New synthesis of 2-benzimidazoleacetates and study of their Knoevenagel reaction

Article abstract of DOI:10.1007/s11164-011-0471-z

To obtain 2-benzimidazolyl acrylate 2, a new efficient synthesis of 2-benzimidazoleacetate, involving esterification of 2-benzimidazole acetic acid at low temperature as the crucial step, was developed. The generality and efficiency of the process was illustrated by the high-yield synthesis of methyl, ethyl, i-propyl, and n-butyl 2-benzimidazoleacetate. The Knoevenagel reaction of 2-benzimidazoleacetate with aromatic aldehydes was studied. It was found that only in the presence of a catalytic amount of morpholine could the Knoevenagel reaction proceed to give the expected 3-aryl-2-benzimidazolyl acrylate. A mechanism for the morpholinecatalyzed reaction is suggested. Springer Science+Business Media B.V. 2011.

Full text of DOI:10.1007/s11164-011-0471-z

Res Chem Intermed (2012) 38:1403–1409
DOI 10.1007/s11164-011-0471-z
New synthesis of 2-benzimidazoleacetates and study
of their Knoevenagel reaction
•
Peng Hui Yang Qun Zheng Zhang Hong Jiang Yu
•
Received: 6 December 2011 / Accepted: 14 December 2011 / Published online: 27 December 2011
Ó Springer Science+Business Media B.V. 2011
Abstract To obtain 2-benzimidazolyl acrylate 2, a new efficient synthesis of
2-benzimidazoleacetate, involving esterification of 2-benzimidazole acetic acid at
low temperature as the crucial step, was developed. The generality and efficiency of
the process was illustrated by the high-yield synthesis of methyl, ethyl, i-propyl, and
n-butyl 2-benzimidazoleacetate. The Knoevenagel reaction of 2-benzimidazoleac-
etate with aromatic aldehydes was studied. It was found that only in the presence of
a catalytic amount of morpholine could the Knoevenagel reaction proceed to give
the expected 3-aryl-2-benzimidazolyl acrylate. A mechanism for the morpholine-
catalyzed reaction is suggested.
Keywords Benzimidazoleacetate Á Synthesis Á Knoevenagel reaction Á Catalysis
Introduction
2-Benzimidazolyl acrylonitriles are important derivatives of benzimidazoles. In
2004, the Bednarski [1] group reported that some 2-benzimidazolyl acrylonitrile
derivatives had cytotoxic activity in vitro and were, on average, 10 and 3-fold more
potent than cisplatin and etoposide, respectively. In 2007, the Botta group identified
2-benzimidzolyl acrylonitrile derivatives as HIV-1 integrase-binding inhibitors [2];
In 2010, Refaat [3] reported 2-benzimidazolyl acrylonitrile derivatives had
antitumor activity; the same year the Hranjec [4] group reported 2-benzimidzolyl
acrylonitrile derivatives had antitumor activity in vitro.
Structure–activity relationships (SAR) indicated that the nitrile group is not an
absolute requirement for cytotoxic activity [1]. Here we are interested in the ester
analogue of 2-benzimidazolyl acrylonitrile derivatives, i.e. 2-benzimidazolyl
P. H. Yang (&) Á Q. Z. Zhang Á H. J. Yu
College of Chemistry and Chemical Engineering, Xi’an Shiyou University, Xi’an 710065, China
e-mail: yaph2001@iccas.ac.cn
123

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P. H. Yang et al.
CN
Scheme 1 2-Benzimidazolyl
acrylonitrile and
2-benzimidazolyl acrylate
N
CO2R
Ar
N
N
H
Ar
N
H
1
2
acrylate 2, as shown in Scheme 1. 2-Benzimidzolyl acrylate also 2 may have
antitumor activity, and serve as a key intermediate in the preparation of fused
heterocyclic ring systems. To obtain these compounds, we have developed a new
efficient synthesis of 2-benzimidazoleacetate and studied the Knoevenagel reaction
of 2-benzimidazoleacetate with aromatic aldehydes. The results are presented in this
communication.
Results and discussion
3-Aryl-2-benzimidazolyl acrylate 2 can be synthesized by the Knoevenagel reaction
of 2-benzimidazoleacetate with aromatic aldehydes. First, 2-benzimidazoleacetate
should be synthesized. Careful investigation of the literature revealed two general
methods for synthesis of 2-benzimidazoleacetate starting from 2-cyanomethylbenz-
imidazole. One is Allan’s synthesis [5]; the other is Dubey’s synthesis [6], which
involves the hydrolysis of 2-cyanomethylbenzimidazole to give 2-benzimidazole
acetic acid and esterification of the acid with alcohols in the presence of catalytic
amount of conc. H2SO4 to give 2-benzimidazoleacetate. Because we found that
preparation of 9% alcoholic hydrogen chloride in Allan’s synthesis was troublesome
in the laboratory, we decided to adopt Dubey’s synthesis of 2-benzimidazoleacetate.
2-Cyanomethylbenzimidazole was hydrolyzed in alkaline solution to give
2-benzimidazoleacetic acid in 96% yield. Esterification of the acid with alcohols
in the presence of a catalytic amount of conc. H2SO4, however, gave 2-benzim-
idazoleacetate in poor yield. The main product was identified as 2-methylbenzimi-
dazole, formed by decarboxylation of 2-benzimidazole acetic acid (Scheme 2).
Esterification with alcohols in the presence of a catalytic amount of phosphoric acid
or hydrochloric acid gave similar results. Unexpectedly, esterification performed in
the presence of a catalytic amount of PTSA under Dean–Stark trap conditions
resulted in complete decomposition of 2-benzimidazole acetic acid. After several
setbacks, it was found that to obtain a high yield of 2-benzimidazoleacetate, the
esterification must be carried performed at low temperature. Thionyl chloride met
this requirement and was an efficient reagent for esterification of 2-benzimidazole
acetic acid affording 2-benzimidazoleacetate in high yield. The generality and
efficiency of the process was illustrated by the high yield synthesis of methyl, ethyl,
i-propyl and n-butyl 2-benzimidazoleacetate, as shown in Table 1.
With 2-benzimidazoleacetate available we began to study the Knoevenagel
reaction of 2-benzimidazoleacetate with aromatic aldehydes. The catalyst is
essential for the Knoevenagel reaction. In the model experiment, a mixture of
2-benzimidazoleacetate 2b (1.0 eq), 2-chlorobenzaldehdye (1.2 eq), and the catalyst
(0.3 eq) in ethanol was heated under reflux. The progress of reaction was monitored
123

New synthesis of 2-benzimidazoleacetates
1405
CO2H
Scheme 2 The decarboxylation
of 2-benzimidazole acetic acid
N
N
-CO2
heat
N
H
N
H
Table 1 Synthesis of 2-benzimidazoleacetates
CO2H
CO2R
N
N
SO2Cl
ROH
N
H
N
H
2a-2d
Product
Entry
R
Yield/%
1
2
3
4
Me
Et
2a
2b
2c
2d
85
85
83
81
i-Pr
n-Bu
by TLC. A series of catalysts were tested for the reaction. The results are
summarized in Table 2. Because of the weak electron-withdrawing nature of the
benzimidazolyl group, the Knoevenagel reaction of 2-benzimidazoleacetate with
aromatic aldehydes proceeded with difficulty compared with the ethyl acetoacetate
or malonate counterparts. It was shown that the Knoevenagel reaction of
2-benzimidazoleacetate 2b with 2-chlorobenzaldehdye did not proceed in the
presence of catalytic amounts of Et3N, sodium acetate, or K2CO3 [7]. Even the ionic
liquid [bmim]OH [8] did not promote the reaction. Eventually it was found that only
in the presence of a catalytic amount of morpholine could the Knoevenagel reaction
Table 2 Screening of the catalyst
CO2Et
Cl
N
CHO
CO2Et
N
catalyst
EtOH
Cl
N
H
N
H
2b
3a
Entry
Catalyst
Product
Yield/%
1
2
3
4
5
6
7
8
Et3N
3a
3a
3a
3a
3a
3a
3a
3a
0
NaOAc
AcOH
0
0
NaOH
0
K2CO3
0
[bmim]OH
Pyridine
Morpholine
0
0
57
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P. H. Yang et al.
O
CHO
CO2Et
N
CO2Et
N
O
N
H
Cl
N
N
H
N
H
H
-H2O
Cl
2b
2b
EtO2C
O
H
CO2Et
N
N
N
H
-H
N
H
NH
O
N
Cl
Cl
3a
Scheme 3 Mechanism of the morpholine-catalyzed Knoevenagel reaction
proceed to give 3-aryl-2-benzimidazolyl acrylate in moderate yield as Z,E mixtures
(Table 2, entry 8).
The fact that only morpholine catalyzed the Knoevenagel reaction could be
rationalized as shown in Scheme 3. Morpholine condensed readily with aromatic
aldehydes to give the iminium salt intermediate. 2-Benzimidazoleacetate 2b
added to the activated C=N double bond of iminium salt, then the adduct
eliminated one molecule of morpholine to afford the 3-aryl-2-benzimidazolyl
acrylate 3a.
The morpholine catalyzed Knoevenagel reaction of 2-benzimidazoleacetate 2b
with other aromatic aldehydes was also performed. The results are summarized
in Table 3. It should be pointed out that reaction of 2-benzimidazoleacetate 2b
with 2-hydroxylaldehdye proceeded smoothly via sequential Knoevenagel and
intramolecular transesterification to give benzimidazolyl coumarin derivatives in
high yield. The intramolecular transesterification process shifted the chemical
equilibrium to the products. This constituted a new method for synthesis of
coumarin derivatives.
Table 3 Synthesis of 3-aryl-2-benzimidazolyl acrylate derivatives
O
O
N
CO2Et
N
CO2Et
Ar
N
morpholine
EtOH
ArCHO
N
H
OR
N
H
N
H
R
2b
3a-3b
3c-3d
Entry
Ar
Product
R
Yield/%
1
2
3
4
2-ClC6H4
4-ClC6H4
2-HOC6H4
3a
3b
3c
3d
–
57
49
87
71
–
H
OH
2,4-(HO)2C6H3
123

New synthesis of 2-benzimidazoleacetates
1407
Conclusions
To obtain 2-benzimidazolyl acrylate 2, we have developed a new efficient synthesis
of 2-benzimidazoleacetate which includes esterification of 2-benzimidazole acetic
acid at low temperature as the crucial step. The generality and efficiency of the
process were illustrated by the high yield synthesis of methyl, ethyl, i-propyl, and n-
butyl 2-benzimidazoleacetate. The Knoevenagel reaction of 2-benzimidazoleacetate
with aromatic aldehydes proceeded to give the expected 3-aryl-2-benzimidazolyl
acrylate only in the presence of a catalytic amount of morpholine. A mechanism for
the morpholine-catalyzed reaction has been suggested.
Experimental
Melting points were uncorrected and determined on a WRS-1A digital melting-
point apparatus. IR spectra were measured in KBr on a Equinox-55 spectrometer.
1H NMR spectra were recorded on an Inova-400, with TMS as internal
reference. All reagents and solvents were obtained from commercial sources and
were used without purification. The ionic liquid [bmim]OH was prepared by
Ranu’s procedure [9]; 2-benzimidazole acetic acid was prepared by Allan’s
procedure [5].
General procedure for preparing 2-benzimidazoleacetates 2a–2d
Thionyl chloride (2.4 eq) was added, dropwise, to a rapidly stirred suspension of
2-benzimidazole acetic acid (1.0 eq) in alcohol cooled to 0 °C. The mixture was
stirred overnight and the temperature was increased slowly to room temperature.
The mixture was then heated under reflux for 1 h. When the mixture had cooled, it
was poured into excess saturated sodium bicarbonate solution and extracted with
dichloromethane. The extract was dried and evaporated. The residue was purified
by flash column chromatography to afford the 2-benzimidazoleacetate as white
solid.
Methyl 2-benzimidazoleacetate (2a)
1
Mp 106–108 °C, lit [6] 0.104–106 °C; H NMR (CDCl3) d: 7.58–7.60 (m, 2H),
7.24–7.26 (m, 2H), 4.09 (s, 2H), 3.80 (s, 3H); IR (KBr) 1742, 1540, 1439, 1274,
745 cm-1
.
Ethyl 2-benzimidazoleacetate (2b)
1
Mp 128–130 °C, lit [5] 0.128–129 °C; H NMR (CDCl3) d: 7.57–7.59 (m, 2H),
7.23–7.27 (m, 2H), 4.23–4.27 (m, 2H), 4.07 (s, 2H), 1.28–1.32 (m, 3H); IR (KBr)
1736, 1541, 1443, 1273, 1032, 745 cm-1
.
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P. H. Yang et al.
i-Propyl 2-benzimidazoleacetate (2c)
1
Mp 157–159 °C; H NMR (CDCl3) d: 7.57–7.59 (m, 2H), 7.23–7.27 (m, 2H),
5.10–5.13 (m, 1H), 4.04–4.05 (m, 2H), 1.26–1.31 (m, 6H); IR (KBr) 1730, 1441,
1273, 1195, 1037, 745 cm-1
.
n-Butyl 2-benzimidazoleacetate (2d)
Mp 66–68 °C; 1H NMR (CDCl3) d: 7.57–7.59 (m, 2H), 7.23–7.27 (m, 2H),
4.16–4.20 (m, 2H), 4.06 (s, 2H), 1.63–1.67 (m, 2H), 1.37–1.41 (m, 2H), 0.91–0.96
(m, 3H); IR (KBr) 1740, 1541, 1443, 1274, 1193, 1030, 743 cm-1
.
General procedure for preparing 3-aryl-2-benzimidazolyl acrylate derivatives 3
Morpholine (0.3 eq) was added to a solution of 2-benzimidazoleacetate (1.0 eq) and
the aldehyde (1.2 eq) in anhydrous ethanol and the resulting mixture was heated
under reflux. The progress of the reaction was monitored by TLC. When reaction
complete, the solvent was removed under vacuum and the residue was purified by
flash column chromatography or recrystallization to afford the 3-aryl-2-benzimi-
dazolyl acrylate derivatives.
3-(2-Chlorophenyl)-2-benzimidazolyl acrylate (3a)
1H NMR (DMSO) d: 12.89 (s, 1H, NH), 7.89 (s, 1H), 7.66 (s, 1H), 7.60 (d, 1H,
J = 7.6 Hz), 7.55 (s, 1H), 7.42–7.47 (m, 3H), 7.24 (s, 2H), 4.24 (q, 2H,
J = 6.8 Hz), 1.10 (t, 3H, J = 7.2 Hz); IR (KBr) 1725, 1277, 1073, 745 cm-1
.
3-(4-chlorophenyl)-2-benzimidazolyl acrylate (3b)
1H NMR (DMSO) d: 12.60 (s, 1H, NH), 8.06 (s, 1H), 7.64 (s, 1H), 7.51 (s, 1H), 7.33
(d, 2H, J = 8.8 Hz), 7.23 (s, 2H), 7.14 (d, 2H, J = 8.4 Hz), 4.23 (q, 2H,
J = 7.2 Hz), 1.21 (t, 3H, J = 7.6 Hz); IR (KBr) 1716, 1249, 1069, 745 cm-1
.
3-(2-Benzimidazolyl)coumarin (3c)
1
Mp246–248 °C (lit [10] 247 °C); H NMR (DMSO) d: 12.57 (s, 1H, NH), 9.16 (s,
1H), 8.02 (dd, 1H, J = 8.0 Hz, 1.6 Hz), 7.66–7.76 (m, 3H), 7.54 (d, 1H,
J = 8.4 Hz), 7.46 (t, 1H, J = 7.6 Hz), 7.22–7.25 (m, 2H); IR (KBr) 3334, 1713,
1416, 1130, 760, 733 cm-1
.
3-(2-Benzimidazolyl)-7-hydroxycoumarin (3d)
1
Mp[270 °C (lit [11][360 °C); H NMR (DMSO) d: 12.42 (s, 1H, NH), 10.91 (s,
1H, OH), 9.06 (s, 1H), 7.84 (d, 1H, J = 8.8 Hz), 7.62–7.67 (m, 2H), 7.17–7.22 (m,
2H), 6.90 (dd, 1H, J = 8.8 Hz, 2.4 Hz), 6.85 (d, 1H, J = 1.6 Hz), 7.22–7.25 (m,
2H); IR (KBr) 3329, 1712, 1597, 1251, 740 cm-1
.
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New synthesis of 2-benzimidazoleacetates
1409
Acknowledgment This work was supported by the Natural Science Foundation of the Education
Bureau of Shaanxi Province, China (2010JK782) and the Foundation of Xi’an Shiyou University
(Z08012).
References
1. F. Sau¨czewski, P. Reszka, P.J. Bednarski et al., J. Med. Chem. 47, 3438–3449 (2004)
2. C. Mugnaini, S. Rajamaki, C. Tintori et al., Bioorg. Med. Chem. Lett. 17, 5370–5373 (2007)
3. H.M. Refaat, Euro. J. Med. Chem. 45, 2949–2956 (2010)
4. M. Hranjec, M. Kralj, G. Karminski-Zamola, Eur. J. Med. Chem. 45, 2405–2417 (2010)
5. R.A.B. Copeland, A.R. Day, J. Am. Chem. Soc. 65(6), 1072–1075 (1943)
6. P.K. Dubey, P.V.V.P. Reddy, Indian J. Heterocycl. Chem. 16(2), 131–134 (2006)
7. Q. Cai, Z.Q. Li, J.J. Wei et al., Org. Lett. 12(7), 1500–1503 (2010)
8. J. Li, H. Sun, X.C. Cai, Chin. J. Org. Chem. 27, 1296–1299 (2007)
9. B.C. Ranu, S. Banerjee, Org. Lett. 7(14), 3049–3052 (2005)
10. R.M. Christie, C.H. Lui, Dye Pigment 47, 79–89 (2000)
11. O.V. Khilya, M.S. Frasinyuk, A.V. Turov et al., Chem. Heterocycl. Compd. 37, 1029–1037 (2001)
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