1,3-Dibromo 5,5-dimethylhydantoin (DBH)-catalyzed solvent-free synthesis of 2-arylbenzimidazoles under microwave irradiation

Article abstract of DOI:10.1155/2012/454213

An expeditious synthesis of 2-aryl-benzimidazoles by the condensation of o-phenylenediamine with various arylaldehydes is described. This greener protocol is catalyzed by 1,3-Dibromo 5,5-dimethylhydantoin (DBH), and proceeds efficiently in the absence of

Full text of DOI:10.1155/2012/454213

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
http://www.ejchem.net
2012, 9(3), 1064-1069
1
,3-Dibromo 5,5-dimethylhydantoin (DBH)-Catalyzed
Solvent-Free Synthesis of 2-arylbenzimidazoles under
Microwave Irradiation
*
1
2
MEHDI FOROUZANI and HASSAN GHASEMNEJAD-BOSRA
1
Department of Chemistry, Payamenoor University, 19395-4697, Tehran, I.R. of Iran
Department of Chemistry, Islamic Azad University-Babol Branch, P.O. Box 755, Babol
2
4
7188-33348 , Iran
Forouzanimehdi@yahoo.com
Received 5 November 2011; Accepted 15 January 2012
Abstract: An expeditious synthesis of 2-aryl-benzimidazoles by the
condensation of o-phenylenediamine with various arylaldehydes is described.
This greener protocol is catalyzed by 1,3-Dibromo 5,5-dimethylhydantoin
(DBH), and proceeds efficiently in the absence of any organic solvent under
thermal condition and microwave irradiation in high yields.
Keywords: 1,3-Dibromo 5,5-dimethylhydantoin (DBH), Benzimidazoles, Microwave irradiation,
Solvent free.
Introduction
Benzimidazoles are very useful intermediates for the development of molecules of
pharmaceutical and biological interest. Substituted benzimidazole derivatives have found
applications in diverse therapeutic areas including antiulcers, antihyperten-sives, antivirals,
1
,2
antifungals, anticancers, and antihistaminics . The widespread interest in benzimidazole
containing structures has prompted extensive studies for their synthesis. There are two
general methods for the synthesis of 2-substituted benzimidazoles. One is the coupling of o-
3
phenylenediamines and carboxylic acids or their derivatives (nitriles, imidates, or
orthoesters), which often require strong acidic conditions and sometimes combine with very
o
4,5-6
high temperatures (i.e., PPA, 180 C) . The other way involves a two-step procedure that
includes the oxidative cyclodehydrogenation of aniline Schiff’s bases, which are often
7-12
generated in situ from the condensation of o-phenylenediamines and aldehydes
.
However, suffer from longer reaction times, unsatisfactory yields, harsh reaction conditions
and excessive use of reagents and catalysts. It is therefore important to find more convenient
methods for the preparation of these compounds.
1
3
Microwave-assisted organic synthesis (MAOS) has attracted considerable interest and
is an important technique in green synthetic chemistry. It could help achieve high yields and
clean reaction out comes at shorter action time. Organic solvent- free reaction conditions
eliminate the toxicity and flammability issues associated with common solvents. Together,

1
,3-Dibromo 5,5-dimethylhydantoin (DBH)-Catalyzed Solvent-Free 5601
solvent-free organic syntheses assisted by microwave irradiation (MW) have being regarded
as environmentally benign methodologies.
Experimental
All the reactions were carried out using a conventional (unmodified) microwave oven (LG,
2
30 V, ~50 Hz). Reactions were monitored on TLC by comparison with the samples
prepared by known procedures. The Infrared spectroscopy (IR) spectra were recorded using
a Shimadzu 435-U-04 spectrophotometer (KBr pellets) and the Nuclear magnetic resonance
(
NMR) spectra were obtained in using a 90 MHz JEOL FT NMR spectrometer. All melting
points were determined on a Büchi 530 melting point apparatus and are reported
uncorrected.
Microwave experiments were conducted using a CEM Discover monomode oven
operating at 2450 MHz monitored by a PC computer, and temp. was maintained at a
constant value by power modulation (0 – 300W). Stirring was provided by an in situ
magnetic stirrer. Reactions were performed in open glass vessels (capacity 10 mL). Reaction
conditions: power 300W; no solvent; ramp time 3 min; hold time 10 min; stirring on; temp.
o
1
45 C.
General Procedure for the Synthesis of 2-aryl-benzimidazoles (Method A)
To a mixture of o-phenylenediamine (1 mmol), aldehyde (1 mmol) and 1,3-dibromo 5,5-
dimethyl hydantoin (DBH) (0.12 mmol, 0.34 mg) was added and the mixture was inserted in
o
an oil bath and heated at 50 C for the appropriate time (Table 1). Completion of the reaction
was indicated by Thin Layer Chromatography (TLC). After which dichloromethane (10 ml)
was added to the mixture and left aside for a few minutes, the solid thus separated was
recrystallized from methanol or subjected to silica gel column chromatography to get the
pure product/s.
General Procedure for the Synthesis of 2-aryl-benzimidazoles (Method B)
A mixture of o-phenylenediamine (1 mmol), aldehyde (1 mmol) and 1,3-dibromo 5,5-
dimethyl hydantoin (DBH) (0.12 mmol, 0.34 mg) was taken in the special open glass vessel.
The mixture was thoroughly mixed, and the tube was then subjected to microwave
irradiation according to the above protocol. (see Table 1). After which dichloromethane (10
ml) was added to the mixture and left aside for a few minutes, the solid thus separated was
recrystallized from methanol or subjected to silica gel column chromatography to get the
pure product/s.
The products were characterized on the basis of their physical and spectral analysis and
1
4-17
by direct comparison with literature data
.
Results and Discussion
In continuation with the search for simple non-hazardous methods for the transformations in
1
8-26
organic synthesis using halogenating agents
, herein we report a highly versatile and
efficient synthesis of 2-aryl-benzimidazoles 3 from o-phenylenediamine, aldehyde and
catalytic amounts of 1,3-dibromo 5,5-dimethyl hydantoin (DBH) under solvent-free and
microwave conditions in high yields (Scheme 1).
To find out the optimum quantity of 1,3-dibromo 5,5-dimethyl hydantoin (DBH), the
reaction of o-phenylenediamine and benzaldehyde was carried out under thermal solvent-
free conditions (Method A) using different quantities of DBH (Table 1). As shown this
table, 0.12 mmole of DBH gave excellent yield in 95 as can be seen from Table 1. Thus, we
prepared arrange of benzimidazoles under the optimized reaction conditions: o-
phenylenediamine (1 mmol) and aldehyde (1 mmol) in the presence of DBH (0.12 mmol). A

5
600 MEHDI FOROUZANI
series of benzimidazoles were prepared in high to excellent yields by two methods (A, B)
(
Table 2).
CHO
NH2
N
R
DBH
+
Solvent Free
N
H
NH2
R
Method A: Thermal condition
Method B: MW (160 W) irradiation
3
1
2
Scheme 1
Table 1. The effect of amount of DBH on the reaction of o-phenylenediamine and
benzaldehyde under thermal solvent free conditions.
a
Entry
Catalyst (mmol)
Time (min)
Yield (%)
1
2
3
4
5
6
0
0.05
0.1
0.12
0.15
0.20
120
85
60
45
45
45
0
51
87
95
95
95
a
Yields refer to the pure isolated products.
To account for the facile formation of benzimidazoles, the following mechanism
Scheme 2) is proposed. The reaction between an aldehyde and a diamine leads to the
(
formation of Schiff base (I) which is stabilized by catalyze. Intermolecular attack by the
second amino group on C=N double bond facilitates the formation of hydro-benzimidazole
23
(
II) which undergoes subsequent air oxidation to give the desired benzimidazole as the
final product.
Table 2. DBH catalyzed synthesis of benzimidazoles.
a
o
c
Entry Product
R
Method A
Method B
M.p., C (Lit.)
Time/Yields Time/Yields
b
b
(
%)
(%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
H
(45 min/95)
(48 min/93)
(49 min/92)
(52 min/94)
(54 min/89)
(5 min/93)
(6 min/94)
(8 min/93)
(5 min/90)
(6 min/95)
(9 min/89)
(7 min/93)
(9 min/92)
(8 min/89)
(6 min/90)
(5 min/94)
(6 min/92)
(7 min/93)
(6 min/92)
(7 min/95)
287-288(288-190)
278-280 (277-279)
215-217 (217-219)
226-228 (227-228)
211-213 (210-210.4)
178-180 (178-179)
250-251 (252-254)
297-299 (298-300)
205-207 (204-206)
169-170 (168-170)
191-193 (192-293)
156-158 (155-156)
221-223 (220-222)
202-203 (203-205)
235-236 (236-237)
4-Me
3-Me
4-OMe
3-OMe
3,4-OMe2 (58 min/89)
4-N(Me)2 (52 min/90)
4-NO2
3-NO2
2-NO2
4-Cl
(44 min/94)
(41 min/93)
(43 min/95)
(45 min/94)
(47 min/92)
(43 min/93)
(42 min/96)
(40 min/94)
1
0
1
2
3
4
5
1
1
1
1
1
2-Cl
3-F
4-F
2-OH
a) Isolated yields. b) All the products are known, characterized by IR, NMR spectral analysis
and compared with the authentic samples. c) Melting points of compounds are consistent with
1
4-16,27
reported values
.

1
,3-Dibromo 5,5-dimethylhydantoin (DBH)-Catalyzed Solvent-Free 560ꢀ
The compares the efficiency of DBH (time, yield, reaction conditions) with the efficiency of
some other catalysts used in the synthesis of benzimidazoles (Table 3). It clearly shows that
the presented method, using DBH as the catalyst, is simple, efficient and comparable with
many catalytic systems for the synthesis of benzimidazoles derivatives.
Table 3. Comparison of efficiently various catalysts in the synthesis of benzimidazoles.
Entry
Catalyst
Condition
Time
min)[h]
(45)
(5)
[2]
[8]
[5]
[2]
(10)
[1-2]
(10)
(30)
Yield
(%)
95
93
98
83
85
92
93
Reference
(
o
1
2
3
4
5
6
7
8
9
DBH
DBH
Solvent-free/50 C
Solvent-free/MW
This work
This work
o
CAN (5 mol %)
Dowex 50 W
PEG/50 C
28
29
10
12
4
30
31
32
o
Water/70 C
+
-
Me S BrBr
MCN/r.t
2
Polyaniline sulfate
HCl
CH CH CL /r.t
2
2
2
Solvent-free/MW
Solvent-free/r.t
DMAc/MW
SiO -Pr-SO H
90
88
95
2
3
NaHSO3
o
1
0
SiO -FeCl
H O /150 C
2
3
2
2
The advantages or the characteristic aspects of the method described in this paper in
comparison with other previously reported ones are the following: the yields of products
were better than the previous reported yields and in addition, the catalyst DBH is
inexpensive, has no moisture sensitivity, and no special measures are required for the
reaction.
+
O Br
O
O
CHO
-
N
O
N Br
H
Br N
O
N
Br
+
+
R
R
..
1
H2N
H2N
2
NH2
Ar
N
H
O
OBr
Br
N
N
O
Br
N
N Br
O
O
NH
2
R
R
H
N
N
CH
Br
N
R
air oxidation
I
N
H
N
H
H
N
O
O
N
3
II
Br
Scheme 2

5
60ꢁ MEHDI FOROUZANI
Conclusion
The present methodology shows that 1,3-dibromo 5,5-dimethyl hydantoin (DBH) is an
efficient catalyst in the one-pot synthesis of benzimidazole derivatives. The main advantages
of the presented protocol are mild, clean and environmentally benign reaction conditions, as
well as the high yields. Furthermore, this method is also expected to find application in
organic synthesis due to the low cost of the reagent. It is believed that this method will be a
useful addition to modern synthetic methodologies.
Acknowledgments
We wish to thank the Department Chemistry-University of Payamnoor Sari, Sari, Iran, for
financial support during the realization of this research.
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