First synthesis of symmetrical and non-symmetrical aza indolocarbazoles derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00315-5

A new family of aza-indolocarbazoles 2-3 was built from protected 3-(3-indolyl)-4-bromo-N-methylmaleimide in a few efficient steps. Symmetrical and non-symmetrical products were obtained. Regioselectivity of anionic condensation was controlled. A possible selective deprotection between an N-Boc and N-benzenesulphonyl group using mild basic conditions was confirmed.

Full text of DOI:10.1016/S0040-4039(02)00315-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2561–2564
First synthesis of symmetrical and non-symmetrical aza
indolocarbazoles derivatives
Sylvain Routier,a,* Ge´rard Coudert,a Jean-Yves Me´roura and Daniel Henri Caignardb
aInstitut de Chimie Organique et Analytique associe´ au CNRS, Universite´ d’Orle´ans, BP 6759, 45067 Orle´ans Ce´dex 02, France
bADIR, 1 rue Carle Hebert, 92415 Courbevoie Cedex, France
Received 5 February 2002; accepted 14 February 2002
Abstract—A new family of aza-indolocarbazoles 2–3 was built from protected 3-(3-indolyl)-4-bromo-N-methylmaleimide in a few
efficient steps. Symmetrical and non-symmetrical products were obtained. Regioselectivity of anionic condensation was controlled.
A possible selective deprotection between an N-Boc and N-benzenesulphonyl group using mild basic conditions was confirmed.
© 2002 Elsevier Science Ltd. All rights reserved.
Indolocarbazoles are natural or synthetic products
from which the Rebeccamycin I, a weak inhibitor of
topoisomerase I is the archetype.1,2 Development of
new DNA topoisomerases I inhibitors as cancer
chemotherapy agents is currently an active area of
research. ED-110 II and NB-506 III are two representa-
tive products in this family.3,4 Arcyriaflavin A–C IV are
the major key intermediates in the preparation of sym-
metrical and non-symmetrical rebeccamycin analogues.5
All these compounds possess an indolocarbazole back-
bone (Fig. 1).
described.6 Structural modifications were realized on
the heterocyclic core where the position and nature of
the indolic substituents were changed. Related com-
pounds lacking an indolic moiety such as granulatimide
V were described.7 For our own part, we chose to
synthesize naphtho[3,4-c]carbazole 1 using the bioiso-
terism indole–naphthalene.8 All these compounds are
potential candidates for novel drug discovery (Fig. 2).
The most convenient synthesis of symmetric or non-
symmetric bisindolylmaleimides generally uses indolyl
Grignard reagents with dibromomaleimides.1–8 A cycli-
sation between the two C-2 indolic carbon atoms com-
Recently, several aglycone rebecamycin isosteres were
Figure 1. Most representative indolocarbazoles derivatives.
* Corresponding author. Tel.: (33) 2.38.49.48.53; fax: (33) 2.38.41.72.81; e-mail: sylvain.routier@univ-orleans.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00315-5

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S. Routier et al. / Tetrahedron Letters 43 (2002) 2561–2564
Figure 2. Some structural modification in indolocarbazoles series.
effect was studied with the use of chloroform, hexane
and benzene but in all cases the reaction failed. The use
of toluene at room temperature was unsuccessfull but
at 50°C, compound 7 was obtained in a 15% yield
(entries 4 and 5). Interestingly a mixture of toluene and
dichloromethane afforded the desired compound 7 in
65% yield (entry 6) after one day of reaction. The
heterogeneous reaction mixture load leads us to
increase the reaction time to 4 days but the yield of 7
was not improved.
pletes the synthesis of the required derivatives. Several
routes were described to perform this intramolecular
ring closure: a photolytic activation9 or the use of
palladium-catalyzed cross-coupling reactions10 were
described. Suzuki reaction of a triflate derivative with
3-indoleboronic acid has also been reported11 and more
recently an oxidative cyclisation with a Wacker-type
catalytic system was used in an industrial process.12
The huge synthetic effort developed in this area
prompted us to report our work regarding a new series
of related derivatives 2 and 3 containing one or two
supplementary nitrogen atoms. In numerous antitumor
series, the presence of a pyridine nitrogen atom rein-
forces the DNA binding properties.13 This observation
guided us to replace one or two indole moieties by a
7-azaindolic group in order to obtain the azaindoloca-
bazoles 2 and 3.
The next step consisted of the protection of indolic NH
atom either by a tert-butyloxycarbonyl or a benzene-
sulphonyl group to afford compounds 8 and 9 in 66
and 74% yield, respectively. Anionic condensation of
compound 8 with 7-azaindole 4 afforded, using previ-
ously described conditions (Table 1, entry 6), only
N-Boc deprotection and compound 7 was recovered.
N-Boc azaindole group was very sensitive to basic
conditions. Another assay was performed using 2 equiv.
of azaindole 4 and LiHMDS as base and only the
deprotected compound 7 was obtained. On the other
hand LiHMDS was used with 9 in toluene at room
temperature, the reaction afforded, after 12 h, com-
pound 10 in 64% yield. Increasing the amount of
7-azaindole 4 to 4 equiv., allowed the reaction time to
be decreased to 6 h.
First, the reaction between 7-azaindole 4 and 2,3-
dibromo-N-methylmaleimide 5 was performed (Table
1, Scheme 1) as previously described.10 In our case,
N1-alkylated product 6 was obtained (entry 1). Differ-
ent conditions were attempted to direct the regioselec-
tivity of the anionic reaction towards the C3-alkylated
product 7. For instance, if a mixture of THF and
hexane was used, the yield of compound 6 decreased
(entry 2) but no formation of 7 was observed.
The coupling reaction performed on compound 10
It was reported that 7-azaindolic Grignard reagent
when condensed on furanose give C3-alkylated if the
reaction was performed in CH2Cl2.14 Thus, we used
ethylmagnesium bromide as base (entry 3) in
diethylether. After complete formation of the indolic
Grignard reagent the diethylether was evaporated and
replaced by dichloromethane (entry 3) in order to per-
form the condensation. For the first time, the regiose-
lectivity was inverted, the C3-alkylation was observed
and compound 7 was obtained in 14% yield. Solvent
3,6
using Pd (OAc)215, Pd (OCOCF3)2 or DDQ in the
presence16 or absence10 of APTS failed. We hypothe-
sized that steric effects due to the protective group and
its strong electron withdrawing effect inhibit the bond
formation between the two indolic C-2 positions. To
confort this hypothesis, compound 10 was deprotected
using Bu4NF in refluxing THF to afford compound 11
in 83% yield. Wathever the methods used, the cyclisa-
tion failed.
Table 1. Anionic condensation of 4 on 2,3-dibromo-N-methylmaleimide 5
Entry
Reagents
Base
Solvent
Conditions
Product (yield)
1
2
3
4
5
6
4 (1 equiv.), 5 (1.2 equiv.)
4 (1 equiv.), 5 (1.2 equiv.)
4 (2 equiv.), 5 (1 equiv.)
4 (2 equiv.), 5 (1 equiv.)
4 (2 equiv.), 5 (1 equiv.)
4 (2 equiv.), 5 (1 equiv.)
LiHMDS, (2 equiv.)
LiHMDS, (2 equiv.)
EtMgBr, (2.05 equiv.)
EtMgBr, (2.05 equiv.)
EtMgBr, (2.05 equiv.)
EtMgBr, (2.05 equiv.)
THF
0°C, 3 h
0°C, 3 h
rt, 12 h
rt, 12 h
50°C, 12 h
50°C, 24 h
6 (25)
6 (15)
7 (14)
No reaction
7 (15)
THF/hexane (3/2)
Ether replaced by CH2Cl2
Toluene
Toluene
Toluene/CH2Cl2 (2/1)
6 (65)

S. Routier et al. / Tetrahedron Letters 43 (2002) 2561–2564
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Scheme 1. Reagents and conditions: (a) Table 1; (b) Boc2O, 2 equiv., 4-DMAP 0.1 equiv., CH2Cl2, rt, 1 h, 66%; (c) NaH 1.6 equiv.,
PhSO2Cl 1.4 equiv., THF 9/DMF 1, rt, 74%; (d) compound 4 2 equiv., LiHMDS 3 equiv., toluene, rt, 12 h, 64%; (e) TBAF 2
equiv., THF, rflx, 2 h, 83%; (f) Boc2O 2 equiv., 4-DMAP 0.1 equiv., THF, 30°C, 92%; (g) TBAF 2 equiv., THF, rt, 2 h, 80%;
(h) TBAF 10 equiv., THF, rflx, 1 h, quant.; (i) hw, 500 W UV lamp TQ-718 DEMA, I2 cat., benzene, 3 h 30, 74%; (j) formic acid,
rt, 2 h, quant.
deprotection was performed using an excess of TBAF
in refluxing THF to afford compound 2 in 88% yield.
An acidic N-Boc deprotection using formic acid was
realized and compound 2 was quantitatively obtained.
It has been reported that the presence of a mono N-Boc
protected bis-indoylmaleimide compound seems to
facilitate the photocyclisation.17 By analogy, we realized
the following sequence to prepare compound 13: 10 was
protected with a Boc group affording compound 12 in
92% yield. The N-benzenesulphonyl group cleavage was
selectively performed on compound 12 by Bu4NF in
THF at room temperature to generate 13 in 80%
yield.18 This reaction was performed in refluxing THF
with an excess of reagent to give compound 11 in a
quantitative yield. Photoirradiation of compound 13
gave the desired product 14 in 74% yield. The final
The synthesis of the non-symmetrical compound 3 was
straightforward (Scheme 2). The lithio derivative of
7-azaindole 4 was condensed on 1510 as described for
compound 9 to afford 16 in 67% yield. No deprotection
of the indolic nitrogen atom was observed. N-Boc
azaindole was more sensitive than N-Boc indole to the
basic conditions. The next step was performed by pho-
tocyclisation on 16 and compound 17 was obtained in
85% yield. Final deprotection was realized using TBAF
in refluxing THF to give the non-symmetrical aglycone
3 in 88% yield. Identification of compounds 2 and 3
were realized by NMR and purity was determinated by
microanalysis.19
In this summary, we have described a straightforward
and efficient preparation of new symmetrical and non-
symmetrical aza indolocarbazoles19 using a photocycli-
sation procedure. The reactivity of 2,3-dibromo-
N-methylmaleimide with 7-azaindole was explored in
different anionic conditions and a regioselective C-3
alkylation was developped. Biological studies are in
progress to evaluate the influence of the newly intro-
duced nitrogen atoms.
Acknowledgements
Scheme 2. Synthesis of the non-symmetrical aglycone 2. (a)
compound 4 3 equiv., LiHMDS 4.1 equiv., toluene, rt, 24 h,
67%; (b) hw, I2, benzene, 1.5 h, 85%; (c) TBAF 10 equiv.,
THF, rflx, 1 h, 88%.
We thank ADIR for financial support and J. Blu for
technical assistance.

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S. Routier et al. / Tetrahedron Letters 43 (2002) 2561–2564
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