Synthesis of 6H-pyrrolo[3′,4′:2,3][1,4]diazepino[6,7,1-hi]indole-8,10(7H,9H)-dion es using 3-bromo-4-(indol-1-yl)maleimide scaffold

Article abstract of DOI:10.1039/b211163b

Series of 3-arylalkyl- or 3-alkylamino-4-(indol-l-yl)maleimides and bis(indol-l-yl)maleimides were synthesised. The cyclization of the 3-substituted 4-(indol-l-yl)maleimides under the action of acids resulted in the formation of diazepine[1,4] derivatives

Full text of DOI:10.1039/b211163b

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Synthesis of 6H-pyrrolo[3Ј,4Ј:2,3][1,4]diazepino[6,7,1-hi]indole-
8,10(7H,9H)-diones using 3-bromo-4-(indol-1-yl)maleimide
scaffold
Sergey A. Lakatosh, Yuri N. Luzikov and Maria N. Preobrazhenskaya*
Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, B. Pirogovskaya 11,
Moscow 119021, Russia. E-mail: lcta@space.ru; Fax: 7 095 245 02 95; Tel: 7 095 245 37 53
Received 14th November 2002, Accepted 9th January 2003
First published as an Advance Article on the web 7th February 2003
Series of 3-arylalkyl- or 3-alkylamino-4-(indol-1-yl)maleimides and bis(indol-1-yl)maleimides were synthesised.
The cyclization of the 3-substituted 4-(indol-1-yl)maleimides under the action of acids resulted in the formation
of diazepine[1,4] derivatives with indoline and maleimide nuclei annelated. These compounds readily produced
the corresponding indolomaleimidodiazepines[1,4] after dehydrogenation.
maleimides under the action of TFA formed aminophenyl-
Introduction
carbazoles 7 accompanied by the opening of one of the indole
Interest in bis(indol-3-yl)maleimides and related compounds
comes from their valuable biological properties, especially high
cytotoxicity and inhibitory activity towards protein kinase C,
the key enzyme that transduces a variety of extracellular signals
from cell periphery to gene transcription mechanisms.1 3-[(3-
Dimethylaminopropyl)indol-3-yl]-4-(indol-3-yl)maleimide (1),
which is a potent inhibitor of protein kinase C represents one of
the most investigated compounds of this type.1 Bis(indol-3-yl)-
maleimides are closely related to the derivatives of maleimido-
indolo[2,3-a]carbazole. Antibiotic rebeccamycin (2) and some
other compounds of this type (e.g. 3) are of great biological
importance due to their inhibitory activities towards topoiso-
merase I and protein kinase C.2
rings.5
Although many derivatives of this type have been studied,
their bis(indol-1-yl)analogues remain to be investigated. The
goal of this work was the synthesis of bis(indol-1-yl)maleimides
and 3-arylalkyl- or 3-dialkylamino-4-(indol-1-yl)maleimides
and the study of the possibility to obtain from them poly-
condensed heterocyclic compounds.
Results and discussion
The initial step of this work was the synthesis of bis(indol-
1-yl)maleimides and 3-(indol-1-yl)maleimides substituted at
position 4 with arylalkyl-, dialkyl- or alkylamino- moieties. The
interaction of 3,4-dibromomaleimides (9a–c) with indoline
in DMF in the presence of Et3N afforded the corresponding 3-
bromo-4-[2,3-dihydroindol-1-yl]maleimides (10a–c) in 75–80%
yields. Only monosubstituted products were obtained; the
second bromine atom could not be substituted by various
amines or the indole Grignard reagent. The surprisingly low
reactivity of the second bromine atom in compounds 10a–c can
be explained by masking the electron withdrawing effect of
the carbonyl groups by the neighbouring indoline introduced
into the maleimide ring. However after the dehydrogenation
of the indoline moiety the bromine atom in 3-bromo-4-(indol-
1-yl)maleimides (11a–c) was substituted successfully with
indoline or various amines (N-ethylaniline, diethylamine, benzyl-
amine) to give compounds 12a–e in 70–80% yields (Scheme 2).
3-(Indol-1-yl)-4-[2,3-dihydroindol-1-yl]maleimides 12a and b
were dehydrogenated with the use of DDQ in boiling toluene
to give the corresponding bis(indol-1-yl)maleimides (13a,b)
(Scheme 3).
In an attempt to effect the 2,2Ј-ring closure 13a,b were treated
with an excess of TFA in CH2Cl2 at rt or in toluene at 90 ЊC
until the full conversion of the starting material was observed
1
by TLC (∼2 h). The H-NMR spectra of the isolated products
(14a and b) displayed the signals of the indole nucleus sub-
stituted at positions 1 and 7 (4 and 9a on Scheme 3) and the
indoline nucleus substituted at positions 1 and 2 (15 and 9b
on Scheme 3). The significant downfield shift of the C5-H
hydrogen signal can be explained by the influence of the neigh-
bouring carbonyl group at C3. In 13C-NMR spectra the signals
corresponding to indoline C9b and C10 carbons were identified
in the high field area. According to the APT-experiments the
C9b atom is bonded with one hydrogen atom, and C10 with two
hydrogens. Based on these data we assigned the structures of
Maleimidoindolo[2,3-a]carbazoles (8) have been obtained
from the corresponding bis(indol-3-yl)maleimides (4) via bis-
(indol-3-yl)succinimides (5) by cyclization in acidic media
with subsequent oxidation.3 2,2Ј-Cyclization of bis(indol-3-
yl)maleimide (4) under the action of acids was successful in the
presence of an oxidant (e.g. DDQ) (Scheme 1).4 Bis(indol-3-yl)-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 2 6 – 8 3 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
826

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Scheme 1
Scheme 2
genated with DDQ in boiling toluene to produce 1H-indolo-
[1Ј,7Ј:4,5,6]pyrrolo[3Ј,4Ј:2,3][1,4]diazepino[1,7-a]indole-1,3-
(2H )-diones 15a and 15b. A significant NOE between C10-
H of the 1,2-disubstituted indole nucleus and C9-H of the 1,7-
disubstituted indole ring in the NMR spectra of compounds
15a is strongly indicative of the diazepine[1,4] framework with
two indoles and maleimide nuclei annelated (the enhancement
of intensity of C9-H was about 20%).
Similar reactivity was described by Mahboobi et al.6 for
3-(indol-3-yl)-4-iminomaleimides 16, which under the action of
TFA in CH2Cl2 at Ϫ78 ЊC formed 7-membered azepine cycles
with the maleimide and indole nuclei annelated (17) (Scheme 4).
Scheme 4
Scheme 3
9b,10-dihydro-2-benzyl-1H-indolo[1Ј,7Ј:4,5,6]pyrrolo[3Ј,4Ј:2,3]-
[1,4]diazepino[1,7-a]indole-1,3(2H )-dione (14a) and the corre-
sponding N2H- derivative (14b) to the compounds formed
from bisindolylmaleimides 13a and b respectively through the
2–7Ј cyclization (Scheme 3). Compounds 14a,b were dehydro-
We suggest that in acidic media bisindolylmaleimide 13 is
protonated at position 3 of one of the indole nuclei. The inter-
mediate 18 then undergoes the intramolecular electrophilic
attack of the iminium ion on the position 7 of the non-
protonated indole nucleus to give 14 (Scheme 5).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 2 6 – 8 3 3
827

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Scheme 5
1-Benzyl-3-(2,3-dihydroindol-1-yl)-4-(carbazol-9-yl)maleim-
3-(Indol-1-yl)-4-(2,3-dihydroindol-1-yl)maleimide
(12a)
ide (12f ) was obtained from 1-benzyl-3-(1,2,3,4,4a,9a-hexa-
hydrocarbazol-9-yl)-4-bromomaleimide (10d) via 1-benzyl-3-
(carbazol-9-yl)-4-bromomaleimide (11d). Dehydrogenation of
12f afforded 1-benzyl-3-(indol-1-yl)-4-(carbazol-9-yl)maleimide
(13c). The treatment of the latter with CH3SO3H in boiling
toluene for 1 h led to the cyclization product 14c in 30% yield.
The indoline moiety of the latter was dehydrogenated to 15c
(Scheme 6). The poor yield and the necessity of relatively harsh
cyclization conditions can be due to the steric hindrance.
treated with TFA in CH2Cl2 gave maleimido[1,4]diazepine with
two indoline nuclei annelated (19) in 55% yield. The TLC
analysis of the reaction mixture showed the presence of a minor
product of the reaction that was identified as 20. Compound
20, isomeric to 14a, was formed presumably by the partial
aromatization of diindolinodiazepine 19. Attempts to separate
the products 19 and 20 by column chromatography (CHCl3)
led to the full conversion of 19 to 20 (isolated in 45% yield
from 12a), although compound 19 was successfully isolated by
1
the crystallisation from n-heptane. The H-NMR spectrum of
the product 19 exhibited signals characteristic of 1,7- and 1,2-
disubstituted indolines, whereas signals corresponding to 1,7-
disubstituted indoline and 1,2-disubstituted indole were present
in the spectrum of 20. Compounds 19 and 20 were smoothly
converted into bisindolodiazepine 15a identical with the com-
pound obtained from 14a by treatment with DDQ (two or one
equivalent respectively) (Scheme 7).
Scheme 7
When treated with TFA in CH2Cl2 at rt or in toluene at 90 ЊC
the N-substituted 3-amino-4-(indol-1-yl)maleimides 12c–e pro-
duced the corresponding 1,2-dihydro-6H-pyrrolo[3Ј,4Ј:2,3]-
[1,4]diazepino[6,7,1-hi]indole-8,10(7H,9H )-diones 21a–c in
good yields (Scheme 8). Indolinodiazepines 21a,b, were con-
verted into the corresponding indolodiazepines 22a,b by treat-
1
ment with DDQ in boiling toluene. The H-NMR spectra of
compounds 21a,b exhibit signals characteristic of a 1,7-di-
substituted indoline ring and a single hydrogen quartet in the
area 4–4.5 ppm (C6-H) coupled with three hydrogen doublet at
1.3–1.5 ppm (C6–CH3), which is indicative of the diazepine[1,4]
structure of the products. The spectra of dehydrogenated
compounds 22a,b exhibit signals of the 1,7-disubstituted
indole. Contrary to the compounds 21a,b, compound 21c
gave, upon the treatment with DDQ, two products according
to TLC. During an attempt to separate them by column
chromatography (toluene–acetone) only indolinodiazepine 23
was isolated.
Scheme 6
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 2 6 – 8 3 3
828

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VXR-400 instrument at 400 MHz (1H-NMR) or at 75 MHz
(13C-NMR) with internal reference. Chemical shifts are given in
ppm and coupling constants in Hz. Assignment of the signals
1
was based on the decoupling experiments for H-NMR and
APT-experiments for 13C-NMR spectra, signals corresponding
to the quaternary carbon atoms are marked (q). Electron
impact mass-spectra (EI-MS) were obtained on an SAQ 710
Finnigan instrument at 70 eV (direct introduction, ion source
temperature 150 ЊC). HRMS mass spectra were registered on a
MAT 8430 Finnigan instrument with data operating system
SS-300 (EI, 70 eV, direct introduction, ion source temperature
250 ЊC). Analytical TLC was performed on Kieselgel F254
plates (Merck) and column chromatography on Silica Gel
Merck 60. Elemental analyses were performed in Organic
Analysis Laboratory of Nesmeyanov Institute of Elemento-
organic Compounds, Moscow, Russia. Extracts were dried
over anhydrous Na2SO4 and evaporated under reduced
pressure. Solvents and reagents were obtained from com-
mercial suppliers. 3,4-Dibromomaleimide7, 1-methyl- and 1-
benzyl-3,4-dibromomaleimide8 were obtained as previously
described.
1-Benzyl-3-bromo-4-(2,3-dihydro-1H-indol-1-yl)-1H-pyrrole-
2,5-dione (10a)
To a stirred solution of 1-benzyl-3,4-dibromomaleimide 9a
(3.4 g, 10 mmol) in DMF (5 mL) were added dropwise indoline
(1.8 mL, 15 mmol) and then Et3N (2.5 mL) and the mixture was
stirred at rt overnight and then poured into 1 N HCl (50 mL).
The water phase was extracted with EtOAc (2 × 50 mL),
extracts were washed with 1 N HCl (3 × 30 mL), aq. NaHCO3
(2 × 20 mL), water and brine, dried and evaporated. The residue
was crystallised from EtOH to give 10a as dark red crystals (4 g,
10.5 mmol, 70%); mp 114–116 ЊC (EtOH); Rf 0.56 (n-heptane–
EtOAc 6:1); (Found C. 59.50; H. 3.99; N 7.38. C19H15BrN2O2
requires C. 59.55; H. 3.95; N 7.31%); δH (d6-DMSO) 3.12 (2H,
t, J 7.95), 4.32 (2H, t, J 7.95), 4.66 (2H, s, CH2Ph), 6.99 (1H, t,
J 7.47), 7.01 (1H, d, J 7.7), 7.16 (1H, t, J 7.47), 7.26 (1H,
t, J 7.7), 7.29–7.36 (5H, m, -CH2C6H6); δC (d6-DMSO) 28.9,
41.4, 54.0, 89.1 (q), 116.2, 123.1, 124.8, 126.1, 127.4, 127.5,
128.5, 132.9 (q), 136.6 (q), 141.8 (q), 141.9 (q), 165.4 (q), 166.2
(q); m/z (EI MS) Mϩ 382 (100%).
Scheme 8
The structure of compounds 21a–c suggests the intra-
molecular electrophilic attack of iminium ion 25 formed by a
proton shift from the protonated indolomaleimide 24 to position
7 of the indoline nucleus as a cyclization step (Scheme 9).
1-Methyl-3-bromo-4-(2,3-dihydro-1H-indol-1-yl)-1H-pyrrole-
2,5-dione (10b)
Obtained similarly from 1-methyl-3,4-dibromomaleimide 9b as
a yellow solid in 78% yield, mp 139–141 ЊC (decomp.) (EtOH);
Rf 0.27 n-heptane–EtOAc, 5:1; (Found C. 50.87; H. 3.68;
N 9.19. C13H11BrN2O2 requires C. 50.84; H. 3.61; N 9.12%);
δH (CDCl3) 3.08 (3H, s, N-CH3), 3.18 (2H, t, J 8.02, indoline
CH2), 4.38 (2H, t, J 8.04, indoline CH2), 6.98 (1H, d, J 8.06),
7.01 (1H, t, J 7.46), 7.19 (1H, t, J 7.87), 7.23 (1H, d, J 7.33);
δC (CDCl3) 24.5, 29.5, 54.2, 89.8 (q), 116.1, 123.4, 124.8, 126.5,
132.5 (q), 141.4 (q), 142.0 (q), 166.2 (q), 166.7 (q); m/z (EI MS)
Mϩ 306 (100%).
Scheme 9
3-Bromo-4-(2,3-dihydro-1H-indol-1-yl)-1H-pyrrole-2,5-dione
(10c)
In conclusion a convenient method for the synthesis of 3-ary-
lalkyl- or 3-alkylamino-4-indolo-maleimides or bis(indol-1-yl)-
maleimides is developed. These compounds undergo cycliz-
ation under the action of acids to form diazepines[1,4] with a
common structural motif of 1,2-dihydropyrrolo[3Ј,4Ј:2,3]-
[1,4]diazepino[6,7,1-hi]indole-8,10(7H,9H )-dione.
Obtained similarly from 3,4-dibromomaleimide 9c as dark red
crystals in 60% yield, mp 125–127 ЊC (decomp.) (n-heptane–
EtOAc), Rf 0.49 (n-heptane–EtOAc 5:2), δH (d6-acetone) 3.20
(2H, t, J 7.95, indoline CH2), 4.40 (2H, t, J 8.02, indoline CH2),
7.00 (1H, t, J 7.36), 7.03 (1H, d, J 8.01), 7.18 (1H, t, J 7.55), 7.27
(1H, d, J 7.36), 9.83 (1H, s, NH ); δC (d6-acetone) 29.9, 54.8,
92.1 (q), 116.8, 123.7, 125.6, 127.0, 133.7 (q), 143.1 (q), 143.3
(q), 167.1 (q), 167.2 (q); m/z (EI MS) Mϩ 294 (90), 292 (100);
Mϩ Ϫ Br 213 (35); Mϩ Ϫ Br Ϫ CO 185 (20); Mϩ Ϫ Br Ϫ CONH
170 (50); Mϩ Ϫ Br Ϫ (CO)2NH 142 (30%).
Experimental
Mps were determined on a Buchi SMP-20 apparatus and
are uncorrected. NMR spectra were recorded with Varian
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 2 6 – 8 3 3
829

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1-Benzyl-3-(1,2,3,4,4a,9a-hexahydro-9H-carbazol-9-yl)-4-
bromo-1H-pyrrole-2,5-dione (10d)
1-Benzyl-3-(indol-1-yl)-4-(2,3-dihydroindol-1-yl)-1H-pyrrole-
2,5-dione (12a)
Obtained similarly to 10a (1,2,3,4,4a,9a-hexahydrocarbazole9
used instead of indoline) in 80% yield as orange crystals, mp
115–117 ЊC (n-heptane–EtOAc); Rf 0.53 n-heptane–EtOAc 6:1;
δH (CDCl3) 1.18–1.28 (4H, m), 1.48–1.56 (2H, m), 1.75–1.83
(1H, m), 2.21 (1H, m), 2.36 (1H, m), 3.50 (1H, m), 4.71 (2H,
s, CH2Ph), 6.97 (1H, d, J 8.59), 7.07 (1H, t, J 7.36), 7.17 (1H,
d, J 7.56), 7.18 (1H, t, J 8.42), 7.27–7.29 (1H, m, phenyl,
H4), 7.31–7.34 (2H, 2 t, phenyl-H3 and -H5), 7.39–7.42 (2H,
2 d, phenyl, H2 and H6); δC (CDCl3) 20.5, 22.3, 24.6, 27.2,
41.7, 42.0, 67.3, 87.2, 118.8, 122.8, 124.0, 125.8, 127.7, 128.6,
136.0, 136.2, 140.8, 141.1, 165.7, 166.5; m/z (EI MS) Mϩ 436
(100%).
To the stirred solution of 11a (1.14 g, 3 mmol) in DMF (10 ml)
were added indoline (550 mg, 4.5 mmol) and TEA (0.6 ml). The
reaction mixture was stirred at 90 ЊC while monitoring by TLC.
Upon the full conversion of 11a the solution was poured into
1 N HCl (50 mL). The resulting mixture was extracted with
EtOAc (2 × 50 mL), extracts were washed with 1 N HCl (2 ×
30 mL), aq. NaHCO3 (2 × 20 mL), water and brine, dried and
evaporated. Residue was crystallised from n-heptane–EtOAc to
give 12a (870 mg, 2.1 mmol, 69%) as yellow crystals, mp 133–
135 ЊC (n-heptane–EtOAc); Rf 0.27 (n-heptane–EtOAc, 7:1);
(Found C. 77.36; H. 5.01; N. 10.06. C27H21N3O2 requires C.
77.31; H. 5.05; N. 10.02%); δH (d6-acetone) signals assigned to
indoline nucleus: 3.18 (2H, t, J 8.06), 4.40 (2H, t, J 8.05), 6.09
(1H, d, J 8.06, H4), 6.49 (1H, t, J 7.00, H5), 6.66 (1H, t, J 7.42,
H6), 7.05 (1H, d, J 7.36, H7), signals assigned to indole nucleus:
6.62 (1H, d, J 3.35, H3), 6.95 (1H, t, J 7.10, H6), 7.00 (1H, t,
J 7.00, H5), 7.20 (1H, d, J 7.69, H4), 7.39 (1H, d, J 3.32, H2),
7.46 (1H, d, J 7.01, H7); benzyl: 4.78 (2H, s, CH2Ph), 7.31 (1H,
t, J 7.14, Ph, H4), 7.38 (2H, t, J 7.55, Ph, H3 and H5), 7.45 (2H,
d, J 7.51, Ph, H2 and H6); δC (d6-acetone) 29.9 (-CH2CH2N-),
42.0 (-CH2CH2N-), 53.8 (CH2Ph), 105.2, 109.1 (q), 111.9,
113.1, 121.2, 121.3, 122.9, 123.5, 125.1, 127.0, 128.3, 128.9,
129.0 (q), 129.3, 129.4, 133.1 (q), 133.4 (q), 138.0 (q), 138.1 (q),
143.7 (q), 167.2 (q), 168.1 (q); m/z (EI MS) Mϩ 419 (100%);
1-Benzyl-3-bromo-4-(1H-indol-1-yl)-1H-pyrrole-2,5-dione (11a)
To a solution of 10a (380 mg, 1 mmol) in toluene (50 mL) was
added DDQ (340 mg, 1.5 mmol). The mixture was refluxed for
6 h, diluted to 100 mL with EtOAc, washed with aq. NaHSO3
(2 × 30 mL), Na2CO3 solution (3 × 30 ml) water, brine, dried
and evaporated. The residue was purified by flash chromato-
graphy (n-heptane
n-heptane–EtOAc, 6:1) to give 11a as
a yellow solid (360 mg, 0.95 mmol, 95%), mp 122–123 ЊC
(n-heptane–acetone), Rf 0.41 (n-heptane–EtOAc, 7:1); δH (d6-
acetone) 4.85 (2H, s, CH2Ph), 6.86 (1H, dd, J32 3.49, J34 0.89,
H3), 7.25 (1H, t, J 7.71) 7.30 (1H, t, J 8.28) 7.33–7.39 (3H, m),
7.45 (2H, d, J 8.4), 7.53, 1H, dd, J45 8.12, J43 0.9, H4), 7.61
(1H, d, J23 3.48, H2), 7.68 (1H, d, J76 7.51, H7) δC (d6-acetone)
43.0, 107.9, 112.0 (q), 114.8, 121.9, 122.9, 123.6, 128.5, 128.7,
128.8, 129.4, 130.5 (q), 135.6 (q), 137.2 (q), 139.8 (q), 165.6 (q),
166.3 (q); m/z (EI MS) Mϩ 380 (100%).
3-(Indol-1-yl)-4-(2,3-dihydroindol-1-yl)-1H-pyrrole-2,5-dione
(12b)
Obtained from 11c similarly to 12a in 67% yield as a red solid,
mp 174–176 ЊC (EtOH) (d); Rf 0.1 (n-heptane–EtOAc, 6:1);
(Found C. 72.99; H. 4.66; N. 12.69. C20H15N3O2 requires 72.94;
H. 4.59; N. 12.76%); δH (d6-DMSO) 3.04 (2H, t, J 8.05, indoline
-CH2-), 4.20 (2H, t, J 8.05, indoline -CH2-), 6.05 (1H, d, J 8.06),
6.46 (1H, d, J 7.57), 6.58 (1H, d, J 3.24, indole C3–H ), 6.61
(1H, t, J 7.32), 6.93 (1H, t, J 7.57), 6.98 (1H, t, J 7.81), 7.01
(1H, d, J 7.21), 7.16 (1H, d, J 7.81), 7.37 (1H, d, J 3.41, indole
C2-H ), 7.45 (1H, d, J 7.57), δC (d6-DMSO) 28.8, 52.4, 103.9,
108.6 (q), 110.9, 111.8, 120.1, 120.2, 121.9, 122.2, 124.2, 125.9,
127.4 (q), 128.7, 131.8 (q), 132.9 (q), 136.5 (q), 142.5 (q), 167.3
(q), 168.4 (q); m/z (EI MS) Mϩ 329 (100%).
1-Methyl-3-bromo-4-(1H-indol-1-yl)-1H-pyrrole-2,5-dione (11b)
Obtained from 10b similarly to 11a as a yellow solid, mp 121–
123 ЊC (n-heptane–EtOAc); Rf 0.3 (n-heptane–EtOAc, 5:1);
δH (d6-DMSO) 3.07 (3H, s, N-CH3), 6.85 (1H, d, J 3.48, H3),
7.22 (1H, t, J 7.71), 7.28 (1H, t, J 7.55), 7.47 (1H, d, J 8.01),
7.53 (1H, d, J 3.47, H2), 7.66 (1H, t, J 7.93); δC (d6-DMSO)
24.6, 106.6, 111.9 (q), 113.7, 120.9, 121.7, 122.6, 128.0, 128.9
(q), 134.1 (q), 138.5 (q), 165.1 (q), 165.6 (q); m/z (EI MS)
Mϩ 304 (100%).
1-Benzyl-3-(N-ethylanilino)-4-(indol-1-yl)-1H-pyrrole-2,5-dione
(12c)
3-Bromo-4-(1H-indol-1-yl)-1H-pyrrole-2,5-dione (11c)
Obtained from 11a and N-ethylaniline similarly to 12a in 85%
yield as yellow crystals, mp 112–114 ЊC (n-heptane–EtOAc);
(Found C. 76.95; H. 5.50; N. 9.98. C27H23N3O2 requires C.
76.94; H. 5.50; N. 9.97%); Rf 0.42 (n-heptane-EtOAc 6:1);
δH (CDCl3) 1.16 (3H, t, J 7.1, NCH2CH3), 4.00 (2H, q, J 7.09,
NCH2CH3), 4.75 (2H, s, CH2Ph), 6.33 (1H, d, J 3.29, indole
H3), 6.76–6.79 (2H, m), 6.80–6.85 (4H, m) includes 6.81 (1H, d,
J 3.34, assigned to indole H2), 7.00 (1H, t, J 6.86), 7.01 (1H,
d, J 7.65), 7.10 (1H, t, J 6.86), 7.32–7.39 (4H, m), 7.45 (2H, d,
J 6.92); δC (CDCl3) 14.1, 41.5, 47.3, 104.0, 104.1, 106.4 (q),
110.7, 120.1, 120.5, 121.9, 122.9, 125.4, 127.7, 127.9, 128.2 (q),
128.6, 128.7, 136.3 (q), 136.4 (q), 137.2 (q), 141.2 (q), 165.8 (q),
167.2 (q); m/z (EI MS) Mϩ 421 (100%).
Obtained from 10c similarly to 11a in 85% yield as a yellow
solid, mp 197–199 ЊC (n-heptane–EtOAc); Rf 0.39 (n-heptane–
EtOAc 3:1); δH (d6-DMSO) 6.83 (1H, d, J 3.48, H3), 7.21 (1H,
t, J 7.16, H5 or H6), 7.27 (1H, t, J 7.23, H5 or H6), 7.46 (1H, d,
J 7.88, H4), 7.55 (1H, d, J 3.49, H2), 7.66 (1H, d, J 7.76, H7)
11.66 (1H, s, N-H ); δC (d6-DMSO) 106.4, 112.9 (q), 113.8,
121.0, 121.8, 122.6, 128.2, 129.0 (q), 134.3 (q), 138.8 (q), 165.8
(q), 166.7 (q); m/z (EI MS) Mϩ 290 (100%).
1-Benzyl-3-bromo-4-(9H-carbazol-9-yl)-1H-pyrrole-2,5-dione
(11d)
Obtained similarly to 11a (3.6 eq. of DDQ were used) in 90%
yield as a yellow solid, mp 175–177 ЊC (n-heptane–EtOAc),
Rf 0.36 (n-heptane–EtOAc, 7:1); δH (d6-DMSO) 4.8 (2H, s,
CH2Ph), 7.32 (1H, t, J 7.68, phenyl H4), 7.37 (2H, t, J 7.64,
carbazole H2 and H7), 7.39 (2H, d, J 7.51, phenyl H2 and H6),
7.43 (2H, t, J 7.54, phenyl H3 and H5), 7.49 (2H, t, J 7.61,
carbazole H3 and H6), 7.57 (2H, d, J 8.24, carbazole H4 and
H5), 8.23 (2H, d, J 7.69, carbazole H1 and H8); δC (d6-DMSO)
42.1, 112.9, 120.4 (q), 120.5, 121.7, 123.9 (q), 126.3, 127.5,
128.6, 136.2 (q), 137.7 (q), 138.1, 164.7 (q), 165.6 (q); m/z (EI
MS) Mϩ 430 (100%).
1-Methyl-3-(N-diethylamino)-4-(1H-indol-1-yl)-1H-pyrrole-2,5-
dione (12d)
Obtained from 11b and diethylamine similarly to 12a in 90%
yield as yellow crystals, mp 88–90 ЊC (EtOH); Rf 0.19 (n-hept-
ane–EtOAc 6:1); (Found C. 68.67; H. 6.44; N. 14.19.
C17H19N3O2 requires C. 68.67; H. 6.44; N. 14.13%); δH (d6-acet-
one) 1.02 (6H, t, J 7.08, N-CH2CH3), 2.05 (4H, m, N-CH2CH3),
2.99 (3H, s, N-CH3), 6.60 (1H, d, J 3.23, H3), 7.08 (1H, t, J
6.92), 7.12 (1H, t, J 7.03), 7.24 (1H, d, J 3.22, H2), 7.27 (1H, d,
J 7.21), 7.59 (1H, d, J 7.81); δC (d6-acetone) 5.25, 14.7, 37.0,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 2 6 – 8 3 3
830

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94.8, 102.5, 111.9, 112.6, 113.9, 120.2 (q), 122.6, 122.7 (q), 130.9
120.0 (q), 120.2, 120.8, 121.5, 121.7, 122.4, 123.7, 126.2 (q),
(q), 133.7 (q), 157.6 (q), 159.9 (q); m/z (EI MS) Mϩ 297 (100%).
127.5, 127.7, 128.0, 128.6, 128.7 (q), 128.8 (q), 134.6 (q), 136.4
(q), 138.5, 166.1 (q), 166.4 (q); m/z (EI MS) Mϩ 467 (100%).
1-Methyl-3-(benzylamino)-4-(indol-1-yl)-1H-pyrrole-2,5-dione
(12e)
2-Benzyl-9b,10-dihydro-1H-indolo[1Ј,7Ј:4,5,6]pyrrolo[3Ј,4Ј:2,3]-
[1,4]diazepino[1,7-a]indole-1,3(2H)-dione (14a)
Obtained from 11b and benzylamine similarly to 12a in 87%
yield as yellow crystals, mp 124–125 ЊC (EtOH); (Found C.
72.52; H. 5.16; N. 12.63. C20H17N3O2 requires C. 72.49; H. 5.17;
N. 12.68%); Rf 0.24 (n-heptane–EtOAc, 3:1); δH (d6-acetone)
2.98 (3H, s, -CH3), 4.15 (2H, br d, -NHCH2Ph), 6.56 (1H, dd,
J32 3.23, J34 0.87, indole H3), 6.83–6.87 (2H, m), 7.06–7.16 (6H,
m), 7.24 (1H, d, J 8.05), 7.44 (1H, br, NH ), 7.59 (1H, d, J 7.51);
δC (d6-acetone) 14.8, 38.1, 94.8, 102.5, 111.9, 112.4, 113.9,
118.9, 119.1, 120.0, 120.1 (q), 122.4, 129.4 (q), 130.9 (q), 133.5
(q), 157.7 (q), 160.9 (q); m/z (EI) Mϩ 331 (100%).
To the stirred solution of 13a (100 mg, 0.24 mmol) in CH2Cl2
(20 mL) was added TFA (2 mL) and the reaction mixture was
left to stir at rt for 2 h, then it was poured into the mixture
of EtOAc (50 mL) and saturated NaHCO3 solution (50 mL).
The organic layer was separated and washed with saturated
NaHCO3 solution (2 × 50 mL), water (30 mL) and brine, dried
and evaporated. The product was isolated by flash chromato-
graphy (n-heptane
n-heptane–acetone, 10:1) as a violet solid
(56 mg, 56%), Rf 0.53 (PhCH3), m/z (EI HRMS) Mϩ 417.1469
(C27H19N3O2 requires 417.1477) (100), Mϩ Ϫ PhCH2N(CO)2
256 (10%); δH (d6-DMSO) signals assigned to indoline ring:
3.74–3.89 (2H, m, C10-H), 5.35 (1H, dd, J9b–10 4.48, J9b–10 9.66,
C9b-H), 6.83 (1H, t, J 7.33, C12-H or C13-H), 6.87 (1H, d,
J 7.86, C11-H), 7.04 (1H, t, J 7.69, C12-H or C13-H),7.21 (1H,
d, J 7.65, C14-H); signals assigned to indole ring: 6.85 (1H, d,
J 3.62, C6-H), 7.18 (1H, t, J 7.70, C8-H), 7.26–7.40 (6H, m, 5H
benzyl hydrogens and C7-H), 7.66 (1H, d, J 7.73, C9-H), 8.45
(1H, d, J 3.62, C5-H); 4.73 (2H, s, CH2Ph); δC (d6-DMSO) 31.3,
40.8, 63.2, 106.2, 111.8, 119.8, 120.1 (q), 120.7, 121.1, 123.4 (q),
124.6, 125.6, 126.9, 127.4 (2C, quaternary and tertiary), 128.1
(q), 128.2, 128.6, 130.0 (q), 134.0 (q), 136.8 (q), 143.5 (q), 164.4
(q), 165.6 (q).
1-Benzyl-3-(2,3-dihydro-1H-indol-1-yl)-4-(9H-carbazol-9-yl)-
1H-pyrrole-2,5-dione (12f)
Obtained from 11d and indoline similarly to 12a in 77% yield
as an orange solid, mp 177–179 ЊC (n-heptane–EtOAc); Rf 0.24
(n-heptane–EtOAc 7:1); (Found C. 79.33; H. 4.97; N. 8.97.
C31H23N3O2 requires C. 79.30; H. 4.94; N. 8.95%); δH (d6-
DMSO) indoline: 3.02 (2H, t, J 7.82), 4.23 (2H, t, J 7.82), 6.09
(1H, d, J 7.77, H4), 6.25 (1H, t, J 7.77, H5), 6.57 (1H, t, J 7.36,
H6), 6.97 (1H, d, J 7.34, H7), carbazole: 7.19 (2H, t, J 7.54, H2
and H7), 7.36 (2H, d, J 7.66, H4 and H5), 7.45 (2H, t, J 7.65,
H3 and H6), 8.06 (2H, d, J 7.61, H1 and H8), benzyl: 4.78
(2H, s, CH2Ph), 7.32 (1H, t, J 6.95, Ph, H4), 7.37–7.44 (4H, m);
δC (d6-DMSO) 28.0, 41.0, 53.1, 104.2, 110.9, 113.1, 120.2, 120.4,
122.8 (q), 123.0, 124.4, 125.7, 126.1, 127.4, 127.5, 128.6, 132.6
(q), 136.4 (q), 137.0 (q), 140.0 (q), 141.9 (q), 165.8 (q), 167.2 (q);
m/z (EI) Mϩ 469 (100%).
9b,10-Dihydro-1H-indolo[1Ј,7Ј:4,5,6]pyrrolo[3Ј,4Ј:2,3][1,4]-
diazepino[1,7-a]indole-1,3(2H)-dione (14b)
Obtained from 13b similarly to 14a as a red solid, Rf 0.19
(n-heptane–EtOAc 3:1), m/z (EI HRMS) Mϩ 327.1021 (C20-
H13N3O2 requires 327.1008); δH (d6-DMSO) signals assigned to
indoline nucleus: 3.75 (1H, dd, J10–9b 9.61, Jgem 16.7, C10-H),
3.85 (1H, dd, J10–9b 4.33, Jgem 16.8, C10-H), 5.30 (1H, dd, J9b–10
9.59, J9b–10 4.33, C9b-H), 6.81 (1H, t, J 7.24), 6.86 (1H, d,
J 8.05), 7.03 (1H, t, J 7.73), 7.26 (1H, d, J 7.25); signals assigned
to indole nucleus: 6.83 (1H, d, J 3.5, C6-H), 7.19 (1H, t, J 7.65,
C8-H), 7.32 (1H, d, J 7.65, C7-H), 7.65 (1H, d, J 7.65, C9-H),
8.43 (1H, d, J 3.5, C5-H), 10.96 (1H, s, NH ); δC (d6-DMSO)
31.3, 63.1, 106.0, 111.6, 119.7, 120.5, 120.6, 121.1, 121.3, 123.9,
124.6, 125.6, 126.9, 127.4, 128.0, 130.0, 134.0, 143.6, 165.5,
166.8.
1-Benzyl-3,4-bis(1H-indol-1-yl)-1H-pyrrole-2,5-dione (13a)
Obtained by the dehydrogenation of 12a in the conditions
described for 11a in 91% yield as a red solid, Rf 0.51 (n-heptane–
EtOAc 5:1); m/z (EI HRMS) Mϩ 417,1484 (C27H19N3O2
requires 417,1477) (100), δH (d6-acetone) 4.90 (2H, s, CH2Ph),
6.61 (2H, d, J45 8.38, H4), 6.72 (2H, t, J 7.85, H5), 6.79 (2H, d,
J32 3.5, H3), 6.93 (2H, t, J 7.5, H6), 7.31–7.41 (3H, m, Ph),
7.47–7.52 (4H, m, indole H7 and Ph), 7.71 (2H, d, J23 3.51, H2);
δC (d6-acetone) 42.5, 107.9, 111.9, 121.6, 122.5 (4C), 123.5,
123.8, 128.5, 129.0, 129.4, 129.8, 136.4, 137.5, 167.3; m/z (EI
MS) Mϩ 417 (100), (Mϩ Ϫ CH2Ph) 326 (20%).
2-Benzyl-11b,12-dihydro-1H-indolo[1Ј,2Ј:4,5]pyrrolo[3Ј,4Ј:2,3]-
[1,4]diazepino[6,7,1-jk]carbazole-1,3(2H)-dione (14c)
3,4-Bis(1H-indol-1-yl)-1H-pyrrole-2,5-dione (13b)
Obtained by the dehydrogenation of 12b in the conditions
described for 11a in 90% yield as an orange solid, mp 147–148
ЊC (n-heptane–EtOAc), Rf 0.12 (n-heptane–EtOAc 6:1), (Found
C. 73.42; H. 3.96; N. 12.81. C20H13N3O2 requires C. 73.38; H.
4.00; N. 12.84%); δH (d6-DMSO) 6.59 (2H, d, J 7.69, H4), 6.71
(2H, t, J 7.75, H5), 6.77 (2H, d, J 3.46, H3), 6.91 (2H, t, J 7.44,
H6), 7.46 (2H, d, J 7.73, H7), 7.65 (2H, d, J 3.46, H2), 11.61
(1H, s, NH ); δC (d6-DMSO) 106.6, 110.8, 120.7, 121.5, 122.5,
123.4, 128.3, 135.1, 167.6; m/z (EI MS) Mϩ 327 (100%).
To a refluxing solution of 13c (200 mg, 0.43 mmol) in toluene
(30 mL) was added CH3SO3H (0.2 mL) the reaction mixture
was refluxed for 1 h diluted with EtOAc to 100 mL and washed
with aq. NaHCO3 (2 × 50 mL), water (50 mL), brine, dried and
evaporated. The residue was subjected to flash chromatography
(n-heptane
n-heptane–acetone 10:1) to give 14c in 30% yield
as a red solid, mp 149–150 ЊC (n-heptane–acetone); Rf 0.26
(n-heptane–EtOAc, 6:1); (Found: C, 79.71; H, 4.55; N, 9.04.
C31H21N3O2 requires C, 79.64; H, 4.53; N, 8.99%) δH (d6-
DMSO) signals assigned to indoline nucleus: 3.43 (1H, dd,
J12–11b 9.29, Jgem 16.52, C12-H), 4.15 (1H, dd, J12–11b 9.78, Jgem
16.51, C12-H), 5.65 (1H, t, J11b–12 9.23, C11b-H), 6.82 (1H, t,
J 7.32, C15-H), 7.00 (1H, d, J 7.87, C13-H), 7.07 (1H, t, J 6.64,
C14-H), 7.20 (1H, d, J 7.28, C16-H); carbazole and phenyl
moieties: 7.29 (1H, t, J 7.28), 7.34–7.49 (9H, m), 7.88 (1H, d,
J 8.42), 8.20 (2H, d, J 7.5); δC (d6-DMSO) 36.3 (C12), 40.7
(CH2Ph), 64.1 (C11b), 112.6, 115.2, 119.5, 119.8, 120.7, 121.7,
122.3, 123.4 (q), 124.3, 124.4 (q), 124.7, 124.9 (q), 125.8, 126.7,
127.3, 127.37 (2C), 127.44 (q), 127.5, 128.3 (q), 128.5 (2C),
128.8 (q), 135.0 (q), 136.8 (q), 137.3 (q), 144.0 (q), 164.0 (q),
164.2 (q); m/z (EI MS) Mϩ 467 (100%).
1-Benzyl-3-(1H-indol-1-yl)-4-(9H-carbazol-9-yl)-1H-pyrrole-
2,5-dione (13c)
Obtained by dehydrogenation of 12f in the conditions described
for 11a in 91% yield as an orange solid, mp 205–206 ЊC (n-
heptane–EtOAc), Rf 0.3 (n-heptane–EtOAc 6:1); (Found C.
79.64; H. 4.53; N. 9.05. C31H21N3O2 requires 79.64; H. 4.53;
N. 8.99%); δH (d6-DMSO) 4.90 (2H, s, CH2Ph), 6.49 (2H, d,
J 3.66), 6.78 (1H, d, J 3.49, indole H3), 6.85 (1H, m), 7.22 (2H,
t, J 7.33), 7.28 (2H, t, J 8.24), 7.34 (1H, t, J 7.32), 7.38–7.45
(5H, m), 7.54 (2H, d, J 7.18), 7.48 (1H, d, J 3.49, indole H2),
8.09 (2H, d, J 8.09); δC (d6-DMSO) 41.6, 107.2, 111.2, 111.5,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 2 6 – 8 3 3
831

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2-Benzyl-1H-indolo[1Ј,7Ј:4,5,6]pyrrolo[3Ј,4Ј:2,3][1,4]diazepino-
[1,7-a]indole-1,3(2H)-dione (15a) A
and evaporated. The residue was refluxed in n-heptane for
30 min the mixture was then hot filtered and filtrate cooled to
Ϫ15 ЊC, the precipitate was filtered off, washed with n-heptane
and dried in vacuo to give 19 as a dark violet solid (110 mg,
55%), m/z (EI HRMS) Mϩ 419.1642 (C27H21N3O2 requires
419.1633), Mϩ Ϫ H2 417, Mϩ Ϫ H2 Ϫ CH2Ph 326; Rf 0.40 (n-
heptane–EtOAc 5:1); mp 75–77 ЊC (n-heptane), δH (d6-DMSO)
3.01–3.19 (2H, m, C6-H ), 3.48 (1H, dd, J 9.53, Jab 16.35,
C10-Ha), 3.68 (1H, dd, J 3.17, Jba 16.36, C10-Hb), 4.30 (1H, m,
C5-Ha), 4.53–4.60 (1H, m, C5-Hb), 4.62 (2H, s, -CH2Ph), 4.94
(1H, dd, J 9.52, J 3.17, C9b-H ), 6.51 (1H, d, J 7.81), 6.65 (1H,
t, J 7.33, C12–H or C13-H ), 6.85 (1H, t, J 7.57, C8-H ), 6.96
(1H, t, J 7.35, C12-H or C13-H ), 7.16 (1H, d, J 7.13), 7.17
(1H, d, J 7.19), 7.24 (1H, d, J 7.88), 7.26–7.38 (5H, m, -CH2-
C6H6); δC (d6-DMSO) 27.4, 31.0, 40.2, 50.2, 62.9, 109.0, 112.8
(q), 118.3, 121.0, 124.0, 124.2, 124.6, 126.6, 126.87 (q), 126.9,
126.95, 127.0, 128.0 (q), 128.1, 128.6 (q), 132.8 (q), 136.9 (q),
143.1 (q), 145.0 (q), 164.4 (q), 165.4 (q).
To the solution of 14a (100 mg, 0.24 mmol) in toluene (10 mL)
was added DDQ (65 mg, 0.28 mmol). The reaction mixture was
refluxed for 1 h, diluted with EtOAc to 70 mL and washed with
NaHSO3 solution (2 × 20 mL), NaHCO3 solution (3 × 20 mL),
water and brine. The product was purified by flash chromato-
graphy (n-heptane
n-heptane–acetone 10:1) to give 15a as a
red crystalline solid (80mg, 80%), mp 193–194 ЊC (n-heptane–
acetone); Rf 0.37 (n-heptane–EtOAc 6:1); (Found: C, 77.79;
H, 4.11; N, 9.98. C27H17N3O2 requires C, 78.06; H, 4.12; N,
10.11%); δH (d6-DMSO) 70 ЊC 4.75 (2H, s, CH2Ph), 6.79 (1H,
d, J 3.66, C6-H), 7.10 (1H, t, J 7.10, C12-H or C13-H), 7.15
(1H, t, J 7.14, C12-H or C13-H), 7.21 (1H, s, C10-H), 7.22
(1H, t, J 7.73, C8-H), 7.34–7.42 (5H, m, Ph), 7.48–7.52 (3H, m,
C11-H, C14-H and C7-H), 7.77 (1H, d, J 7.68, C9-H), 8.21
(1H, d, J 3.66, C5-H); δC (d6-DMSO) 41.0, 107.6, 107.7, 114.6,
116.8 (q), 116.9 (q), 120.0, 120.6, 120.8, 121.9, 122.9, 123.0,
125.0 (q), 127.0, 127.1, 128.1, 129.8 (q), 130.1 (q), 135.0 (q),
135.9 (q), 136.0 (q), 137.2, 163.7 (q), 163.9 (q); m/z (EI MS)
Mϩ 415 (100), Mϩ Ϫ CH2Ph 324 (22), Mϩ Ϫ PhCH2N(CO)2
254 (10%). B. A sample of 19 (50 mg, 0.12 mmol) was
dehydrogenated with 2.2 eq. of DDQ in boiling toluene to give
15a (40 mg, 80%) identical with the sample of 15a obtained
by the method A. A sample of 20 (50 mg, 0.12 mmol) was
dehydrogenated with 1.1 eq. of DDQ in boiling toluene to give
15a (45 mg, 90%) identical with the sample of 15a obtained by
the method A.
2-Benzyl-5,6-dihydro-1H-indolo[1Ј,7Ј:4,5,6]pyrrolo[3Ј,4Ј:2,3]-
[1,4]diazepino[1,7-a]indole-1,3(2H)-dione (20)
Obtained in the attempt to isolate 19 from the reaction mixture
by column chromatography (eluent CHCl3). Full conversion
of 19 into 20 was observed and the product 20 was obtained by
the evaporation of the corresponding fractions in 45% yield
from 12a as a violet solid, mp 160–163 ЊC (n-heptane–CHCl3);
Rf 0.48 (n-heptane–EtOAc 5:1); EI HRMS Mϩ 417.1467
(C27H19N3O2 requires 417.1477), Mϩ Ϫ CH2Ph 326, Mϩ
Ϫ
CH2PhN(CO)2 256; δH (d6-DMSO) 3.06 (2H, t, J 8.54, C6-H),
4.35 (2H, t, J 8.54, C5-H), 4.67 (2H, s, CH2Ph), indole nucleus:
6.89 (1H, s, H3, C10-H), 6.92 (1H, t, J 7.54, C8-H), 7.01 (1H, t,
J 7.28, C13-H), 7.07 (1H, t, J 8.34, C12-H), 7.09 (1H, d, J 7.65,
C7-H), 7.21 (1H, d, J 8.28, C11-H), 7.33–7.39 (5H, m, phenyl
hydrogens), 7.44 (1H, d, J 7.61, C14-H), 7.58 (1H, d, J 8.2,
C9-H); δC (d6-DMSO) 27.5, 40.6, 48.8, 108.9, 110.4 (q), 114.0,
116.8 (q), 120.2, 121.2, 123.0, 123.8, 125.0, 126.3, 127.2, 127.3,
128.5, 129.6 (q), 132.9 (q), 135.0 (q), 135.7 (q), 136.6 (q), 136.9
(q), 144.3 (q), 163.9 (q), 164.5 (q).
1H-Indolo[1Ј,7Ј:4,5,6]pyrrolo[3Ј,4Ј:2,3][1,4]diazepino[1,7-a]-
indole-1,3(2H)-dione (15b)
Obtained from 14b similarly to 15a as a red solid in 75% yield,
mp 135 ЊC (decomp.) (EtOAc); Rf 0.3 (n-heptane–EtOAc, 3:1);
m/z (EI HRMS) Mϩ 325.0859 (C20H11N3O2 requires 325.0851);
Mϩ Ϫ HN(CO)2 254; δH (d6-DMSO) 6.79 (1H, d, J 3.58, C6-H),
7.09 (1H, t, J 7.14, C12-H or C13-H), 7.14 (1H, t, J 7.14, C12-H
or C13-H), 7.18 (1H, s, C10-H), 7.19 (1H, t, J 7.75, C8-H),
7.47–7.50 (3H, m, C11-H, C14-H and C7-H), 7.74 (1H, d,
J 7.75, C9-H), 8.16 (1H, d, J 3.58, C5-H), 11.31 (1H, s, NH );
δC (d6-DMSO) 107.7, 110.0, 115.2, 117.0, 117.6, 120.3, 120.9,
121.1, 122.2, 123.2, 123.3, 125.4, 126.5, 129.9, 130.3, 135.2,
136.1, 137.3, 165.1, 165.5.
1,2-Dihydro-6-methyl-7-phenyl-9-benzyl-6H-pyrrolo[3Ј,4Ј:2,3]-
[1,4]diazepino[6,7,1-hi]indole-8,10(7H,9H)-dione (21a)
To a solution of 1-benzyl-3-(ethylanilino)-4-(indol-1-yl)male-
imide 12c (200 mg, 0.47 mmol) in CH2Cl2 (20 mL) TFA (2 mL)
was added, the reaction mixture was stirred at the ambient tem-
perature for 2 h, then it was diluted with EtOAc (100 mL) and
washed with sat. aq. NaHCO3 (2 × 30 mL), water (50 mL) and
brine (50 mL). The dry residue was purified by flash chromato-
2-Benzyl-1H-indolo[1Ј,2Ј:4,5]pyrrolo[3Ј,4Ј:2,3][1,4]diazepino-
[6,7,1-jk]carbazole-1,3(2H)-dione (15c)
Obtained by the dehydrogenation of 14c similarly to 15a in 90%
yield as a red solid, mp 138–140 ЊC (n-heptane–EtOAc); Rf 0.41
(n-heptane–EtOAc 6:1), m/z (EI HRMS) Mϩ 465.1462
graphy (n-heptane
n-heptane–acetone, 10:1) to give 21a as
dark red crystals (110 mg, 55%), mp 138–140 ЊC (cyclohexane);
Rf 0.24 (n-heptane–EtOAc 6:1); (Found C, 76.94; H, 5.51;
N, 9.91. C27H23N3O2 requires C, 76.94; H, 5.5; N, 9.97%);
δH (d6-DMSO) 1.42 (3H, d, J 6.77, -CH3), 3.05–3.19 (2H, m,
C2-H), 4.35 (1H, m, C1-Ha), 4.55 (1H, m, C1-Hb), 4.67 (2H,
s, CH2Ph), 5.31 (1H, m, C6-H), 6.73 (1H, t, J 7.32), 6.81 (1H, t,
J 7.37), 6.92 (2H, d, J 8.37), 7.12 (2H, t, J 6.91), 7.14–7.18 (2H,
m), 7.27–7.32 (3H, m, -CH2Ph), 7.35–7.41 (2H, m, -CH2Ph);
δC (d6-DMSO) 20.3, 25.7, 38.4, 48.3, 55.1, 108.9 (q), 114.2,
117.3, 120.1, 122.2, 125.0, 125.2, 125.5, 126.5, 126.9, 129.8 (q),
131.3 (q), 134.0 (q), 135.2 (q), 139.8 (q), 145.8 (q), 163.2 (q),
164.7 (q); δH (CDCl3) 1.46 (3H, d, J 6.96, -CH3), 2.96–3.14
(2H, m, C2-H), 4.35 (1H, m, C1-Ha), 4.43 (1H, m, C1-Hb), 4.62
(2H, d, J 5.67, -CH2Ph), 4.97 (1H, m, C6-H), 6.69 (1H, t, J 7.5,
C4-H), 6.74 (1H, t, J 7.32, N–Phenyl, C4-H), 6.82 (2H, d,
J 7.83, phenyl C2-H and C6-H), 6.86 (1H, d, J 7.37, C3-H), 6.96
(1H, d, J 7.36, C5-H), 7.10 (2H, two triplets, N-Phenyl C3-H
and C5-H), 7.18–7.22 (1H, m, -CH2Ph,C4-H), 7.24–7.28 (2H,
m, -CH2Ph), 7.29–7.33 (2H, m, -CH2Ph); δC (CDCl3) 22.9, 28.2,
41.2, 50.5, 59.4, 112.8 (q), 117.2, 120.5, 122.0, 124.2, 127.5,
128.2, 128.4, 128.5, 128.8, 131.8 (q), 132.9 (q), 134.1 (q), 136.8
(C31H19N3O2 requires 465.1477), Mϩ Ϫ CH2Ph 374, Mϩ
Ϫ
CH2PhN(CO)2 256; δH (d6-DMSO) 4.69 (2H, s, CH2Ph), 7.14
(1H, t, J 7.18, carbazole H3 or H6), 7.18 (1H, s, C12-H), 7.21
(1H, t, J 7.46, C7-H or C10-H), 7.28 (1H, t, J 7.33, C15-H),
7.32–7.37 (3H, m), 7.38–7.42 (3H, m), 7.45 (1H, t, J 7.14, C14-
H), 7.55 (2H, d, J 8.23, C8-H and C9-H), 7.92 (1H, d, J 8.20,
C13-H), 7.96 (1H, d, J 7.83, C11-H), 8.04 (1H, d, 7.65, C5-H),
8.11 (1H, d, J 7.77, C16-H); δC (d6-DMSO) 41.1, 109.3, 114.7,
117.4, 117.6 (q), 119.85, 119.87, 120.5, 121.6 (q), 122.2, 123.2,
123.3, 123.8, 124.4, 124.9 (q), 125.8, 126.2, 127.3, 127.5, 128.3
(q), 128.4, 129.6 (q), 136.1 (q), 136.5 (q), 137.2 (q), 137.8 (q),
141.5 (q), 163.0 (q), 164.0 (q).
2-Benzyl-5,6,9b,10-tetrahydro-1H-indolo[1Ј,7Ј:4,5,6]pyrrolo-
[3Ј,4Ј:2,3][1,4]diazepino[1,7-a]indole-1,3(2H)-dione (19)
The solution of 12a (200 mg, 0.48 mmol) in CH2Cl2 (10 mL)
was treated with 1 ml of TFA, the resulting dark violet mixture
was allowed to stir at rt for 2 h. The reaction mixture
was diluted with EtOAc (100 mL) and washed with sat. aq.
NaHCO3 (2 × 30 mL), water (50 mL) and brine (50 mL), dried
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 2 6 – 8 3 3
832

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(q), 142.3 (q), 147.7 (q), 165.9 (q), 167.0 (q); m/z (EI MS) Mϩ
crystals in 90% yield, mp 99–100 ЊC (n-hexane); Rf 0.38 (n-
421 (100%).
heptane–EtOAc 6:1); (Found C, 69.18; H, 5.84; N, 14.21.
C17H17N3O2 requires C, 69.14; H, 5.8; N, 14.23%); δH (d6-
DMSO) 1.17 (3H, t, J 7.03, N-CH2CH3), 1.33 (3H, d, J 6.83,
N-CHCH3), 2.98 (3H, s, N-CH3), 3.54 (1H, m, J 7.05, N-
CH2CH3), 3.87 (1H, m, J 7.05, N-CH2CH3), 4.62 (1H, d, J 6.83,
C6-H), 6.69 (1H, d, J 3.45, C2-H), 7.01 (1H, t, J 7.43, C4-H),
7.08 (1H, d, J 6.84, C3-H), 7.51 (1H, d, J 7.76, C5-H), 8.48, 1H,
d, J 3.43, C1-H); δC (d6-DMSO) 14.3, 23.26, 23.31, 47.1, 60.2,
104.5, 111.3 (q), 119.9, 120.2, 120.3, 124.9, 128.5 (q), 129.2 (q),
130.0 (q), 133.4 (q), 166.2 (q), 164.4 (q); m/z (EI MS) Mϩ 295
(100%).
7-Ethyl-1,2-dihydro-6,9-dimethyl-6H-pyrrolo[3Ј,4Ј:2,3][1,4]-
diazepino[6,7,1-hi]indole-8,10(7H,9H)-dione (21b)
Obtained from 1-methyl-3-(diethylamino)-4-(indol-1-yl)male-
imide 12d similarly to 21a in 86% yield as violet crystals,
mp 80–82 ЊC (cyclohexane); Rf 0.41 (n-heptane–EtOAc 3:1);
(Found C, 68.71; H, 6.45; N, 14.16. C17H19N3O2 requires C,
68.67; H, 6.44; N, 14.13%); δH (d6-DMSO) 1.02 (3H, t, J 7.03,
N-CH2CH3), 1.23 (3H, d, J 6.96, C6-CH3), 2.95 (2H, m,
N-CH2CH3), 3.13 (2H, m, C2-H), 4.05 (1H, m, C1-Ha), 4.36
(2H, m, C1-Hb), 6.74 (1H, t, J 7.42, C4-H), 7.02 (1H, d, J 7.51,
C3-H or C5-H), 7.09 (1H, d, J 7.38, C3-H or C5-H); δC (d6-
DMSO) 14.0, 22.8, 23.2, 27.6, 49.6, 50.3, 59.1, 118.2 (q), 120.8,
123.9, 127.1, 129.2 (q), 132.2 (q), 132.3 (q), 143.4 (q), 166.5 (q),
167.9 (q); m/z (EI MS) Mϩ 297 (100%).
1,2-Dihydro-9-methyl-6-phenyl-8H-pyrrolo[3Ј,4Ј:2,3][1,4]-
diazepino[6,7,1-hi]indole-8,10(9H)-dione (23)
Compound 21c was subjected to dehydrogenation with 1.1 eq.
of DDQ in the conditions described for the synthesis of
15a. The reaction mixture obtained exhibited the presence
of two products with Rf 0.21 and 0.41 (n-heptane–EtOAc, 3:1).
We suggested by analogy with the compounds 22a,b that
the product with Rf 0.41 has the structure of 22c. During the
attempt to separate them by column chromatography only the
product with the Rf of 0.21 was isolated in 25% yield (from 12e)
as dark blue crystals, mp 235–237 ЊC (toluene–acetone); (Found
C, 72.82; H, 4.53; N, 12.61. C20H15N3O2 requires C, 72.94;
H, 4.59; N, 12.76%); δH (d6-DMSO) 2.80 (3H, s, N-CH3), 2.81
(2H, t, J 8.38, C2-H), 3.97 (2H, t, J 8.18, C1-H), 6.15 (1H, dd,
J 7.69, Jmeta 0.98, C3-H), 6.64 (1H, t, J 7.57, C4-H), 7.04
(1H, dd, J 7.48, Jmeta 0.97, C5-H), 7.32–7.44 (5H, m, phenyl);
δC (d6-DMSO) 22.8, 26.7, 46.8, 124.6, 125.4, 127.4, 128.0, 129.1,
130.0, 132.6, 133.4, 137.3, 139.6, 152.4, 163.8, 166.8, 176.6;
m/z (EI MS) Mϩ 329 (100%).
1,2-Dihydro-9-methyl-6-phenyl-6H-pyrrolo[3Ј,4Ј:2,3][1,4]-
diazepino[6,7,1-hi]indole-8,10(7H,9H)-dione (21c)
Obtained from 1-methyl-3-(benzylamino)-4-(indol-1-yl)male-
imide 12e similarly to 21a in 65% yield as dark violet crystals
mp 168–170 ЊC (n-heptane–acetone); Rf 0.27 (n-heptane–
EtOAc, 6:1); (Found C, 72.46; H, 5.17; N, 12.68. C20H17N3O2
requires C, 72.49; H, 5.17; N, 12.68%); δH (CDCl3) 2.95 (3H,
s, N-CH3), 3.21 (2H, t, J 8.49, C2-H), 4.41 (1H, m, C1-Ha), 4.55
(1H, m, C1-Hb), 4.77 (1H, br s, NH ), 5.35 (1H, s, C6-H),
6.70 (1H, t, J 7.57, C4-H), 6.77 (1H, d, J 7.76, C3-H), 7.09
(1H, d, J 7.29, C5-H), 7.13–7.16 (2H, m), 7.25–7.34 (3H, m);
δC (CDCl3) 23.5, 28.3, 50.1, 64.2, 116.8 (q), 119.9, 120.5 (q),
124.2, 125.0 (q), 127.2, 127.6, 129.0, 129.2, 132.1 (q), 142.9 (q),
144.1 (q), 167.96 (q), 167.99 (q); m/z (EI MS) Mϩ 331 (100%).
6-Methyl-7-phenyl-9-benzyl-6H-pyrrolo[3Ј,4Ј:2,3][1,4]-
diazepino[6,7,1-hi]indole-8,10(7H,9H)-dione (22a)
Acknowledgements
This work was supported by the Russian Fund for Basic
Obtained by dehydrogenation of 21a with 1.2 eq. of DDQ
similarly to 15a as red crystals in 80% yield, mp 153–154 ЊC
(n-heptane–acetone); Rf 0.4 (n-heptane–EtOAc, 6:1); (Found C,
77.24; H, 5.05; N, 9.97. C27H21N3O2 requires C, 77.31; H, 5.05;
N, 10.02%); δH (d6-DMSO) 1.56 (3H, d, J 6.97, CH-CH3), 4.68
(2H, s, -CH2Ph), 5.52 (1H, q, J 6.96, C6-H), 6.83 (1H, d, J 3.48,
C2-H), 6.95 (1H, t, J 7.32, ∼N-Ph H4), 7.07 (1H, t, J 7.33,
C4-H), 7.13–7.16 (3H, m), 7.24 (2H, t, J 7.36, ∼N-Ph H3 and
H5), 7.29–7.38 (5H, m, CH2-C6H6), 7.57 (1H, d, J 7.73, C5-H),
8.46 (1H, d, J 3.49, C1-H); δC (d6-DMSO) 23.5, 40.8, 60.3,
106.4, 119.8, 120.5, 121.5, 121.8, 122.3, 122.9 (q), 123.8 (q),
125.2, 127.1, 127.3, 128.6, 129.0, 130.1 (q), 130.5 (q), 133.6 (q),
136.7 (q), 146.2 (q), 165.5 (q), 165.8 (q); m/z (EI MS) Mϩ 419
(100%).
Research, grant number 01–03–33028.
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7-Ethyl-6,9-dimethyl-6H-pyrrolo[3Ј,4Ј:2,3][1,4]diazepino[6,7,1-
hi]indole-8,10(7H,9H)-dione (22b)
Obtained similarly to 15a by dehydrogenation of 21b as red
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 2 6 – 8 3 3
833