Introduction of pharmacophore groups into bis(indol-1-yl)maleimides and 6H-pyrrolo[3,4: 2,3][1,4]diazepino[6,7,1-hi]-indolo-8,10(7H,9H)-diones

Article abstract of DOI:10.1007/s11094-006-0147-y

The synthesis of bis(indol-1-yl)maleimides and polycondensed [1,4]diazepines containing various functional groups, which are the analogs of biologically active indolo[2,3-a]carbazoles, is described. Functional groups were introduced directly into [1,4]dia

Full text of DOI:10.1007/s11094-006-0147-y

Pharmaceutical Chemistry Journal
Vol. 40, No. 8, 2006
INTRODUCTION OF PHARMACOPHORE GROUPS
INTO BIS(INDOL-1-YL)MALEIMIDES
AND 6H-PYRROLO[3,4:2,3][1,4]DIAZEPINO[6,7,1-hi]-
INDOLO-8,10(7H,9H)-DIONES
S. A. Lakatosh,1 A. Yu. Simonov,1 Yu. N. Luzikov,1
and M. N. Preobrazhenskaya1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 8, pp. 29 – 34, August, 2006.
Original article submitted April 5, 2005.
The synthesis of bis(indol-1-yl)maleimides and polycondensed [1,4]diazepines containing various functional
groups, which are the analogs of biologically active indolo[2,3-à]carbazoles, is described. Functional groups
were introduced directly into [1,4]diazepine and bis(indol-1-yl)maleimide molecules via electrophilic substi-
tution reactions using precursors containing such functional groups.
R
Previously, we described the synthesis of bis(indol-1-
N
yl)maleimides (I) capable of forming, [1,4]diazepines (II)
containing annelated indole, indoline, and maleimide rings
under the action of protonic acids [1]. Diazepines II are
readily dehydrated with the formation of 6H-pyrrolo-
[3,4:2,3][1,4]diazepino[6,7,1-hi]indolo-8,10(7H,9H)-diones
(III). Maleimides I are the isomers of bis(indol-3-yl)-
maleimides (IV), some of which exhibit high biological ac-
tivity (protein kinase C and/or topoisomerase I inhibition).
Diones III are the analogs of indolo[2, 3-a]carbazoles (V),
which are used as initial compounds for the synthesis of vari-
ous biologically active substances.
O
O
N
H
N
H
V
The aim of this study was to develop methods for the in-
troduction of various pharmacophore groups or their precur-
sors into bis(indol-1-yl)maleimides I and [1,4]indolodiazepi-
nes II and III.
R
R
2
Introduction of Pharmacophore Groups into Initial
Compounds for the Synthesis of Bis(indol-1-yl)maleimides
and Polycondensed [1,4]Diazepines Containing
Pharmacophore Moieties
1
N
N
O
3
O
O
O
14
13
15
4
12
5
N
N
N
N
11
9a
6
9b
10
(2,3-Dihydroindol-3-yl)acetic acid methyl ester (VII) [2]
was obtained via the reduction of (indol-3-yl)acetic acid
I
II
9
7
R
8
R
methyl ester (VI) under the action of NaBH CN in glacial
2
3
1
N
O
3
O
N
acetic acid (yield, 70%):
O
O
14
13
15
4
12
5
N
O
N
O
11
9a
6
9b
O
O
10
NaBH3CN
AcOH
N
H
N
H
9
7
III
IV
8
N
H
N
H
1
Gauze Institute of New Antibiotics, Russian Academy of Medical Sci-
ences, Moscow, 119021 Russia.
VI
VII
435
0091-150X/06/4008-0435 © 2006 Springer Science+Business Media, Inc.

436
S. A. Lakatosh et al.
The subsequent condensation of ester VII with 1-ben-
pines containing two indoline fragments and a maleimide cy-
cle (compounds XVI and XVII, respectively).
zyl-3,4-dibromomaleimide (VIII) in DMF in the presence of
CH2Ph
CH2Ph
Et N led to the formation of methyl ester IX (yield, 72%).
3
O
N
O
N
N
N
Then, dehydration of the indoline moiety of ester IX by
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDBQ) in tolu-
ene led to compound X (yield, 70%), and the reaction of
CF3COOH
CH2Cl2
O
O
N
N
compound X with indoline in DMF in the presence of Et N
3
yielded methyl ester XI (yield, 70%):
O
CH2Ph
CH2Ph
O
O
N
O
O
O
N
O
XI
VII, Et3N
DMF
DDBQ
PhCH3
O
XVI
CH2Ph
O
N
Br
Br
Br
N
N
CH2Ph
N
VIII
O
CF3COOH
O
O
CH2Cl2
O
N
IX
O
N
N
O
CH2Ph
O
CH2Ph
O
N
N
O
Indoline,
Et3N
N
O
O
O
O
DMF
Br
N
XVII
XIV
N
R
2
O
1
N
O
3
O
O
14
13
O
15
4
12
O
X
XI
5
N
N
11
9a
6
9b
10
The interaction of 1-benzyl-3-bromo-4-(indol-1-yl)male-
9
imide (XIII) with ester VII in DMF in the presence of Et N
7
3
8
led to methyl ester XIV (yield, 70%), which is an isomer of
ester XI. Then, fully aromatized bisindole derivative XV was
obtained via dehydration of ester XI or XIV under the action
of DDBQ in boiling toluene (yield, 70%).
Compounds XVI and XVII contain two asymmetric at-
oms: C10, C9b (XVI) and C6, C9b (XVII). It is interesting to
1
note that the H NMR spectrum of compound XII displays
two sets of signals (which is characteristic of a mixture of
two racemic isomers), whereas the spectrum of compound
XVI exhibits only one set of signals, which implies that the
latter compound represents a single diastereomer. Protona-
tion of the indole fragment of compound XI at position 3
leads to the formation of an indolinium ring with an asym-
metric center at position 3. Closing of the seven-member cy-
cle leads to the formation of the second indoline ring with the
second asymmetric atom. It is naturally assumed that the for-
mation of a trans product is preferred.
CH2Ph
CH2Ph
O
O
N
N
Indoline,
Et3N
VII, Et3N
DMF
DDBQ
PhCH3
O
O
VIII
DMF
Br
Br
N
N
XII
XIII
CH2Ph
O
N
O
N
CH2Ph
N
O
N
MeO2CH2C
N
MeO2CH2C
*
O
H
O
O
+
H+
O
N
H
N
N
XI
H
XIV
N
N
R
O
R
DDBQ
PhCH3
··
N
+
N
XI or XIV
O
O
O
O
XV
XVI
H+
Isomers XI and XIV exhibited cyclization in the presen-
ce of CF COOH in CH Cl with the formation of [1,4]diaze-
3
2
2

Introduction of Pharmacophore Groups
437
CH3
N
O
NCH2Ph
O
N
O
O
N
+
DDBQ 2.2 eq
PhCH3
XVI
N
CHO
N
O
CHO
XXII
XVIII
O
The formylation of compound II under analogous condi-
tions led to compound XXIII (yield, 70%).
CH2Ph
N
O
O
CH3
DDBQ
1.1 or 2.2 eq
N
O
O
O
XVII
N
N
PhCH3
POCl3
O
N
N
DMF,
90°Ñ,
1 h
XIX
DDBQ
PhCH3
II
CH2Ph
N
CH3
N
O
O
O
O
O
N
N
O
N
N
XX
COH
XXIII
Dehydration of diindolinodiazepine XVI with DDBQ
(2.2 eq.) in boiling toluene yields diindolodiazepine XVIII,
while dehydration of diindolinodiazepine XVII (isomeric to
XVI) leads to indoloindolinodiazepine XIX. Even in the
presence of excess DDBQ, dehydration of the second
indoine fragment with the formation of diazepine XX was
not observed even upon 6-h boiling in toluene.
EXPERIMENTAL CHEMICAL PART
The NMR spectra were measured using a Varian
VXR-400 spectrometer operating at a working frequency of
400 MHz (1H NMR) and 100.6 MHz (13C NMR), using
DMSO-d , CDCl , and (CD ) CO as solvents; the chemical
6
3
3 2
shifts were determined relative to the solvent signals (inter-
nal standard). Analytical TLC was performed on Kieselgel
(Merck, Germany) plates, and column chromatography,
Introduction of Pharmacophore Groups or Their Precursors
into Existing Polycondensed Systems
F
294
An alternative approach to the synthesis of bis(indol-1-
yl)maleimides and [1,4]diazepines with annelated indole and
maleimide rings is based on the introduction of pharmaco-
phore groups or their precursors into polycondensed systems.
We have used bis(indol-1-yl)maleimide (I) and [1,4]diazepi-
on Kieselgel 60 silica gel. The melting points were deter-
mined using a Buchi SMP-20 device without corrections.
The high-resolution mass spectra were obtained using a
Finnigan MAT Model 8430 spectrometer equipped with a
system of direct sample introduction (electron impact energy,
70 eV; ion source temperature, 250°C) and with a com-
puter-controlled SS-300 data acquisition and processing sys-
tem. The survey electron-impact mass spectra were recorded
on a Finnigan SAQ Model 710 spectrometer (70 eV; 150°C).
The organic extracts were dried over anhydrous Na SO
nes II and III (R = CH ).
3
The formylation of compound I in DMF in the presence
of POCl led to the formation of a mixture of mono- and
3
dialdehydes (XXI + XXII), which was separated into compo-
nents by chromatography with a yield of 70% (XXI) and
12% (XXII).
2
4
and evaporated in vacuum. The initial 3,4-dibromomalei-
mide VIII was obtained using a classical method [3], 1-me-
thyl- and 1-benzyl-3,4-dibromomaleimides were obtained as
described previously [1].
CH3
CH3
O
O
N
N
N
POCl3
O
O
+
DMF,
90°Ñ,
3 h
1-[4-Bromo-2, 5-dioxo-1H-pyrrol-3-yl]-(1H-2,3-di-
hydroindol-3-yl)acetic acid methyl ester (IX). To a solu-
tion of 2 g (10.5 mmole) of 2,3-dihydroindol-3-yl)acetic acid
methyl ester (VII) and 2.29 g (8 mmole) of 1-benzyl-3,4-di-
bromomaleimide (VIII) in 5 ml DMF was added 2 ml
N
N
CHO
N
XXI
I

438
S. A. Lakatosh et al.
(14.2 mmole) of Et N. The mixture was stirred for 12 h at
with a yield of 0.26 g (70%); m.p., 63 – 65°C; R , 0.40
3
f
room temperature, diluted with 50 ml of EtOAc, washed se-
(n-heptane – EtOAc, 3 : 1).
1H NMR spectrum in DMSO-d (d, ppm): 3.06 (2H, t,
quentially with 1 – 2 M aqueous HCl solution (2 ´ 50 ml),
6
J 7.87 Hz), 3.61 (3H, s), 3.77 (2H, s), 4.23 (2H, t, J 7.87 Hz),
4.72 (2H, s), 6.10 (1H, d, J 7.86 Hz), 6.48 (1H, t, J 7.76 Hz),
6.64 (1H, t, J 7.41 Hz), 6.91 – 7.03 (3H, m), 7.18 (1H, d,
J 7.38 Hz), 7.29 (1H, m), 7.36 – 7.42 (6H, m);
aqueous NaHCO solution (2 ´ 50 ml), and saturated NaCl
3
solution (50 ml), dried in air, and evaporated to obtain an
orange-red oil residue, which was recrystallized from ethanol
to yield 2.58 g (72%) of compound IX; m.p., 62 – 63°C; R ,
f
13C NMR spectrum in DMSO-d (d, ppm): 28.8, 30.2,
0.15 (n-heptane–EtOAc, 1 : 6).
6
1H NMR spectrum in DMSO-d (d, ppm): 2.67 (dd, 1H,
40.8, 51.6, 52.6, 107.2, 110.4, 111.0, 112.2, 118.7, 120.0,
122.1, 122.6, 124.2, 126.0, 127.0, 127.2, 127.4, 127.5, 128.5,
131.9, 132.9, 136.8, 136.9, 142.3, 165.9 (C = O), 167.2
(C = O), 171.5 (COOMe);
6
J 9.03 Hz, 16.6 Hz), 2.86 (dd, 1H, J 5.19 Hz, 18.84 Hz),
3.69 – 3.76 (m, 1H), 4.09 (dd, 1H, J 6.35 Hz, 10.99 Hz), 4.50
(dd, 1H, J 8.55 Hz, 10.80 Hz), 4.64 (s, 2H), 6.99 (t, 2H,
J 7.82 Hz), 7.18 (t, 2H, J 7.76 Hz), 7.26 – 7.36 (m, 5H);
Mass spectrum, m/z (I , %): 491 (100), 344 (80).
rel
13C NMR spectrum in DMSO-d (d, ppm): 37.2, 37.3,
[1-(Benzyl-4-indol-1-yl)-2, 5-dioxo-2, 3-dihydro-1H-
pyrrol-3-yl]-(1H-indol-3-yl)acetic acid methyl ester (XV).
To a solution of 50 mg (0.1 mmole) of compound XI, in
10 ml toluene was added 45 mg (0.2 mmole) of DDBQ and
the mixture was boiled with reflux for 1 h, cooled to room
temperature, and poured into 50 ml of saturated aqueous
6
41.3, 51.5, 59.2, 89.5, 116.2, 123.1, 124.0, 126.7, 127.3,
127.4, 128.4, 134.9, 136.6, 141.8, 141.7, 165.3, (C = O),
116.1 (C = O), 171.9 (COOMe);
Mass spectrum, m/z (I , %): 456 (100), 380 (60).
rel
1-[4-Bromo-2,5-dioxo-1-benzyl-1H-pyrrol-3-yl]-(1H-
indol-3-yl)acetic acid methyl ester (X). To a solution of
2.58 g (5.8 mmole) of compound IX in 50 ml toluene was
added 1.52 g (6.70 mmole) of DDBQ and the mixture was
boiled with reflux for 1 h, cooled to room temperature, and
NaHCO solution. The mixture was stirred for 20 min and al-
3
lowed to stand until phase separation. The organic layer was
separated, and the aqueous phase was repeatedly extracted
with EtOAc (2 ´ 10 ml). The organic phases were combined
poured into 200 ml of saturated aqueous NaHCO solution.
3
and washed sequentially with saturated aqueous NaHCO so-
3
The mixture was stirred for 20 min and allowed to stand until
phase separation. The organic layer was separated, and the
aqueous phase was repeatedly extracted with 50 ml EtOAc.
The organic phases were combined and washed sequentially
lution (2 ´ 15 ml) and saturated NaCl solution (10 ml), dried
in air, and evaporated. The residue was purified by chroma-
tography on
a silica gel column eluted with an
n-heptane – EtOAc (4.5 : 1) mixture. Compound X was ob-
with saturated aqueous NaHCO solution (2 ´ 50 ml) and
3
tained in the form of an orange-red oil with a yield of 35 mg
saturated NaCl solution (50 ml), dried in air, and evaporated
to obtain compound X in the form of an orange oil of with a
(70%); R , 0.39 (n-heptane – EtOAc, 3 : 1).
f
1H NMR spectrum in DMSO-d (d, ppm): 3.65 (s, 3H),
6
yield of 1.85 g (72%); m.p., 63 – 64 g; R , 0.13 (n-heptane –
f
3.87 (s, 2H), 4.83 (s, 2H), 6.55 (d, 1H, J 8.24 Hz), 6.62 (d,
1H, J 8.42 Hz), 6.69 – 6.74 (m, 2H), 6.77 (d, 1H, J 3.48 Hz),
6.91 (tt, 2H, J 7.04), 7.32 (d, 1H, J 7.33 Hz), 7.37 – 7.41 (m,
3H), 7.46 (d, 1H, J 3.48 Hz), 7.68 (s, 1H);
EtOAc, 6 : 1).
1H NMR spectrum in DMSO-d (d, ppm): 67 (s, 3H),
6
3.89 (s, 2H), 4.77 (s, 2H), 7.25 (t, 1H, J 7.50 Hz), 7.28 – 7.32
(m, 2H), 7.35-7.42 (m, 5H, Ph), 7.49 (d, 1H, J 7.87 Hz), 7.58
(s, 1H, indole H2), 7.62 (d, 1H, J 7.63 Hz);
13C NMR spectrum in DMSO-d (d, ppm): 30.1, 41.4,
6
51.8, 106.7, 111.0, 111.1, 113.1, 119.2, 120.7, 121.4, 121.5,
122.7, 122.8, 126.4, 127.6, 127.7 (2C), 128.0, 128.1, 128.2,
128.6 (2C), 135.1, 135.2, 136.4, 166.4 (2C, C=O), 171.3
(COOMe);
13C NMR spectrum in DMSO-d (d, ppm): 29.9, 41.8,
6
51.6, 111.1, 113.0, 114.0, 119.2, 121.7, 122.8, 126.4, 127.4,
127.4 (2C), 128.7, 134.3, 136.0, 138.3, 164.9 (C=O), 165.3
(C=O), 171.0 (COOMe);
High-resolution mass spectrum, m/z (I , %): anal. calcd.
rel
Mass spectrum, m/z (I , %): 454 (83), 395 (100).
rel
for C H N O , 489.1688; found, 489.1689 [M]+ (100), 430
30 23
3
4
1-[4-(2, 3-Dihydro-1H-indol-1-yl)-2.5-dihydro-2, 5-di
(45) [M+–COOMe], 416 (20) [M+–CH COOMe], 338 (10)
oxo-1-benzyl-1H-pyrrol-3-yl]-(1H-indol-3-yl)acetic
acid
2
[M+–COOMe–C H ].
methyl ester (XI). To a solution of 0.36 g (8.1 mmole) of
7
7
1-[2, 5-Dihydro-4-(1H-indol-1-yl)-2.5-dioxo-1-benzyl-
1H-pyrrol-3-yl]-2,3-dihydro-(1H-indol-3-yl)acetic acid
methyl ester X and 0.2 ml (0.9 mmole) of indoline in 10 ml
DMF was added 0.2 ml (1.4 mmole) of Et N. The mixture
3
methyl ester (XIV). To a solution of 0.33 g (1 mmole) of
was stirred for 24 h at room temperature, diluted with 30 ml
of EtOAc, washed sequentially with 1 – 2 M aqueous HCl
compound XIII and 0.23 ml (1.2 mmole) of compound VII
in 5 ml DMF was added 0.2 ml (1.4 mmole) of Et N. The
solution (2 ´ 30 ml), saturated aqueous NaHCO solution
3
3
mixture was stirred for 24 h at room temperature, diluted
with 50 ml of EtOAc, washed sequentially with 1 – 2 M
aqueous HCl solution (2 ´ 20 ml), saturated aqueous
(20 ml), and saturated NaCl solution (20 ml), dried in air, and
evaporated. The residue was purified by chromatography on
a silica gel column eluted with an n-heptane – (CH ) CO
3 2
NaHCO solution (2 ´ 20 ml), and saturated NaCl solution
(10 : 1) mixture. Upon recrystallization, compound XI was
obtained in the form of an orange-red crystalline powder
3
(20 ml), dried in air, and evaporated to obtain compound

Introduction of Pharmacophore Groups
439
XIV in the form of an orange-red oil with a yield of 0.3 g
pound XVII was obtained in the form of a dark violet oil
(70%); R , 0.41 (n-heptane – EtOAc, 3 : 1).
with a yield of 250 mg (80%); R , 0.48 (n-heptane – EtOAc,
f
f
1H NMR spectrum in DMSO-d (d, ppm): 2.72 (dd, 1H,
3 : 1). The NMR spectrum exhibit two sets of signals, which
corresponds to a mixture of two diastereomers.
6
J 9.34 Hz, 16.84 Hz), 2.85 (dd, 1H, J 5.30 Hz, 16.66 Hz),
3.68 (s, 3H), 3.73 (m, 1H), 4.14 (dd, 1H, J 5.96 Hz, 11.25
Hz), 4.59 (dd, 1H, J 9.20 Hz, 11.16 Hz), 4.74 (s, 2H), 5.93 (d,
1H, J 6.06 Hz), 6.46 (t, 1H, J 7.73 Hz), 6.61 (d, 1H, J 3.35
Hz), 6.65 (t, 1H, J 7.41 Hz), 6.95 – 6.99 (m, 2H), 7.06 (d, 1H,
J 7.33 Hz), 7.26 (d, 1H, J 7.42 Hz), 7.31 (d, 1H, J 6.81 Hz),
7.36 – 7.43 (m, 5H), 7.47 (d, 1H, J 6.15 Hz);
High-resolution mass spectrum, m/z (I , %): anal. calcd.
rel
for C H N O , 491.1845; found, 491.1836 [M]+ (100), 432
30 25
3
4
(5)[M+-COOMe], 418 (20)[M+- CH COOMe].
2
(2-Benzyl-1,3-dioxy-2,3-dihydro-1H-indolo[1¢,7¢:4,5,6]-
pyrrolo[3¢,4¢:2,3][1,4]diazepino[1,7-a]indol-10-yl)acetic
acid methyl ester (XVIII). A solution of 200 mg
(0.4 mmole) of compound XVI and 180 mg (0.8 mmole)
DDBQ in 30 ml of toluene was boiled for 3 h, cooled to
room temperature, poured into 50 ml of saturated aqueous
13C NMR spectrum in DMSO-d (d, ppm): 37.1, 37.7,
6
40.9, 51.5, 104.3, 107.4, 111.3, 111.9, 120.27, 120.33, 121.9,
122.7, 123.7, 126.6, 127.4 (2C), 127.6 (2C), 128.5 (2C),
128.6, 132.4, 134.1, 136.5, 136.8, 142.1, 166.2 (C = O),
167.2 (C = O), 171.9 (COOMe);
NaHCO solution, stirred for 20 min, and allowed to stand
3
until phase separation. The organic layer was separated, and
the aqueous phase was repeatedly extracted with EtOAc
(30 ml). The organic phases were combined and washed se-
Mass spectrum, m/z (I , %): 491 (100), 344 (50).
rel
(2-Benzyl-1,3-dioxo-2,3,5,6,9b,10-hexahydro-1H-indo-
lo[1¢,7¢:4,5,6]pyrrolo[3¢,4¢:2,3][1,4]diazepino[1,7-a]-indol-
10-yl)acetic acid methyl ester (XVI). To a solution of
165 mg (0.37 mmole) of compound XI in 20 ml of CH Cl
quentially with saturated aqueous NaHCO solution
3
(2 ´ 50 ml) and saturated NaCl solution (50 ml), dried in air,
and evaporated. The residue was purified by chromatography
on a silica gel column eluted with an n-heptane – EtOAc
(4.5 : 1) mixture. Compound XVIII was obtained in the form
2
2
was added 0.33 ml (3.7 mmole) of CF COOH and the reac-
3
tion mixture was stirred at room temperature for three days
and poured into 50 ml of EtOAc. This mixture was washed
of an orange-red oil with a yield of 150 mg (75%); R , 0.36
f
sequentially with saturated aqueous NaHCO solution
3
(n-heptane – EtOAc, 3 : 1).
(2 ´ 20 ml) and saturated NaCl solution (20 ml), dried in air,
and evaporated. The residue was purified by chromatography
on a silica gel column eluted with an n-heptane – EtOAc
(6 : 1) mixture. Compound XVI was obtained in the form of
1H NMR spectrum in DMSO-d (d, ppm): 3.67 (s, 3H),
6
3.91 (s, 2H), 4.73 (s, 2H), 6.83 (d, 1H, J 3.6 Hz), 7.17 (t, 1H,
J 7.83 Hz), 7.24 (t, 1H, J 8.04 Hz), 7.28 – 7.32 (m, 2H),
7.33 – 7.41 (m, 5H), 7.49 (d, 1H, J 8.28 Hz), 7.57 – 7.61 (m,
2H), 8.08 (d, 1H, J 3.57 Hz);
a dark violet oil with a yield of 100 mg (60%); R , 0.53
f
(n-heptane – EtOAc, 3 : 1).
13C NMR spectrum in DMSO-d (d, ppm): 31.0, 41.2,
1H NMR spectrum in DMSO-d (d, ppm): 2.71 (m, 2H),
6
6
52.2, 108.6, 113.9, 114.1, 116.6, 118.0, 119.1, 121.4, 121.9,
123.1, 123.2, 124.2, 127.35 (2C), 127.4, 128.4, 128.5 (2C),
130.7, 130.8, 132.8, 136.1, 136.5, 136.8, 164.1 (C=O), 165.7
(C=O), 171.2 (COOMe);
3.07 – 3.17 (m, 2H), 3.60 (s, 3H), 4.26 – 4.34 (m, 2H),
4.58 – 4.69 (m, 4H), 6.51(t, 1H, J 7.69 Hz), 6.68 (t, 1H,
J 7.37 Hz), 6.88 (t, 1H, J 7.69 Hz), 7.02 (t, 1H, J 7.54 Hz),
7.18 – 7.23 (m, 2H), 7.30 (d, 1H, J 8.10 Hz), 7.34 – 7.39 (m,
5H);
High-resolution mass spectrum, m/z (I , %): anal. calcd.
rel
for C H N O , 487.1532; found, 491.1539 [M]+ (100), 428
13C NMR spectrum in DMSO-d (d, ppm): 27.7, 38.5,
30 21
3
4
(50) [M+–COOHMe], 369 (10) [M+–C H ].
6
7
7
40.4, 50.5, 51.5, 68.3, 109.1, 112.2 (p), 118.7, 121.5, 124.58,
124.6, 124.8, 127.3, 127.4, 127.8, 127.9, 128.6, 129.3, 129.5,
133.4, 137.2, 143.5, 144.6, 164.8 (C=O), 165.7 (C=O), 171.7
(COOMe);
(2-Benzyl-1,3-dioxy-2,3-dihydro-1H-indolo[1¢,7¢:4,5,6]-
pyrrolo[3¢,4¢:2,3][1,4]diazepino[1,7-a]indol-6-yl)acetic
acid methyl ester (XIX) was obtained from compound XVII
using a procedure analogous to that described above for
compound XVIII. After purification on a silica gel column in
an n-heptane – EtOAc (4.5 : 1) mixture, compound XIX was
obtained in the form of an orange-red oil with a yield of
High-resolution mass spectrum, m/z (I , %): anal. calcd.
rel
for C H N O , 491.1845; found, 491.1839 [M]+ (100), 432
30 25
3
4
(5) [M+–COOMe], 418 (20) [M+–CH COOMe].
2
(2-Benzyl-1,3-dioxo-2,3,5,6,9b,10-hexahydro-1H-indo-
lo[1¢,7¢:4,5,6]pyrrolo[3¢,4¢:2,3][1,4]diazepino[1,7-a]indol-
6-yl)acetic acid methyl ester (XVII).To a solution of
265 mg (0.59 mmole) of compound XIV, in 30 ml of CH Cl
75 mg (75%); R , 0.64 (n-heptane – EtOAc, 6 : 1).
f
1H NMR spectrum in DMSO-d (d, ppm): 2.65 (dd, 1H,
6
J 9.28 Hz, 17.02 Hz), 2.87 (dd, 1H, J 5.15 Hz, 16.82 Hz),
3.64 (m, 4H, multiplet from C6-H of indole fragment and
2
2
was added 0.5 ml (5.7 mmole) of CF COOH and the mixture
3
singlet from OCH ), 4.11 (dd, 1H, J 6.10 Hz, 12.21 Hz), 4.55
was stirred at room temperature for 1 h and poured into
50 ml of EtOAc. This mixture was washed sequentially with
3
(dd, 1H, J 9.46 Hz, 12.14 Hz), 4.66 (s, 2H), 6.90 (s, 1H,
C10-H), 6.94 (t, 1H, J 7.63 Hz), 7.01 (t, 1H, J 7.02 Hz), 7.07
(t, 1H, J 7.86 Hz), 7.13 (d, 1H, J 7.39 Hz), 7.22 (d, 1H, J 8.06
Hz), 7.28 – 7.31 (m, 1H), 7.33 – 7.38 (m, 4H), 7.44 (d, 1H,
J 7.86 Hz), 7.61 (d, 1H, J 7.63 Hz);
saturated aqueous NaHCO solution (2 ´ 20 ml) and satu-
3
rated NaCl solution (20 ml), dried in air, and evaporated. The
residue was purified by chromatography on a silica gel col-
umn eluted with an n-heptane – EtOAc (6 : 1) mixture. Com-

440
S. A. Lakatosh et al.
13C NMR spectrum in DMSO-d (d, ppm): 30.6, 35.8,
1H NMR spectrum in DMSO-d (d, ppm): 3.20 (s, 3H,
6
6
38.4, 51.6, 54.5, 109.0, 110.7 (p), 113.9, 116.9 (p), 120.3,
121.2, 123.1, 123.9, 124.4, 127.0, 127.3 (2C), 127.4, 128.5
(2C), 129.6 (p), 134.9 (p), 135.0 (p), 135.7 (p), 136.9 (p),
137.0 (p), 144.2 (p), 164.0 (C=O), 164.5 (C=O), 171.9
(COOMe);
NCH ), 6.78 (d, 2H, J 8.32 Hz), 6.92 (t, 2H, J 7.23 Hz), 7.11
3
(t, 2H, J 7.33 Hz), 8.01 (d, 1H, J 7.77 Hz), 8.61 (s, 3H), 10.15
(s, 2H, –CHO);
13C NMR spectrum in DMSO-d (d, ppm): 24.51 (CH ),
6
3
111.19, 121.25, 121.38, 124.08, 124.12, 124.73, 136.03,
High-resolution mass spectrum, m/z (I , %): anal. calcd.
139.39, 165.76 (C = O), 186.53 (CHO). C H N O .
rel
23 15
3
4
for C H N O , 487.1688; found, 489.1695 [M]+ (100), 369
2-Methyl-1,3-dioxo-1,3,9b,10-tetrahydro-1H-in-dolo[
1¢,7¢:4,5,6]pyrrolo[3¢,4¢:2,3][1,4]diazepino[1,7-a]in-
dole-6-carbaldehyde (XXIII). To a solution of 200 mg
(0.58 mmole) of compound II in 20 ml DMF cooled to 0°C
was gradually added with stirring 0.3 ml (3.21 mmole) of
30 23
3
4
(120) [M+–C H ].
7
7
2,5-Dihydro-2,5-dioxo-3-(3-formylindol-1-yl)-4-(indol-
1-yl)-methyl-1H-pyrrole (XXI) and 2,5-dihydro-2,5-di-
oxo-3,4-bis(3-formylindol-1-yl)-1-methylpyrrole-2,5-dione
(XXII). To a solution of 250 mg (0.73 mmole) of compound
I in 10 ml DMF cooled to 0°C was gradually added with stir-
POCl and the stirring was continued at this temperature for
3
10 min. Then, the reaction mass was heated to 80°C and
stirred at this temperature for 2 h, cooled to room tempera-
ture, diluted with 40 ml of EtOAc, and neutralized by pour-
ing into 60 ml of saturated aqueous Na CO solution. The or-
ring 0.4 ml (4.27 mmole) of POCl and the stirring was con-
3
tinued at this temperature for 10 min. Then, the reaction
mass was heated to 80°C and stirred at this temperature for
1 h, cooled to room temperature, diluted with 20 ml of
EtOAc, and neutralized by pouring into 50 ml of saturated
aqueous Na CO solution. The organic layer was separated,
2
3
ganic layer was separated, and the aqueous layer was ex-
tracted with EtOAc (2 ´ 20 ml). The organic extracts were
combines, washed with saturated aqueous NaCl solution
(2 ´ 20 ml), dried in air, and evaporated to obtain a mixture
of products in the form of an crimson amorphous powder.
Separation of this substance on a silica gel column eluted
with an n-heptane – EtOAc (2 : 1) followed by recrystalliza-
tion yields compound XXIII in the form of a crimson crystal-
2
3
and the aqueous layer was extracted with EtOAc (2 ´ 20 ml).
The organic extracts were combines, washed with saturated
aqueous NaCl solution (2 ´ 20 ml), dried in air, and evapo-
rated to obtain a mixture of products in the form of an or-
ange-red amorphous powder. Separation of this substance on
a silica gel column eluted with an n-heptane – EtOAc (2 : 1)
yields the following individual compounds:
line powder with a yield of 130 mg (31%); m.p., > 300°C; R ,
f
Compound XXI was obtained in the form of an orange
crystalline powder upon recrystallization from ethanol with a
0.37 (n-heptane–EtOAc, 2 : 1).
1H NMR spectrum in DMSO-d (d, ppm): 3.03 (s, 3H),
6
yield of 170 mg (70%); m.p., 262 – 264°C; R , 0.30
3.82 (dd, 1H, J 17.11 Hz, 9.3 Hz), 3.92 (dd, 1H, J 18.32 Hz,
3.62 Hz), 5.47 (dd, 1H, J 4.79 Hz, 4.13 Hz), 6.88 (t, 1H,
J 6.26 Hz), 7.00 (d, 1H, J 7.01 Hz), 7.07 (t, 1H, J 7.07 Hz),
7.30 (d, 1H, J 6.19 Hz), 7.39 (t, 1H, J 7.67 Hz), 7.50 (d, 1H,
J 7.50 Hz), 8.21 (d, 1H, J 7.37 Hz), 9.24 (s, 1H), 10.17 (c,
1H).
f
(n-heptane – EtOAc, 2 : 1).
1H NMR spectrum in DMSO-d (d, ppm): 3.16 (s, 3H,
6
NCH ), 6.68 (d, 2H, J 8.28 Hz), 6.84 (d,1H, J 3.58 Hz), 6.88
3
(t, 1H, J 7.32 Hz), 6.93 (t, 1H, J 7.83 Hz), 7.09 (t, 1H, J 7.83
Hz), 7.47 (d, 1H, J 7.69 Hz), 7.68 (d, 1H, J 3.48 Hz), 8.01 (d,
1H, J 7.83 Hz), 8.57 (s, 1H), 10.13 (s, 1H, CHO);
Mass spectrum, m/z (I , %): 369 (100), 284 (29).
rel
13C NMR spectrum in DMSO-d (d, ppm): 24.35 (CH ),
6
3
107.68, 110.88, 111.21, 120.50, 120.79, 121.01, 121.18,
122.01, 122.88, 123.75, 123.92, 124.45, 126.42, 127.84,
128.62, 134.84, 136.32, 139.60, 166.16 (C=O), 166.28
(C=O), 186.29 (CHO). C H N O .
REFERENCES
1. S. A. Lakatosh, Yu. N. Luzikov, and M. N. Preobrazhenskaya,
Org. Biomol. Chem., No. 1, 826 – 833 (2003).
22 15
3
3
Compound XXII was obtained in the form of an orange
2. A. M. Korolev, L. N. Lysenkova, and M. N. Preobrazhenskaya,
Abstracts of Papers. The 20th Eur. Coll. Heterocyclic Chemistry
(August 18 – 21, 2002), Stockholm (2002).
crystalline powder upon recrystallization from ethanol with a
yield of 30 mg (12%); m.p., 262 – 264°C; R , 0.28
f
(n-heptane – EtOAc, 2 : 1).
3. G. L. Ciamician and P. Silber, Chem. Ber., 17, 353 – 357 (1884).