 1 Reductive N-Heterocyclization of Benzyliden(2-nitrophenyl)aminea
cat. Se
N
Ph
N
MS 3Å
+ CO
Ph
Solvent
N
H
NO2
1a
2a
Entry
Base
Solvent
Temp (°C)
120
CO (atm)
Yield (%)b
1
2
Et3N
1,4-Dioxane
1,4-Dioxane
30
30
32
40
120
NMe
3
4
5c
6
7
8
9
DBN
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
MeCN
120
120
120
120
120
120
120
140
100
80
30
30
30
30
30
30
30
30
30
30
10
52
99
64
82
78
86
75
88
96
59
91
Toluene
DMF
THF
10
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
11
12
13
120
a Reaction conditions: benzyliden(2-nitrophenyl)amine (1a, 0.5 mmol), Se (0.1 mmol), base (2 mmol), MS 3 Å (0.3 g) and solvent (5 mL) for
3 h.
b GC yield based on benzyliden(2-nitrophenyl)amine.
c In the absence of MS 3 Å.
Table 2 Synthesis of Various 2-Aryl-1H-imidazolesa
by the reductive deoxygenating of the nitro group with
SeCO is the first step in this reaction. The insertion of the
nitrenoid into the sp2 C–H bond affords the 2-aryl-1H-
benzimidazoles (Scheme 3).10
cat. Se
N
Ar
N
MS 3Å
+ CO
Ar
DBU
N
H
NO2
1,4-dioxane
N
N
Ar
Entry
Ar
Yield (%)b
2
CO
1
2
3
4
5
6
7
2-CH3C6H4
89
79
88
99
76
85
82
Se
3-CH3C6H4
4-CH3C6H4
4-CNC6H4
4-ClC6H4
N
Ar
SeCO
N=Se
1
CO2
CO2
4-CH3OC6H4
2-C10H7
N
Ar
N
Ar
a Reaction conditions: substrate (0.5 mmol), Se (0.1 mmol), MS 3 Å
(0.3 g), DBU (2 mmol), 1,4-dioxane (5 mL) and CO (30 atm) at
120 °C for 3 h.
N=O
N=O
SeCO
Se
b GC yield based on substrate.
CO
Scheme 3
Synlett 2006, No. 1, 109–111 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Aryl-1H-benzimidazoles
111
(3) It has already been reported that the reaction of benzyl-
In summary, we succeeded in the synthesis of 2-aryl-1H-
benzimidazoles by the reaction of benzylidene(2-nitro-
aryl)amine with carbon monoxide in the presence of a
catalytic amount of selenium. Further studies on the syn-
thetic application and mechanism of the reaction are now
in progress.
idene(2-nitrophenyl)amine with triethyl phosphite affords 2-
phenyl-1H-benzimidazole in 47% yield. See: Cadogan, J. I.
G.; Marshall, R.; Smith, D. M.; Todd, M. J. J. Chem. Soc. C.
1970, 2441.
(4) We have recently reported the selenium-catalyzed reductive
N-heterocyclization of 2-nitrostyrenes,5 N-(2-nitro-
benzoyl)amides,6 or 2-nitrobenzyl alcohols7 with carbon
monoxide that produced indoles, 3,4-dihydroquinazolin-4-
ones, or 1,4-dihydro-2H-3,1-benzoxazin-2-ones.
(5) Nishiyama, Y.; Maema, R.; Ohno, K.; Hirose, H.; Sonoda,
N. Tetrahedron Lett. 1999, 40, 5717.
Acknowledgment
This research was supported by a Grant-in-Aid for Science Re-
search (No.15550096) and Research and Development Organiza-
tion of Industry–University Cooperation from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
(6) Nishiyama, Y.; Hirose, H.; Kitagaito, W.; Sonoda, N.
Tetrahedron Lett. 2002, 43, 1855.
(7) Nishiyama, Y.; Naitoh, Y.; Sonoda, N. Synlett 2004, 886.
(8) A typical procedure is as follows: in a 50 mL stainless steel
autoclave were placed benzylidene(2-nitroaryl)amine (0.5
mmol), selenium (8 mg, 0.1 mmol), DBU (304 mg, 2 mmol),
1,4-dioxane (5 mL), MS 3 Å (0.3 g) and a magnetic stirring
bar. The mixture was stirred under pressurized carbon
monoxide (30 atm) at 120 °C for 3 h. After evacuation of the
excess carbon monoxide at r.t., the deposited selenium and
MS 3 Å were filtered off. DBU was removed by reduced
distillation. The residual solution was purified by
chromatography on neutral aluminum oxide (CHCl3 as
eluent) to give the 2-aryl-1H-benzimidazoles.
References and Notes
(1) For recent reviews; see: Grimmett, M. R. Imidazoles and
their Benzo Derivatives, In Comprehensive Heterocyclic
Chemistry, Vol. 5; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984, 457–498.
(2) (a) Tolari, S.; Cenini, S.; Crotti, C.; Gianelloy, E. J. Mol.
Catal. 1994, 87, 203. (b) Crotti, C.; Cenini, S.; Ragaini, F.;
Porta, F.; Tolari, S. J. Mol. Catal. 1992, 72, 283.
(c) Watanabe, Y.; Suzuki, N.; Tsuji, Y. Bull. Chem. Soc. Jpn.
1982, 55, 2445. (d) Watanabe, Y.; Takatsuki, K.; Shim, S.
C.; Mitsudo, T.; Takegami, Y. Bull. Chem. Soc. Jpn. 1978,
51, 3397.
(9) Kondo, K.; Yokoyama, S.; Miyoshi, N.; Murai, S.; Sonoda,
N. Angew. Chem., Int. Ed. Engl. 1979, 18, 691.
(10) For the transition-metal-catalyzed N-heterocyclization, it
was suggested that the generation of the nitrene (or
nitrenoid) intermediate was the key step in the reaction. For
a review, see: Soderberg, B. C. G. Curr. Org. Chem. 2000,
4, 727.
Synlett 2006, No. 1, 109–111 © Thieme Stuttgart · New York