The convenient synthesis of benzimidazole derivatives catalyzed by I 2 in aqueous media

Article abstract of DOI:10.1002/jhet.5570430338

In the presence of catalytic amount of iodine, in THF-H₂O, the condensation of aldehydes with 1,2-phenylenediamine gave the benzimidazole derivatives under mild conditions in good yields. The method can be used for the synthesis of 2-substituted benzimidazoles or 1,2-disubstituted benzimidazoles.

Full text of DOI:10.1002/jhet.5570430338

May-Jun 2006
773
The Convenient Synthesis of Benzimidazole Derivatives Catalyzed by
I in Aqueous Media
2
*
Peipei Sun and Zhixin Hu
College of Chemistry and Environmental Science, Nanjing Normal University, Nanjing, 210097, P. R. China
E-mail: sunpeipei@njnu.edu.cn
Recveiced September 2 2005
NH
2
N
N
N
I
2
R
+
RCHO
R
+
2
THF-H O
NH
2
N
H
R
1(a~j)
2(a~j)
In the presence of catalytic amount of iodine, in THF–H O, the condensation of aldehydes with 1,2-
2
phenylenediamine gave the benzimidazole derivatives under mild conditions in good yields. The method
can be used for the synthesis of 2-substituted benzimidazoles or 1,2-disubstituted benzimidazoles.
J. Heterocyclic Chem., 43, 773 (2006).
Benzimidazole Derivatives have received much
of 2-nitroaniline with benzaldehyde in the presence of
In/BNP, as well as the reductive cyclization of 2-nitro-
aniline with aldehydeꢀ in the presence of Na S O
were also used for the synthesis of benzimidazole
derivatives [11]. However, many of these methods
have several drawbacks. For example, expansive
reagent was used, a special oxidation process and a
long reaction time were required. In some case, 2-
substituted and 1,2-disubstituted benzimidazoles were
generated simultaneously with poor selectivity.
Our research interest focuses on the Lewis acids
catalyzed organic reactions in recent years. As an
inexpensive and easily available catalyst for various
organic transformations, iodine has received consider-
able attention [12]. We found that in the presence of
catalytic amount of iodine, the condensation of
aldehydes with 1,2-phenylenediamine gave the benzimi-
dazole derivatives under mild conditions.
The realization of simple and green synthetic
procedures constitutes an important goal in organic
synthesis. To make organic reactions in water or in
aqueous media has gained in popularity in recent years. It
interest in the field of medicinal chemistry [1]. For
example, they have been shown to exhibit fungicide,
antitumour, immunosuppressant and anti-convulsant
properties [2]. Recently, they have also been used as
ligands for asymmetric catalysis [3]. Many methods
have been reported for the synthesis of these hetero-
cycles. The condensation of 1,2-phenylenediamines
with carboxylic acids or their derivatives is a common
method, but it needs harsh conditions, for example, in
the presence of polyphosphoric acid at 170–180°C [4].
Some methods using transition metal catalyzed
coupling reactions to construct benzimidazole nucleus
were also reported. Those involved palladium-
catalyzed carbonylation reaction of an 1,2-phenylene-
diamine followed by cyclodehydration [5], palladium-
catalyzed intramolecular N-arylation reaction of (o-
bromophenyl)amidines [6], et al. In recent years, some
solid-phase synthetic methods have been applied to the
synthesis of benzimidazole derivatives [7]. Another
alternative approache is the condensation of aldehyde
with 1,2-phenylenediamine [8]. Recently, the conden-
sations in the presence of triflate salts such as
Sc(OTf) or Yb(OTf) were reported [9]. A method
2
2
4
was found that the I catalyzed condensation of aldehydes
2
with 1,2-phenylenediamine could take place in aqueous
media in air to give 2-substituted benzimidazole (1) and
N-alkylated 2-substituted benzimidazole (2). In pure
water, as the poor solubility of the reactants and catalyst,
3
3
from activated alcohols and 1,2-phenylenediamine
using TOP methodology was also described [10]. In
these procedures, the oxidation using O or MnO as
2
2
an oxidant was needed for the aromatization of the
intermediate dihydrobenzimidazoles. The SET reaction
the reaction proceeded slowly. But in THF-H
v/v), it could complete within a short time at room
O (1:1,
2
Scheme 1
NH2
NH2
N
N
N
I2
R
+
RCHO
R
+
THF-H2O
N
H
R
1(a~j)
2(a~j)

7
74
P. P. Sun and Z. X. Hu
Vol 43
Table 1
The Formations of Benzimidazole Derivatives
[
a]
[a]
Entry
Aldehyde
PhCHO
Time (h)
Yield of 1 (%)
Yield of 2 (%)
[
c]
[b]
1
2
3
4
5
6
7
8
9
2.0
2.0
2.5
1.5
2.5
1.5
3.0
2.0
2.5
2.5
72 1a [13]
20 / 88 2a [13]
12 / 82 2b [13]
10 / 85 2c [13]
25 / 90 2d [13]
[
b]
p-ClC
p-BrC
p-FC
o-NO
o-ClC
p-CH OC
Furfural
6
H
4
CHO
78 1b [13]
75 1c [13]
70 1d [13]
67 1e [14]
70 1f [11a]
56 1g [13]
75 1h [11a]
Trace 1i [16]
58 1j [18]
[
b]
6
H
4
CHO
[
b]
6
H
4
CHO
CHO
CHO
CHO
2
C
6
H
4
15
22
25
2e [15]
2f [11a]
2g [13]
6
H
4
3
6
H
4
[
b]
16 / 86 2h [11a]
67 / 76 2i [17]
Trace 2j
[
b]
CH
(CH
3
3
CH
2
CHO
1
0
)
2
CHCHO
[
a]
[b]
[c]
Isolated yields; 2 Equivalent of aldehyde reacted with 1,2-phenylenediamine for 3 h; Literature reference for the product. All products
1
are known compounds. The structures of the products are confirmed by IR and HNMR spectra.
temperature. It showed that I2 exhibited a powerful
catalytic activity in an amount as low as 2 mol%,
which was enough to complete the reaction within less
than 3 hours for all of the substrates we used. Without
I2, to the reaction of 1,2-phenylenediamine and
benzaldehyde, only trace of the product was generated
even refluxing for 24 hours. The reaction was found to
be general and applicable to both aromatic and
aliphatic aldehydes. The aromatic aldehydes bearing
electron-donating and electron-withdrawing substi-
uents gave the similar results. The results of the
reaction are summarized in Table 1. When the mole
ratio of 1,2-phenylenediamine to aldehyde was 1:1,
both 2-substituted benzimidazole (1) and N-alkylated
benzimidazoles and N-alkylated 2-substituted benzimi-
dazoles. The further application of this catalytic system in
the synthesis of heterocyclic compounds is currently
being explored in our laboratory.
EXPERIMENTAL
Melting points were determined on MP-3 digital melting
1
point apparatus and were not corrected. H NMR spectra were
obtained on a Bruker-300 spectrometer using TMS as an internal
reference. IR spectra were recorded on a Perkin-Elmer FT-IR
spectrometer. All reagents are commercially available and were
used without further purification. All manipulations were
conducted under air.
General Procedure for The Synthesis of Benzimidazole
Derivatives.
2
-substituted benzimidazole (2) were obtained, and 2-
substituted benzimidazole (1) was the main product in
the most case. It indicated that this iodine catalyzed
reaction has a favorable selectivity for the synthesis of
Iodine (0.02 mmol) was dissolved in 4 mL THF–H O (1:1,
2
v/v). To this solution was added 1,2-phenylenediamine (1.0 mmol)
and p-florobenzaldehyde (1.0 mmol). The resulting mixture was
stirred at room temperature for 1.5 h (monitored by TLC) then
extracted with CH Cl and purified by column chromatography on
2
-substituted benzimidazoles. The latter compound (2)
was thought to be produced when both of two amino
groups of 1,2-phenylenediamine and aldehyde reacted
before imidazoline ring was formed [9a]. But when 2
equivalent of aldehyde was used, almost only N-
alkylated product 2 was obtained. The reaction gave
the products (1) or (2) with moderate to good yields.
Compared with the known methods for the synthesis
of this type of compounds, it was a versatile and
environmental friendly route.
2
2
silica gel with hexane/ethyl acetate (5:1) as eluent to yield the
products 2-(4-florophenyl)benzimidazole (1d) and 1-(4-floro-
phenylmethyl)-2-(4-florophenyl)benzimidazole (2d). 1d: white
1
solid; mp 247ꢀ248ꢀꢁꢂ H-nmr (CDCl
): ꢁ 8.10 (m, 2H), 7.65 (m,
3
2
1
ꢁ
3
3
H), 7.30 (m, 1H), 7.10 (m, 3H); IR (KBr): 3445, 3067, 2846,
-1
1
435, 1266 cm . 2d: white solid; mp 88ꢀ90ꢀꢁꢂ H-nmr (CDCl ):
3
8.15 (m, 1H), 7.88 (d, J=7.4 Hz, 1H), 7.65 (m, 2H), 7.30 (m,
H), 7.15 (m, 2H), 7.07 (m, 3H), 5.43 (s, 2H); IR (KBr): 3045,
-1
067, 2934, 2846, 1435, 1096 cm .
In summary we have developed a new and efficient
procedure for the condensation of aldehydes with 1,2-
Acknowledgment.
phenylenediamine catalyzed by I . The method offers
2
Financial supports of this research from the Natural Science
Foundation of Jiangsu province (Project BK2005139) and the
Natural Science Foundation of the Education Department of
Jiangsu province (Project 03KJD150109) are gratefully
acknowledged.
several advantages like mild reaction conditions, short
reaction time, high yields of products, and simple
experimental operation, which leads to a useful and
attractive process for the preparation of both 2-substituted

May-Jun 2006
The Convenient Synthesis of Benzimidazole Derivatives
775
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