Regioselective animation of 3-Bromoindolylmaleimide with amines

Article abstract of DOI:10.2174/157017810790796200

3-Bromoindolylmaleimide and bisindolylmaleimide were synthesized from succinimide in three steps sequnence consisting of bromination, N-methylation and indole addition in the presence of magnesium and bromoethane. They were subjeced to the regioselective amination with substituted amines to provide 3-aminoindolylmaleimides, 3- amino-N-alkylated indolylmaleimides and N-alkylated bisindolylmaleimides in good yields. The resulting indolylmaleimides represent a new class of potentially bioactive compounds.

Full text of DOI:10.2174/157017810790796200

144
Letters in Organic Chemistry, 2010, 7, 144-148
Regioselective Amination of 3-Bromoindolylmaleimide with Amines
Di-Fa Jiang, Yan-Wu Yang, Zhi-Yu Shao and Sheng-Yin Zhao*
Department of Chemistry, Donghua University, Shanghai 201620, P.R. China
Received June 24, 2009: Revised November 21, 2009: Accepted November 24, 2009
Abstract: 3-Bromoindolylmaleimide and bisindolylmaleimide were synthesized from succinimide in three steps
sequnence consisting of bromination, N-methylation and indole addition in the presence of magnesium and bromoethane.
They were subjeced to the regioselective amination with substituted amines to provide 3-aminoindolylmaleimides, 3-
amino-N-alkylated indolylmaleimides and N-alkylated bisindolylmaleimides in good yields. The resulting
indolylmaleimides represent a new class of potentially bioactive compounds.
Keywords: 3-Bromoindolylmaleimide, bisindolylmaleimide, regioselective amination, reaction mechanism.
INTRODUCTION
RESULTS AND DISCUSSION
Protein kinase C (PKC) represents an important family of
serine/threonine kinases that is involved in the transduction
of signals for cell proliferation and differentiation [1]. The
important role of PKC in processes relevant to neoplastic
transformation, carcinogenesis and tumour cell invasion
renders it a potentially suitable target for anticancer therapy.
Furthermore, there is accumulating evidence that selective
targeting of PKC may improve the therapeutic efficacy of
established neoplastic agents and sensitise cells to ionising
radiation [2,3]. The natural product staurosporine, although a
potent inhibitor of PKC, has limited selectivity in vitro for
both ATP-dependent kinases and individual PKC isozymes
[4]. Hence, over the past few years there have been
significant research activities towards selective inhibitors for
PKC. A series of novel indolylmaleimides were developed
for clinical trail [5,6], such as Ruboxistaurin [7], Enzastaurin
[8] and Sotrastaurin [9]. Structurally related derivatives, in
which one indole substitutent was replaced by other
(hetero)arenes, have been identified as strong protein kinase
C inhibitors as well [9-12]. Ruboxistaurin, a macrocyclic
bisindolylmaleimide, was widely known because of its
marked PKC ꢀ selectivity. More recently Enzastaurin,
another bisindolylmaleimide, was reported as PKC ꢀ
selective inhibitor, which is now evaluated for the treament
of B-cell lymphomas[7].
The general route for the synthesis of 3-amino-4-
indolylmaleimides is outlined in the Fig. (1). Firstly, 2-
bromo-3-(1H-indol-3-yl)-N-methymaleimide 4 as the key
intermediate could be easily synthesized from succinimide
by bromination with bromine, methylation with methyl
idodide and by reation of indole with 2,3-dibromo-N-
methylmaleimide in the presence of magnesium and ethyl
bromide in 39% overall yield in there steps [13,14]. With the
compound 4 in hand, we treated this compound (1.0 equiv.)
with ethanolamine (1.2 equiv.), in the presence of
triethylamine (1.5 equiv.) as a base, in DMF at 100ꢀ to give
3-(2-hydroxyethylamino)-4-indolyl-N-methylmaleimide 5a
as main product with 78% isolated yield. When treating
ethanolamine (2.0 equiv.) with 4 (1.0 equiv.), a new
compound was detected by a TLC analysis besides the
compound 5a. With increasing the amount of ethanolamine,
the yield of the new compound increased. It was turn to be a
main product when ethanolamine was used as a solvent.
After the purification with flash column chromatography, a
red crystal was isolated and carried out spectral detection. 1H
NMR spectrum showed the signal of methyl group at ꢁ 3.0
ppm disappeared, one more signals exhibited in the range of
ꢁ 2~4 ppm. Furthermore, the EI mass spectrum of this
compound showed a molecular ion at 315 (M+). On the basis
of spectral data, we supposed the ring opening and closing
happened in this reaction and assigned to the obtained
compound the structure of 1-(2-hydroxylethyl)-3-(2-
hydroxyethylamino)-4-indolylmaleimide 6a (Fig. 1).
Recently, our research group has been interested in the
synthesis and development of indolylmaleimide derivatives
as anticancer agents [5,13]. In continuation of this research,
we tried to synthesize some water-soluble 3-amino-4-
indolylmaleimide derivatives. When 3-bromo-4-indolyl-N-
methylmaleimide was treated with substituted amines, we
found 3-amino-4-indolyl-N-methylmaleimides and 3-amino-
N-alkyl-4-indolylmaleimides were obtained in good yields,
respectively. In this paper, we described the regioselective
amination of 3-bromoindolyl-N-methylmaleimide and
bisindolylmaleimide with different N-substituted amines.
Dodo, K. and co-workers reported that 3-amino-4-
indolylmaleimide derivatives were synthesized from 3-
bromoindolylmaleimides as starting material by treating with
different amines in dichloromethane [15]. Among others,
untill recently, Beller M. and co-workers presented the
amination of 3-bromoindolylmaleimides [16]. However,
limited information was available for this amination, and a
detailed reaction process was not discussed in above
literature. In order to investigate this reaction,
bisindolylmaleimide 7, prepared by the reaction of indole
with 3,4-dibromo-N-methylmaleimide in the presence of
magnesium and ethyl bromide, was used as the substrate.
Treatment of compound 7 with isopropanolamine gave
*Address correspondence to this author at the Department of Chemistry,
Donghua University, 2999 North Renmin Road, Shanghai, P.O. Box 201620,
P.R. China; Tel: +86 21 67792776; Fax: +86 21 67792608;
E-mail: syzhao8@dhu.edu.cn
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Regioselective Amination of 3-Bromoindolylmaleimide with Amines
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
CH3
145
H
H
N
O
O
N
O
O
N
O
O
Br2
CH3I
1) CH3CH2Br, Mg
2) indole,THF
Br
Br
Br
Br
1
2
3
CH3
N
O
O
NHR1
N
CH3
5
H
NH2R1
N
5a R1=-CH2CH2OH;
5b R1=-CH2CHOHCH3
O
O
DMF,NEt3
NH2R1
R1
Br
N
O
O
N
H
NHR1
4
6
N
H
6a R1=-CH2CH2OH;
6b R1=-CH2CHOHCH3
Fig. (1). Synthetic route for compounds 5 and 6.
CH3
N
CH3
O
O
1) CH3CH2Br, Mg
2) indole,THF
N
O
O
Br
Br
N
H
N
H
3
7
CH2CHOHCH3
N
O
O
NH2CH2CHOHCH3
N
N
H
H
8
Fig. (2). Regioselective amination of bisindolylmaleimide.
compounds 8 with 80% isolated yield (Fig. 2). However,
when compound 4 was treated with the secondary amines,
such as pyrrolidine, or diethanolamine, a main product 3-
aminoindolylmaleimides were obtained in 75~86% yield. No
other related N-alkylated compounds were isolated from the
reaction mixture. These results made we believe maleimide
ring can be opened and reclosed under primary amines (Fig.
3). This reaction proved to be a suitable procedure to prepare
N-alkylated indolylmaleimide derivatives. The structures of
all new compounds were unambiguously confirmed by
spectroscopic methods.
Based on the experimental results, a plausible mechanism
can be proposed in Fig. (4). Initially, bisindolylmaleimide 7
reacted with isopropanolamine to give the intermediate 10.
Secondly, the intermediate 10 was subjected to ring
openning to give compound 11. Thirdly, nitrogen atom in
compound 11 bound to the isopropyl group attacked the
carbonyl of the mehlylamide group to provide the
intermediate 12, then subjected to demethylamination to give
the compound 8. Herein, methylamine was released from the
nucleophile addition reaction and made this reaction
complete. In case of secondary amines, nitrogen atom was
unable to attack at the carbonyl group in maleimide ring due

146 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Jiang et al.
CH3
CH3
N
N
O
O
O
O
NHR1R2
Br
NR1R2
DMF,NEt3
N
H
N
H
9
4
9a R1=-CH2CH2OH,R2= -CH2CH2OH;
9b R1=-(CH2)3CH3,R2= -(CH2)3CH3;
9c R1,R2= -CH2CH2CH2CH2-
Fig. (3). Synthetic route for compounds 9.
CH3
CH3
OH
N
N
O
O
O
NH2CH2CHOHCH3
NHCH2CHOHCH3
N
N
N
N
H
H
H
H
10
7
CH3
NH
CH2CHOHCH3
NHCH2CHOHCH3
O
O
HO
N
O
CH3HN
N
N
H
H
N
H
N
H
12
11
CH2CHOHCH3
N
O
O
NH2CH3
+
N
N
H
H
8
Fig. (4). Supposed the mechanism for the regioselective amination.
1
to steric hindrance. All isolated product are bright coloured
crystalline compounds.
pellets on a Shimadzu model 470 spectrophotometer. H
NMR spectra were recorded using a Bruker AV 400 MHz
spectrometer in DMSO-d6, CDCl3 and acetone-d6 with
tetramethylsilane as internal standard. EI mass spectra were
recorded on Shimadzu QP-2010 GC-MS system. ESI mass
spectra were obtained on Shimadzu 2010A LC-MS
instrument. Elemental analyses were performed on a Vario
EL ꢀ elemental analyser. All chemicals and reagents were
purchased from known commerical suppliers and were used
without further purification. 3,4-Diboromaleimide, 3,4-
dibromo-N-methylmaleimide, 2-bromo-3-(1H-indol-3-yl)-N-
methymaleimide and bisindolyl-N-methylmaleimide were
synthesized according to the literature procedures with minor
change[13,14]. The target compounds were prepared
according to the synthetic routes shown in Figs. (1, 3).
In conclusion, we have demonstrated that 3-
bromoindolyl-N-methylmaleimide and bisindolylmaleimide
can sucessfully be regioselectively aminated with primary
amines to provide 3-amino-4-indolylmaleimides, 3-amine-N-
alkyl-4-indolylmaleimide, respectivily and N-alklylated
bisindolylmaleimide in 70~88% yields. This reaction
provided a suitable procedure to prepare N-alkylated
indolylmaleimide derivatives. Further biological evaluation
of the synthesized compounds are currently in progress.
EXPERIMENTAL
Melting points were determined with RY-1 apparatus,
and were uncorrected. IR spectra were determined as KBr

Regioselective Amination of 3-Bromoindolylmaleimide with Amines
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
147
General Procedure for Preparation of Compounds 5
1-(2-hydroxypropyl)-3,4-di-(1H-indol-3-y)-1H-pyrrole-2,5-
dione (8)
4 (5 mmol) and triethylamine (10 mmol) were mixed
thoroughly in DMF (10 mL). To this solution, ethanolamine
(6 mmol) was added. The reaction mixture was stirred at
100ꢀ for 16 h. Water (10 mL) was added. The mixture was
extracted with ethyl acetate(40 mLꢀ2), and washed with
saturated NaHCO3(40 mLꢀ2) and water(40 mLꢀ2). The
solvent was removed and purified by flash column
chromatography (dichloromethane / methanol=10:1, v/v) to
give a red-yellow solid 5. Compounds 9 were synthesized
from 4 following the procedure given above. Compounds 6
were synthesized from 4 by using amines as solvent. The
physical and spectral data of the compounds 5a-5b、6a-
6b、8 and 9a-9c are as follows.
Red crystalline solid; m.p. 265-268ºC; yield: 79%; IR
1
(cm-1): 1712(C=O), 1657(C=O). H NMR (DMSO-d6): ꢀ
0.98(d, J=6.8Hz, 3H, CH3), 3.51(m, 2H, CH2), 3.94(m, 1H,
CH), 4.91(s, 1H, OH), 6.66(m, 2H, Ar-H), 7.81(m, 2H, Ar-
H), 6.95(m, 2H, Ar-H), 7.35(m, 2H, Ar-H), 7.75(m, 2H, Ar-
H), 11.67(s, 2H, NH); MS(EI) m/e [M]+385. Anal. Calcd. for
C23H19N3O3: C, 71.68; H, 4.97; N, 10.90. Found: C, 71.32;
H, 5.81; N, 11.19%.
3-(bis(2-hydroxyethyl)amino)-4-(1H-indol-3-yl)-1-methyl-
1H-pyrrole-2,5-dione (9a)
Red crystalline solid; m.p. 260-262ºC; yield: 78%; IR
(cm-1): 1710(C=O), 1669(C=O). 1H NMR(DMSO-d6): ꢀ
2.89(s, 3H, CH3), 3.43(m, 4H, 2CH2), 3.57 (m, 4H, 2CH2),
4.66(s, 2H, 2OH), 6.98(m, 1H, Ar-H), 7.07(m, 1H, Ar-H),
7.29(s, 1H, Ar-H), 7.36(d, 1H, Ar-H), 7.47(d, 1H, Ar-H),
11.24(s, 1H, NH); MS(EI, m/z): 329 [M]+. Anal. Calcd. for
C17H19N3O4: C, 62.00; H, 5.81; N, 12.76. Found: C, 62.29;
H, 5.71; N, 12.96%.
3-(2-hydroxyethylamino)-4-(1H-indol-3-yl)-1-methyl-1H-
pyrrole-2,5-dione (5a)
Red crystalline solid; m.p. 219-222 ꢀ; yield:78%; IR
(cm-1): 1701(C=O), 1638(C=O). 1H NMR(DMSO-d6): ꢀ
2.91(s, 3H, CH3), 3.11(t, J=5.8Hz, 2H, CH2), 3.24(t,
J=5.8Hz, 2H, CH2), 4.58(s, 1H, OH), 6.90(s, 1H, NH),
7.00(m, 1H, Ar-H), 7.09(m, 1H, Ar-H), 7.29(m, 1H, Ar-H),
7.37(m, 2H, Ar-H), 11.17(s, 1H, NH); MS(ESI, m/z):
286.2[(M+H)]+, 308.3 [(M+Na)]+. Anal. Calcd. for
C15H15N3O3: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.08;
H, 5.01; N, 14.42%.
3-dibutylamino-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-
dione (9b)
Red crystalline solid; m.p. 197-199ºC; yield: 84%; IR
(cm-1):1695(C=O), 1646(C=O). 1H NMR(acetone-d6): ꢀ
0.72(m, 6H, 2CH3), 1.04(m, 4H, 2CH2), 1.48(m, 4H, 2CH2),
3.01(s, 3H, CH3), 3.50(m, 4H, 2CH2), 7.04(m, 1H, Ar-H),
7.12(m, 1H, Ar-H), 7.31(s, 1H, Ar-H), 7.42(m, 2H, Ar-H),
10.55(s, 1H, NH); MS(ESI, m/z): 354.3 [(M+H)]+, 376.4
[M+Na]+. Anal. Calcd. for C21H27N3O2: C, 71.36; H, 7.70; N,
11.89. Found: C, 71.02; H, 7.41; N, 11.59%.
3-(2-hydroxypropylamino)-4-(1H-indol-3-yl)-1-methyl-1H-
pyrrole-2,5-dione (5b)
Red crystalline solid; m.p. 248-250 ꢀ; yield: 72%; IR
1
(cm-1): 1704(C=O), 1642 (C=O). H NMR(DMSO-d6): ꢀ
0.66(d, J=6.2Hz, 3H, CH3), 2.91(s, 3H, CH3), 2.93(m, 1H,
CH2), 3.47(m, H, CH), 4.63(s, H, OH), 6.86(s, 1H, NH),
7.00(m, 1H, Ar-H), 7.09(m, 1H, Ar-H), 7.28(d, 1H, Ar-H),
7.37(m, 2H, Ar-H), 11.21(s, 1H, NH); MS(EI, m/z):299[M]+.
Anal. Calcd. for C16H17N3O3: C, 64.20; H, 5.72; N, 14.04.
Found: C, 64.45; H, 5.51; N, 14.39%.
3-(1-pyrrolidino)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-
2,5-dione(9c)
Red crystalline solid; m.p. 209-212ºC; yield:88%; IR(cm-
1):1683(C=O), 1630(C=O); H NMR(CDCl3): ꢁ1.75(m, 4H,
1
2CH2), 3.06(s, 3H, CH3), 3.55(m, 4H, 2CH2), 7.12(m, 2H,
Ar-H), 7.20(m, 1H, Ar-H), 7.35(m, 1H, Ar-H), 7.46(m, 1H,
Ar-H), 8.28(s, 1H, NH);MS(ESI, m/e):[M+H]+ 296.3,
[M+Na]+ 318.1. Anal. Calcd. for C17H17N3O2: C, 69.14; H,
5.80; N, 14.23. Found: C, 69.04; H, 5.57; N, 14.12%.
3-(2-hydroxyethylamino)-1-(2-hydroxyethyl)-4-(1H-indol-
3-yl)-1H-pyrrole-2,5-dione (6a)
Red crystalline solid; m.p. 232-235ºC; yield:77%; IR
(cm-1): 1697(C=O), 1648(C=O). 1H NMR(DMSO-d6): ꢀ
3.12(t, J=5.8Hz, 2H, CH2), 3.22(t, J=5.8Hz, 2H, CH2),
3.49(m, 4H, 2CH2), 4.60(m, 1H, OH), 4.84(m, 1H, OH),
6.92(m, 1H, Ar-H), 7.01(m, 1H, Ar-H), 7.07(m, 1H, Ar-H),
7.30(s, 1H, NH), 7.39(m, 2H, Ar-H); 11.23(s, 1H, NH);
MS(ESI, m/z): 315[M]+. Anal. Calcd. for C16H17N3O4: C,
60.94; H, 5.43; N, 13.33. Found: C, 60.58; H, 5.76; N,
12.99%.
ACKNOWLEDGEMENT
We thank the funding for outstanding young faculty in
Donghua University for financial support.
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