Aza-Michael addition of acrylonitrile with 2-aryloxymethylbenzimidazole derivatives under microwave irradiation

Article abstract of DOI:10.3184/030823410X12798039968476

A simple, rapid, and highly efficient method has been developed for the aza-Michael addition of acrylonitrile to 2-aryl-oxymethylbenzimidazole derivatives in the presence of anhydrous potassium carbonate under microwave irradiation. A series novel of 1-cyanoethyl-2-aryloxymethylbenzimidazole derivatives have been prepared and characterised by ¹H NMR, ¹³C NMR, IR spectra and elemental analysis.

Full text of DOI:10.3184/030823410X12798039968476

452 RESEARCH PAPER
JOURNAL OF CHEMICAL RESEARCH 2010
AUGUST, 452–454
Aza-Michael addition of acrylonitrile with 2-aryloxymethylbenzimidazole
derivatives under microwave irradiation
Tai-Bao Wei, Mao-Tang Hua, Hai-Xiong Shi, Yong Liu and You-Ming Zhang*
College of Chemistry and Chemical Engineering, Key Laboratory of Polymer Materials of Gansu Province, Northwest Normal University,
Anning East Road No. 967, Lanzhou, Gansu, 730070, P. R. China
A simple, rapid, and highly efficient method has been developed for the aza-Michael addition of acrylonitrile to
2-aryl-oxymethylbenzimidazole derivatives in the presence of anhydrous potassium carbonate under microwave
irradiation. A series novel of 1-cyanoethyl-2-aryloxymethylbenzimidazole derivatives have been prepared and
characterised by 1H NMR, 13C NMR, IR spectra and elemental analysis.
Keywords: Aza-Michael reaction, cyanoethylation, benzimidazoles, microwave irradiation
Benzimidazoles derivatives have been examined as antibacte-
rial,1 anticancer,2,3 and antiulcer agents.4,5 Organonitriles are
useful intermediates in the construction of C–N bonds and
in the preparation of β amino carbonyl or nitrile compounds
by the aza-Michael addition. However, reports on the cyano-
ethylation of substituted benzimidazole derivatives with α,
β-unsaturated nitriles are rare.
The aza-Michael addition is an important carbon–nitrogen
bond-forming reaction which has been explored in organic
synthesis. There are some reports on the base-catalysed aza-
Michael addition of heterocyclic compounds6–7, but they have
some disadvantages due to the long reaction time (several
days), vigorous reaction conditions and tedious workup.
In recent years, microwave technology has become a well-
established procedure in organic synthesis which can increase
the purity of the products, enhance the chemical yield, and
shorten the reaction time.8,9 In continuation of our earlier
work on the synthesis and study of the biological activity of
benzimidazole derivatives,10,11 we synthesised a series of new
compounds containing the 2-aryloxymethylbenzimidazole
and acrylonitrile groups using microwave irradiation. The
reactions are shown in the Scheme 1.
We found that the yields of 4a were 84% in the presence of
anhydrous potassium carbonate. This was the most efficient
catalyst for this reaction.
Secondly, organic solvents strongly affected the aza-Michael
addition. In order to improve the activity of K2CO3, some con-
ventional organic solvents were screened in Table 2. The yields
of 4a were more than 80% in highly polar aprotic solvents.
DMF was the appropriate solvent for this reaction.
Finally, to investigate the effect of microwave irradiation
on this reaction, we compared it with the classical method.7
It required 8 hours to prepare 4a by the classic method, while
only 3 minutes of microwave activation was required for the
synthesis of 4a. Obviously, the latter method considerably
reduced the reaction time. This method was used in the
preparation of other products. The results are listed in Table 3.
In conclusion, we have developed a facile, clean, efficient
procedure for the preparation of a series of novel 1-cyanoethyl-
2-aryloxymethylbenzimidazole derivatives in the presence of
anhydrous potassium carbonate under microwave irradiation.
In comparison with other conditions for the reaction, this
methodology has led to a great improvement in shortening
the reaction time, affording high yields and simplifying the
work-up.
Results and discussion
In order to select the best reaction condition for synthesis 4a–j,
we carried out a series of experiments as following: firstly,
we examined as a model reaction the preparation of compound
4a using different catalysts. The results are shown in Table 1.
Experimental
Melting points were determined on the X-4 micro melting point
apparatus and are uncorrected. IR spectra were recorded using
KBr disc on TFS-3000 spectrophotometer and 1H NMR spectra on a
Scheme 1
* Correspondent. E-mail: zhangnwnu@126.com

JOURNAL OF CHEMICAL RESEARCH 2010 453
Table 1 Yields of 4a in different catalysts in DMF
1-Cyanoethyl-2-o-methyl-aryloxymethylbenzimidazole (4b): Yellow
crystals; yield; 89%; m.p. 141–143 °C; IR（KBr）ν: 2249 (C≡N),
1599 (C=N,C=C) cm−1.1H NMR (DMSO-d6, 400 MHz) δ2.19 (3H, s,
CH3), 3.10 (2H, t, J = 6.8Hz, CH2C≡N), 4.73 (2H, t, J = 6.8Hz, NCH2),
5.48 (2H, s, CH2O),6.89–7.78 (8H, m, ArH); 13C NMR (DMSO-d6,
100 MHz) δ 18.25, 39.50,62.64, 109.31, 110.89, 111.91, 118.57,
119.54, 121.09, 122.26, 123.08, 125.85, 127.03,130.70, 134.98,
141.90, 149.45, 155.83; Anal. Calcd for C18H17N3O: C, 74.20; H, 5.88;
N, 14.42. Found: C, 74.21; H, 5.61; N, 14.40%.
Entry
Solvents
Yields of 4a / %
1
2
3
4
5
K2CO3
Na2CO3
Na OH
KOH
84
77
52
61
68
Na3PO4
1-Cyanoethyl-2-m-methyl-aryloxymethylbenzimidazole (4c): Yel-
lowish crystals; yield; 82%; m.p. 128–129 °C; IR（KBr）ν: 2247
(C≡N), 1612 (C=N, C=C) cm−1.1H NMR (DMSO-d6, 400 MHz) δ2.29
(3H, s, CH3), 3.10 (2H, t, J = 6.8Hz, CH2C≡N), 4.65 (2H, t,
J = 6.8Hz, NCH2), 5.44 (2H, s, CH2O),6.81–7.77 (8H, m, ArH);
13C NMR (DMSO-d6, 100 MHz) δ 18.21, 21.12, 39.50,62.43, 110.86,
111.74, 115.46, 118.63, 119.50, 122.18, 122.23, 123.05, 129.35,
134.39,139.17, 141.85, 149.42, 157.68; Anal. Calcd for C18H17N3O:
C, 74.20; H, 5.88; N, 14.42. Found: C, 74.21; H, 5.87; N, 14.41%.
1-Cyanoethyl-2-p-methyl-aryloxymethylbenzimidazole (4d): Yel-
lowish solids; yield; 89%; m.p. 138–139 °C; IR（KBr）ν: 2249
(C≡N), 1613 (C=N, C=C) cm−1.1H NMR (DMSO-d6, 400 MHz) δ2.23
(3H, s, CH3), 3.10 (2H, t, J = 6.4Hz, CH2C≡N), 4.67 (2H, t,
J = 6.8Hz, NCH2), 5.42 (2H, s, CH2O),7.02–7.76 (8H, m, ArH); 13C
NMR (DMSO-d6, 100 MHz) δ 18.16, 20.07, 62.58,110.82, 114.67,
118.58,119.46,122.20,123.02,129.91,130.20,134.97,141.83,149.47,
155.54; Anal. Calcd for C18H17N3O: C, 74.20; H, 5.88; N, 14.42.
Found: C, 74.22; H, 5.90; N, 14.40%.
1-Cyanoethyl-2-o-nitryl-aryloxymethylbenzimidazole (4e): Yellow-
ish crystals; yield; 81%; m.p. 181–183 °C; IR（KBr）ν: 2253 (C≡N),
1608 (C=N, C=C) cm−1.1H NMR (DMSO-d6, 400 MHz) δ3.11 (2H,
t, J = 6.8Hz, CH2C≡N), 4.75 (2H, t, J = 6.8Hz, NCH2), 5.70 (2H,
s, CH2O), 7.17–7.95 (8H, m, ArH); 13C NMR (DMSO-d6, 100 MHz)
δ 18.07, 63.54, 111.05, 115.63, 118.54,119.63, 121.42, 122.41,
123.33, 125.21, 134.56, 135.01, 139.49, 141.78, 148.18,150.35; Anal.
Calcd forC17H14N4O3: C, 63.35; H, 4.38; N, 17.38. Found: C, 63.38;
H, 4.36; N, 17.41%.
1-Cyanoethyl-2-m-nitryl-aryloxymethylbenzimidazole (4f):Yellow-
ish solids; yield; 80%; m.p. 149–151 °C; IR（KBr）ν: 2249 (C≡N),
1616 (C=N, C=C) cm−1.1H NMR (DMSO-d6, 400 MHz) δ3.13 (2H,
t, J = 6.8Hz, CH2C≡N), 4.71 (2H, t, J = 6.8Hz, NCH2), 5.64 (2H,
s, CH2O), 7.25 – 8.02 (8H, m, ArH); 13C NMR (DMSO-d6, 100 MHz)
δ 18.24, 62.98, 109.48, 110.96, 116.29,116.40,118.63, 119.57, 122.26,
123.20, 130.74, 134.94, 141.86, 148.65, 148.70, 158.23; Anal. Calcd
for C17H14N4O3: C, 63.35; H, 4.38; N, 17.38. Found: C, 63.34; H, 4.42;
N, 17.36%.
1-Cyanoethyl-2-p-nitryl-aryloxymethylbenzimidazole (4g): Yellow
crystals; yield; 87%; m.p. 195–196 °C; IR（KBr）ν: 2248 (C≡N),
1592 (C=N, C=C) cm−1.1H NMR (DMSO-d6, 400 MHz) δ3.18 (2H,
t, J = 6.8Hz, CH2C≡N), 4.70 (2H, t, J = 6.4Hz, NCH2), 5.67 (2H,
s, CH2O), 7.20 – 8.30 (8H, m, ArH); 13C NMR (DMSO-d6, 100 MHz)
δ 18.23, 63.08, 110.98, 115.42, 115.53,118.61, 119.59, 122.38,
123.24, 125.85, 125.91, 134.94, 141.44, 141.86, 148.47,162.89; Anal.
Calcd forC17H14N4O3: C, 63.35; H, 4.38; N, 17.38. Found: C, 63.36; H,
4.37; N, 17.37%.
Table 2 Yields of 4a in different solvents using K2CO3
Entry
Solvents
Yields of 4a / %
1
2
3
4
5
6
DMF (10 mL)
84
81
78
60
48
15
DMSO (10 mL)
Acetone (10 mL)
Ethyl acetate (10 mL)
Ethanol (10 mL)
H2O (10 mL)
Table 3 Reaction times, melting points and yields of the
products 4a–j in DMF
Entry
R
Timea / min
M.p. / °C Yieldc / %
230W
400W
4a
4b
4c
4d
4e
4f
R= H
1
2
148–149
141–143
128–129
138–139
181–183
149–151
195–196
187–189
118–119
149–150
84
89
82
89
81
80
87
91
93
85
R=o-CH3
R=m-CH3
R=p-CH3
R=o-NO2
R=m-NO2
R=p-NO2
R=o-Cl
1
2.5
2.5
2.5
0.3b
0.3b
0.3b
2
1
1
1.5b
1.5b
1.5b
1.5
1.5
1
4g
4h
4i
R=p-Cl
R=p-OCH3
2
3
4j
a Reactions were carried out with pulse of 30s (1min cooling
time).
b Reactions were carried out with pulse of 20s (1min cooling
time).
c Isolated yield from three runs.
Varian Mercury plus-400 MHz instrument using TMS as the internal
reference. Elemental analyses were determined on PE-2400 CHN
instrument. The reactions were monitored by TLC. For the microwave
irradiation experiments described below, a conventional microwave
oven was equipped with a condenser-Allihn type (Whirlpool Micro
V-100 having maximum output of 850 W).
All the compounds 3a–j had been reported previously11 by 1H NMR,
13C NMR, IR spectra and elemental analysis.
Aza-Michael reaction of acrylonitrile with 4a; general procedure
It should be noted that the conventional domestic microwave oven was
modified by equipping it with a condenser-Allihn type in order to
improve the reproducibility.
To a 50 mL round bottom flask was successively added 3a
(5 mmol), anhydrous potassium carbonate (5 mmol), DMF (10 mL)
and acrylonitrile (5 mmol) and thoroughly mixed properly. The flask
was placed into a microwave oven, and the mixture was irradiated
at 230 W and 400 W for the appropriate time. (The progress of the
reaction was monitored by TLC). After irradiation, ice-cold water
(10 mL) was added, and the product obtained was filtered, washed
with H2O (15 mL) three times, and dried. The product was crystallised
from DMF–EtOH–H2O.
1-cyanoethyl-2-aryloxymethylbenzimidazole (4a): Yellow crystals;
yield; 84%; m.p. 148–149 °C ; IR (K Br) ν: 2246 (C≡N), 1594 (C=N,
C=C) cm−1.1H NMR (DMSO-d6, 400 MHz) δ3.11 (2H, t, J = 6.4Hz,
CH2C≡N), 4.69 (2H, t, J = 6.8Hz, NCH2), 5.47 (2H, s, CH2O), 6.98–
7.77 (9H, m, ArH); 13C NMR (DMSO-d6, 100 MHz) δ 18.18, 39.50,
62.44, 110.85, 114.80, 118.59,119.48, 121.41, 122.23, 123.05, 129.60,
134.97, 141.83, 149.36, 157.64; Anal. Calcd for C17H15N3O: C, 73.63,
H, 5.45; N, 15.15. Found: C, 73.62; H, 5.47; N, 15.16%.
1-Cyanoethyl-2-o-chloro-aryloxymethylbenzimidazole (4h): Yellow
crystals; yield; 91%; m.p. 187–189 °C; IR（KBr）ν: 2249 (C≡N),
1616 (C=N, C=C) cm−1.1H NMR (DMSO-d6, 400 MHz) δ3.15 (2H,
t, J = 6.8Hz, CH2C≡N), 4.76 (2H, t, J = 6.8Hz, NCH2), 5.59 (2H,
s, CH2O), 7.01–7.80 (8H, m, ArH); 13C NMR (DMSO-d6, 100 MHz)
δ 18.28, 63.28, 110.95, 114.51, 118.53,119.58, 121.30, 122.34,
122.41, 123.22, 128.38, 130.10, 135.04, 141.78, 148.67,152.91; Anal.
Calcd foC17H14ClN3O: C, 65.49; H, 4.53; N, 13.48. Found: C, 65.47;
H, 4.55; N, 13.46%.
1-Cyanoethyl-2-p-chloro-aryloxymethylbenzimidazole (4i): White
solids; yield; 93%; m.p. 118–119 °C; IR（KBr）ν: 2249 (C≡N),
1595 (C= N, C= C) cm−1.1H NMR (DMSO-d6, 400 MHz) δ3.12 (2H,
t, J = 6.4Hz, CH2C≡N), 4.69 (2H, t, J = 6.8Hz, NCH2), 5.50 (2H,
s, CH2O), 7.18–7.82 (8H, m, ArH); 13C NMR (DMSO-d6, 100 MHz)
δ 18.22, 62.77, 110.89, 116.66, 118.61,119.53, 122.29, 123.12,
125.20, 129.34, 134.96, 141.84, 149.06, 156.53; Anal. Calcd for:
C17H14ClN3O: C, 65.49; H, 4.53; N, 13.48. Found: C, 65.51; H, 4.51;
N, 13.50%.

454 JOURNAL OF CHEMICAL RESEARCH 2010
1-cyanoethyl-2-p-methoxyl-aryloxymethylbenzimidazole (4j): White
solids; yield; 93%; m.p. 118–119 °C; IR（KBr）ν：2248 (C≡N),
1591 (C=N, C=C) cm−1. 1H NMR (DMSO-d6, 400 MHz) δ3.10 (2H, t,
J = 6.8Hz, CH2C≡N), 3.70 (3H, s, OCH3), 4.68 (2H, t, J = 6.8Hz,
NCH2), 5.40 (2H, s, CH2O),6.89–7.77 (8H, m, ArH); 13C NMR
(DMSO-d6, 100 MHz) δ 18.18, 55.37, 63.09,110.84, 114.67, 115.85,
118.63, 119.47, 122.21, 123.03, 134.97, 141.82, 149.55,151.60,
153.60; Anal. Calcd for C18H17N3O2: C, 70.34; H, 5.58; N, 13.67.
Found: C, 70.14; H, 5.61; N, 13.66%.
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Received 20 May 2010; accepted 9 July 2010
Paper 1000144 doi: 10.3184/030823410X12798039968476
Published online: 30 August 2010
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