Synthesis of carbazoles by a balanced four component condensation

Article abstract of DOI:10.1016/j.tetlet.2003.12.099

An access to functionalised tetrahydrocarbazoles by a multicomponent reaction including 2-substituted indoles, aromatic aldehydes and Meldrum's acid is described.

Full text of DOI:10.1016/j.tetlet.2003.12.099

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1703–1707
Synthesis of carbazoles by a balanced four component condensation
Fabien Cochard, Marie Laronze, Philippe Sigaut, Janos Sapi* and Jean-Yves Laronze
UMR 6013 ‘Isolement, Structure, Transformations et Synthꢀese de Substances Naturelles’, IFR 53 Biomolꢁecules, Facultꢁe de Pharmacie,
Universitꢁe de Reims-Champagne-Ardenne, 51, rue Cognacq-Jay, F-51096 Reims Cedex, France
Received 21 November 2003; revised 11 December 2003; accepted 17 December 2003
Abstract—An access to functionalised tetrahydrocarbazoles by a multicomponent reaction including 2-substituted indoles, aromatic
aldehydes and MeldrumÕs acid is described.
Ó 2003 Elsevier Ltd. All rights reserved.
Since its discovery, the combinatorial chemistry has
become an integrated part of the modern drug discovery
process for both finding and optimisation of lead com-
pounds. However, despite early encouraging results, the
preparation of large libraries was unsatisfying, owing to
low diversity and lack of rational ligand selection
methods. Facing the challenge of generating smaller,
more diverse libraries, multicomponent reactions
(MCR) have proved to be an effective tool,1 allowing the
easy and rapid preparation of drug-like heterocycle
based libraries. Recently Lehn2 and Sanders and
co-workers3 proposed a dynamic approach in which the
target (biomolecule) could organise the connection
between the elements of the library, selecting Ôtailor
madeÕ ligands. For this purpose, the basic components
of the library should react with each other reversibly,
shifting the library towards the best target fitting ones.
reoisomer was isolated from the trimolecular mixture in
dichloromethane, in the presence of POCl3 (2 equiv).
In this letter we focus our attention on the preparation
of the four-component (4-CR) derivatives 5 bearing a
MeldrumÕs acid moiety, suitable for further functional
group transformations. One of these structures has
already been obtained serendipitously in low quantities
(4, Ar ¼ Ph) in our previous work.6
Initially, we tried to drive our condensation exclusively
towards the four-component products 5. As both
malonic and indolyl acetate carbons are able to stabilise
a negative charge, various conditions were tried. Finally,
we found that on heating a benzene solution of a stoi-
chiometric mixture of ethyl 2-indolyl acetate 1, Mel-
drumÕs acid and benzaldehyde in
a Dean–Stark
apparatus, the expected carbazole 5a, accompanied by
an inseparable stereoisomer (50a) was isolated in modest
yield (43%) (Scheme 2, Table 1).8 This low yield prob-
ably derives from the varying quality of benzaldehyde
owing to its Cannizzaro-type disproportionation.
For some years we have been working on the Yonemitsu
condensation4 between indole, MeldrumÕs acid and
various aldehydes.5 Extending this three-component
reaction to 2-substituted indoles 1,6 a variety of scaffolds
2–6 was prepared depending on the conditions of the
reaction (temperature, solvent, catalyst, reagents)
(Scheme 1).
When we used aldehydes such as 2,5-dimethoxybenzal-
dehyde or 2-nitrobenzaldehyde (entries 2, 3) under the
same conditions, compounds 5b (50b) or 5c (50c) were
isolated9 in slightly better yields (53–54%). Further
improvements in chemical yield, selectivity and purity
were achieved by microwave assisted condensation. A
strong and short activation gave the highest yield (64%)
of the series (entry 4). This tetramolecular condensation
was successfully expanded to other 2-substituted indoles
and arylaldehydes with different substitution patterns
(entries 5–7). Detailed NMR measurements (COSY,
HMBC, HMQC, NOE and coupling constants) allowed
The intermediate Knoevenagel adduct 2 was sometimes
observed, while the well-known bis-indoles 3 were
obtained nearly quantitatively when Yb(OTf)3 was
added to the mixture.7 Dimer 6, accompanied by a ste-
Keywords: Indoles; Multicomponent reaction; Tetrahydrocarbazoles.
* Corresponding author. Tel.: +33-0326918022; fax: +33-0326918029;
e-mail: janos.sapi@univ-reims.fr
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.099

1704
F. Cochard et al. / Tetrahedron Letters 45 (2004) 1703–1707
O
4-CR
3-CR
O
O
Ar
Ar
N
R1
O
R2
N
R1
N
R1
R2
R2
4
3
c
b
4-CR
O
O
O
Ar
Ar
O
O
O
O
O
O
Ar
O
O
O
a
c
R2
N
N
O
Et3NH
R2
R1
R1
2
1
4-salt
e
d
R1:H
R2:CO2Et
H
4-CR
EtO2C
Ph
O
N
O
O
Ar
O
Ph
CO2Et
Ar
R2
N
H
N
R1
6
5
Scheme 1. Reagents and conditions: (a) benzene, reflux, silica gel; (b) Yb(OTf)3; (c) Ref. 6; (d) this work; (e) POCl3 (2 equiv).
Ar
of the MeldrumÕs acid moiety of 4 via a ketene inter-
O
O
mediate could be proposed.10
O
O
O
+
+
R2
N
R1
Mechanistically, the pivotal Knoevenagel adduct 2
could react either with the indoloquinodimethane
intermediate 8 or with the 2-vinyl indole 9 in a Diels–
Alder reaction,11 or via a tandem Michael addition–
cyclisation (Scheme 3).
1
O
O
O
O
O
O
Ar
Ar
+
3
4
O
O
2
1
When 1,2-dimethylindole, benzaldehyde and N-methyl-
maleimide were heated under reflux in toluene, the
Diels–Alder adduct 10 was obtained in 26% yield
(Scheme 4). If toluene was replaced by benzene no
reaction occurred even after a 1-day reflux. However,
Ar
R2
Ar
R2
N
R1
N
R1
5'
5
addition of MeldrumÕs acid and
to the dienophile-containing mixture gave tetrahydro-
D,L-proline as catalyst
carbazoles 5d and 50d.
COOH
R2
Ar
Ar
N
Other arguments, such as the role of proline as a
Michael reaction catalyst,12 and the reversibility and
stereochemistry of the major stereoisomers are all in
favour of a stepwise ionic process.
R1
+
R2
N
N
R2
R1
R1
7
3
This condensation is not reserved to 2-carbon substi-
tuted indoles, as indole-2-thione reacted smoothly with
benzaldehyde and MeldrumÕs acid to give thiacarbazole
1113 in 67% yield, as the sole isomer (Scheme 5).
Scheme 2.
the complete assignment of the signals of both isomers
(5 + 50) as depicted in Scheme 2.
Although the reversibility was a major drawback to
higher yields, it is essential for the preparation of tetra-
molecular condensation-guided dynamic libraries. For
these purposes, we carried out two sets of experiments,
the first starting from a trimolecular adduct 4 (Scheme
1), the second using two different aldehydes in a tetra-
molecular condensation.
Inevitably, in all cases side products resulting from
competing reactions, like di-indole 3 or the substituted
indolyl-propionic acid derivatives 7 were also isolated.
For the formation of the latter thermal decomposition

F. Cochard et al. / Tetrahedron Letters 45 (2004) 1703–1707
1705
Table 1. Tetramolecular condensations between 2-substituted indoles, MeldrumÕs acid and arylaldehydes
Entry
1
R1
R2
Ar
Ph
Method
A
5 + 50a (%)
3 (%)
7b (%)
a
b
H
CO2Et
43 (95/5)
15
18
CH3O
2
3
4
H
H
H
CO2Et
CO2Et
CO2Et
A
A
B
53 (86/14)
54 (70/30)
64 (93/7)
8
––
OCH3
c
c
c
––
––
NO2
NO2
13
c
5
6
d
e
CH3
CH3
H
H
Ph
A
A
53 (87/13)
41 (95/5)
7
CH3O
14
––
OCH3
c
7
f
CH3
H
A
26 (84/16)
21
NO2
a Diastereomeric ratios were determined by 1H NMR.
b Determined after methylation by CH2N2.
c Detected by 1H NMR but not isolated.
Ar
O
O
Ar
O
O
O
O
Ar
R2
R2
N
O
N
O
R1
R1
Ar
1
8
2
Ar
+
R2
N
Ar
R1
R2
N
O
Ar
R1
5/5'
+
9
+
O
O
O
O
COOH
R2
O
O
O
Ar
Ar
O
O
N
R1
7
N
R2
R1
4
Scheme 3.
In both cases, p-fluorobenzaldehyde was chosen as the
ÔsecondÕ aldehyde in order to facilitate the study of the
reaction mixture on the basis of 19F NMR and low
resolution mass spectrometry.
thermolysis to the acid 7, a mixture of inseparable
nonfluorinated carbazoles 5a/50a and fluorinated ones
5h/50h was isolated in about 20% yield. The presence of a
nonfluorinated phenyl substituent attached at the C-2
position of the carbazole ring proved that the starting
trimolecular adduct 4a had reversed to its starting
materials, especially to benzaldehyde, which was also
incorporated into the carbazole ring system. Apart from
In the first experiment the triethylammonium salt 4a was
heated at 70 °C with p-fluorobenzaldehyde in aceto-
nitrile for 1 day. Although 22% of 4a decomposed by

1706
F. Cochard et al. / Tetrahedron Letters 45 (2004) 1703–1707
.
.
+
+
CH3
CH3
O
O
N
O
O
O
O
O
O
Ph
Ph
O
O
O
O
110°C
80°C
80°C
O
O
N
H
N
H
F
CO2Et
CO2Et
O
O
D,L-proline
5a/5'a
5h/5'h
N CH3
N CH3
M+ . 523
M+ . 541
O
O
O
O
O
O
CH3
F
Ph
N
Ph
.
.
+
+
O
O
Ph
N
N
CH3
CH3
10
5d/5'd
N
H
N
H
CO2Et
CO2Et
Scheme 4.
v
w
M+ . 291
M+ . 309
O
S
O
.
.
Ph
O
+
+
Ph
F
F
O
O
O
O
O
O
O
Ph
O
O
S
+
O
O
O
N
H
N
H
O
O
O
Ph
11
N
H
F
N
H
CO2Et
CO2Et
Scheme 5.
5j/5'j
5i/5'i
M+ . 541
M+ . 559
1
the signals Carom–F at about d ¼ 161 ppm, neither H,
nor 13C NMR spectra allowed the determination of the
composition of this inseparable mixture. However, the
location of the p-fluorophenyl group at C-2 in 5h/50h
(and not at C-4) was ascertained by mass spectrometry
studies. The retro-diene fragment v m=z 291, including
the ÔsouthernÕ position (C-2) is derived from both
molecular ions C32H29NO6 (m=z 523) and C32H28NO6F
(m=z 541).
Scheme 6.
decomposition studies of the molecular ions by linked-
scan methods unambiguously showed that ion v is a
common daughter of two fathers 5a/50a and 5h/50h, as
well as w is that of 5i/50i and 5j/50j (Scheme 6).
To summarise, we have found a multicomponent con-
densation of various aldehydes with 2-substituted
indoles and MeldrumÕs acid for the preparation of
functionalised 1,2,3,4-tetrahydrocarbazoles. As these
reactions appear to be reversible, they could be a first
step towards the development of a combinatorial ver-
sion of the Yonemitsu reaction.
In the second set of experiments, the two aldehydes
(benzaldehyde and p-fluorobenzaldehyde) were mixed
in equimolar quantity with MeldrumÕs acid and ethyl
2-indolyl acetate in acetonitrile in the presence of 0.1
equivalents of D,L-proline. After 4 days, an inseparable
mixture of four carbazoles 5a/50a, 5h/50h, 5i/50i, 5j/50j was
obtained by column chromatography (27%).
The presence of peaks m=z 523, and m=z 559 in the mass
spectrum of the isolated mixture supported the presence
of the two homogenous derivatives 5a and 5j. As for the
mixed structures, a study of the above mentioned frag-
mentations unambiguously confirmed that both regio-
isomers 5h and 5i were formed in the reaction. Ion v
(m=z 291) originates from 5a and 5h, whereas fragment
w (m/z 309) results from 5i and 5j. Metastable ion
Acknowledgements
ꢀ
The authors thank the ÔMinistere de lÕEducation
Nationale, de la Recherche et de la TechnologieÕ for a
Ph.D. fellowship to F.C. They also express their thanks
to C. Petermann for NMR measurements.

F. Cochard et al. / Tetrahedron Letters 45 (2004) 1703–1707
1707
CEM Discoverâ apparatus). After evaporation of the
solvent under reduced pressure the residue was purified by
chromatography on silica gel (CH2Cl2/cyclohexane 10%,
or CH2Cl2/MeOH 0–6%) to give a mixture of diastereo-
mers 5 and 50.
References and notes
€
€
1. For review, see: (a) Ugi, I.; Domling, A.; Horl, W.
Endeavour 1994, 18, 115; (b) Armstrong, R. W.; Combs,
A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
Chem. Res. 1996, 29, 123; (c) Tietze, L. F. Chem. Rev.
1996, 96, 115; (d) Kobayashi, S. Chem. Soc. Rev. 1999, 28,
1; (e) Weber, L.; Illgen, K.; Almstetter, M. Synlett. 1999,
366; (f) Tietze, L. F.; Modi, F. Med. Res. Rev. 2000, 20,
304; (g) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879; (h)
9. All new compounds gave satisfactory spectral data. For
example, selected data for major isomer 5c: 1H NMR
(CDCl3, 300 MHz): d 8.50 (s, 1H), 7.90–7.79 (m, 3H), 7.67
(d, J ¼ 7.9 Hz, 1H), 7.51 (t, J ¼ 7.4 Hz, 2H), 7.42–7.24 (m,
4H), 7.16 (t, J ¼ 7.1 Hz, 1H), 6.99 (t, J ¼ 7.1 Hz, 1H), 6.05
(s, 1H), 5.50 (d, J ¼ 10.9 Hz, 1H), 5.06 (d, J ¼ 10.9 Hz,
1H), 4.20 (q, J ¼ 7.2 Hz, 2H), 1.70 (s, 3H), 1.17 (t,
J ¼ 7.2 Hz, 3H), 0.97 (s, 3H); 13C NMR (CDCl3, 75 MHz):
d 170.9, 166.7, 165.8, 151.5, 149.4, 136.7, 136.6, 132.2,
130.9, 129.3, 129.0, 125.7, 125.6, 125.1, 122.9, 120.1, 118.5,
111.2, 107.9, 106.5, 62.1, 60.5, 46.5, 42.3, 35.6, 30.4, 26.1,
13.7; HREIMS calcd for C32H27N3O10: 613.1696, found:
613.1695; Anal. calcd for C32H27N3O10: C, 62.64; H, 4.43;
N, 6.85. Found C, 62.67; H, 4.06; N, 6.77.
ꢁ
Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.
Eur. J. 2000, 6, 3321; (i) Ugi, I.; Domling, A.; Werner, B.
€
€
J. Heterocycl. Chem. 2000, 37, 647; (j) Domling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 39, 3168; (k) Weber, L. Drug
Discov. Today 2002, 7, 143.
2. Lehn, J.-M. Nat. Rev. Drug Discovery 2002, 1, 26.
3. Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Drug Discov.
Today 2002, 7, 117.
4. Oikawa, Y.; Yonemitsu, O. Tetrahedron Lett. 1978, 19,
1759.
5. Nemes, C.; Jeannin, L.; Sapi, J.; Laronze, M.; Seghir, H.;
Auge, F.; Laronze, J.-Y. Tetrahedron 2000, 56, 5479.
6. Cochard, F.; Sapi, J.; Laronze, J.-Y. Tetrahedron Lett.
2001, 42, 6291.
10. For a review on MeldrumÕs acid chemistry, see: (a) Chen,
B. C. Heterocycles 1991, 32, 529; (b) For a thermal
cycloreversion of MeldrumÕs acid derivatives generating
ketenes, see: Sato, M.; Ban, H.; Kaneko, C. Tetrahedron
Lett. 1997, 38, 6689.
ꢁ
€ꢁ
11. Diker, K.; Doe de Maindreville, M.; Royer, D.; Le
7. Chen, D.; Yu, L.; Wang, G. Tetrahedron Lett. 1996, 37,
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Provost, F.; Levy, J. Tetrahedron Lett. 1999, 40, 7463.
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13. Selected data for 11: mp 157–158 °C; H NMR (DMSO-
8. General procedure for the preparation of compounds 5a–g
Method A: To a stirred solution of 2-substituted indoles
(2 mmol) in benzene (15 mL), MeldrumÕs acid (2 mmol),
1
d6, 300 MHz): d 10.20 (s, 1H), 7.60–6.88 (m, 12H), 6.64 (t,
J ¼ 7.7 Hz, 1H), 5.96 (d, J ¼ 7.7 Hz, 1H), 5.40 (s, 1H), 5.20
(s, 1H), 0.70 (s, 3H), 0.46 (s, 3H); 13C NMR (DMSO-d6,
75 MHz): d 167.5, 167.3, 137.3, 136.1, 134.4, 133.0, 130.9,
130.2, 129.9, 129.3, 129.0, 128.9, 128.7, 128.6, 128.5, 128.4,
126.6, 120.4, 118.5, 118.1, 110.6, 105.8, 105.7, 59.5,
52.9, 49.0, 29.7, 28.1; MS (FAB+) 470 [M+H]þ (37), 238
(100).
the arylaldehydes (4 mmol) and
D,L-proline (0.2 mmol)
were added successively. The mixture was warmed at 80 °C
for 3 of 11 h. Method B: To a solution of the 2-substituted
indoles (1.5 mmoles) in dry benzene (3 mL), molecular
ꢂ
sieves (4 A),
D,L-proline (0.1 mmol), MeldrumÕs acid
(1.5 mmol) and the arylaldehydes (3 mmol) were added
successively. The mixture was heated under a Dean–Stark
trap by microwave irradiation: 250 W (5 min at 85 °C,