Synthesis of symmetric and non-symmetric indolo[2,3-c]carbazole derivatives: Preparation of indolo[2,3-c]pyrrolo[3,4-a]carbazoles

Article abstract of DOI:10.1039/a802852d

Symmetric and non-symmetric indolo[2,3-c]carbazoles have been prepared from 3,3′-biindolyls 9a-d by two strategies; step by step, by thermal electrocyclic reaction, or directly. Indolo[2,3-c]pyrrolo-[3,4-a]carbazoles 28aa-db, a new class of indolopyrroloc

Full text of DOI:10.1039/a802852d

View Article Online / Journal Homepage / Table of Contents for this issue
Synthesis of symmetric and non-symmetric indolo[2,3-c]carbazole
derivatives: preparation of indolo[2,3-c]pyrrolo[3,4-a]carbazoles
Eric Desarbrea and Jan Bergman*,a,b
a Department of Organic Chemistry, CNT, Novum Research Park, S-14157 Huddinge, Sweden
b Department of Organic Chemistry, Royal Institute of Technology, S-100 44 Stockholm,
Sweden
Symmetric and non-symmetric indolo[2,3-c]carbazoles have been prepared from 3,3Ј-biindolyls 9a–d
by two strategies; step by step, by thermal electrocyclic reaction, or directly. Indolo[2,3-c]pyrrolo-
[3,4-a]carbazoles 28aa–db, a new class of indolopyrrolocarbazoles, have been obtained in a one step
reaction from readily available precursors.
H
Introduction
N
The indolocarbazole family is composed of five possible iso-
meric compounds and possess a wide range of biological activ-
ities. Thus, staurosporine 11 (inhibits protein Kinase C) and
rebeccamycin 22 (exhibits antibiotic and antitumor activities)
certainly are the most well-known of the indolo[2,3-a]carbazole
derivatives. Three general methods exist to prepare the [2,3-a]
framework; Fischer indolization,3,4 Diels–Alder reaction,5–7 or
oxidative cyclization of bisindolylmaleimides.8–11 The latter
method is the one most frequently used. Indolo[3,2-b]carbazole
3 has recently attracted considerable interest due to its affinity
N
N
N
H
H
H
4
5
N
N
H
H
6
H
N
H
N
O
O
O
A
N
E
B
G
N
N
N
N
N
C
N
N
O
H
H
H
H
Cl
H
Cl
Me
H
O
OH
R
MeO
R
NHMe
HO
MeO
OH
Step by step
Direct
1
2
H
N
N
N
H
N
N
H
H
H
CHO
N
H
Scheme 1
3
These two routes capitalize on 3,3Ј-biindolyl as a readily
available starting material as it can be prepared by conden-
sation of isatin 7 and indole 8, followed by reduction with lith-
ium aluminium hydride. Symmetric or non-symmetric 3,3Ј-
biindolyl derivatives 9a–c have been prepared according to ref.
23 or 24 (Scheme 2).
to the TCDD receptor.12,13 However no generally applicable
synthetic methods are available for these systems.14–18
The other indolocarbazoles 4–6 have been scantily studied.
This is probably due to the lack of connection with any sort of
biological activities or natural compounds. Indolo[2,3-
b]carbazole 419 is sometimes obtained during the preparation
of 3 and the synthesis of indolo[3,2-a]carbazole 5 has only been
reported by Mann and Willcox.20
In the case of the indolo[2,3-c]carbazole 6, only the prepar-
ation of N,NЈ-dimethylindolo[2,3-c]carbazole has been des-
cribed from N,NЈ-dimethyl-N,NЈ-diphenyl-1,4-phenylene-
diamine by irradiation.21 Now, we have developed three general
methods to prepare indolo[2,3-c]carbazoles 622 by C-ring con-
struction from readily available 3,3Ј-biindolyl derivatives.23,24
Two routes could be expected as outlined in the retrosynthetic
Scheme 1; step by step, which uses thermal electrocyclic
reaction, or by direct synthesis.
Results and discussion
Synthesis of indolo[2,3-c]carbazoles: step by step
Thermal electrocyclic reactions25 have previously been used
to form aromatic rings during various preparations of carb-
azoles,26–29 carbolines30,31 or ellipticine32,33 derivatives. Only a
few workers have described this type of strategy to obtain the
indolocarbazole framework. Thus, Wallace and co-workers7
and Pindur et al.6 have prepared indolo[2,3-a]carbazole
derivatives from 2,2Ј-biindolyl by irradiation or by Lewis acid
J. Chem. Soc., Perkin Trans. 1, 1998
2009

View Article Online
O
H
H
R5
N
N
O
R7
N
R1
R5
R1
N
OH
v
R
R7
7a–c
i or ii
N
i, ii
N
N
+
H
H
16
12 R = H
13a R = CO2Et
H
N
N
N
R1′
H
8
9a–d
a R1 = R1′ = R5 = R7 = H
b R1 = R1′ = H, R5 = R7 = Cl
c R1 = Me, R1′ = R5 = R7 = H
d R1 = R1′ = Me, R5 = R7 = H
CHO
N
H
11a
Scheme 2 Reagents and conditions: i, Et2NH (cat), EtOH; ii, LiAlH4 or
NaBH4, BF3, Et2O, DME; iii dimethyl oxalate, ButOK
H
H
N
iv
iii
N
catalysis. Marchesini and co-workers34 have performed a
6π-electrocyclisation to obtain 10b from 10a (Scheme 3).
NO2
CO2Et
CO2Et
N
N
CO2Et
N
H
H
OCO2Et
15
14
Scheme 5 Reagents and conditions: i, Ph3PϩCH3BrϪ, K2CO3, triglyme;
ii, (EtO)2POCH2CO2Et, NaH, THF; iii diethylmalonate, piperidine
(cat.), toluene; iv, MeNO2, MeCO2NH4; v, NH2OH, HCl, EtOH
i
OCO2Et
OCO2Et
N
N
N
CO2Et CO2Et
Cl
CO2Et
10a
H
Me
N
N
10b
Scheme 3 Reagents and conditions: i, HPK 125 W, hv
Cl
CO2Et
CO2Et
The first step of our approach was to prepare 2-formyl-3,3Ј-
biindolyls 11. By treating the appropriate 3,3Ј-biindolyl deriv-
atives 9a–d with N,N-dimethylchloromethaniminium chloride35
(1.3 equiv.) in CH3CN at room temperature; the desired com-
pounds 11a–d were obtained in good yields (Scheme 4). The
N
N
H
H
13b
13c
15 in 81% yield by the classic Henry reaction. The ratio between
the two isomeric oximes 16, obtained in 95% yield in ethanol at
reflux in the presence of NH2OH and HCl was 1:1 (Scheme 5).
The construction of the C-ring was effected by heating the
precursor 15 during 8 h at 190 ЊC in Ph2O under an inert
atmosphere which resulted in the formation of 17 in only 30%
yield (Scheme 6). The reaction performed with Pd/C led to the
R7
R1
N
i, ii
R5
9a–d
CHO
N
R1′
11a–d
Scheme 4 Reagents and conditions: i, ClCH᎐N(Me)2ϩ ClϪ (1.3 equiv.),
i
᎐
15
MeCN, RT; ii, NaHCO3 sat.
N
N
H
H
structures of compounds 11b and 11c have been studied by
2D-NMR to establish the correct position of the formyl group
on the 3,3Ј-biindolyl framework. No 2,2Ј-diformyl derivatives
were observed as side-products and were not even formed on
attempted formylation of 11a under forcing conditions. The
electronic withdrawing effect of the formyl group in the 2-
position exerts its lowering effect on the nucleophilic nature of
the 2Ј-position.
From 11a, many 2-substituted-3,3Ј-biindolyls could be pre-
pared. Wittig or Horner–Emmons reactions led to compounds
12 or (E)-13a in 85% and 80% yield. The (Z) isomer of 13a was
isolated in 10% yield as a side-product (Scheme 5). Similarly,
2-formyl-3,3Ј-biindolyls 9b,c yielded α,β-ethylenic esters (E)-
13b and (E)-13c in 95% yield each.
17
Scheme 6 Reagents and conditions: i, Ph2O, 190 ЊC
desired compound 17 in 28% yield as well. The low yield was
due to a quick degradation of the compound observed during
the reaction.
The stability of the N,NЈ-dimethylindolo[2,3-c]carbazole 18
contrasts with its non-substituted analog 17. Henry aldolisation
with the formyl compound 11d during 48 h gave compound
1921 in 20% yield, whereas the expected compound 18 was
obtained in only 8% yield. A large amount (69%) of starting
material was recovered. From 19, in Ph2O at 160 ЊC, N,NЈ-
dimethylindolo[2,3-c]carbazole 1821 could be prepared in 58%
yield (Scheme 7).
The aldehyde 11a led to the gem-diethyl ester 14 in 75% yield,
by aldolisation in the presence of diethyl malonate in toluene at
reflux with piperidine as catalyst or to the nitrovinyl derivative
Other electrocyclisations have been executed under the same
conditions (Ph2O at 190 ЊC); either from (E)-13a–c to obtain
2010
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
H
N
N
N
i
ii
Me
Me
Me
N
18
N
H
9a
i
+
CHO
ii
N
Me
11d
N
N
N
N
H
Me
H
H
H
N
RO2C
CO2R
CO2Et
24 R = Me
25 R = H
20a
iii
NO2
Scheme 10 Reagents and conditions: i, diethyl acetylenedicarboxylate,
neat 210 ЊC; ii, ethyl propiolate, neat, 120 ЊC ; iii, MeOH, KOH
N
Me
19
prevent further attack of dimethyl acetylenedicarboxylate and
no 2:1 adduct was formed. However, in the 2,2Ј-biindolyl series
the adduct 26 is formed when the reactants are heated in
Scheme 7 Reagents and conditions: i, MeNO2, MeCO2NH4; ii, Ph2O,
160 ЊC
O
O
R5
MeO
OMe
i
R7
13a–c
N
N
N
N
H
R1
MeO
OMe
CO2R
O
O
26
20a R = Et, R1 = R5 = R7 = H; 78%
20b R = Et, R1 = H, R5 = R7 = Cl; 50%
20c R = Et, R1 = Me, R5 = R7 = H; 30%
21 R = H, R1 = H, R5 = R7 = H
ii
o-dichlorobenzene.5 Saponification of 24 led to the diacid 25 in
97% yield (Scheme 10). The monoester 20a was analogously
obtained in 23% yield when 3,3Ј-biindolyl 9a was heated in
ethyl propiolate (Scheme 10).
Scheme 8 Reagents and conditions: i, Ph2O, 190 ЊC; ii, KOH, MeOH
The results outlined in Scheme 10 induced us to carry out this
similar procedure in the presence of maleimide derivatives 27 to
obtain the framework involved in rebeccamycin compounds.
Unfortunately, attempted generation of a maleimide ring from
the diacid 25 to lead to 28ac gave complex mixtures which were
impossible to purify.
Nevertheless, heating of 9a–c in Ph2O at 200 ЊC (condition
A) in the presence of N-methyl- or N-phenyl-maleimide 27a–d
resulted in the formation of the indolo[2,3-c]pyrrolo[3,4-a]-
carbazoles 28 indicated in Scheme 11, Table 1. The starting
i
+
16
N
N
N
N
H
H
N
H
H
CN
22
23
Scheme 9 Reagents and conditions: i, Ph2O, 190 ЊC
indolocarbazoles 20a–c in respectable yields (30–78%) (Scheme
8) or from any isomer of the oxime 16 which gave 2-cyano-3,3Ј-
biindolyl 22 (31 %) and pyridodiindolyl 23 (51%) (Scheme 9).
During the formation of 20a, we have followed (Z)-13a on the
mixture by TLC control. Attempts to cyclize (E)-13a at lower
temperatures (reflux in xylene or acetic acid, 110 ЊC in Ph2O)
failed or gave 20a in low yields (less than 5%) and using a Lewis
acid was unsuccessful. Saponification of 20a led to the parent
acid 21 in 96% yield.
R5
R7
R1
N
R7
R5
N
N
Conditions A or B
R1′
R1
O
O
N
R
O
O
In connection with the studies of staurosporine and rebec-
camycin derivatives, the direct synthesis of indolo[2,3-c]pyrrolo-
[3,4-a]carbazoles has also been expected.
N
R1′
N
R
27a R = Me
27b R = CH2Ph
27c R = H
9a–d
28aa–db
Indolo[2,3-c]pyrrolo[3,4-a]carbazoles: direct synthesis
Scheme 11 Reagents and conditions: conditions A, Ph2O, 190 ЊC;
Conditions B, AcOH, 100 ЊC
In the 2,2Ј-biindolyl series, attempts to prepare directly
indolo[2,3-a]carbazoles via Diels–Alder cycloaddition is
fraught with difficulties and low yields. Michael addition prod-
ucts have been obtained but only traces of 1:1 cycloadducts
have been identified.5,7 We have studied the behaviour of 3,3Ј-
biindolyl in the presence of certain dienophiles. Thus, the
3,3Ј-biindolyl 9a, when heated in neat dimethyl acetylenedicar-
boxylate, gave directly the expected 1:1 adduct 24 in 75% yield
(Scheme 10). Steric hindrance of the ester groups in 24 will
material 9a remained unchanged when maleic anhydride was
used instead of an N-substituted maleimide.
Recently, treatment of 2,2Ј-biindolyl with maleimide 27c in
toluene in presence of TFA has been reported to yield the
unnatural indolo[2,3-a]carbazole 29.36 In our case, at 100 ЊC in
acetic acid (condition B, Scheme 11), 3,3Ј-biindolyl 9a and
maleimide derivative 27b did not give the expected compound
J. Chem. Soc., Perkin Trans. 1, 1998
2011

View Article Online
Table 1 Preparation of indolo[2,3-c]pyrrolo[3,4-a]carbazoles 28aa–db
Entry
28
aa
ab
R1
H
R1Ј
H
R5
H
R7
H
R
Conditions
Reaction time/h
Yield(%)
1
2
Me
A
B
A
B
B
A
B
A
A
12
36
12
24
24
24
36
6
42
44
69
55
55
53
41
56
37
H
H
H
H
CH2Ph
3
4
5
6
7
ac
bb
bc
cb
db
H
H
H
H
H
H
H
Me
Me
H
Cl
Cl
H
H
H
Cl
Cl
H
H
H
CH2Ph
H
CH2Ph
CH2Ph
Me
12
O
Conclusions
H
A new class of indolocarbazoles have been prepared by two
general methods; step by step via 2-formyl-3,3Ј-biindolyl or by
direct synthesis to prepare symmetric and non-symmetric
indolo[2,3-c]pyrrolo[3,4-a]carbazoles. Both routes, started with
readily available 3,3Ј-biindolyl derivatives, led to different com-
pounds in respectable yields. This easy access to indolo[2,3-c]-
carbazole derivatives will help us to look for any kind of
structural or conformational similarities with known receptor
ligands.
N
N
N
H
H
N
N
N
PhCH2
H
H
O
29
30
30 but the indolocarbazole 28ab in 55% yield. The indolocarb-
azoles 28aa,ac,bc could be similarly prepared. These results
have further established that formal cycloaddition reactions are
easier to control with 3,3Ј-biindolyls compared with 2,2Ј-
biindolyls.
Compound 24 was obtained in 55% yield when 9a was heated
in acetic acid at 100 ЊC in the presence of dimethyl acetylene-
dicarboxylate. The reaction, performed in the presence of
maleic anhydride during 2 days, yielded compound 31 in 46%
yield (Scheme 12).
Experimental
Melting points were determined on a Reichert WME Kofler
hot stage and are uncorrected. IR spectra were recorded on a
Perkin-Elmer 1600 FTIR instrument. NMR spectra were
obtained on a Varian UNITY plus (400 MHz) or on a Bruker
AM400 (400 MHz) instrument. J Values are given in Hz. Mass
spectra were obtained on a Finnigan MAT SSQ710 instrument
with a direct inlet at 70 eV. The 13C NMR spectra of compounds
28bb,bc could not be recorded due to their low solubility.
3,3Ј-Biindolyl derivatives 9a–c
3,3Ј-Biindolyl derivative 9a–c was prepared according to pro-
cedures reported in refs. 23 or 24. Yields of 9a–c were calculated
from starting indoles or isatins.
i
N
N
9a
H
H
3,3Ј-Biindolyl 9a. Yield 61%; mp >250 ЊC (lit.,24 mp 285–
287 ЊC); IR and NMR spectra data were identical with previous
publications.
O
O
O
31
5,7-Dichloro-3,3Ј-biindolyl 9b. Yield 31%; mp 174–176 ЊC;
νmax(KBr)/cmϪ1 3398, 3081, 1556, 1454, 1067, 747, 574;
δH([2H6]DMSO) 7.08 (1 H, t, J 7.3, ArH), 7.16 (1 H, t, J 7.3,
ArH), 7.33 (1 H, d, J 1.2, ArH), 7.47 (1 H, d, J 7.3, ArH), 7.65–
7.78 (4 H, m, ArH), 11.26 (1 H, s, NH), 11.80 (1 H, s, NH);
δC([2H6]DMSO) 108.0 (s), 111.1 (d), 111.6 (s), 116.7 (s), 117.9
(d), 119.0 (d), 119.1 (d), 120.3 (d), 121.3 (d), 122.6 (d), 123.4 (s),
124.7 (d), 125.8 (s), 128.3 (s), 131.8 (s), 136.3 (s).
1-Methyl-3,3Ј-biindolyl 9c. Yield 29%; mp 138–141 ЊC;
νmax(KBr)/cmϪ1 3421, 3410, 3046, 1612, 1456, 1333, 1231, 742,
736; δH([2H6]DMSO) 3.87 (3 H, s, CH3), 7.04–7.25 (4 H, m,
ArH), 7.44–7.50 (2 H, m, ArH), 7.66 (1 H, d, J 2.0, ArH), 7.68
(1 H, s, ArH), 7.79–7.85 (2 H, m, ArH), 11.18 (1 H, s, NH);
δC([2H6]DMSO) 32.3 (q), 108.9 (s), 109.3 (s), 109.6 (d),
111.5 (d), 118.7 (d), 118.8 (d), 119.5 (d), 119.7 (d), 121.1 (d),
121.2 (d), 121.7 (d), 125.8 (s), 126.2 (d), 126.3 (s), 136.3 (s),
136.6 (s).
Scheme 12 Reagents and conditions: i, maleic anhydride, AcOH,
100 ЊC
The mechanism of formation of 28 in these two conditions is
not clear. Nevertheless, for protic as well as aprotic conditions,
it is reasonable to assume that a Michael addition occurs at the
2-position on the 3,3Ј-biindolyl. In accord with this, diethyl
azodicarboxylate (DEAD), a good dienophile for Diels–Alder
reactions, has been heated in toluene at 110 ЊC in the presence
of 1,1Ј-dimethyl-3,3Ј-biindolyl 9d and the Michael adduct 32
has been isolated in 87% yield (Scheme 13). This fact probably
Me
N
i
9d
CO2Et
N
CO2Et
N
N
1,1Ј-Dimethyl-3,3Ј-biindolyl 9d
Me
H
1,1Ј-Dimethyl-3,3Ј-biindole 9d was prepared from 9a according
to a procedure reported in ref. 37. Yield 65%; mp 185–187 ЊC
(lit.,38 mp 186–188 ЊC); νmax(KBr)/cmϪ1 2922, 2851, 1466, 1327,
1241, 739; δH([2H6]DMSO) 3.87 (3 H, s, CH3), 7.11 (1 H, t, J 7.3,
ArH), 7.22 (1 H, t, J 7.3, ArH), 7.48 (1 H, d, J 7.3, ArH), 7.69
(1 H, s, ArH), 7.85 (1 H, d, J 7.3, ArH); δC([2H6]DMSO) 32.3
(q), 108.5 (s), 109.7 (d), 118.8 (d), 119.7 (d), 121.3 (d), 126.1 (d),
136.6 (s).
Scheme 13 Reagents and conditions: i, DEAD, toluene, 110 ЊC
eliminates the hypothesis of a [4 ϩ 2] cycloaddition mechanism
for the aprotic conditions. However, in neither solvent, have
any intermediates have been clearly isolated and the conditions
of cyclization and aromatization of the C-ring have not been
determined and are still under investigation.
2012
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
3,3Ј-Biindolyl-2-carboxaldehyde derivatives 11a-d: general
procedure
under an inert atmosphere was added at 0 ЊC diethyl phos-
phonoethylacetate (1.3 mmol). The NaH suspension disap-
peared and, after 5 min, a solution of THF (10 ml) containing
11a–c (1 mmol) was slowly added at 0 ЊC. The resulting solution
was stirred during 15 min at 0 ЊC and 1 h at room temperature.
The THF solution was quenched with water (40 ml) and the
mixture was extracted with CH2Cl2 (4 × 20 ml). The combined
organic phases were dried (MgSO4), filtered and the solvent
evaporated in vacuo. The residue was chromatographed on a
silica gel column (CH2Cl2) giving yellow compound 13a–c.
Ethyl (E)-3-(3,3Ј-biindolyl-2-yl)propenoate 13a. Yield 80%;
mp 232–234 ЊC (Found: C, 76.25; H, 5.55; N, 8.59. C21H18N2O2
requires C, 76.34; H, 5.49; N, 8.48%); νmax(KBr)/cmϪ1 3425,
3304, 2978, 1684, 1625, 1193, 750; δH([2H6]DMSO) 1.21 (3 H, t
br, CH3), 4.14 (2 H, q br, CH2), 6.59 (1 H, d, J 15.9, Heth), 6.95–
7.10 (2 H, m, ArH), 7.20 (1 H, t, J 7.3, ArH), 7.28 (1 H, t, J 7.3,
ArH), 7.35–7.55 (5 H, m, ArH), 7.69 (1 H, d, J 15.9, Heth), 11.48
(1 H, s, NH), 11.64 (1 H, s, NH); δC([2H6]DMSO) 14.1 (q), 59.7
(t), 107.1 (s), 111.4 (d), 111.8 (d), 114.3 (d), 116.6 (s), 119.1 (d),
119.2 (d), 119.5 (d), 120.6 (d), 121.4 (d), 124.6 (d), 124.9 (d),
126.8 (s), 127.5 (s), 130.0 (s), 133.4 (d), 136.4 (s) 137.8 (s), 166.4
(s); m/z 330 (Mϩ, 100%), 257 (40%).
Ethyl (Z)-3-(3,3Ј-biindolyl-2-yl)propenoate 13a. Yield 10%;
mp 226–228 ЊC; νmax(KBr)/cmϪ1 3410, 2975, 1690, 1620, 740;
δH(CDCl3) 1.37 (3 H, t, J 7.3, CH3), 4.31 (2 H, q, J 7.3, CH2),
5.71 (1 H, d, J 12.8, Heth), 7.08 (1 H, t, J 7.0, ArH), 7.12 (1 H, d,
J 12.8, Heth), 7.15 (1 H, t, J 7.0, ArH), 7.28 (1 H, t, J 7.0, ArH),
7.30–7.35 (2 H, m, ArH), 7.46–7.53 (2 H, m, ArH), 7.59 (1 H, d,
J 7.0, ArH), 7.62 (1 H, d, J 7.0, ArH), 8.39 (1 H, s, NH), 8.77
(1 H, s, NH).
Ethyl (E)-3-(5Ј,7Ј-dichloro-3,3Ј-biindolyl-2-yl)propenoate 13b.
Yield 95%; mp 150–152 ЊC (Found: C, 63.28; H, 4.10; N, 7.14.
C21H16Cl2N2O2 requires C, 63.17; H, 4.04; N, 7.02%);
νmax(KBr)/cmϪ1 3468, 3313, 2972, 1693, 1681, 1610, 1281, 750;
δH([2H6]DMSO) 1.22 (3 H, t, J 7.0, CH3), 4.15 (2 H, q, J 7.0,
CH2), 6.61 (1 H, d, J 16.2, Heth), 7.07 (1 H, t, J 7.3, ArH), 7.25–
7.31 (2 H, m, ArH), 7.37 (1 H, d, J 1.5, ArH), 7.44 (1 H, d, J 7.3,
ArH), 7.46 (1 H, d, J 7.3, ArH), 7.55 (1 H, d, J 16.2, Heth), 7.69
(1 H, d, J 2.6, ArH), 11.76 (1 H, s, NH), 12.13 (1 H, s, NH);
δC([2H6]DMSO) 14.1 (q), 59.8 (t), 108.3 (s), 111.6 (d), 114.5 (s),
115.2 (d), 117.2 (s), 117.4 (d), 119.8 (d), 120.2 (d), 120.7 (d),
123.8 (s), 124.7 (d), 127.3 (s), 127.8 (d), 129.2 (s), 130.5 (s), 132.0
(s), 132.7 (d), 137.7 (s), 166,3 (s).
To a stirred suspension of 3,3Ј-biindolyl derivative 9a–d (1
mmol) in CH3CN (10 ml), N,N-dimethylchloromethaniminium
chloride (1.3 mmol) was added at room temperature. After dis-
solution, a new precipitate soon appeared. The solvent was
evaporated in vacuo after TLC control of the total disappear-
ance of the starting material (2–12 h). Saturated aqueous
NaHCO3 (15 ml) was added and the aqueous phase was
extracted with EtOAc (3 × 15 ml). The combined organic
phases were dried (MgSO4), filtered and evaporated in vacuo.
The residue, chromatographed on a silica gel column (CH2Cl2),
gave compound 11a–d as a yellow solid.
3,3Ј-Biindolyl-2-carboxaldehyde 11a. Yield 85%; mp 189–
191 ЊC (Found: C, 78.34; H, 4.68; N, 10.74. C17H12N2O requires
C, 78.44; H, 4.65; N, 10.76%); νmax(KBr)/cmϪ1 3385, 3278, 2923,
1645, 1612, 748; δH(CDCl3) 7.12–7.25 (2 H, m, ArH), 7.31(1 H,
t, J 8.1, ArH), 7.41–7.54 (4 H, m, ArH), 7.71 (1 H, d, J 8.1,
ArH), 7.80 (1 H, d, J 8.1, ArH), 8.51 (1 H, s, NH), 9,12 (1 H, s,
NH), 9.92 (1 H, s, CHO); δC([2H6]DMSO) 105.9 (s), 111.1 (d),
112.9 (d), 119.0 (d), 119.5 (d), 120.1 (d), 121.7 (d), 122.2 (s),
122.4 (d), 126.1 (d), 126.5 (s), 126.7 (d), 126.8 (s), 131.8 (s),
136.5 (s), 138.1 (s), 182.0 (d); m/z 260 (Mϩ, 100%).
5Ј,7Ј-Dichloro-3,3Ј-biindolyl-2-carboxaldehyde 11b. Yield
85%; mp 188–190 ЊC; νmax(KBr)/cmϪ1 3422, 3286, 2849, 1640,
1613, 744; δH([2H6]DMSO) 7.14 (1 H, t, J 8.1, ArH), 7.34–7.45
(3 H, m, ArH), 7.53 (1 H, d, J 8.1, ArH), 7.59 (1 H, d, J 8.1,
ArH), 7.90 (1 H, s, ArH), 9.80 (1 H, s, CHO), 12.05 (1 H, s, NH),
12.20 (1 H, s, NH); δC([2H6]DMSO) 107.1 (s), 113.0 (d), 117.2 (s),
117.4 (d), 119.9 (s), 120.4 (d), 120.8 (s), 121.9 (d), 124.0 (s), 126.3
(s), 126.8 (d), 128.9 (d), 129.1 (s), 132.1 (s) 137.8 (s), 182.0 (d).
1Ј-Methyl-3,3Ј-biindolyl-2-carboxaldehyde 11c. Yield 95%;
mp 166–168 ЊC; νmax(KBr)/cmϪ1 3325, 2925, 1640, 1612, 740;
δH([2H6]DMSO) 3.91 (3 H, s, CH3), 7.07–7.16 (2 H, m, ArH),
7.27 (1 H, t, J 8.1, ArH), 7.39 (1 H, t, J 8.1, ArH), 7.51–7.59
(3 H, m, ArH), 7.68 (1 H, d, J 8.1, ArH), 7.74 (1 H, s, ArH),
9.86 (1 H, s, CHO), 11.94 (1 H, s, NH); δC([2H6]DMSO) 32.6
(q), 105.0 (s), 110.2 (d), 112.9 (d), 119.2 (d), 119.7 (d), 120.1 (d),
121.7 (s), 121.8 (d), 122.3 (d), 126.4 (s), 126.8 (d), 127.0 (s),
130.2 (d), 131.7 (s) 136.9 (s), 138.1 (s) 182.0 (d).
1,1Ј-Dimethyl-3,3Ј-biindolyl-2-carboxaldehyde 11d. Yield
80%; mp 172–174 ЊC; νmax(KBr)/cmϪ1 2925, 2825, 1643, 1387,
744; δH([2H6]DMSO) 3.91 (3 H, s, CH3), 4.12 (3 H, s, CH3), 7.11
(1 H, t, J 7.3, ArH), 7.16 (1 H, t, J 7.3, ArH), 7.26 (1 H, t, J 8.1,
ArH), 7.44–7.52 (2 H, m, ArH), 7.56 (1 H, d, J 7.3, ArH), 7.62–
7.72 (3 H, m, ArH), 9.90 (1 H, s, CHO); δC([2H6]DMSO) 31.5
(q), 32.6 (q), 104.5 (s), 110.2 (d), 110.9 (d), 119.1 (d), 119.7 (d),
120.4 (d), 121.8 (d), 122.3 (d), 124.1 (s), 125.4 (d), 127.2 (s),
127.2 (s), 130.4 (s), 130.5 (d), 136.8 (s), 139.6 (s), 183.0 (d).
Ethyl (E)-3-(1-methyl-3,3Ј-biindolyl-2-yl)propenoate 13c.
Yield 95%; mp 198–200 ЊC (Found: C, 76.67; H, 6.02; N, 8.27.
C22H20N2O2 requires C, 76.72; H, 5.85; N, 8.13%); νmax(KBr)/
cmϪ1 3330, 2921, 1682, 1609, 1277, 742, 733; δH([2H6]DMSO)
1.21 (3 H, t, J 7.0, CH3), 3.92 (3 H, s, CH3), 4.14 (2 H, q, J 7.0,
CH2), 6.59 (1 H, d, J 16.0, Heth), 7.07–7.12 (2 H, m, ArH), 7.20–
7.32 (2 H, m, ArH), 7.38–7.46 (2 H, m, ArH), 7.48–7.58 (3 H,
m, ArH), 7.65 (1 H, d, J 16.0, Heth), 11.65 (1 H, s, NH);
δC([2H6]DMSO) 14.1 (q), 32.5 (q), 59.7 (t), 106.3 (s), 110.1 (d),
111.4 (d), 114.4 (d), 116.1 (s), 119.3 (d), 119.5 (d), 120.6 (d),
121.6 (d), 124.6 (d), 127.1 (s), 127.4 (s), 129.0 (d), 130.0 (s),
133.3 (d), 136.8 (s), 137.8 (s), 166.4 (s).
2-Vinyl-3,3Ј-biindolyl 12
A solution of triglyme (2,5,8,11-tetraoxadodecane) (1 ml) con-
taining aldehyde 11a (90 mg, 0.34 mmol), methyltriphenyl-
phosphonium bromide (154 mg, 0.43 mmol) and K2CO3 (72
mg, 0.52 mmol) was heated during 4.5 h at 120 ЊC. After cool-
ing, the solution was chromatographed on a silica gel column
[CH2Cl2–light petroleum 50:50 (v/v)] affording 75 mg (85%) of
12; mp 207–209 ЊC (dec.); νmax(KBr)/cmϪ1 3398, 2919, 1602,
1454, 741; δH(CDCl3) 5.22 (1 H, d, J 11.3, Heth), 5.52 (1 H, d,
J 17.7, Heth), 6.89 (1 H, dd, J 11.3, 17.7, Heth), 7.10 (1 H, t, J 8.0,
ArH), 7.15 (1 H, t, J 8.0, ArH), 7.20–7.32 (3 H, m, ArH), 7.40
(1 H, d, J 8.0, ArH), 7.46 (1 H, d, J 8.0, ArH), 7.57–7.66 (2 H,
m, ArH), 8.29 (2 H, s, NH); δC(CDCl3) 109.6 (s), 110.6 (d),
110.9 (t), 111.0 (s), 111.1 (d), 119.7 (d), 119.8 (d), 120.6 (d),
120.7 (d), 122.2 (d), 123.2 (d), 123.5 (d), 126.9 (d), 127.6 (s),
129.0 (s) 132.8 (s), 136.2 (s), 136.3 (s).
Diethyl 3,3Ј-biindolyl-2-ylmethylenemalonate 14
A mixture of compound 11a (130 mg, 0.5 mmol) and diethyl
malonate (0.091 µl, 0.6 mmol) was heated in toluene at reflux
during 5 h. After evaporation of toluene in vacuo, the residue
was chromatographed on a silica gel column (CH2Cl2) affording
152 mg (75%) of 14 as an orange solid; mp 160–162 ЊC (Found:
C, 71.54; H, 5.51; N, 6.87. C24H22N2O4 requires C, 71.63; H,
5.51; N, 6.96%); νmax(KBr)/cmϪ1 3425, 2972, 1689, 1585, 1202,
741, 738; δH(CDCl3) 1.23 (3 H, t, J 7.1, CH3), 1.41 (3 H, t, J 7.1,
CH3), 4.21 (2 H, q, J 7.1, CH2), 4.44 (2 H, q, J 7.1, CH2), 7.11
(1 H, t, J 8.0, ArH), 7.16 (1 H, t, J 8.0, ArH), 7.28 (1 H, t, J 8.0,
ArH), 7.32 (1 H, t, J 2.4, ArH), 7.36 (1 H, t, J 8.0, ArH), 7.45–
7.51 (2 H, m, ArH), 7.64 (1 H, d, J 8.0, ArH), 7.69 (1 H, d, J 8.0,
ArH), 7.98 (1 H, s, Heth), 8.45 (1 H, s, NH), 10.50 (1 H, s, NH);
Ethyl 3-(3,3Ј-biindolyl-2-yl)propenoate derivatives 13a–c: general
procedure
To a suspension of NaH (1.3 mmol) in dried THF (10 ml)
J. Chem. Soc., Perkin Trans. 1, 1998
2013

View Article Online
δC(CDCl3) 14.1 (q, 2C), 61.3 (t), 61.9 (t), 109.3 (s), 111.4 (d),
112.1 (d), 118.1 (s), 120.3 (d), 120.4 (d), 120.6 (d), 122.2 (d),
122.8 (d), 124.6 (d), 126.4 (d), 127.4 (s), 128.8 (s), 135.5 (d),
136.4 (s), 138.2 (s), 166.4 (s), 168.3 (s); m/z 402 (Mϩ, 100%), 286
(30%), 257 (35%).
1,1Ј-Dimethyl-2-(2-nitroethenyl)-3,3Ј-biindolyl 19. Mp 195–
197 ЊC; νmax(KBr)/cmϪ1 2922, 1557, 1318, 738; δH([2H6]DMSO)
3.95 (3 H, s, CH3), 4.03 (3 H, s, CH3), 7.07–7.16 (2 H, m, ArH),
7.28 (1 H, t, J 7.4, ArH), 7.38 (1 H, d, J 7.4, ArH), 7.42 (1 H, t,
J 7.4, ArH), 7.56 (1 H, d, J 7.4, ArH), 7.60 (1 H, d, J 7.4, ArH),
7.63 (1 H, s, ArH), 7.68 (1 H, d, J 7.4, ArH), 7.82 (1 H, d, J 14.0,
Heth), 8.21 (1 H, d, J 14.0, Heth).
2-(2-Nitroethenyl)-3,3Ј-biindolyl 15
A mixture of CH3NO2 (5 ml), 11a (260 mg, 1 mmol) and
NH4OAc (58 mg, 0.75 mmol) was heated at reflux during 3 h.
After evaporation in vacuo, the residue was chromatographed
on a silica gel column (CH2Cl2) affording 245 mg (81%) of 15 as
brownish solid; mp 205–207 ЊC (Found: C, 70.63; H, 4.81; N,
13.67. C18H15N3O2 requires C, 70.81; H, 4.95; N, 13.76%);
νmax(KBr)/cmϪ1 3399, 3364, 1588, 1308, 1292, 1256, 1203, 746;
δH([2H6]DMSO) 7.05–7.15 (2 H, m, ArH), 7.21 (1 H, m, ArH),
7.37 (1 H, m, ArH), 7.45–7.65 (5 H, m, ArH), 8.03 (1 H, d,
J 13.3, Heth), 8.09 (1 H, d, J 13.3, Heth), 11.63 (1 H, s, NH), 11.84
(1 H, s, NH); δC([2H6]DMSO) 106.7 (s), 111.8 (d), 112.0 (d),
118.9 (d), 119.6 (d), 120.1 (d), 121.4 (d), 121.8 (d), 122.5 (s),
125.7 (d), 125.8 (s), 126.4 (s), 126.5 (d), 127.1 (s), 128.5 (d),
133.6 (d), 136.6 (s), 139.0 (s); m/z 303 (Mϩ, 100%), 231 (24%).
Conversion of 1,1Ј-dimethyl-2-(2-nitroethenyl)-3,3Ј-biindolyl 19
to compound 18
A suspension of compound 19 (35 mg, 0.1 mmol) in Ph2O (1 ml)
was heated at 160 ЊC during 3 h. After cooling, the solution was
chromatographed on a silica gel column [50:50 CH2Cl2–light
petrolum (v/v)] affording 16 mg (58%) of 18; mp, IR, NMR spec-
tral data were identical with the descriptions reported above.
Ethyl 5,8-dihydroindolo[2,3-c]carbazole-6-carboxylate 20a–c:
general procedure
A suspension of compound 13a–c (0.5 mmol) in Ph2O (3 ml)
was heated at 190–200 ЊC during 24–72 h. After cooling, the
solution was chromatographed on a silica gel column [75:25,
CH2Cl2–light petroleum (v/v)] giving compound 20a–c.
Ethyl 5,8-dihydroindolo[2,3-c]carbazole-6-carboxylate 20a.
Yield 78%; mp 240–242 ЊC (Found: C, 76.65; H, 4.91; N, 8.38.
C21H16N2O2 requires C, 76.81; H, 4.91; N, 8.53%); νmax(KBr)/
cmϪ1 3401, 2978, 1672, 1254, 1202, 741; δH([2H6]DMSO) 1.48
(3 H, t, J 7.0, CH3), 4.53 (2 H, q, J 7.0, CH2), 7.37 (2 H, t,
J 7.4, ArH), 7.50 (1 H, t, J 7.4, ArH), 7.56 (1 H, t, J 7.4,
ArH), 7.67 (1 H, d, J 7.4, ArH), 7.91 (1 H, d, J 7.4, ArH), 8.32
(1 H, s, ArH), 8.78 (1 H, d, J 7.4, ArH), 8.83 (1 H, d, J 7.4,
ArH), 11.50 (1 H, s, NH) 11.70 (1 H, s, NH); δC([2H6]DMSO)
14.3 (q), 60.6 (t), 109.8 (s), 111.3 (d), 111.4 (d), 112.3 (d),
116.5 (s), 118.7 (d), 118.9 (d), 120.1 (s), 121.0 (s), 121.1 (s),
122.4 (d), 123.6 (d), 125.0 (d), 126.4 (d), 133.5 (s), 133.6 (s),
139.7 (s), 141.2 (s), 166.4 (s); m/z 328 (Mϩ, 100%), 282 (68%),
254 (37%).
Ethyl 2,4-dichloro-5,8-dihydroindolo[2,3-c]carbazole-6-carb-
oxylate 20b. Yield 50%; mp 244–246 ЊC (Found: C, 63.39; H,
3.65; N, 6.94. C21H14Cl2N2O2 requires C, 63.49; H, 3.55; N,
7.05%); νmax(KBr)/cmϪ1 3465, 3318, 2975, 1692, 1623, 1273,
1223, 767; δH([2H6]DMSO) 1.45 (3 H, t, J 7.0, CH3), 4.44 (2 H,
q, J 7.0, CH2), 7.34 (1 H, t, J 7.4, ArH), 7.54 (1 H, t, J 7.4,
ArH), 7.59 (1 H, d, J 1.2, ArH), 7.63 (1 H, d, J 7.4, ArH), 8.16
(1 H, s, ArH), 8.33 (1 H, d, J 1.2, ArH), 8.39 (1 H, d, J 7.4,
ArH), 10.23 (1 H, s, NH); 11.71 (1 H, s, NH); δC([2H6]DMSO)
14.3 (q), 61.2 (t), 109.5 (s), 111.8 (d), 113.3 (d), 115.7 (s), 118.8
(s), 119.3 (d), 119.7 (d), 120.6 (s), 120.7 (s), 123.3 (d), 123.4 (s),
123.6 (d), 124.0 (s), 126.9 (d), 130.2 (s), 134.1 (s), 134.2 (s), 141.2
(s), 166.4 (s); m/z 400 (10%), 398 (61%), 396 (Mϩ, 100%), 352
(33%), 350 (61%).
3,3Ј-Biindolyl-2-carbaldehyde oxime 16
A solution of EtOH (2 ml) containing 11a (130 mg, 0.5 mmol),
NaOAc (82 mg, 1 mmol) and NH2OHؒHCl (69.5 mg, 1 mmol)
was heated at reflux during 1.5 h. After evaporation of EtOH in
vacuo, the residue was chromatographed on a silica gel column
[99.5:0.5, CH2Cl2–MeOH, (v/v)] affording 65 mg of (E)-16 and
65 mg (Z)-16 (95%).
(E)-3,3Ј-Biindolyl-2-carbaldehyde oxime 16. Mp 82–84 ЊC
(dec.) (Found: C, 74.24; H, 4.78; N, 15.12. C17H13N3O requires
C, 74.17; H, 4.76; N, 15.26%); νmax(KBr)/cmϪ1 3401, 2919, 1602,
1451, 1408, 955, 738; δH(CDCl3) 7.09–7.20 (2 H, m, ArH), 7.24–
7.33 (3 H, m, ArH), 7.38 (1 H, d, J 8.2, ArH), 7.47 (1 H, d, J 8.2,
ArH), 7.62–7.68 (2 H, m, ArH), 8.29 (1 H, s, CH), 8.32 (1 H, s,
NH), 8.98 (1 H, s, NH); δC(CDCl3) 108.7 (s), 111.2 (d), 111.4
(d), 120.2 (d), 120.3 (d), 120.4 (d), 121.2 (d), 122.7 (d), 123.7 (d),
124.8 (d), 126.8 (s), 127.5 (s), 128.2 (s), 136.4 (s), 137.0 (s), 142.8
(d); m/z 275 (Mϩ, 100%), 257 (54%).
(Z)-3,3Ј-Biindolyl-2-carbaldehyde oxime 16. Mp 108–110 ЊC;
νmax(KBr)/cmϪ1 3401, 2919, 1610, 1451, 1409, 914, 738;
δH(CDCl3) 7.11–7.20 (2 H, m, ArH), 7.27–7.38 (3 H, m, ArH),
7.46–7.52 (2 H, m, ArH), 7.63 (1 H, d, J 8.1, ArH), 7.66–7.70
(2 H, m, ArH), 8.40 (1 H, s, NH), 10.12 (1 H, s, NH).
5,8-Dihydroindolo[2,3-c]carbazole 17
A suspension of compound 15 (182 mg, 0.6 mmol) and Pd/C
(10 mg) in Ph2O (5 ml) was heated at 200 ЊC for 12 h. After
cooling, the solution was chromatographed on a silica gel
column [50:50 CH2Cl2–light petroleum (v/v)] affording 47 mg
(30%) of 17; mp 155–157 ЊC (dec.); νmax(KBr)/cmϪ1 3384, 2923,
2853, 1457, 1328, 737; δH([2H6]DMSO) 7.31 (2 H, t, J 7.4, ArH),
7.44 (2 H, t, J 7.4, ArH), 7.61 (2 H, d, J 7.4, ArH), 7.65 (2 H, s,
ArH), 8.73 (2 H, d, J 7.4, ArH), 11.48 (2 H, s, NH);
δC([2H6]DMSO) 110.2 (d), 111.0 (d), 115.1 (s), 118.1 (d), 122.0
(s), 122.4 (d), 124.2 (d), 134.4 (s), 139.3 (s); m/z 256 (Mϩ, 100%).
Ethyl 5-methyl-5,8-dihydroindolo[2,3-c]carbazole-6-carboxyl-
ate 20c. Yield 30%; mp 180–182 ЊC; νmax(KBr)/cmϪ1 3348, 2922,
2852, 1686, 1621, 1267, 1206, 741; δH([2H6]DMSO) 1.44 (3 H, t,
J 7.0, CH3), 3.90 (3 H, s, CH3), 4.50 (2 H, q, J 7.0, CH2), 7.37
(1 H, t, J 7.4, ArH), 7.44 (1 H, t, J 7.4, ArH), 7.55 (1 H, t, J 7.4,
ArH), 7.60 (1 H, t, J 7.4, ArH), 7.68 (1 H, d, J 7.4, ArH), 7.77
(1 H, d, J 7.4, ArH), 8.04 (1 H, s, ArH), 8.80–8.86 (2 H, m,
ArH), 11.72 (1 H, s, NH); δC([2H6]DMSO) 14.1 (q), 33.6 (q),
61.1 (t), 109.9 (d), 111.4 (d), 111.8 (d), 114.4 (s), 118.2 (s), 118.7
(d), 119.3 (d), 121.0 (s), 121.3 (s), 122.5 (d), 123.4 (d), 125.5 (d),
126.0 (d), 133.5 (s), 140.8 (s), 141.6 (s), 167.4 (s); m/z 342
(Mϩ, 100%), 296 (52%).
5,8-Dimethyl-5,8-dihydroindolo[2,3-c]carbazole 18 and 1,1Ј-
dimethyl-2-(2-nitroethenyl)-3,3Ј-biindolyl 19 from compound 11d
A mixture of CH3NO2 (3 ml), 11d (144 mg, 0.5 mmol) and
NH4OAc (19 mg, 0.25 mmol) was heated at reflux during 48 h.
After evaporation in vacuo, the residue was chromatographed
on a silica gel column (CH2Cl2) affording 29 mg (20%) of 19,
15 mg (8%) of 18 and 100 mg (69%) of starting material 11d.
5,8-Dimethyl-5,8-dihydroindolo[2,3-c]carbazole 18. Mp 240–
244 ЊC (lit.,21 mp 257.6–258.2 ЊC); νmax(KBr)/cmϪ1 2925, 1449,
1320, 738; δH([2H6]DMSO) 4.03 (6 H, s, CH3), 7.37 (2 H, t, J 7.5,
ArH), 7.55 (2 H, t, J 7.5, ArH), 7.73 (2 H, d, J 7.5, ArH), 7.87
(2 H, s, ArH), 8.79 (2 H, d, J 7.4, ArH); δC([2H6]DMSO) 29.3
(q), 108.3 (d), 109.2 (d), 115.0 (s), 118.3 (d), 121.2 (s), 122.6 (d),
124.7 (d), 135.8 (s), 140.2 (s).
Preparation of ethyl 5,8-dihydroindolo[2,3-c]carbazole-6-
carboxylate 20a from compound 9a
Ethyl propiolate (2 ml) and 9a (116 mg, 0.5 mmol) were heated
at 120 ЊC during 24 h. After evaporation in vacuo, the residue
was chromatographed on a silica gel column (CH2Cl2) afford-
ing 37 mg (23%) of 20a; mp, IR and NMR spectra data were
identical with the descriptions reported above.
2014
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
5,8-Dihydroindolo[2,3-c]carbazole-6-carboxylic acid 21
Preparation of indolo[2,3-c]pyrrolo[3,4-a]carbazole derivatives
28 using Ph2O as solvent (conditions A)
The ester 20a (148 mg, 0.45 mmol), EtOH (9 ml) and a solution
of aq. NaOH (10%) (9 ml) were heated at reflux during 1 h.
After cooling and acidification (pH 2–3), the precipitate was
collected affording 130 mg (96%) of the yellow acid 21; mp
>250 ЊC (Found: C, 76.04; H, 4.03; N, 9.49. C19H12N2O2
requires C, 75.99; H, 4.03; N, 9.33%); νmax(KBr)/cmϪ1 3584,
3395, 1661, 1623, 1586, 1415, 1327, 1219, 740; δH([2H6]DMSO)
7.37 (2 H, t, J 7.4, ArH), 7.48 (1 H, t, J 7.4, ArH), 7.55 (1 H, t,
J 7.4, ArH), 7.67 (1 H, d, J 7.4, ArH), 7.93 (1 H, d, J 7.4, ArH),
8.30 (1 H, s, ArH), 8.78 (1 H, d, J 7.4, ArH), 8.83 (1 H, d, J 7.4,
ArH), 11.47 (1 H, s, NH), 11.74 (1 H, s, NH), 13.22 (1 H, s,
CO2H); δC([2H6]DMSO) 110.7 (s), 111.4 (d), 111.9 (d), 112.3
(d), 116.3 (s), 118.6 (d), 118.8 (d), 119.7 (s), 121.1 (s), 121.2 (s),
122.3 (d), 123.5 (d), 124.3 (d), 126.2 (d), 133.5 (s), 133.8 (s),
139.6 (s), 141.1 (s), 168.2 (s).
7-Methyl-6,7,8,9-tetrahydro-5H-indolo[2,3-c]pyrrolo[3,4-a]-
carbazole-6,8-dione 28aa. A suspension of compound 9a
(0.5 mmol) and maleimide 27a (0.6 mmol) in Ph2O (3 ml) was
heated at 190–200 ЊC for 12 h. The solution was chromato-
graphed on a silica gel column (CH2Cl2) to give 28aa; yield
42%; mp >250 ЊC (Found: C, 74.18; H, 3.80; N, 11.89. C21-
H13N3O2 requires C, 74.33; H, 3.86; N, 12.38%); νmax(KBr)/cmϪ1
3367, 2922, 2849, 1731, 1667, 1381, 1325, 1090, 736; δH([2H6]-
DMSO) 3.16 (3 H, s, CH3), 7.42 (2 H, t, J 8.1, ArH), 7.59 (2 H,
t, J 8.1, ArH), 7.80 (2 H, d, J 8.1, ArH), 8.82 (2 H, d, J 8.1,
ArH), 12.05 (2 H, s, NH); δC([2H6]DMSO) 23.5 (q) 110.4 (s),
112.4 (d), 119.7 (d), 120.6 (s), 122.5 (s). 123.4 (d), 127.0
(d), 128.5 (s), 142.4 (s), 168.6 (s); m/z 339 (Mϩ, 100%), 254
(20%).
7-Benzyl-6,7,8,9-tetrahydro-5H-indolo[2,3-c]pyrrolo[3,4-a]-
carbazole-6,8-dione 28ab. A suspension of compound 9a
(0.5 mmol) and maleimide 27b (0.6 mmol) in Ph2O (3 ml) was
heated at 190–200 ЊC for 12 h. The solution was chromato-
graphed on a silica gel column (CH2Cl2) to give 28ab; yield
69%; mp >250 ЊC; νmax(KBr)/cmϪ1 3403, 2922, 2850, 1741,
1691, 1682, 1613, 1461, 1325, 1224, 742; δH([2H6]DMSO) 4.90
(2 H, s, CH2), 7.25–7.46 (7 H, m, ArH), 7.60 (2 H, t, J 8.1,
ArH), 7.80 (2 H, d, J 8.1, ArH), 8.84 (2 H, d, J 8.1, ArH), 12.09
(2 H, s, NH); δC([2H6]DMSO) 40.5 (t), 110.1 (s), 112.4 (d), 119.8
(d), 120.6 (s), 122.8 (s), 123.5 (d), 127.2 (d), 127.3 (d), 128.5 (d),
128.6 (d), 128.7 (s), 137.5 (s), 142.5 (s), 168.2 (s); m/z 415
(Mϩ, 100%), 254 (32%).
7-Benzyl-2,4-dichloro-6,7,8,9-tetrahydro-5H-indolo[2,3-c]-
pyrrolo[3,4-a]carbazole-6,8-dione 28bb. A suspension of com-
pound 9b (0.5 mmol) and maleimide 27b (0.6 mmol) in Ph2O
(3 ml) was heated at 190–200 ЊC during 24 h. Table 1. After
cooling, Et2O was added and the resulting precipitate was
filtered and washed with Et2O to give 28bb; yield 53%; mp
>250 ЊC (Found: C, 67.09; H, 3.10; N, 8.57. C27H15Cl2N3O2
requires C, 66.96; H, 3.12; N, 8.68%); νmax(KBr)/cmϪ1 3448,
3378, 3060, 1752, 1681, 1399, 1281, 720; δH([2H6]DMSO)
4.91 (2 H, s, CH2), 7.26–7.51 (7 H, m, ArH), 7.63 (1 H, t,
J 8.1, ArH), 7.81–7.85 (2 H, m, ArH), 8.66 (1 H, d, J 8.1, ArH),
8.69 (1 H, d, J 1.2, ArH), 11.94 (1 H, s, NH), 12.28 (1 H, s,
NH).
3,3Ј-Biindolyl-2-carbonitrile 22 and 5,8-dihydropyrido[2,3-b:
5,4-bЈ]diindole 23
A suspension of 16 (138 mg, 0.5 mmol) in Ph2O (4 ml) was
heated during 5 h at 190–200 ЊC. After cooling, the solution was
chromatographed on a silica gel column [99:1 CH2Cl2–MeOH,
(v/v)] affording 40 mg (31%) of 22 and 65 mg (51%) of 23.
3,3Ј-Biindolyl-2-carbonitrile 22. Mp 222–224 ЊC (Found: C,
79.26; H, 4.47; N, 16.25. C17H11N3 requires C, 79.36; H, 4.31; N,
16.33%); νmax(KBr)/cmϪ1 3378, 2922, 2215, 1337, 1095, 745;
δH([2H6]DMSO) 7.09 (1 H, t, J 7.3, ArH), 7.15–7.24 (2 H, m,
ArH), 7.40 (1 H, t, J 7.3, ArH), 7.48–7.55 (2 H, m, ArH), 7.57
(1 H, d, J 7.3, ArH), 7.65–7.72 (2 H, m, ArH), 11.56 (1 H, s,
NH), 12.34 (1 H, s, NH); δC([2H6]DMSO) 103.0 (s), 105.7 (s),
111.9 (d), 112.3 (d), 115.2 (s), 119.2 (d), 119.4 (d), 120.6 (d),
121.1 (d), 121.6 (d), 121.8 (s), 124.7 (d), 125.0 (s), 125.7 (s),
125.8 (d), 136.4 (s), 137.2 (s).
5,8-Dihydropyrido[2,3-b:5,4-bЈ]diindole 23. Mp >250 ЊC;
νmax(KBr)/cmϪ1 3383, 2915, 2841, 1623, 1415, 1331, 740;
δH([2H6]DMSO) 7.33–7.43 (2 H, m, ArH), 7.50 (1 H, t, J 7.4,
ArH), 7.58–7.65 (2 H, m, ArH), 7.70 (1 H, d, J 7.4, ArH), 8.68
(1 H, d, J 7.4, ArH), 8.77 (1 H, d, J 7.4, ArH), 8.85 (1 H, s, ArH),
11.75 (1 H, s, NH), 11.88 (1 H, s, NH); δC([2H6]DMSO) 106.9
(s), 111.1 (d), 111.9 (d), 118.8 (d), 118.9 (d), 120.1 (s), 120.3 (s),
122.1 (s), 122.9 (d), 123.9 (d), 125.1 (d), 127.3 (d), 131.1 (d),
131.5 (s), 138.2 (s), 140.8 (s), 145.8 (s); m/z 257 (Mϩ, 100%).
7-Benzyl-5-methyl-6,7,8,9-tetrahydro-5H-indolo[2,3-c]-
pyrrolo[3,4-a]carbazole-6,8-dione 28cb. A suspension of com-
pound 9c (0.5 mmol) and maleimide 27b (0.6 mmol) in Ph2O
(3 ml) was heated at 190–200 ЊC during 6 h. After cooling, Et2O
was added and the resulting precipitate was filtered and washed
with Et2O to give 28cb; yield 56%; mp >250 ЊC (Found: C,
78.31; H, 4.44; N, 9.78. C28H19N3O2 requires C, 78.31; H, 4.46;
N, 9.78%); νmax(KBr)/cmϪ1 3342, 3031, 2928, 1737, 1684, 1609,
1396, 1343, 1322, 739; δH([2H6]DMSO) 4.49 (3 H, s, CH3), 4.90
(2 H, s, CH2), 7.26–7.46 (6 H, m, ArH), 7.49 (1 H, t, J 8.1,
ArH), 7.61 (1 H, t, J 8.1, ArH), 7.70 (1 H, t, J 8.1, ArH), 7.79
(1 H, d, J 8.1, ArH), 7.83 (1 H, d, J 8.1, ArH), 8.86 (1 H, d,
J 8.1, ArH), 8.91 (1 H, d, J 8.1, ArH), 12.05 (1 H, s, NH); m/z
325 (Mϩ, 100%), 278 (34%), 254 (23%).
7-Benzyl-5,9-dimethyl-6,7,8,9-tetrahydro-5H-indolo[2,3-c]-
pyrrolo[3,4-a]carbazole-6,8-dione 28db. A suspension of com-
pound 9d (0.5 mmol) and maleimide 27b (0.6 mmol) in Ph2O (3
ml) was heated at 190–200 ЊC during 12 h. After cooling, Et2O
was added and the resulting precipitate was filtered and washed
with Et2O to give 28db; yield mp >250 ЊC (Found: C, 78.60; H,
4.84; N, 9.34. C29H21N3O2 requires C, 78.54; H, 4.77; N, 9.47%);
νmax(KBr)/cmϪ1 3051, 2934, 1744, 1694, 1589, 1480, 1393, 1333,
1128, 737, 698; δH(CDCl3) 4.26 (6 H, s, CH3), 4.75 (2 H, s, CH2),
7.25–7.39 (7 H, m, ArH), 7.50 (2 H, d, J 7.3, ArH), 7.56 (2 H, t,
J 7.3, ArH), 8.62 (2 H, d, J 7.3, ArH); δC(CDCl3) 34.2 (q), 41.5
(t), 109.5 (d), 119.5 (d), 121.2 (s), 123.2 (s), 123.9 (d), 127.5 (d),
127.7 (d), 128.6 (d), 128.7 (d), 129.8 (s), 132.5 (s), 137.1 (s),
143.7 (s), 167.8 (s); m/z 443 (Mϩ, 100%), 352 (38%).
Dimethyl 5,8-dihydroindolo[2,3-c]carbazole-6,7-dicarboxylate 24
3,3Ј-Biindolyl 9a (2.32 g, 10 mmol) was heated together with
dimethyl acetylenedicarboxylate (5 ml) during 2 h at 210 ЊC
under nitrogen atmosphere. TLC analysis showed the absence
of 9a and the excess of ester was removed under reduced pres-
sure. The residue, chromatographed on silica gel with CH2Cl2 as
eluent, gave 2.80 g (75%) of the title compound 24 as yellow
crystals; mp 180–182 ЊC (Found: C, 70.95; H, 4.41; N, 7.39.
C22H16N2O2 requires C, 70.96; H, 4.33; N, 7.52%); νmax(KBr)/
cmϪ1 3464, 3351, 2953, 1713, 1618, 1404, 1212, 1133, 738;
δH([2H6]DMSO) 4.05 (6 H, s, CH3), 7.42 (2 H, t, J 8.1, ArH),
7.59 (2 H, t, J 8.1, ArH), 7.83 (2 H, d, J 8.1, ArH), 8.85 (2 H, d,
J 8.1, ArH), 11.54 (2 H, s, NH); δC([2H6]DMSO) 52.7 (q), 112.0
(d), 112.2 (s), 118.9 (s), 119.3 (d), 120.6 (s), 123.2 (d), 126.5 (d),
131.7 (s), 141.1 (s), 167.1 (s); m/z 372 (Mϩ, 100%), 341 (47%).
5,8-Dihydroindolo[2,3-c]carbazole-6,7-dicarboxylic acid 25
A suspension of compound 24 (186 mg, 0.5 mmol) in MeOH
(12 ml) and aqueous KOH (5 , 5 ml) was heated during 90
min. After cooling and acidification (pH 2–3), a precipitate
appeared which was collected, affording 170 mg (98%) of 25 as
an orange solid; mp >250 ЊC; νmax(KBr)/cmϪ1 3587, 3392, 3199,
1706, 1671, 1461, 1321, 1233, 1146, 728; δH([2H6]DMSO) 7.37
(2 H, t, J 8.1, ArH), 7.52 (2 H, t, J 8.1, ArH), 7.87 (2 H, d, J 8.1,
ArH), 8.82 (2 H, d, J 8.1, ArH), 11.65 (2 H, s, NH);
δC([2H6]DMSO) 112.1 (d), 114.8 (s), 118.1 (s), 118.8 (d), 120.6
(s), 123.0 (d), 125.8 (d), 133.2 (s), 140.6 (s), 169.2 (s).
J. Chem. Soc., Perkin Trans. 1, 1998
2015

View Article Online
Preparation of indolo[2,3-c]pyrrolo[3,4-a]carbazole derivatives
28 using acetic acid as solvent (conditions B)
125.3 (s), 127.2 (s), 128.1 (d), 132.1 (s), 134.1 (s), 136.7 (s) 154.5
(s), 156.3 (s); m/z 434 (Mϩ, 100%), 346 (46%), 272 (23%), 259
7-Methyl-6,7,8,9-tetrahydro-5H-indolo[2,3-c]pyrrolo[3,4-a]-
carbazole-6,8-dione 28aa. A solution of AcOH (5 ml) contain-
ing compound 9a (0.5 mmol) and maleimide 27a (1 mmol) was
heated at 90–100 ЊC during 36 h. After evaporation, the residue
was treated with Et2O and the resulting precipitate was filtered
and washed with Et2O to give compound 28aa; yield 44%; mp,
IR and NMR spectra data were identical with the descriptions
reported above.
7-Benzyl-6,7,8,9-tetrahydro-5H-indolo[2,3-c]pyrrolo[3,4-a]-
carbazole-6,8-dione 28ab. A solution of AcOH (5 ml) contain-
ing compound 9a (0.5 mmol) and maleimide 27b (1 mmol) was
heated at 90–100 ЊC during 24 h. After evaporation, the residue
was treated with Et2O and the resulting precipitate was filtered
and washed with Et2O to give compound 28ab; yield 55%; mp,
IR and NMR spectra data were identical with the descriptions
reported above.
6,7,8,9-Tetrahydro-5H-indolo[2,3-c]pyrrolo[3,4-a]carbazole-
6,8-dione 28ac. A solution of AcOH (5 ml) containing com-
pound 9a (0.5 mmol) and maleimide 27c (1 mmol) was heated
at 90–100 ЊC during 24 h. After evaporation, the residue was
treated with Et2O the resulting precipitate was filtered and
washed with Et2O to lead to compound 28ac; yield 55%; mp
>250 ЊC (Found: C, 73.65; H, 3.53; N, 12.82. C20H11N3O2
requires C, 73.84; H, 3.41; N, 12.92%); νmax(KBr)/cmϪ1 3416,
3351, 3175, 1742, 1712, 1688, 1613, 1461, 1415, 1312, 1245, 742;
δH([2H6]DMSO) 7.42 (2 H, t, J 8.1, ArH), 7.59 (2 H, t, J 8.1,
ArH), 7.80 (2 H, d, J 8.1, ArH), 8.84 (2 H, d, J 8.1, ArH), 11.10
(1 H, s, NH), 12.06 (2 H, s, NH); δC([2H6]DMSO) 111.4 (s),
112.4 (d), 119.7 (d), 120.6 (s), 122.5 (s). 123.4 (d), 126.9 (d),
128.4 (s), 142.3 (s), 170.0 (s); m/z 325 (Mϩ, 100%), 254 (45%).
2,4-Dichloro-6,7,8,9-tetrahydro-5H-indolo[2,3-c]pyrrolo-
[3,4-a]carbazole-6,8-dione 28bc. A solution of AcOH (5 ml)
containing compound 9b (0.5 mmol) and maleimide 27c (1
mmol) was heated at 90–100 ЊC during 36 h. After evaporation,
the residue was treated with Et2O and the resulting precipitate
was filtered and washed with Et2O to lead to compound 28bc;
yield 41%; mp >250 ЊC (Found: C, 63.39; H, 3.65; N, 6.94.
(17%).
Acknowledgements
This work was supported by grants to E. D. from the Swedish
Natural Science Research Council and the Wenner Gren Center
Foundation for the Scientific Research. We also thank BASF,
Ludwigshafen am Rhein (Germany), for a generous gift of
dimethyl acetylenedicarboxylate.
References
1 J. T. Link, S. Raghavan, M. Gallant, S. Danishefsky, T. C. Chou and
L. M. Ballas, J. Am. Chem. Soc., 1996, 118, 2825 and refs. therein.
2 Y. Yamashita, N. Fujii, C. Murkata, T. Ashizawa, M. Okabe and
H. Nakano, Biochemistry, 1992, 31, 12 069.
3 J. Bergman and B. Pelcman, J. Org. Chem., 1989, 54, 824.
4 G. W. Gribble and S. J. Berthel, Tetrahedron, 1992, 48, 8869.
5 M. Somei and A. Kadama, Heterocycles, 1992, 34, 1285.
6 U. Pindur, Y.-S. Kim and D. Schollmeyer, Heterocycles, 1994, 38,
2267.
7 J. F. Barry, T. W. Wallace and N. D. A. Walshe, Tetrahedron, 1995,
51, 12 797.
8 S. M. Weinreb, R. S. Garigipati and J. A. Gainer, Heterocycles, 1984,
21, 309.
9 J. Bergman and B. Pelcman, Tetrahedron Lett., 1987, 28, 4441.
10 M. F. Margaret, A. S. Kevin and L. W. Leonard, Synthesis, 1995,
1511.
11 M. Ohkubo, T. Nishimura, H. Jona, T. Honna, S. Ito and
H. Morishima, Tetrahedron, 1995, 53, 5937.
12 M. Gillner, B. Fernström, J.-Å. Gustafsson, J. Bergman and
G. Cambillau, Chemosphere, 1986, 15, 1673.
13 U. Rannug, A. Rannug, U. Sjöberg, H. Li, R. Westerholm and
J. Bergman, Chem. & Biol., 1995, 2, 841.
14 J. Bergman, Tetrahedron, 1970, 26, 3353.
15 (a) A. Kistenmacher and K. Müller, J. Heterocycl. Chem., 1992, 29,
1237; (b) S. Hünig and H.-C. Steinmetzer, Liebigs Ann. Chem., 1976,
1090.
16 B. Robinson, J. Chem. Soc., 1963, 3067.
17 J. Lehman and U. Hartmann, Arch. Pharm., 1989, 322, 451.
18 A. R. Katritzky, J. Li and C. V. Stevens, J. Org. Chem., 1995, 60, 3401.
19 D. StC. Black, A. J. Ivory and N. Kumar, Tetrahedron, 1995, 51,
11 801.
20 F. Mann and T. Willcox, J. Chem. Soc., 1958, 1525.
21 H. Weller and K. H. Grellmann, J. Am. Chem. Soc., 1983, 105, 6268.
22 J. Bergman and E. Desarbre, Synlett, 1997, 603.
23 J. Bergman, Acta Chim. Scand., 1971, 25, 1277.
24 U. Berens, J. M. Brown, J. Long and R. Selke, Tetrahedron:
Asymmetry, 1996, 7, 285.
25 S. Hibino and E. Sugino, Adv. Nitrogen Heterocycl., 1995, 1, 205.
26 J. H. Cardinella, M. P. Kirkup, R. E. Moore, J. S. Mynderse, K. Seff
and C. J. Simmons, Tetrahedron Lett., 1979, 20, 4915.
27 U. Pindur and R. Adam, Heterocycles, 1990, 31, 587.
28 S. Hibino, A. Tonari, T. Choshi and E. Sugino, Heterocycles, 1993,
35, 441.
C21H14Cl2N2O2 requires C, 63.49; H, 3.55; N, 7.05%); νmax
-
(KBr)/cmϪ1 3416, 3222, 1749, 1709, 1613, 1453, 1314, 1309,
1272, 1237, 762, 642; δH([2H6]DMSO) 7.45 (1 H, t, J 7.7, ArH),
7.61 (1 H, t, J 7.7, ArH), 7.79 (1 H, s, ArH), 7.82 (1 H, t, J 7.7,
ArH), 8.59 (1 H, t, J 7.7, ArH), 8.63 (1 H, s ArH), 11.20 (1 H, s,
NH), 11.68 (1 H, s, NH), 12.17 (2 H, s, NH).
6,7,8,9-Tetrahydro-5H-indolo[2,3-c]carbazole-6,7-dicarb-
oxylic anhydride 31. Similarly prepared as for compounds 28
using acetic acid as solvent and maleic anhydride (conditions B)
during 2 days, yield 46%; mp >250 ЊC (Found: C, 73.01; H,
3.74; N, 8.10. C20H10N2O3 requires C, 73.62; H, 3.09; N, 8.58%);
νmax(KBr)/cmϪ1 3402, 3361, 3206, 1808, 1740, 1715, 1613, 1460,
1329, 1208, 737; δH([2H6]DMSO) 7.44 (2 H, t, J 8.1, ArH), 7.63
(2 H, t, J 8.1, ArH), 7.79 (2 H, d, J 8.1, ArH), 8.82 (2 H, d, J 8.1,
ArH), 12.38 (2 H, s, NH); δC([2H6]DMSO) 109.2 (s), 112.5 (d),
120.2 (d), 120.3 (s), 123.8 (d), 127.8 (d), 129.1 (s), 142.5 (s),
163.5 (s); m/z 326 (Mϩ, 100%), 254 (38%).
29 S. G. Tilve, A. S. Tilve and V. G. Desai, Synth. Commun., 1996, 26,
1921.
30 S. Hibino, E. Sugino, T. Kuwada, N. Ogura, K. Sato and T. Choshi,
J. Org. Chem., 1992, 57, 5917.
31 A. L. Germain, T. L. Gilchrist and P. D. Kemmitt, Heterocycles,
1994, 37, 697.
32 J. Bergman and R. Carlsson, Tetrahedron Lett., 1978, 19, 4055.
33 A. K. Mohanakrishnan and P. C. Srinivasan, J. Org. Chem., 1995,
60, 1939.
34 E. M. Beccalli, A. Marchesini and T. Pilati, Tetrahedron, 1993, 21,
4741.
35 T. Fujisawa and T. Sato, Org. Synth., 1987, 66, 121.
36 (a) R. L. Hudkins and J. L. Diebold, Tetrahedron Lett., 1997, 38,
915; (b) R. L. Hudkins, J. L. Diebold, T. S. Angeles and E. Knight,
Jr., J. Med. Chem., 1997, 40, 2994.
37 J. Bergman, P. O. Norrby and P. Sand, Tetrahedron, 1990, 46, 6113.
38 T. Hino, K. Yamada and S. Akaboshi, Chem. Ind. (London), 1967,
275.
Diethyl
(1,1Ј-dimethyl-3,3Ј-biindolyl-2-yl)hydrazine-1,2-di-
carboxylate 32. A suspension of 9d (130 mg, 0.5 mmol) in tolu-
ene (3 ml) and diethyl azodicarboxylate (115 µl, 0.6 mmol) was
heated at 130 ЊC under an inert atmosphere. After 1 h, the
green–brown solution was evaporated and the residue, chrom-
atographed on a silica gel column (CH2Cl2), gave 190 mg (87%)
of 32; mp 168–170 ЊC; νmax(KBr)/cmϪ1 3258, 2984, 2926, 2909,
1757, 1703, 1510, 1478, 1329, 1235, 1075, 739; δH([2H6]DMSO)
1.10–1.30 (6 H, m, CH3), 3.75–4.30 (10 H, m, CH2 ϩ CH3), 7.01
(1 H, t, J 7.3, ArH), 7.07 (1 H, t, J 7.3, ArH), 7.19 (1 H, t, J 7.3,
ArH), 7.26 (1 H, t, J 8.1, ArH), 7.31–7.54 (5 H, m, ArH), 9.90
(1 H, s, NH); δC([2H6]DMSO) 13.7 (q), 14.3 (q), 29.2 (q), 32.5
(q), 61.0 (t), 68.5 (t), 104.3 (s), 105.5 (s), 109.7 (d), 110.1 (d),
118.5 (d), 119.3 (d), 119.6 (d), 120.2 (d), 121.0 (d), 122.2 (d),
Paper 8/02852D
Received 16th April 1998
Accepted 23rd April 1998
2016
J. Chem. Soc., Perkin Trans. 1, 1998