A simple KHSO4 promoted synthesis of 2-arylsubstituted benzimidazoles by oxidative condensation of aldehydes with o-phenylenediamine

Article abstract of DOI:10.3987/COM-06-10785

KHSO₄ is used to promote the oxidative condensation of o-phenylenediamine with aldehydes in DMF and afford corresponding 2-substituted benzimidazoles efficiently. Simple and convenient procedure, use of inexpensive promoter, easy purification and shorter reaction time are the advantageous features of this method.{A figure is presented}.

Full text of DOI:10.3987/COM-06-10785

HETEROCYCLES, Vol. 68, No. 8, 2006
1669
HETEROCYCLES, Vol. 68, No. 8, 2006, pp. 1669 - 1673. © The Japan Institute of Heterocyclic Chemistry
Received, 9th May, 2006, Accepted, 26th June, 2006, Published online, 27th June, 2006. COM-06-10785
4
A SIMPLE KHSO PROMOTED SYNTHESIS OF 2-ARYLSUBSTITUTED
BENZIMIDAZOLES BY OXIDATIVE CONDENSATION OF ALDEHYDES
WITH o-PHENYLENEDIAMINE
1
2
Huiqiang Ma, Yulu Wang,* and Jinye Wang*
1
College of Chemical and Environmental Science, Henan Normal University,
Xinxiang, 453007, Henan, P. R. China
2
Biomedical Engineering, Shanghai Jiao Tong University,1954 Huashan Road,
Shanghai, 200030, P. R. China
2
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai,
2
00032, P. R. China
Abstract ― KHSO
o-phenylenediamine with aldehydes in DMF and afford corresponding
-substituted benzimidazoles efficiently. Simple and convenient procedure, use of
4
is used to promote the oxidative condensation of
2
inexpensive promoter, easy purification and shorter reaction time are the
advantageous features of this method.
2
-Substituted benzimidazoles are very useful intermediates for the development of molecules of
pharmaceutical or biological interest. Benzimidazole derivatives exhibit significant activity against
1
2
3
4a
several viruses such as HIV, herpes (HSV-1), RNA, influenza, and human cytomegalovirus
1
(
HCMV) . The widespread interest in benzimidazole-containing structures has promoted extensive
7
-14
studies for their synthesis. While many strategies are available for benzimidazole synthesis.
There are
two general methods for the synthesis of 2-substituted benzimidazoles. One is the coupling of
4b
5
phenylenediamines and carboxylic acids or their derivatives (nitriles, imidates, or orthoesters), which
often requires strong acidic conditions, and sometimes combines with very high temperatures or the use
6
of microwave irradiation. The other way involves a two-step procedure that includes the oxidative
cyclo-dehydrogenation of Schiff’s bases, which are often generated from the condensation of
7
8
2
phenylenediamines and aldehydes. Various oxidative and catalytic reagents such as sulfamic acid, I ,
9
10
11
12
13
14
15
16
DDQ, Air, Oxone, FeCl
3
·6H
2
O, ionic liquid, In(OTf)
3
,
Yb(OTf)
3
, Sc(OTf)
3
,
have been
employed. Because of the availability of a vast number of aldehydes, the later method has been
extensively used. While many published methods are effective, some of these methods suffer from one or
more disadvantages such as high reaction temperature, prolonged reaction time, and toxic solvents etc.
Therefore, the discovery of mild and practical routes for synthesis of 2-substituted benzimidazoles
continues to attract the attention of researchers.

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HETEROCYCLES, Vol. 68, No. 8, 2006
The aim of our work was to develop a simple and convenient procedure for synthesis of benzimidazoles.
1
7
Urea-hydrogen peroxide is a stable, eco-friendly and easily handled reagent in organic synthesis. We
tried to synthesize benzimidazoles using urea-hydrogen peroxide as oxidant, but failed. However, we
4
found that KHSO was a efficient promoter in synthesis of 2-substituted benzimidazoles (3) by the
6 5
condensation of arylaldehyde (2: R=Ar) and cinnamicaldehyde (2: R=C H CH=CH-) with o-phenyl-
enediamine (1) (Scheme 1).
NH2
promoter
N
+
RCHO
R
o
DMF, 80 C
N
H
NH2
1
2
3
Scheme 1
In order to establish the optimum condition for this reaction, various promoters and various solvents were
examined. Using o-phenylenediamine (1) and 4-chlorobenzaldehyde (2b) as a model, various promoter
was added in DMF at 80 °C. As shown in Table 1, different results were obtained with different promoter.
3
0 mol % KHSO
4
or NaHSO
4
was the best promoter in this reaction. The use of less than 30 mol %
. Next the effect of
KHSO took longer to react and more by-product were obtained with too much KHSO
4
4
solvent was examined. As shown in Table 2, different solvents might cause different yields. With the
increase in the boiling point of solvents, the product we got also increases, except for the case of xylene.
Alcoholic solvents (methanol and ethanol) and DMSO gave good yields. Clearly DMF stands out as the
solvent of choice, with its fast conversion, high yield and less toxic.
Table1. Variation of promoter in condensation of o-phenylenediamine (1) with 4-chlorobenzaldehyde (2b)
a
Entry
Promoter
mmol% (Promoter)
pKa(Promoter)
Time (min)
3b: Yield (%)
1
2
3
4
5
6
7
8
9
Ab
A
100
200
500
100+30
30
-
-
20
20
trace
trace
trace
82
A
-
20
A+KHSO
KHSO
NaHSO
4
-
14-15
14-15
14-15
15
4
1.92
1.92
7.21
7.21
7.21
12.66
10.32
1.92
-
82
4
30
81
NaH
NaH
2
PO
4
30
trace
trace
trace
trace
trace
30
2
PO
4
100
100
100
100
30
15
KH
Na HPO
NaHCO
2
PO
4
15
10
11
12
13
2
4
15
3
15
KHSO
4
(N
2
)c
15
-
-
15
trace
a
b
c
All yields refer to isolated 3b. A= CO(NH
2 2 2
)·H O . Operated in nitrogen atmosphere.
2
The possible mechanism are shown below (Scheme 2).

HETEROCYCLES, Vol. 68, No. 8, 2006
1671
H
N
NH2
N
KHSO4
R
=
KHSO , O (air10)
4
2
RCHO
R
+
NH2
-
H O
-H2O
2
NH2
N
1
2
4
3
-
2 -
SO4
H+
HSO4
+
pKa
1.92
Scheme 2
Table 2. Effect of solvent in condensation of o-phenylenediamine (1) with 4-chlorobenzaldehyde (2b)
Entry
Solvent
Conditionsb
3b: Yield a ( %)
1
CH2Cl2
THF
reflux
reflux
reflux
reflux
80°C
80°C
80°C
80°C
18
33
57
64
54
78
30
82
2
3
4
5
6
7
8
CH3OH
CH3CH2OH
H2O
DMSO
Xylene
DMF
a
b
All yields refer to isolated product.
Reaction time: 15 min
To test the general scope and versatility of this procedure in the synthesis of a variety of 2-substituted
benzimidazole, we examined a number of differently substituted arylaldehydes. We are pleased to find
that moderate to high yields were obtained in the condensation of o-phenylenediamine with aldehydes. As
Table 3 shows, arylaldehydes bearing both electron-donating and electron-withdrawing substituents gave
desired benzimidazoles in excellent yields. Heteroarylaldehyde (2h) (Entry 8) and α,β-unsaturated
cinnamicaldehyde (2i) (Entry 9) gave acceptable yields. Little product was obtained when aliphatic
aldehyde was used. To extend the scope of this method, we examined the condensation of arylcarboxylic
acid and o-phenylenediamine (1), but failed. We also tried to synthesize 2-arylsubstituted benzothiazoles
and benzoxazoles using this method, but little product were obtained.
Table 3. Synthesis of benzimidazoles catalyzed and oxidized by KHSO
4
Entry
2
Time (min)
3: Yield a (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
(a) : C
(b) : 4-ClC
(c) :4-NO
(d) :3-NO
(e) :2-HOC
(f) :4-CH
(g) :4-CH
(h) :2-furyl
(i) :C CH=CH
(CH
6
H
5
15
(a) :87
(b) :82
(c) :73
(d) :81
(e) :78
(f) :80
6
H
4
15
2
6
C H
4
45
2
C
6
H
4
30
6
H
4
4
6
40
3
C
6
H
15
3
OC
H
4
30
(g) :79
(h) :58
(i) :50
10
6
H
5
10
0
1
2
3
(j) :CH
3
2
)
5
120
120
120
120
(j) :trace
(k) :trace
(l) :0
(k) :CH
3
CH
2
CH
2
(l) :C
6
H
COOHb
5
(m) :4-ClC
6
H
4
COOHb
(m) :0
a
1
All yields refer to isolated product, characterized by melting points, GC-MS, IR, H NMR.
We tried to use arylcarboxylic acid as the substrtate, but failed.
b

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HETEROCYCLES, Vol. 68, No. 8, 2006
In conclusion, we have developed a simple, one-pot synthesis of 2-arylsubstituted benzimidazoles (3) by
the condensation of o-phenylenediamine (1) with arylaldehyde (2) promoted by KHSO . Simple and
4
convenient procedure, use of inexpensive promoter, easy purification and shorter reaction time are the
advantageous features of this method.
EXPERIMENTAL
All melting points were determined on a Kofler micro melting point apparatus and were uncorrected. IR
1
spectra were recorded on a SP3-300 spectrophotometer using KBr discs. H NMR spectra were measured
on a Bruker DPX-400M spectrophotometer using TMS as internal standard and DMSO as solvent.
Typical procedure for synthesis of benzimidazoles: o-Phenylenediamine (1) (0.5 mmol) and aldehyde
(
4
2) (0.5 mmol)were mixed in DMF ( 1.5 mL ) thoroughly, then KHSO (0.17 mmol) was added, heated
and stirred at 80 °C for appropriate time ( monitored by TLC ). When the reaction was finished, the
solution was cooled to rt. The reaction mixture was added dropwise with vigorous stirring into a mixture
of Na
solid (Table 3, Entries 1-6), it was collected by filtration, washed with H
gummy material precipitated the product (3) (Table 3, Entries 7-9) was extracted into EtOAc, the organic
phace was washed with H O, brine and dried (Na SO4). Evaporation of solvent gave the crude product,
2
CO
3
(0.17 mmol) and H
2
O (20 mL). In cases where the product (3) precipitated as a free flowing
2
O and dried. In cases where
2
2
the crude products were purified by column chromatography over SiO
2
(cyclohexane:AcOEt 3:1 ) to
afford the corresponding benzimidazole (3).
1
All the compounds are known compounds. They were identified from their H NMR spectroscopic data
and by comparing their mps with those reported in the literature (references cited). 3a: mp 287-288 °C
1
8a
18a
18a
(
lit., 292 °C); 3b: mp 288-291 °C (lit., 294 °C); 3c: mp 308-310 °C (lit., 316 °C); 3d: mp
1
8b
18a
18a
2
3
2
00-202 °C (lit., 204-206 °C); 3e: mp 240-242 °C (lit., 242 °C); 3f: mp 261-263 °C (lit., 270 °C);
1
8a
18a
18a
g: mp 228-230 °C (lit., 226 °C); 3h: mp 284-286 °C (lit., 288 °C); 3i: mp 199-201 °C (lit.,
03-205 °C).
ACKNOWLEDGEMENTS
This work was supported by the National Program on Key Basic Research Projects of China(973 Program,
005 CB724306).
2
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