Microwave-assisted synthesis of aryl and heteroaryl derivatives of benzimidazole

Article abstract of DOI:10.3987/com-03-9760

A series of benzimidazoles containing aryl and heteroaryl substituents were efficiently and quickly synthesized by condensation of 1,2phenylenediamine with carboxylic acids in the presence of polyphosphoric acid under microwave irradiation.

Full text of DOI:10.3987/com-03-9760

HETEROCYCLES, Vol. 60, No. 6, 2003
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HETEROCYCLES, Vol. 60, No, 6, 2003, pp. 1457 - 1460
Received, 7th March, 2003, Accepted, 9th April, 2003, Published online, 14th April, 2003
MICROWAVE-ASSISTED SYNTHESIS OF ARYL AND HETEROARYL
DERIVATIVES OF BENZIMIDAZOLE
Haitao Yu, Hirohisa Kawanishi, and Hideko Koshima*
Department of Applied Chemistry, Faculty of Engineering, Ehime University,
Matsuyama 790-8577, Japan
Abstract - A series of benzimidazoles containing aryl and heteroaryl substituents
were efficiently and quickly synthesized by condensation of 1,2-
phenylenediamine with carboxylic acids in the presence of polyphosphoric acid
under microwave irradiation.
1
-3
Microwave-assisted organic synthesis is a quickly growing area in synthetic organic chemistry. The
signature of microwave-enhanced chemistry is that the rates of reactions involving polar components are
usually very fast. Reactions that require hours or days of conventional heating may often be
accomplished in minutes by microwave heating. Benzimidazole and some substituted compounds have
4
been widely investigated in medical industrial fields. At the same time, some of them belong to highly
5
,6
7
stable fluorescent derivatives as well as metal coordinate ligands. A number of methods are available
8
-10
for the synthesis of benzimidazoles. Traditional method is the reaction between phenylenediamine and
1
1
carboxylic acid under harsh dehydrating reaction conditions. In continuation of our studies on high-
1
2
throughput synthesis under microwave irradiation, we decided to explore the synthesis of benzimidazole
compounds for fluorescence emitters. Although microwave-assisted synthesis of benzimidazole from 1,2-
1
3
phenylenediamine and acetoacetic ester or aldehydes has been reported, the reactions were promoted
with mineral supports such as Montmorillonite KSF or SiO which prevented facile isolation of the
2
products. Microwave-assisted reaction using readily available reagents would be desirable to enhance
synthetic throughput for benzimdazoles. Herein we report rapid synthesis of benzimidazoles by
condensation of 1,2-phenylenediamine with carboxylic acids in the presence of polyphosphoric acid
(
PPA) using microwave irradiation.
A limitation with the majority of benzimidazole syntheses is that N-substitution is generally non-
regioselective and a mixture of isomers is often obtained. Purification and characterization of the two

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HETEROCYCLES, Vol. 60, No. 6, 2003
regioisomers can also be problematic. With these difficulties in mind, we choose unsubstituted 1,2-
phenylenediamine as precursors. PPA seems to be suitable acid for the procedure, it behaves as a strong
catalyst as well as a good dehydrating agent. The attempts to use ZnCl or p-toluenesulfonic acid in place
2
of PPA were unsuccessful. Preliminary optimization of reaction conditions was done using the 1:1
(
equiv.) mixture of 1 (10 mmol) and 2a (10 mmol). Comparison of different amount of PPA showed that
0 g of PPA was the most suitable amount for the synthesis of 3a, and therefore it was used in all
1
subsequent experiments. The excess of PPA probably played a role of solvents, despite other solvents
were not added to the reaction mixtures. The every reaction temperature was measured by fiber
thermometer and regulated to be kept in the range 200-270 °C. To circumvent the problem of the
localized heating of the mixture, we conducted the reaction with intermittent heating and mixing at a
moderate power level to provide better yields. After the first irradiation for one minute, the reaction
mixture was then take out, mixed again for 20 seconds and then heated at the same power level for an
additional 30 seconds. This step was repeated until the starting materials were disappeared using TLC
analysis.
H
NH2
NH2
N
MW
+
R
R-COOH
PPA
N
1
2
3
R =
a :
N
N
N
c :
f :
i :
b :
N
N
N
d :
g :
e :
h :
C
H
2
N
(CH ) CH
3
2
7
N
N
The results are summarized in Table 1. All the reactions were completed within several minutes. The
reactivities with 2a-c, 2f and 2i under microwave irradiation were high to afford the corresponding
products (3) in good yields. The desired products (3d, 3e, 3g and 3h) can be provided in moderate yields.
For comparison, conventional heating was applied for the preparation of benzimidazoles (3a, 3c, 3f and
3
i). The conventional heating method gave the corresponding products (3a, 3c, 3f and 3I) in comparable
yields, but longer reaction time from 4 to 16 h and presence of twice amount of PPA (20 g) were needed
to complete the reactions (Table 1).

HETEROCYCLES, Vol. 60, No. 6, 2003
1459
Table 1. Reaction of 1,2-phenylenediamine with carboxylic acids
Microwave heating
Irradiation
time
Conventional heating
Reaction Reaction
Carboxylic
acid
Product
Ref.
Yield
Yield
(%)
temp.
(°C)
time
(h)
4
(
%)
(
min)
3
2
a
3a
3b
3c
3d
3e
3f
96
85
85
48
61
78
73
59
97
170
95
61
14a
11
2
b
4
2
c
2.5
2
170
170
200
12
4
14b
14c
14d
14e
2
d
2
e
2
2
f
3
60
91
2
g
3g
3h
3i
2.5
6.5
4
2
h
14f
6
2
i
16
All of the benzimidazole derivatives prepared revealed blue emissions under balck light irradiation in
methanol solutions. The fluorescence spectra of the compounds were centered around the range from 370
6
to 430 nm. The fluorescence intensity of compound (3i) has been recently reported to be very strong. We
have found that the compound (3h) also has comparable strong fluorescence intensity at around 397 nm.
In conclusion, we have developed the simple and rapid synthesis of substituted benzimidazole
compounds that occurs under solvent-free condition using readily available inexpensive reagents and a
microwave oven.
EXPERIMENTAL
1
H-NMR spectra were measured on a JEOL JNM-GSX270 spectrometer with tetramethylsilane as an
internal standard. IR spectra were recorded on a JASCO FT/IR-300E spectrophotometer. Melting
points were not corrected. MS spectra were carried out with a Perkin Elmer ELAN 600. All the
reagents were commercially available and used without further purification.
General procedure for preparation by microwave irradiation
1
,2-Phenylenediamine (1.08 g, 10.0 mmol), carboxylic acid (10.0 or 20.0 mmol) and polyphosphoric acid
10 g) were introduced in a breaker (50 mL) and properly mixed with the help of a glass rod. The so-
obtained mixture was irradiated in a household microwave oven (Crystal AM-533WA-960W) with 200
(

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HETEROCYCLES, Vol. 60, No. 6, 2003
W (2.45 GHz) at 210-270 °C for appropriate minutes. After irradiation, the mixture was poured onto cold
water and then slowly neutralized with a solution of concentrated ammonium hydroxide to pH 8. The
precipitate was collected by filtration, washed with water, dried and recrystallized. Several products were
separated by silica gel column chromatography using ethyl acetate and methanol.
1
2
-(p-Octylphenyl)-1H-benzimidazole (3g). Recrystallized from methanol; mp 152-153°C.; H-NMR
(
DMSO-d ) δ: 8.09 (d, 2H, J = 8.1 Hz), 7.56 (m, 2H), 7.36 (d, 2H, J = 8.1 Hz), 7.18 (m, 2H), 2.61 (t, 2H,
6
-
1
J = 7.6 Hz), 1.58 (m, 2H), 1.25 (m, 10H), 0.86 (t, 3H, J = 6.8 Hz); IR (KBr) 3038, 1495, 1477 cm . MS
+
+
m/z (rel intensity): 307 (M+1 , 100), 306 (M , 15).
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