Synthesis of 2-hetaryl-3-(indol-1-yl)-and -(3-pyrrol-1-yl)maleimides and study of their conversions under the action of protic acids

Article abstract of DOI:10.1007/s10593-011-0656-9

A series of 3-(indol-1-yl)maleimides has been synthesized, substituted at position 2 by residues of amines or various nitrogenous heterocycles. The possibility of obtaining new polycondensed heterocyclic structures from them has been studied. Experimental

Full text of DOI:10.1007/s10593-011-0656-9

Chemistry of Heterocyclic Compounds, Vol. 46, No. 10, 2011
SYNTHESIS OF 2-HETARYL-3-(INDOL-1-YL)-
AND -(3-PYRROL-1-YL)MALEIMIDES AND STUDY
OF THEIR CONVERSIONS UNDER THE ACTION
OF PROTIC ACIDS*
S. A. Lakatosh1**, E. E. Bykov1, and M. N. Preobrazhenskaya1
A series of 3-(indol-1-yl)maleimides has been synthesized, substituted at position 2 by residues of
amines or various nitrogenous heterocycles. The possibility of obtaining new polycondensed
heterocyclic structures from them has been studied. Experimental investigations confirmed theoretical
predictions made on the basis of results of quantum-chemical calculations.
Keywords: indole, indolylmaleimides, quantum chemistry, cyclization reaction.
2-Aryl-3-indolylmaleimides, and also 2-aminoaryl-3-indolylmaleimides and their derivatives are of
interest as potential inhibitors of protein kinases, which may serve as a basis for constructing new medicinal
preparations. A series of derivatives of bis(indolyl)maleimides are undergoing clinical testing at present [1, 2].
Derivatives of bis(indol-1-yl)-, 2-alkylamino-3-(indol-1-yl)maleimides (for example compounds 1 and 2 ) were
synthesized previously [3]. It was shown that under the action of protic acids these compounds are cyclized with
the formation of a diazepine seven-membered ring with annelated indoline and maleimide fragments (3 and 4
respectively) in difference to bis(indol-3-yl)maleimides 5, which form compounds with a six-membered central
ring 6 under similar conditions [4] (Scheme 1).
In the present work the preparation is described of various 3,4-bis(hetaryl)maleimides, including
2-hetaryl-3-(indol-1-yl)maleimides, and also 2-amino-3-(indol-1-yl)maleimides, and the transformation of some
of them under the action of protic acids has been studied. For the purpose of predicting the direction of
cyclization of 2-hetaryl-3-(indol-1-yl)maleimides under the action of protic acids, quantum-chemical
calculations were carried out of the electron density distribution at the reaction centers of hetarylmaleimides and
their indoleninium cations formed on protonation, and also of the energy parameters of the respective
cyclization reactions.
_______
*Dedicated to the shining memory of A. N. Kost.
**To whom correspondence should be addressed, e-mail: mnp@space.ru.
1 G. F. Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, Moscow 119021, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1515-1525, October, 2010.
Original article submitted August 17, 2010.
1224
0009-3122/11/4610-1224©2011 Springer Science+Business Media, Inc.

Scheme 1
H
N
O
O
H
O
N
H
N
O
N
H
N
N
O
O
O
O
N
H+
N
H+
N
N
N
N
4
2
1
3
H
H
O
O
N
N
O
O
H+
[O]
N
N
H
H
N
N
H
H
6
5
Derivatives of (indol-1-yl)maleimide 8a-j were obtained by the condensation of 2-bromo-3-(indol-
1-yl)maleimide (7) with the appropriate amines or nitrogenous heterocycles in DMF on heating in the presence
of ethyldiisopropylamine. 2-Amino-3-(indol-1-yl)maleimide (8k) was obtained by the interaction of compound
7 with ammonia in methanol at room temperature (Scheme 2).
Scheme 2
H
H
O
O
N
N
O
O
NuH,
Br
Nu
N
N
i-Pr2EtN, DMF
7
8a–j
MeOH NH3
O
H
N
O
O
N
O
Ac2O
O
NH2
NH2
N
N
8l
8k
H
N
H
N
H
N
H
N
,
,
N
d
,
c
8 a
NuH=
, b
N
N
N
N
NH2
NH2
NH2
H
N
NH2
,
,
,
,
,
g
e
j
i
h
f
N
N
O
N
NH2
H2N
OH
1225

Heating compound 8k in acetic anhydride led to acetylation at the maleimide nitrogen atom but not at
the nitrogen in position 2 of the maleimide fragment. The possibility and direction of cyclization of analogs of
2-hetaryl-3-(indol-1-yl)maleimides, in which 2-hetaryl = pyrrol-1-yl (9), pyrazol-1-yl (8b), or imidazol-1-yl
(8a), were investigated by methods of oquantum chemistry. Calculations of the distribution of limiting electron
density in their HOMO were carried out in a study of the direction of protonation of these molecules.
In spite of the fact that the values of the Fukui indexes in pyrrolediones 8, 9 are greater at N(1) than at
C(3), the C(3) atom must be considered to be the more nucleophilic, according to the results of calculations by
the functional density method using B3LYP/6-31G(d) and the AM1 method. Consequently it may be suggested
that protonation will occur at position 3 of the indole fragment of each of the molecules listed above.
To assess the reactivity of the conjugate acids of compounds 8a, 8b, and 9 (8a', 8b', and 9' respectively)
in intramolecular cyclization reactions the Fukui indices f were calculated for these particles corresponding to
LUMO and HOMO  fLUMO and fHOMO
.
H
N
H
N
H
N
O
O
O
O
O
O
0.121
0.063
0.105
0.260
0.255
0.135
0.073
0.104
0.083
0.089
0.085
0.085 N
N
0.443
0.069
N
0.008
0.043
N
N
0.437
0.112
0.424
0.084
0.003
0.049
0.002 N
N
0.213
0.037
0.002
0.234
0.309
N
0.016
0.022
0.008
0.242
0.062
0.321
0.361
0.025
9
8b
8a
H
N
H
H
O
+
O
N
N
O
O
O
O
0.031
0.028
0.000
0.052
0.058
0.050
0.000
0.030
0.000
0.024
N
N
0.055
0.035
0.035
+
0.066
0.031
+
0.199 N
N
N
0.291 N
0.030
0.048
N
0.043
0.073
0.681
0.002
0.910
0.930
0.077
0.045
0.001
0.006
0.002
N
0.024
0.048
0.007
0.005
0.044
9'
8b'
8a'
Distribution of limiting electron density fLUMO in cations 8a', 8b', and 9'
H
N
H
H
O
N
O
N
O
O
O
O
0.003
0.012
0.055
0.000
0.000
+
0.0005
0.006
0.000
0.118
0.222 N
+
0.408
N
N
0.000
0.000
0.553
0.308
N
+
N
0.013
0.044
0.061
0.159
N
0.504
0.478
N
0.004
0.121
0.002
0.658
0.314
0.017
0.010
N
0.011
0.000
0.061
0.205
0.003
0.006
0.220
9'
8b'
8a'
Distribution of limiting electron density fHOMO in cations 8a', 8b', and 9'
The greatest values of fLUMO for the represented indoleninium cations are centered at position 2 of the
indole ring and the values of fHOMO were maximal at position 2 of the pyrrole ring for cation 9', at position 5 of
the imidazole fragment for cation 8a' and in position 4 of the pyrazole fragment for cation 8b'. In this way the
1226

favorable directions for cyclization are 2-2', 2-5', and 2-4' for cations 9', 8a', and 8b' respectively. It must be
noted that the cyclization of 8b' according to the 2-4' direction has a low probability due to the strong distortion
of valence angles in the prospective product.
The activation barriers ΔE# and heats ΔE for intramolecular cyclization of cations 8a', 8b', and 9' were
also calculated and analyzed (Scheme 3).
Scheme 3
H
H
N
N
O
O
O
O
–1
.
E = -13.94 kcal mol
#
–1
– H+
.
+
+
E = 9.62 kcal mol
N
N
N
N
H
N
O
9''
9'
O
N
N
10
H
H
N
O
N
–1
O
.
O
E = 13.57 kcal mol
O
#
–1
.
E = 16.02 kcal mol
+
+
N
N
N
N
N
N
8b''
8b'
H
N
H
O
O
N
O
O
–1
.
E = -8.65 kcal mol
#
–1
+
.
E = 14.47 kcal mol
N
N
+
N
N
N
N
8a''
8a'
H
H
N
O
O
N
O
O
–1
.
E = -4.43 kcal mol
+
#
–1
.
E = 15.59 kcal mol
N
+
N
N
N
N
N
8a'''
8a'
The calculations showed that ΔE# and ΔE for the intramolecular cyclization of the pyrrole system 9' are
lower than those of the 8a' and 8b' systems. A correlation was therefore established between the results of the
calculation of energy parameters and the results of the calculation of the electron density distribution in the
systems 8a', 8b', and 9' (Scheme 3).
The condensation product 8f on treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone gave
2-(indol-1-yl)-3-(pyrrol-1-yl)maleimide (9) (Scheme 4). Treatment of imide 9 with trifluoroacetic acid in
dichloromethane led to a derivative of pyrazine 10 with annelated pyrrole, maleimide, and indoline fragments,
1227

namely 7a,8-dihydro-1H-dipyrrolo[2',1':3,4;3",4":5,6]pyrazino[1,2-a]indole-1,3(2H)-dione (Scheme 4).
1
Conclusions on the structure of the product were made on the basis of analysis of the H NMR spectra and
double resonance spectra. In the spectrum of the product two one-proton doublets of doublets (3.28 and
3.74 ppm) were present, corresponding to the proton in position 3 of the indoline fragment, and also a one-
proton triplet (5.33 ppm) corresponding to the proton in position 2 of the indoline fragment. The one-proton
doublet (6.14), triplet (6.31), and multiplet (7.29 ppm) correspond to the protons in positions 3, 4, and 5 of the
pyrrole fragment. Attempts to oxidize the indoline fragment in compound 10 to indole with the help of MnO2 or
2,3-dichloro-5,6-dicyano-1,4-benzoquinone did not lead to the desired product (Scheme 4).
Scheme 4
H
H
O
N
O
N
N
O
O
H+
[O]
DDQ
N
8f
no reaction
N
N
PhMe
10
9
H+
H+
mixture
of oligomerization
products
no reaction
8b
8a
The pyrazole derivative 8b (Scheme 4) was unchanged by the action of CF3COOH in dichloromethane,
but on treatment with MsOH gave a mixture of oligomerization products (data of mass spectroscopy). The
imidazole derivative 8a was unchanged by the action of protic acids.
Scheme 5
H
H
N
O
N
H
O
O
N
[O]
O
Br
Et3N,
DMF
N
Br
Br
12
11
H
H
H
H
O
N
O
O
N
N
N
N
N
O
O
O
[O]
Br
N
N
N
Et3N,
DMF
16
14
13
H+
HNEt2
H+
H
O
N
H+
O
no reaction
N
N
15
1228

TABLE 1. Physicochemical Characteristics of the Obtained Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
N
8a
C15H10N4O2
C15H10N4O2
C18H11N5O2
C19H12N4O2
C18H14N4O2
C16H13N3O2
C18H14N4O2
C20H18N4O2
C22H20N4O3
C18H21N3O3
C12H9N3O2
C14H11N3O3
C16H11N3O2
C16H11N3O2
C8H7BrN2O2
C8H5BrN2O2
C12H11N3O2
C12H15N3O2
C12H9N3O2
64.78
64.74
64.79
64.74
65.72
65.65
69.62
69.51
67.88
67.91
68.79
68.81
67.96
67.91
69.39
69.35
68.09
68.03
66.09
66.04
63.47
63.43
62.40
62.45
69.34
69.31
69.39
69.31
39.59
39.53
39.92
39.86
3.57
3.62
3.68
3.62
3.30
3.37
3.58
3.68
4.49
4.43
4.72
4.69
4.42
4.43
5.29
5.24
5.22
5.19
6.55
6.47
4.02
3.99
4.14
4.12
3.95
4.00
4.03
4.00
2.94
2.90
2.03
2.09
20.23
20.13
20.19
20.13
21.20
21.27
17.15
17.06
17.64
17.60
15.09
15.05
17.61
17.60
16.13
16.17
14.38
14.42
12.89
12.84
18.41
18.49
15.68
15.61
15.18
15.15
15.09
15.15
11.49
11.53
11.67
11.62
233-235
70
75
83
74
80
69
77
75
76
73
80
68
85
62
70
72
75
92
76
148-149
199-200
245-246
214-215
209-210
180-181 (dec.)
189-190
221-222
110-112
185-186
221-222
225-226
229-230
163-164
135-136
219-220
187-188
143-144
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
9
10
12
13
14
15
16
62.90
62.87
61.82
61.79
63.46
63.43
4.80
4.84
6.50
6.48
4.02
3.99
18.32
18.33
17.97
18.01
18.51
18.49
2,3-Bis(pyrrol-1-yl)maleimide (16) and 2-diethylamino-3-(pyrrol-1-yl)maleimide (15), analogs of the
previously synthesized 2,3-bis(indol-1-yl)maleimide (1) and 2-diethylamino-3-(indol-1-yl)maleimide (2), were
obtained from pyrroline and 2,3-dibromomaleimide (11) by sequential replacement of bromine atoms and
aromatization (Scheme 5) with the aim of studying the possibility of obtaining cyclization products from them
analogous to compounds 3 and 4.
However, treatment of compounds 15 or 16 with trifluoroacetic acid did not lead to a cyclization product
similar to 3 or 4. On using stronger acids and more rigorous conditions (heating) resinification was observed.
EXPERIMENTAL
1
13
The H and C NMR spectra were recorded on a Varian VXR-400 (400 and 100 MHz respectively) in
DMSO-d6, internal standard was TMS. Melting points were determined on a Buchi SMP-20 instrument and are
given uncorrected. Analytical TLC was carried out on plates of silica gel F254 (Merck), column
1229

TABLE 2. 1H NMR Spectra of the Obtained Compounds
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
8a
8b
8c
8d
8e
6.80 (1H, dd, J = 8.3, J = 0.7); 6.84 (1H, d, J = 3.5); 6.95-7.04 (3H, m);
7.14 (1H, t, J = 7.5); 7.52 (1H, d, J = 3.5); 7.64 (1H, d, J = 7.7); 7.76 (1H, s);
11.71 (1H, s)
6.56 (1H, dd, J = 2.6, J = 1.7); 6.71 (1H, d, J = 8.4); 6.74 (1H, dd, J = 3.4, J = 0.9);
6.95 (1H, t, J = 7.8); 7.08 (1H, t, J = 7.8); 7.52 (1H, d, J = 3.5); 7.58 (1H, d, J = 7.8);
7.61 (1H, d, J = 1.8); 8.36 (1H, d, J = 3.5); 11.63 (1H, s)
6.25 (1H, d, J = 8.4); 6.65 (1H, t, J = 7.6); 6.85 (1H, d, J = 3.1); 6.97 (1H, t, J = 7.3);
7.39-7.43 (1H, m); 7.49-7.54 (3H, m); 7.71 (1H, d, J = 3.1); 8.09 (1H, d, J = 8.4);
11.94 (1H, s)
6.55 (1H, d, J = 8.1); 6.69 (1H, d, J = 7.9); 6.76 (1H, t, J = 7.4); 6.82 (1H, d, J = 3.4);
6.85 (1H, t, J = 7.5); 6.94 (1H, t, J = 7.4); 7.07 (1H, t, J = 7.6); 7.49 (1H, d, J = 7.9);
7.60 (1H, d, J = 8.0); 7.69 (1H, d, J = 3.4); 8.53 (1H, s); 11.80 (1H, s)
3.93 (2H, br. s); 6.48 (1H, d, J = 2.7); 6.65 (2H, d, J = 5.1); 6.99-7.07 (4H, m);
7.53 (1H, m); 8.22 (2H, d, J = 5.5); 8.43 (1H, t, J = 6.7); 10.77 (1H, s)
8f
4.58 (4H, s); 5.76 (2H, s); 6.58 (1H, d, J = 3.1); 7.09 (1H, t, J = 7.5); 7.16 (1H, t, J = 7.5);
7.30 (1H, d, J = 7.6); 7.34 (1H, d, J = 3.2); 7.59 (1H, d, J = 7.6); 10.71 (1H, s)
8g
4.82 (2H, s); 6.04 (2Н, d, J = 8.9); 6.34 (1Н, d, J = 3.3); 6.60 (2Н, d, J = 8.8); 6.82 (1Н, s);
6.89 (1Н, d, J = 3.3); 6.99 (1Н, t, J = 7.1); 7.03 (1Н, t, J = 8.1); 7.11 (1Н, d, J = 8.3);
7.41 (1Н, d, J = 6.0); 9.73 (1Н, s); 10.74 (1Н, s)
8h
8i
2.61 (6Н, s); 6.02 (2Н, d, J = 8.9); 6.32 (1Н, d, J = 3.3); 6.52 (2Н, d, J = 8.8); 6.79 (1Н, s);
6.87 (1Н, d, J = 3.3); 6.95 (1Н, t, J = 7.1); 7.01 (1Н, t, J = 8.1); 7.11 (1Н, d, J = 8.3);
7.41 (1Н, d, J = 6.0); 9.65 (1Н, s); 10.54 (1Н, s)
2.77 (4Н, t, J = 4.7); 3.6 (4H, t, J = 4.7); 6.23 (2H, d, J = 8.7); 6.37 (1H, d, J = 3.3);
6.52 (2H, d, J = 8.8); 6.91-7.00 (3H, m); 7.07 (1Н, d, J = 8.1); 7.40 (1Н, d, J = 8.1);
9.59 (1Н, s); 10.84 (1Н, s)
8j
0.63-0.73 (2H, m); 0.79-0.87 (2Н, m); 1.04-1.18 (4Н, m); 2.55 (2Н, m); 3.20-3.24 (2Н, m);
4.29 (1H, t, J = 5.2); 6.59 (1H, d, J = 3.1); 7.08 (1H, t, J = 7.4); 7.15 (1H, t, J = 7.4);
7.24 (1H, d, J = 7.9); 7.31 (1H, d, J = 3.2); 7.59 (1H, d, J = 7.8); 7.90 (1H, t, J = 6.3);
10.64 (1H, s)
8k
8l
9
6.62 (1H, d, J = 3.3); 7.07-7.14 (2H, m); 7.17 (2H, m); 7.28 (1H, d, J = 3.3); 7.36 (2H, s);
7.62 (1H, d, J = 7.9); 10.55 (1H, s)
2.46 (3H, s); 6.66 (1H, d, J = 3.3); 7.12 (1H, t, J = 7.25); 7.18 (1H, t, J = 7.28);
7.26 (1H, d, J = 7.1); 7.29 (1H, d, J = 3.2); 7.63 (1H, d, J = 7.5); 7.78 (2H, s)
6.19 (2H, t, J = 2.3); 6.80 (1H, d, J = 3.3); 6.83 (2H, t, J = 2.2); 6.97 (1H, d, J = 8.1);
7.04 (1H, t, J = 7.1); 7.13 (1H, t, J = 7.2); 7.47 (1H, d, J = 3.3); 7.64 (1H, d, J = 7.7);
11.53 (1H, s)
10
3.28 (1H, dd, J = 15.7, J = 9.7); 3.74 (1H, dd, J = 15.7, J = 9.5); 5.33 (1H, t, J = 9.6);
6.14 (1H, d, J = 3.3); 6.31 (1H, t, J = 3.1); 6.92 (1H, t, J = 7.3); 7.14 (1H, t, J = 7.3);
7.21 (1H, d, J = 7.3); 7.29 (1H, m); 7.93 (1H, d, J = 7.3); 10.7 (1H, s)
12
13
14
15
4.66 (4H, s); 5.95 (2H, s); 10.78 (1H, s)
6.39 (2H, s); 7.62 (2H, s); 11.56 (1H, s)
4.16 (4H, s); 5.86 (2H, s); 6.11 (2H, t, J = 2.0); 6.78 (2H, t, J = 2.1); 10.60 (1H, s)
1.01 (6H, t, J = 7.0); 3.28 (4H, q, J = 7.0); 6.13 (2H, t, J = 2.0); 6.74 (2H, t, J = 2.0);
10.61 (1H, s)
16
6.32 (4H, t, J = 2.2); 6.87 (4H, t, J = 2.2); 11.43 (1H, s)
chromatography on silica gel Merck 60. Extracts were dried over anhydrous Na2SO4 and were evaporated under
reduced pressure. Commercial reagents (Acros, Fluka) and solvents (Khimmed) were used. Elemental analysis
was carried out in the analytical laboratory of the Center for Drug Chemistry of the All-Russia Research
Institute of Pharmaceutical Chemistry.
Synthesis of 2-Substituted 3-(Indol-1-yl)maleimides 8a-j (General Method). The appropriate
nucleophile (1.2 equiv.) and Et(2-Pr)2N (1.2 equiv.) were added to a solution of 2-bromo-3-(indol-
1-yl)maleimide (7) (290 mg, 1 mmol) in DMF (10 ml), the reaction mixture was stirred at 60oC, checking the
1230

progress of the reaction by TLC (eluent n-hexane–ethyl acetate, 1:1), until complete conversion of the initial
imide 7. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 ml), washed with
0.1 N HCl (2×20 ml), with saturated NaHCO3 solution (10 ml), dried and evaporated. The residue was
recrystallized from 2-PrOH.
2-Amino-3-(indol-1-yl)maleimide (8k). A solution of compound 7 (100 mg, 0.34 mmol) in saturated
ammonia in methanol solution (5 ml) was stirred at room temperature until complete disappearance of the initial
compound 7 (3-4 h). The reaction mixture was filtered and evaporated. The residue was dissolved in ethyl
acetate (10 ml) and washed with 0.1 N HCl (2×3 ml), with saturated NaHCO3 solution (5 ml), dried, and
evaporated. The residue was recrystallized from 2-PrOH. Compound 8k (63 mg, 0.28 mmol) was obtained as a
yellow solid (yield 80%).
N-Acetyl-2-amino-3-(indol-1-yl)- maleimide (8l). A solution of imide 8k (30 mg, 0.13 mmol) in acetic
anhydride (3 ml) was heated at 70oC for 2 h. The mixture was cooled to ~20oC and poured into saturated
NaHCO3 solution (50 ml). After decomposition of the excess of acetic anhydride, the reaction product was
extracted with ethyl acetate (2×10 ml), the organic extracts were dried and evaporated. The residue was
recrystallized from 2-PrOH. Compound 8l (24 mg, 0.09 mmol) was obtained as a yellow solid (yield 68%).
2-(Indol-1-yl)-3-(pyrrol-1-yl)maleimide (9). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (200 mg,
0.88 mmol) was added to a solution of compound 8f (200 mg, 0.72 mmol) in toluene (50 ml). The reaction
mixture was stirred while boiling for 2 h, cooled to room temperature, washed with a saturated solution of
NaHSO3 (2×10 ml), with a saturated solution of NaHCO3 (4×5 ml), dried, and evaporated. The residue was
recrystallized from 2-PrOH. Product 9 (179 mg, 0.61 mmol) was obtained as a dark-red solid (yield 85%).
7a,8-Dihydro-1H-dipyrrolo[2',1':3,4;3",4":5,6]pyrazino[1,2-a]indole-1,3(2H)-dione (10). Trifluoro-
acetic acid (2 ml) was added to a solution of imide 9 (100 mg, 0.36 mmol) in CH2Cl2 (20 ml). The reaction
mixture was stirred for 2 h at room temperature, and then evaporated. The residue was dissoloved in ethyl
acetate (10 ml), and the solution washed with saturated NaHCO3 solution (2×5 ml), then dried, and evaporated.
The solid was recrystallized from toluene. Product 10 (62 mg, 0.22 mmol) was obtained as a dark-red solid
(yield 62%).
2-Bromo-3-(2,5-dihydropyrrol-1-yl)maleimide (12). Pyrroline (300 mg, 4.3 mmol) and triethylamine
(430 mg, 4.3 mmol) were added to a solution of 3,4-dibromomaleimide (1 g, 3.9 mmol) in DMF (20 ml). The
reaction mixture was stirred for 3 h at room temperature, then diluted with ethyl acetate (150 ml). The mixture
was washed with saturated citric acid solution (2×20 ml), with saturated NaHCO3 solution (2×30 ml), dried, and
evaporated. The residue was recrystallized from 2-PrOH. Imide 12 (663 mg, 2.7 mmol) was obtained as a
yellow solid (yield 70%).
2-Bromo-3-(pyrrol-1-yl)maleimide (13). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (530 mg,
2.3 mmol) was added to a solution of compound 12 (500 mg, 2.1 mmol) in toluene (50 ml). The reaction mixture
was stirred while boiling for 2 h, cooled to room temperature, washed with saturated NaHSO3 solution
(2×10 ml), with saturated NaHCO3 solution (4×10 ml), dried, and evaporated. The residue was recrystallized
from 2-PrOH. Imide 13 (363 mg, 1.51 mmol) was obtained as a yellow solid (yield 72%).
2-(2,5-Dihydropyrrol-1-yl)-3-(pyrrol-1-yl)maleimide (14). Pyrroline (112 mg, 1.6 mmol) and
triethylamine (160 mg, 1.6 mmol) were added to a solution of imide 13 (300 mg, 1.3 mmol) in DMF (10 ml). The
reaction mixture was stirred for 3 h at room temperature, diluted with ethyl acetate (100 ml), washed with saturated
citric acid solution (2×20 ml), with saturated NaHCO3 solution (2×30 ml), dried, and evaporated. The residue was
recrystallized from 2-PrOH. Compound 14 (223 mg, 0.98 mmol) was obtained as a yellow solid (yield 75%).
2-Diethylamino-3-(pyrrol-1-yl)maleimide (15). Diethylamine (220 mg, 3 mmol) was added to a
solution of imide 13 (300 mg, 1.3 mmol) in DMF (10 ml). The reaction mixture was stirred for 3 h at room
temperature, diluted with ethyl acetate (100 ml), washed with saturated citric acid solution (2×20 ml), with
saturated NaHCO3 solution (2×30 ml), dried, and evaporated. The residue was recrystallized from 2-PrOH.
Imide 15 (280 mg, 1.2 mmol) was obtained as a yellow solid (yield 92%).
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2,3-Bis(pyrrol-1-yl)maleimide (16). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (220 mg, 0.97 mmol)
was added to a solution of compound 14 (200 mg, 0.87 mmol) in toluene (50 ml). The reaction mixture was stirred
while boiling for 2 h, cooled to room temperature, washed with a saturated solution of NaHSO3 (2×10 ml), with
saturated NaHCO3 solution (4×10 ml), dried, and evaporated. The residue was recrystallized from 2-PrOH.
Compound 16 (150 mg, 0.66 mmol) was obtained as a yellow solid (yield 76%).
The work was supported by the Federal Agency for Science and Innovation (State Contract
02.512.12.2035 from May 12, 2009), and also by Grant NSh-5290-2010.4.
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