Two-step synthesis of some novel monoindolylmaleimides

Article abstract of DOI:10.14233/ajchem.2014.16751

Monoindolylmaleimides have been identified as potent glycogen synthase kinase-3β inhibitors. In this paper, a convenient methodology for the preparation of some new monoindolylmaleimides was developed by microwave assisted condensation of substituted monochloromaleimides with N-containing heterocycles followed by ammonolysis in good overall yield (up to 80 %). The products were characterized by ¹H NMR and ESI-MS.

Full text of DOI:10.14233/ajchem.2014.16751

Asian Journal of Chemistry; Vol. 26, No. 14 (2014), 4399-4404
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16751
Two-Step Synthesis of Some Novel Monoindolylmaleimides
†
†
*
JIAN ZHONG , PING JIA , SHAN XU, LIANG HAN, YUJING LI, JIANRONG GAO and QING YE
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, P.R. China
*Corresponding author: E-mail: yeqing1975@zjut.edu.cn; yeqing1975@yeah.net
†These authors contributed equally
Received: 25 November 2013;
Accepted: 16 January 2014;
Published online: 5 July 2014;
AJC-15484
Monoindolylmaleimides have been identified as potent glycogen synthase kinase-3β inhibitors. In this paper, a convenient methodology
for the preparation of some new monoindolylmaleimides was developed by microwave assisted condensation of substituted
monochloromaleimides with N-containing heterocycles followed by ammonolysis in good overall yield (up to 80 %). The products were
characterized by 1H NMR and ESI-MS.
Keywords: Monindolylmaleimides, GSK-3β inhibitors, Microwave assisted condensation, Microwave assisted ammonolysis.
triazolylindolylmaleimides and benzisoxazolylindolylmale-
imides, suffered from poor yields, rigid reaction conditions
and difficulty to obtain pure products9,10. Here we report a
convenient method to synthesize some novel monoindolyl-
maleimides through microwave assisted condensation and
ammonolysis reaction by using substituted monochloroindolyl-
maleimides and N -containing heterocycles as the raw materials
(Scheme-I).
INTRODUCTION
Monoindolylmaleimides such as imidazo[1,2-a]pyri-
dinylindolylmaleimides, indazolyl-indolylmaleinides and
benzofuranylindolylmaleimides have been identified as potent
inhibitors of Glycogen synthase kinase-3β (GSK-3β)1-3, which
are useful for the treatment of diseases such as cancer, diabetes
type-2, chronic inflammatory processes, stroke, bipolar disorders
and Alzheimer's disease4-8. These compounds were generally
synthesized via condensation of a substituted indolyl-3-glyoxylate
and a heteroaryl-3-acetamide using potassium tert-butoxide
as a base1-3. In former, we have found that the traditional synthe-
tic route was not suitable for some kinds of monoindolyl-
maleimides such as imidazolylindolyl-maleimides, 1,3,4-
EXPERIMENTAL
The reagents were obtained from commercial sources.
DMF, MeCN were dried with CaH2 and toluene was dried
with Na. Microwave reactions were carried out using a CEM
H
N
O
O
N
N
O
O
O
O
Cs2CO3
NH4OAC
Heterocycle
+
R
Het
Toluene/DMF=1/2,
MW, 90 °C, 20 min
R
Cl
R
MW 140 °C, 20 min
Het
N
N
N
4 (4a-4j)
3 (3a-3j)
1(1a-1f)
2 (2a-2e)
N
N
N
N
,
,
Heterocycle
=
,
,
,
,
N
N
N
H
N
H
N
H
N
H
N
H
N
H
N
N
1a
1d
1b
1c
1f
1e
N
N
N
N
N
Het
R
=
,
,
,
,
N
N
N
N
,
N
N
N
,
,
,
=
5-Cl
5-Br
5-OMe
7-Me
Scheme-1
H

4400 Zhong et al.
Asian J. Chem.
Discover instrument (CEM Corporation), in a 10 mL glass
tube (CEM designed 10 mL pressure-rated reaction vial).
Temperature was monitored by an infrared monitoring system.
Nuclear magnetic resonance spectra were recorded on Bruker
Avance III 500 MHz and chemical shifts are expressed in ppm
using TMS as an internal standard. ESI (positive) was recorded
on an Esquire-LC-00075 spectrometer.
1H), 7.61-7.52 (m, 4H), 7.50 (d, J = 8.3 Hz, 1H), 7.48-7.41 (m,
2H), 7.04 (t, J = 7.6 Hz, 1H), 6.97-6.87 (m, 2H), 6.57 (t, J =
7.5 Hz, 1H), 6.00 (d, J = 8.1 Hz, 1H), 3.93 (s, 3H); EI-MS:
419 [M + 1]+.
3-(1-Methyl-1H-indol-3-yl)-1-phenyl-4-(1H-pyrrolo-
[2,3-c]pyridin-1-yl)-1H-pyrrole-2,5-dione (3g): Orange
1
solid, m.p. 162-163 °C; H NMR (500 MHz, DMSO-d6) δ
General procedure for the synthesis of 3a-3j: A mixture
of substituted monochloromaleimide (0.15 mmol), nitrogen-
containing heterocycle (0.18 mmol), Cs2CO3 (0.3 mmol) and
mixed solvent (3 mL, toluene/DMF =1/2, v/v) was heated by
microwave irradiation at 90 °C for 20 min. After cooling, the
resulted mixture was poured into water (20 mL) and extracted
with ethyl acetate (3 × 20 mL). The organic phase was combined,
washed with brine (3 × 60 mL), dried over Na2SO4 and concen-
trated in vacuo. The residue was purified by flash column
chromatography on silica gel using ethyl acetate/petroleum
8.42 (s, 1H), 8.26 (s, 1H), 8.07 (d, J = 5.4 Hz, 1H), 7.85 (d,
J = 3.3 Hz, 1H), 7.61-7.52 (m, 5H), 7.49-7.42 (m, 2H), 7.04
(td, J = 7.6, 0.6 Hz, 1H), 6.88 (d, J = 3.1 Hz, 1H), 6.56 (t, J =
7.5 Hz, 1H), 5.97 (d, J = 8.1 Hz, 1H), 3.94 (s, 3H); EI-MS:
419 [M + 1]+.
3-(1-Methyl-1H-indol-3-yl)-1-phenyl-4-(1H-pyrrolo-
[2,3-b]pyridin-1-yl)-1H-pyrrole-2,5-dione (3h): Orange
1
solid, m.p. 199-200 °C; H NMR (500 MHz, DMSO-d6) δ
8.30 (s, 1H), 8.05 (dd, J = 7.8, 1.5 Hz, 1H), 8.00 (dd, J = 4.7,
1.5 Hz, 1H), 7.74 (d, J = 3.7 Hz, 1H), 7.59-7.50 (m, 4H),
7.48-7.44 (m, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.08-7.02 (m,
1H), 7.02 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 3.7 Hz, 1H), 6.52
(t, J = 7.7 Hz, 1H), 5.90 (d, J = 8.1 Hz, 1H), 3.91 (s, 3H); EI-
MS: 419 [M + 1]+.
ether (1/2, v/v) as eluent to afford compound 3a-3j11,12
.
3-(1-Methyl-1H-indol-3-yl)-1-phenyl-4-(1H-pyrrolo-
[3,2-c]pyridin-1-yl)-1H-pyrrole-2,5-dione (3a): Orange
solid, m.p. > 250 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.30
(dd, J = 4.6, 1.3 Hz, 1H), 8.24 (s, 1H), 7.89 (d, J = 3.5 Hz,
1H), 7.60-7.52 (m, 4H), 7.50 (d, J = 8.3 Hz, 1H), 7.48-7.42
(m, 2H), 7.05 (t, J = 7.7 Hz, 1H), 6.96-6.89 (m, 2H), 6.57 (t,
J = 7.5 Hz, 1H), 6.00 (d, J = 8.1 Hz, 1H), 3.93 (s, 3H); EI-MS:
419 [M + 1]+.
3-(1H-Benzo[d]imidazol-1-yl)-4-(1-methyl-1H-indol-3-
yl)-1-phenyl-1H-pyrrole-2,5-dione (3i): Red solid, m.p. 200-
201 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.29
(s, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.63-7.51 (m, 4H), 7.51-7.43
(m, 2H), 7.30-7.16 (m, 2H), 7.14-7.03 (m, 2H), 6.61 (t, J =
7.4 Hz, 1H), 6.08 (d, J = 7.9 Hz, 1H), 3.94 (s, 3H); EI-MS:
419 [M + 1]+.
3-(5-Chloro-1-methyl-1H-indol-3-yl)-1-phenyl-4-(1H-
pyrrolo[3,2-c]pyridin-1-yl)-1H-pyrrole-2,5-dione (3b):
Orange solid, m.p. 107-109 °C; 1H NMR (500 MHz, DMSO-
d6) δ 8.32 (dd, J = 4.6, 1.3 Hz, 1H), 8.25 (s, 1H), 7.90 (d, J =
3.5 Hz, 1H), 7.60-7.51 (m, 4H), 7.49-7.44 (m, 3H), 7.06 (dd,
J = 8.7, 2.0 Hz, 1H), 6.97-6.92 (m, 2H), 5.91 (d, J = 2.0 Hz,
1H), 3.92 (s, 3H); EI-MS: 453 [M + 1]+.
3-(1-Methyl-1H-indol-3-yl)-1-phenyl-4-(1H-1,2,4-
triazol-1-yl)-1H-pyrrole-2,5-dione (3j): Orange solid, m.p.
174-176 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H),
8.28 (s, 2H), 7.60-7.53 (m, 3H), 7.53-7.44 (m, 3H), 7.23 (t,
J = 7.5 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.22 (d, J = 8.0 Hz,
1H), 3.95 (s, 3H); EI-MS: 370 [M + 1]+.
3-(5-Bromo-1-methyl-1H-indol-3-yl)-1-phenyl-4-(1H-
pyrrolo[3,2-c]pyridin-1-yl)-1H-pyrrole-2,5-dione (3c):
Orange solid, m.p. 103-105 °C; 1H NMR (500 MHz, DMSO-
d6) δ 8.32 (dd, J = 4.6, 1.3 Hz, 1H), 8.23 (s, 1H), 7.89 (d, J =
3.5 Hz, 1H), 7.61-7.50 (m, 4H), 7.50-7.39 (m, 3H), 7.17 (dd,
J = 8.6, 1.6 Hz, 1H), 6.98-6.91 (m, 2H), 6.06 (d, J = 1.6 Hz,
1H), 3.92 (s, 3H); EI-MS: 498 [M + 1]+.
General procedure for the synthesis of 4a-4j: A mixture
of compound 3 (0.1 mmol) and ammonium acetate (1.39 g,
18 mmol) was heated by microwave irradiation at 140 °C for
20 min.After cooling, the resulted reaction mixture was poured
into water (50 mL), adjusted to weak alkalinity with Na2CO3
and extracted with ethyl acetate (3 × 50 mL). The organic
layer was washed with brine (3 × 150 mL), dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel using ethyl acetate/petro-
leum ether (2:1, v/v) as eluent to afford compound 4a-4i.
3-(1-Methyl-1H-indol-3-yl)-4-(1H-pyrrolo[3,2-
c]pyridin-1-yl)-1H-pyrrole-2,5-dione (4a): Orange solid,
m.p. > 250 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.30 (brs,
1H), 8.27 (dd, J = 4.6, 1.2 Hz, 1H), 8.17 (s, 1H), 7.84 (d, J =
3.5 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H),
7.01 (t, J = 7.6 Hz, 1H), 6.90-6.85 (m, 2H), 6.52 (t, J = 7.5 Hz,
1H), 5.91 (d, J = 8.0 Hz, 1H), 3.90 (s, 3H); EI-MS: 343 [M + 1]+.
3-(5-Chloro-1-methyl-1H-indol-3-yl)-4-(1H-pyrrolo-
[3,2-c]pyridin-1-yl)-1H-pyrrole-2,5-dione (4b): Orange
solid, m.p. > 250 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.33
(brs, 1H), 8.29 (dd, J = 4.6, 1.3 Hz, 1H), 8.19 (s, 1H), 7.86 (d,
J = 3.5 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 8.3 Hz,
1H), 7.02 (dd, J = 8.7, 2.0 Hz, 1H), 6.92 (d, J = 3.5 Hz, 1H),
6.90-6.86 (m, 1H), 5.80 (d, J = 20 Hz, 1H), 3.91
(s, 3H); EI-MS: 377 [M + 1]+.
3-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-4-
(1H-pyrrolo[3,2-c]pyridin-1-yl)-1H-pyrrole-2,5-dione (3d):
Orange solid, m.p. 123-125 °C; 1H NMR (500 MHz, DMSO-
d6) δ 8.35 (dd, J = 4.6, 1.3 Hz, 1H), 8.21 (s, 1H), 7.86 (d, J =
3.5 Hz, 1H), 7.68-7.63 (m, 1H), 7.59-7.51 (m, 4H), 7.47-7.43
(m, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.03-7.00 (m, 1H), 6.88 (d,
J = 3.5 Hz, 1H), 6.64 (dd, J = 8.8, 2.4 Hz, 1H), 5.48 (d, J = 2.4
Hz, 1H), 3.91 (s, 3H), 2.97 (s, 3H); EI-MS: 499 [M + 1]+.
3-(1,7-Dimethyl-1H-indol-3-yl)-1-phenyl-4-(1H-
pyrrolo[3,2-c]pyridin-1-yl)-1H-pyrrole-2,5-dione (3e): Red
solid, m.p. 134-135 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.31
(dd, J = 4.6, 1.3 Hz, 1H), 8.11 (s, 1H), 7.84 (d, J = 3.6 Hz, 1H),
7.59-7.51 (m, 5H), 7.47-7.43 (m, 1H), 6.98-6.94 (m, 1H), 6.89-6.87
(m, 1H), 6.72 (d, J = 7.1 Hz, 1H), 6.40 (t, J = 7.9 Hz, 1H), 5.88
(d, J = 8.0 Hz, 1H), 4.19 (s, 3H), 2.68 (s, 3H); EI-MS: 433 [M + 1]+.
3-(1-Methyl-1H-indol-3-yl)-1-phenyl-4-(1H-pyrrolo-
[3,2-b]pyridin-1-yl)-1H-pyrrole-2,5-dione (3f): Orange
solid, m.p. > 250 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.30
(dd, J = 4.5, 1.1 Hz, 1H), 8.24 (s, 1H), 7.89 (d, J = 3.5 Hz,

Vol. 26, No. 14 (2014)
Two-Step Synthesis of Some Novel Monoindolylmaleimides 4401
3-(5-Bromo-1-methyl-1H-indol-3-yl)-4-(1H-pyrrolo-
[3,2-c]pyridin-1-yl)-1H-pyrrole-2,5-dione (4c):Yellow solid,
m.p. > 250 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.33 (brs,
1H), 8.29 (dd, J = 4.6, 1.3 Hz, 1H), 8.17 (s, 1H), 7.85 (d, J =
3.5 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H),
7.13 (dd, J = 8.7, 1.8 Hz, 1H), 6.92 (d, J = 3.2 Hz, 1H), 6.90-
6.86 (m, 1H), 5.94 (d, J = 1.8 Hz, 1H), 3.89 (s, 3H); EI-MS:322
[M + 1]+.
1H NMR (500 MHz, DMSO-d6) δ 11.32 (brs, 1H), 8.27 (s,
1H), 8.19 (s, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.81 (d, J = 3.2 Hz,
1H), 7.55 (d, J = 5.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.01 (t,
J = 7.6 Hz, 1H), 6.84 (d, J = 3.1 Hz, 1H), 6.51 (t, J = 7.6 Hz,
1H), 5.88 (d, J = 8.1 Hz, 1H), 3.92 (s, 3H); EI-MS: 343 [M + 1]+.
3-(1-Methyl-1H-indol-3-yl)-4-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)-1H-pyrrole-2,5-dione (4h): Orange solid, m.p.
> 250 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.28 (brs, 1H),
8.23 (s, 1H), 8.03 (dd, J = 7.8, 1.5 Hz, 1H), 7.98 (dd, J = 4.7,
1.4 Hz, 1H), 7.67 (d, J = 3.6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H),
7.08-7.04 (m, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 3.6
Hz, 1H), 6.48 (t, J = 7.5 Hz, 1H), 5.83 (d, J = 8.1 Hz, 1H),
3.88 (s, 3H); EI-MS: 343 [M + 1]+.
3-(5-Methoxy-1-methyl-1H-indol-3-yl)-4-(1H-pyrrolo-
[3,2-c]pyridin-1-yl)-1H-pyrrole-2,5-dione (4d): Orange
solid, m.p. > 250 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.28
(s, 1H), 8.27 (dd, J = 4.5, 1.0 Hz, 1H), 8.03 (s, 1H), 7.80 (d, J
= 3.4 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 6.93-6.88 (m, 1H),
6.84 (d, J = 3.3 Hz, 1H), 6.69 (d, J = 7.2 Hz, 1H), 6.35 (t, J =
7.6 Hz, 1H), 5.79 (d, J = 8.1 Hz, 1H), 4.16 (s, 3H), 2.66 (s,
3H); EI-MS: 357 [M + 1]+.
3-(1H-Benzo[d]imidazol-1-yl)-4-(1-methyl-1H-indol-3-
yl)-1H-pyrrole-2,5-dione (4i): Brown solid, m.p. > 250 °C;
1H NMR (500 MHz, DMSO-d6) δ 11.41 (brs, 1H), 8.42 (s,
1H), 8.22 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.2 Hz,
1H), 7.17 (m, J = 7.20-7.15 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H),
7.06-7.01 (m, 2H), 6.56 (t, J = 7.5 Hz, 1H), 5.99 (d, J = 8.0
Hz, 1H), 3.91 (s, 3H); EI-MS: 343.2 [M + 1]+.
3-(1,7-Dimethyl-1H-indol-3-yl)-4-(1H-pyrrolo[3,2-
c]pyridin-1-yl)-1H-pyrrole-2,5-dione (4e): Orange solid,
1
m.p. > 250 °C; H NMR (500 MHz, DMSO-d6) δ 11.28
(s, 1H), 8.32 (dd, J = 4.6, 1.3 Hz, 1H), 8.15 (s, 1H), 7.82 (d, J
= 3.4 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8.9 Hz,
1H), 6.98 - 6.94 (m, 1H), 6.84 (d, J = 3.8 Hz, 1H), 6.60 (dd,
J = 8.9, 2.4 Hz, 1H), 5.40 (d, J = 2.4 Hz, 1H), 3.88 (s, 3H),
2.95 (s, 3H); EI-MS: 373 [M + 1]+.
3-(1-methyl-1H-indol-3-yl)-4-(1H-1,2,4-triazol-1-yl)-
1H-pyrrole-2,5-dione (4j): Dark red solid, m.p. 232-234 °C;
1H NMR (500 MHz, DMSO-d6) δ 10.22 (brs, 1H), 7.64 (d, J =
8.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.19-7.16 (m, 1H), 7.05 (t,
J = 7.3 Hz, 1H), 6.69 (brs, 2H), 3.81 (s, 3H); EI-MS: 294.1
[M + 1]+.
3-(1-Methyl-1H-indol-3-yl)-4-(1H-pyrrolo[3,2-b]pyridin-
1-yl)-1H-pyrrole-2,5-dione (4f): Orange solid, m.p. > 250 °C;
1H NMR (500 MHz, DMSO-d6) δ 11.30 (brs, 1H), 8.27 (d, J =
4.1 Hz, 1H), 8.17 (s, 1H), 7.84 (d, J = 3.3 Hz, 1H), 7.41 (d,
J = 8.2 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.01 (t, J = 7.6 Hz,
1H), 6.91-6.85 (m, 2H), 6.52 (t, J = 7.6 Hz, 1H), 5.91 (d, J =
8.0 Hz, 1H), 3.90 (s, 3H); EI-MS: 343 [M + 1]+.
RESULTS AND DISCUSSION
To get a good yield for the synthesis of 3, the condensation
of 1a with 2a to afford 3a was selected as a model reaction to
survey the reaction condition. In a mild reaction environment,
different solvents were first investigated (Table-1, Entry 1-5,
7-9). Polar solvents such as DMF or MeCN afforded a
3-(1-Methyl-1H-indol-3-yl)-4-(1H-pyrrolo[2,3-c]pyridin-
1-yl)-1H-pyrrole-2,5-dione (4g): Orange solid, m.p. > 250 °C;
TABLE-1
SYNTHESIS OF 3aa
N
O
O
N
O
O
N
base
+
N
H
Cl
solvent, MW
N
N
N
N
1a
2a
3a
Yield of 3a (%)b
Entry
Heat method
Solvent
Base
Temp. (°C)
Time (min)
1
2
MW
MW
MW
MW
MW
Oil bath
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
DMF
MeCN
Toluene
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
90
90
90
90
90
90
90
90
90
90
90
90
90
90
120
60
20
20
20
20
20
120
20
20
20
20
20
20
20
20
20
20
49
57
Trace
55
73
32
52
80
68
42
50
19
6
3
4
Toluene/MeCN = 1/1c
Toluene/DMF = 1/1
Toluene/DMF = 1/1
Toluene/DMF = 2/1
Toluene/DMF = 1/2
Toluene/DMF = 1/5
Toluene/DMF = 1/2
Toluene/DMF = 1/2
Toluene/DMF = 1/2
Toluene/DMF = 1/2
Toluene/DMF = 1/2
Toluene/DMF = 1/2
Toluene/DMF = 1/2
5
6
7
8
9
10
11
12
13
14
15
16
t-BuOK
LiHMDS
DBU
Et3N
3
Cs2CO3
68
Cs2CO3
79
aReactions were run using 0.12 mmol of 1a, 0.1 mmol of 2a, and 0.2 mmol of base in 2.0 mL of solvent. bIsolated yields. cThe solvent was mixed in
volume ratio, and the total volume was 2 mL.

4402 Zhong et al.
Asian J. Chem.
moderate yield (50 %). However, only trace of 3a could be
found when nonpolar toluene was used as the solvent. The
yield was improved by using a mixed solution of DMF and
toluene and the best yield (80 %) was obtained when the
volume of DMF was 2 times of toluene. We next shifted our
focus to other bases such as K2CO3, t-BuOK, LiHMDS, DBU
and Et3N (Table-1, Entry 10-14). However, no better yields
were obtained. Finally, different reaction temperatures were
studied. When the reaction temperature was increased to 120 °C
or decreased to 60 °C, it was not helpful to increase the yield
(Table-1, Entry 15-16). As compared to using a conventional
reaction condition (entry 6), the microwave irradiation
displayed extreme efficiency, which promoted the reaction to
completion in 20 min and also in high yield (entry 5). There-
fore, optimized conditions involved microwave assisted conden-
sation of 1a (1.2 equiv) with 2b (1.0 equiv) at 90 °C in a mixed
solution (DMF: toluene = 2:1 v:v), using Cs2CO3 (2 equiv) as
the base, which gave 3a in 80 % yield.
N
N
O
O
N
H
5
75
2e: R = 7-Me
N
N
1a
1b
1c
N
3e
N
N
O
O
N
H
6
2a: R = H
N
76
N
N
3f
N
O
O
N
7
N
H
2a: R = H
81
N
N
N
3g
To investigate the scope of the microwave assisted conden-
sation reaction, several N-containing heterocycles 1a-1f were
selected to react with different substituted monochloro-
maleimides 2 and the results were listed in Table-2.
N
O
O
N
H
N
N
8
43
2a: R = H
2a: R = H
2a: R = H
N
1d
N
TABLE-2
SYNTHESIS OF 3 (3a-3j)
3h
N
N
O
O
N
H
N
9
61
N
O
O
N
O
O
Cs2CO3
1e
Heterocycle
+
N
N
Toluene/DMF=1/2,
MW,90 oC, 20min
R
Cl
R
Het
3i
N
N
1(1a-1f)
2 (2a-2e)
3 (3a-3j)
H
N
Entry
Yield
(%)a
N
1 (1a-1f)
2 (2a-2e)
Product 3 (3a-3j)
O
O
N
10
39
N
N
N
1f
N
N
N
N
O
O
3j
N
H
1
80
2a: R = H
aReactions were carried out using 0.15 mmol of 2, 0.18 mmol of 1 and
0.3 mmol of cesium carbonate in mixed solvent of DMF (2 mL) and
Toluene (1.0 mL); isolated yields
N
N
1a
N
3a
It is observed that the azaindoles, benzoimidazole and
1,3,4-trizazole are all able to react with different substituted
monochloromaleimide to get the target products and the yields
were affected to some extent by the structure of heterocycle
and monochloromaleimide. When 4-azaindole, 5-azaindole or
6-azaindole was employed in the microwave assisted conden-
sation, the yield was relatively high (Table-2, Entry 1, 6, 7).
However, using 7-azaindole or 1,3,4-triazole in the reaction
was unfavorable for the yield (Table 2, Entry 8, 10). All the
synthesized 3a-3j can be converted to potential GSK-3 inhi-
bitors 4a-4j easily by a microwave assisted ammonolysis in
yield 55-98 % (Table-3) and the microwave irradiation was
also superior to the conventional reaction condition.
N
N
O
O
Cl
N
H
2
2b: R = 5-Cl
60
71
N
N
1a
N
3b
N
N
O
O
Br
N
H
3
2c: R = 5-Br
N
N
1a
N
3c
N
N
O
O
O
2d: R = 5-
OMe
Conclusion
N
H
4
70
N
N
We have reported a convenient, simple and efficient
synthesis of some new monoindolylmaleimides via microwave
assisted condensation of substituted monochloro-maleimides
1a
N
3d

Vol. 26, No. 14 (2014)
Two-Step Synthesis of Some Novel Monoindolylmaleimides 4403
TABLE-3
SYNTHESIS OF 4 (4a-4j)
H
N
O
O
N
O
O
N
NH4OAc
R
MW, 140 oC, 20 min
Het
R
Het
N
4(4a-4j)
3 (3a-3j)
Entry
Heat method
Product 4
Yield (%) a
3
H
N
N
O
O
O
O
1.
MW
98
N
N
N
N
N
N
3a
4a
H
N
N
O
O
O
O
O
O
2b
Oil bath
85
N
N
N
N
N
N
3a
4a
H
N
N
O
O
O
Cl
Cl
3
MW
91
N
N
N
N
N
N
3b
4b
H
N
N
O
O
O
Br
Br
4
MW
MW
MW
82
98
90
N
N
N
N
N
N
3c
4c
H
N
N
O
O
O
O
O
O
5
N
N
N
N
N
N
3d
4d
H
N
N
O
O
O
O
6
N
N
N
N
N
N
3e
4e

4404 Zhong et al.
Asian J. Chem.
H
N
N
O
O
O
O
O
O
O
O
O
O
7
MW
MW
MW
MW
MW
99
N
N
N
N
N
N
N
N
N
N
N
N
4f
3f
H
N
N
O
O
8
72
55
89
69
N
N
N
N
4g
3g
H
N
N
O
O
9
N
N
N
N
4h
3h
H
N
N
O
O
10
N
N
N
N
4i
3i
H
N
N
O
O
O
O
11
N
N
N
N
N
N
N
N
4j
3j
aReactions were carried out using 0.1 mmol of 3 and 240 mmol ammonium acetate for 20 min; isolated yields. bReaction was carried out for 4 h
3. H.C. Zhang, C.K. Derian, D.F. McComsey, K.B.White, H.Ye, L.R. Hecker,
J. Li, M.F. Addo, D. Croll, A.J. Eckardt, C.E. Smith, Q. Li, W.M. Cheung,
with N-containing heterocycles followed by ammonolysis.
Further studies of the scope of the reaction and the pharma-
B.R. Conway, S. Emanuel, K.T. Demarest, P. Andrade-Gordon, B.P.
Damiano and B.E. Maryanoff, J. Med. Chem., 48, 1725 (2005).
cological activity of the new monoindolylmaleimides are
currently in progress.
4. L. Kim and A.R. Kimmel, Curr. Opin. Genet. Dev., 10, 508 (2000).
5. A.S. Wagman and J.M. Nuss, Curr. Pharm. Des., 7, 417 (2001).
6. P. Cohen, Eur. J. Biochem., 268, 5001 (2001).
REFERENCES
7. C. Sasaki, T. Hayashi, W.R. Zhang, H. Warita, Y. Manabe, K. Sakai
and K. Abe, Neurol. Res., 23, 588 (2001).
1. T.A. Engler, J.R. Henry, S. Malhotra, B. Cunningham, K. Furness, J.
Brozinick, T.P. Burkholder, M.P. Clay, J. Clayton, C. Diefenbacher, E.
Hawkins, P.W. Iversen,Y. Li, T.D. Lindstrom,A.L. Marquart, J. McLean,
D. Mendel, E. Misener, D. Briere, J.C. O'Toole, W.J. Porter, S. Queener,
J.K. Reel, R.A. Owens, R.A. Brier, T.E. Eessalu, J.R. Wagner, R.M.
Campbell and R. Vaughn, J. Med. Chem., 47, 3934 (2004).
8. A. Castro and A. Martinez, Exp. Opin. Ther. Pat., 10, 1519 (2000).
9. Q. Ye, M. Li, Y. Zhou, T. Pang, L. Xu, J. Cao, L. Han, Y. Li, W. Wang,
J. Gao and J. Li, Molecules, 18, 5498 (2013).
10. Q. Ye, M. Li, Y.-B. Zhou, J.-Y. Cao, L. Xu, Y.-J. Li, L. Han, J.-R. Gao,
Y.-Z. Hu and J. Li, Arch. Pharm. (Weinheim), 346, 349 (2013).
11. X.H. Liu, J.Q. Weng and C.X. Tan, Asian J. Chem., 23, 4064 (2011).
12. X.H. Liu, J.Q. Weng, C.X. Tan, B.L. Wang and Z.M. Li, Asian J. Chem.,
23, 4031 (2011).
2. I.N. Gaisina, F. Gallier, A.V. Ougolkov, K.H. Kim, T. Kurome, S. Guo,
D. Holzle, D.N. Luchini, S.Y. Blond, D.D. Billadeau and A.P.
Kozikowski, J. Med. Chem., 52, 1853 (2009).