A rapid and convenient synthesis of derivatives of imidazoles under Microwaveirradiation

Article abstract of DOI:10.1002/jccs.200500078

Anefficient and a quick microwave-assisted synthesis of benzimidazoles and trisubstituted imidazoles was developed. Three benzimidazoles were obtained as a result of the condensation of 1,2-phenylenediamine with carboxylic acids and acetoacetic ester without catalyst. A series of trisubstituted imidazoles were syn thesized by condensation of benzil, aromatical dehyde and ammonium acetate in the presence of glacial acetic acid.

Full text of DOI:10.1002/jccs.200500078

Journal of the Chinese Chemical Society, 2005, 52, 535-538
535
A Rapid and Convenient Synthesis of Derivatives of Imidazoles under
Microwave Irradiation
Na Zhaoa (
), Yu-Lu Wanga* (
) and Jin-Ye Wangb* (
)
aCollege of Chemical and Environmental Science, Key Laboratory of Environmental Pollution Control
Technology of Henan Province, Henan Normal University, Xinxiang 453007, P. R. China
bShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
An efficient and a quick microwave-assisted synthesis of benzimidazoles and trisubstituted imidazoles
was developed. Three benzimidazoles were obtained as a result of the condensation of 1,2-phenylenediamine
with carboxylic acids and acetoacetic ester without catalyst. A series of trisubstituted imidazoles were synthe-
sized by condensation of benzil, aromatic aldehyde and ammonium acetate in the presence of glacial acetic
acid.
Keywords: Microwave-assisted; Imidazoles; Condensation; Ammonium acetate; Glacial acetic acid.
INTRODUCTION
Microwave-assisted organic synthesis (MAOS) is an
phoric acid), H3BO3 or p-toluenesulfonic acid. Some new
methods reported under microwave irradiation require PPA
as catalyst,5,7 or Montmorillonite KSF or SiO2 as a solid sup-
port.8 Many methods for synthesizing substituted imidazoles
have been reported. Traditional synthesis in refluxing HOAc
or HCON(Me)2 require a long reaction time of about 3 hours.9
Two research groups have recently reported microwave-
assisted synthesis of trisubstituted imidazoles on solid sup-
port.10 But all these methods involve fussy treatment and a
relatively long reaction time. Herein we report a simple and
rapid synthesis of benzimidazoles (Scheme I) and trisub-
stituted imidazoles (Scheme II) with microwave assistance.
acknowledged quick alternative and green technology in syn-
thetic organic chemistry.1 Many organic reactions proceed
much faster and with higher yields under microwave irradia-
tion compared to conventional heating. Moreover, this tech-
nology provides easier work-up procedures.
Compounds with imidazole ring systems have many
pharmaceutical activities and play important roles in bio-
chemical processes.2 Benzimidazoles and substituted imi-
dazoles have been widely used in the medical field.3 At the
same time, some of them belong to highly stable fluorescent
derivatives.4,5 A number of methods are available for synthe-
sis of these compounds. A traditional method for synthesis of
benzimidazoles is the reaction between phenylenediamine
and carboxylic acid under harsh dehydrating reaction condi-
tions,6 for example, in the presence of HCl, PPA (polyphos-
RESULTS AND DISCUSSION
At first, we synthesized three benzimidazoles based on
the condensation of 1,2-phenylenediamine with carboxylic
Scheme I
O
R1CR2
N
NH2
solvent-free
R1
+
MW
NH2
N
H
1
a: R1 = C6H5OCH2-, R2 = OH
c: R1 = -CH3, R2 = -CH2COOEt
e: R1 = a-C10H7CH2-, R2 = OH
b: R1 = 2,4-(Cl)2C6H3OCH2-, R2 = OH
d: R1 = C6H5-, R2 = OH
f : R1 = -CH3, R2 = OEt
* Corresponding author. E-mail: wangyulu_youji01@sina.com

536 J. Chin. Chem. Soc., Vol. 52, No. 3, 2005
Zhao et al.
Scheme II
Table 1. Solvent-free synthesis of benzimidazoles under
microwave irradiation
Ph
Ph
Ph
Ph
O
O
Entry Products Time (min) Yield (%) m. p. (°C) Ref.
N
HOAc
MW
+
ArCHO
NH4OAc
+
Ar
a
b
c
d
e
f
1a
1b
1c
1d
1e
1f
15
15
04
30
30
30
90
86
92
0
0
0
162-164
185-187
174-176
11a
11b
7
-
-
N
H
2
-
-
-
acids and acetoacetic ester under solvent-free conditions us-
ing microwave irradiation without a catalyst. The yields are
excellent (Table 1).
-
tic acid. Preliminary optimization of reaction conditions was
done by using benzil, aldehydes, ammonium acetate, and ace-
tic acid (1:1:8:20). Ammonium acetate and acetic acid play
an important role in the reaction. If ammonium acetate and
acetic acid are deficient, benzil can’t transform completely.
From Table 2, it can be seen that when there is an elec-
tron-donating group on the aromatic aldehydes we can still
obtain good yields by prolonging the reaction time. This
method has obvious superiority for its short reaction time and
easy work-up process. In conclusion, a facile and environ-
mentally benign method for synthesis of trisubstituted imida-
zoles by a simple component condensation under microwave
irradiation was developed.
In our study, we failed to synthesize benzimidazoles
when benzoic acid, a-Naphthylacetic acid and ethyl acetate
were used as starting material. The attempts to use 2 equiv. of
ZnCl2, H3BO3, FeCl3·6H2O or p-toluenesulfonic acid as a cat-
alyst were unsuccessful. To our surprise, 1,2-phenylenedi-
amine would disappear but not the carboxylic acids (moni-
tored by TLC) when we added p-toluenesulfonic acid in this
reaction system. It was proposed that 1,2-phenylenediamine
reacts with p-toluenesulfonic acid. In the meantime, we used
the microwave with 495W as the optimal power. When low-
ering the power, the reaction time would be prolonged. On
the contrary, the mixture would carbonize. In a word, we have
developed a simple and efficient synthesis of substituted
benzimidazole compounds under solvent-free and cata-
lyst-free conditions.
EXPERIMENTAL SECTION
At the same time, we synthesized nine trisubstituted
imidazoles by condensation of benzil, aromatic aldehyde and
ammonium acetate in the presence of glacial acetic acid un-
der microwave irradiation in good yields (Table 2).
Melting points were determined with a Kolfer micro
melting point apparatus and were uncorrected. IR spectra
1
were recorded on a FTS-40 spectrophotometer in KBr. H
Our investigation suggested that only 50% of benzil is
transformed to corresponding imidazole along with forma-
tion of triphenyloxazole as by-product. If we use formic acid
instead of glacial acetic acid, the yield can be improved
somewhat. But it is still lower compared to using glacial ace-
NMR were measured on a Bruker DPX-400M spectrometer
using TMS as internal standard and DMSO as solvent. Ele-
mental analyses were performed on PE-2400 CHN elemental
analyzer. All the reactions were conducted in a household mi-
Table 2. Microwave-assisted synthesis of trisubstituted imidazoles
Microwave irradiation
Time (min)
Entry
Ar
Yield (%) m. p. (°C)
Ref.
a
b
c
d
e
f
g
h
i
C6H5
p-OMeC6H4
p-CH3C6H4
p-(CH3)2NC6H4
p-(C2H5)2NC6H4
m-O2NC6H4
p-ClC6H4
5
5
5
5
5
3
3
3
3
82
90
94
89
88
90
86
89
93
274-275
233-235
234-236
254-256
223-224
300-301
261-262
260-262
206-208
9b, 10b
10b, 12a
12b
9b, 10b
12c
10b, 12b
12c
12b
p-FC6H4
o-BrC6H4
12d

Microwave Mediated Synthesis of Imidazoles
crowave oven (Galanz Cambi-Grill 750W).
J. Chin. Chem. Soc., Vol. 52, No. 3, 2005 537
1486, 1448; 1H NMR (DMSO) d: 12.74 (s, 1H, NH), 8.11 (d,
2H, J = 8.4 Hz, C6H4), 7.55 (d, 2H, J = 8.4 Hz, C6H4), 7.48-
7.37 (m, 10H, 2C6H5); Anal. Calcd. for C21H15ClN2: C, 76.25;
H, 4.54; N, 8.47. Found: C, 76.18; H, 4.43; N, 8.43.
Typical procedure for preparation of benzimidazoles
1,2-Phenylenediamine (1 mmol) and phenoxy acetic
acid (1 mmol) were mixed thoroughly in an agate mortar and
then placed in a little glass bottle. The mixture was irradiated
in the microwave oven with 495W for 15 minutes. After the
reaction was completed (monitored by TLC), the crude prod-
ucts were recrystallized with 70% ethanol.
2-(p-Fluorophenyl)-4,5-diphenylimidazole (2h)
White needles; IR (KBr) n (cm-1): 3067, 3033, 1609,
1494, 1454; 1H NMR (DMSO) d: 12.65 (s, 1H, NH), 8.13 (d,
2H, J = 8.8 Hz, C6H4), 7.53-7.34 (m, 10H, 2C6H5), 7.31 (d,
2H, J = 8.8 Hz, C6H4); Anal. Calcd. for C21H15FN2: C, 80.25;
H, 4.78; N, 8.92. Found: C, 80.13; H, 4.72; N, 8.87.
Typical procedure for the synthesis of trisubstituted
imidazoles
Benzil (0.5 mmol), p-methylbenzaldehyde (0.5 mmol)
ammonium acetate (4 mmol) and glacial acetic acid (0.6 g)
were placed in a tube and mixed thoroughly. The mixture was
irradiation in the microwave oven with 638W for 5 minutes.
After the reaction was completed (monitored by TLC), the
products were cooled to room temperature. A small amount
of ethanol was dropped into the tube and then cool water was
poured into the tube slowly. After 10 minutes, the resulting
precipitate was filtrated, dried and then recrystallized from
95% ethanol.
2-(o-Bromophenyl)-4,5-diphenylimidazole (2i)
White needles; IR (KBr) n (cm-1): 3065, 3029, 1602,
1
1503, 1479, 1446; H NMR (DMSO) d: 12.58 (s, 1H, NH),
7.80-7.24 (m, 14H, 2C6H5, C6H4); Anal. Calcd. for C21H15BrN2:
C, 67.20; H, 4.00; N, 7.47. Found: C, 67.15; H, 3.94; N, 7.39.
ACKNOWLEDGEMENT
We are grateful to the Chinese Acadamy of Science and
Technology (KGCX 2-SW-602-5).
2-Phenoxy-methyl-benzimidazole (1a)
White needles; IR (KBr) n (cm-1): 3094, 3058, 1600,
1
1590, 1496, 1445; H NMR (DMSO) d: 12.61 (s, 1H, NH),
Received September 23, 2004.
7.56-6.95 (m, 9H, C6H4, C6H5), 5.33 (s, 2H, CH2); Anal.
Calcd. for C14H12N2O: C, 75.00; H, 5.36; N, 12.50. Found: C,
74.89; H, 5.33; N, 12.41.
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