Novel clay-mediated, tandem addition-elimination-(Michael) addition reactions of indoles with 3-formylindole: An eco-friendly route to symmetrical and unsymmetrical triindolylmethanes

Article abstract of DOI:10.1016/S0040-4039(01)02380-2

Dry reaction of 3-formylindole (1) with indole (2a) on Montmorillonite K10 clay at room temperature furnished within minutes tris(indol-3-yl)methane (3a) in high yield. The reaction of 1 with other mono- and dialkylindoles (2b-c, skatole, 8a-c) under simi

Full text of DOI:10.1016/S0040-4039(01)02380-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1351–1353
Novel clay-mediated, tandem addition–elimination-(Michael)
addition reactions of indoles with 3-formylindole: an eco-friendly
route to symmetrical and unsymmetrical triindolylmethanes
Manas Chakrabarty* and Sandipan Sarkar
Department of Chemistry, Bose Institute, 93/1, A.P.C. Road, Kolkata 700009, India
Received 12 November 2001; revised 6 December 2001; accepted 14 December 2001
Abstract—Dry reaction of 3-formylindole (1) with indole (2a) on Montmorillonite K10 clay at room temperature furnished within
minutes tris(indol-3-yl)methane (3a) in high yield. The reaction of 1 with other mono- and dialkylindoles (2b–c, skatole, 8a–c)
under similar conditions yielded either or both of symmetrical (3b–c, 9) and unsymmetrical (4b–c, 5b–c, 10, 11a–c) triindolyl-
methanes. © 2002 Elsevier Science Ltd. All rights reserved.
In organic syntheses and reactions, increasing attention
is being focused on green chemistry using environmen-
tally benign reagents and conditions and particularly,
methanes (TIMs). The experiments, their outcome and
the significance of our findings have been briefly pre-
sented in this communication.
1
solvent-free procedures, i.e. dry reactions which often
lead to clean, eco-friendly and highly efficient proce-
dures involving simplified work-ups. A large number of
reactions have been carried out on the surface of silica
When a solution of 3-formylindole (1) and three molar
equivalents of indole (2a) was adsorbed on M. clay
and the solvent allowed to evaporate off at room
temperature, 1 was consumed (TLC) within 5 min to
furnish tris(indol-3-yl)methane (3a) as the only product
11
2
2,3
4
5
1,2a,6
gel, alumina, zeolites, clays and polymers,
fre-
7
quently in conjunction with microwave irradiation
which lead to accelerated reaction rates and enhanced
yields resulting from microwave dielectric heating. Of
the various solid supports used, Montmorillonite K10
(
Scheme 1). This method is better than the previous
synthesis of 3a by a protic acid-catalysed condensation
12
of 1 and 2 in solution, since the yields are comparable
but the present one is faster and requires milder condi-
tions (75%, room temperature, 5 min as against 80%,
reflux, 0.6 h in the previous case).
(
M. K10) clay is being more and more used with
success because of its large specific surface area (500–
2
8
7
60 m /gm) and high Brønsted acidity (Hammett acid-
9
ity function H : −6 to −8).
0
With N-methylindole (2b) under similar conditions, 1
was again consumed within 5 min and furnished the
TIMs, tris(N-methylindol-3-yl)methane (3b), (indol-3-
yl)-bis(N-methylindol-3%-yl)methane (4b), bis(indol-3-
yl)-(N-methylindol-3%-yl)methane (5b) and indole in an
In continuation of our interest in clay-mediated reac-
tions of indoles, we have successfully carried out a
novel, dry reaction of indole and alkylindoles with
1
0
3
-formylindole on M. K10 clay, leading to either or
both of symmetrical and unsymmetrical triindolyl-
Scheme 1.
Keywords: condensation; 3-formylindole; (alkyl)indoles; clay; triindolylmethanes.
*
Corresponding author. Tel.: 91 33 350 2402/2403/6619; fax: 91 33 350 6790; e-mail: manas@boseinst.ac.in
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02380-2

1
352
M. Chakrabarty, S. Sarkar / Tetrahedron Letters 43 (2002) 1351–1353
1
3
overall yield of 68%. N-Ethylindole (2c) behaved sim-
In order to ascertain the influence of alkyl substitution
at the fused pyrrole ring, the reaction of 1 was next
carried out with skatole, 2-methylindole (8a), 1,2-
dimethylindole (8b), 1,3-dimethylindole (8c) and 2,3-
dimethylindole (8d) separately. No reaction took place
with 8d. With skatole, both a symmetrical TIM (9) and
an unsymmetrical TIM (10) were formed. With each of
1
4
ilarly with 1, furnishing the symmetrical TIM 3c and
15
16
the unsymmetrical TIMs 4c and 5c in addition to
indole (Scheme 2).
The reaction of 1 with 2a–c clearly proceeded through
the successive intermediacies of the related bis(indol-3-
yl)carbinols 6a–c and the indoleninium species 7a–c
both of which were obviously formed through the
mediation of clay) to form the symmetrical TIMs 3a
and 4b–c. The subsequent loss of a molecule of indole
or N-alkylindole), followed by Michael addition of
N-alkylindole (or indole), resulted in the unsymmetrical
TIMs 3b–c (or 5b–c) (Scheme 3). The isolation of indole
and N-alkylindoles from the respective experiments
lends support to the suggested mechanism.
8
a–c, however, only one type of unsymmetrical TIM,
viz. 11a/b/c was formed (Scheme 4). In all likelihood,
steric crowding in 8a–c is responsible for the lack of
formation of the respective symmetrical TIMs and for
the formation of only one type of unsymmetrical TIM.
Pertinently, the reactions with skatole and 8c were
sluggish, requiring 48 h for the completion of the
reactions using twice the amount of clay, thereby point-
ing to the roles of both 3-alkylation and the surface
area of clay in influencing the rate of the reactions.
(
(
Scheme 2.
Scheme 3.
Scheme 4.

M. Chakrabarty, S. Sarkar / Tetrahedron Letters 43 (2002) 1351–1353
1353
To our knowledge, this is the first report of the forma-
tion of both symmetrical and unsymmetrical triindolyl-
alkanes by tandem addition–elimination-(Michael)
addition reaction of indoles, and that too on a clay
surface. This reaction should be typical of the indole
ring, provided the nucleophilicity of the latter is not
destroyed by, for example, N-acylation/aroylation. Our
findings are significant in view of the recent identifica-
11. When two mol equiv. of indole was used, the reaction
was very sluggish and did not go to completion. Three
mol equiv. of indole or alkylindole was, therefore, used
in all the experiments.
12. Bahner, C. T.; Kinder, H.; Gutman, L. J. Med. Chem.
1965, 8, 397.
13. In a typical experiment, a solution of 1 (0.6 mmol) in
EtOAc:MeOH (1:1; 0.5 ml) was mixed with a solution of
2c (1.8 mmol) in EtOAc (0.5 ml) and adsorbed on M.
K10 clay (5 g), and the solvent was allowed to evaporate
off at room temperature. After 5 min of mixing, leaching
17
tion of a bacterial metabolite as a triindolylalkane, the
conversion of derivatised triarylalkanes into important
1
8
cage compounds and the physicochemical studies of
19
several triarylalkyl cations. Additionally, the present
work opens up the possibility of the development of a
new, general synthesis of symmetrical TIMs without the
use of any protic or Lewis acid. This lead is at present
being explored by us.
with CH Cl2 (3×15 ml), removal of the solvent and
2
preparative TLC of the resulting residue in petrol–EtOAc
(
4:1) furnished 3c, 2a (28%), 4c and 5c which, along with
products from other reactions, were crystallised from
petroleum ether (bp 60–80°C)–CH Cl and identified by
2
2
correct elemental analyses, IR (KBr), (LR/HR)EI MS,
1
13
H (500 MHz) and C (125 MHz) NMR (CDCl ), DEPT
3
1
35, HMQC and HMBC spectra.
Acknowledgements
1
4. 3c: 24 mg (9%); orange needles, mp 216–218°C; IR: 1440,
−
1
+
1360, 740 cm ; HRMS: m/z 445.2501 (C H N ; M ;
31 31 3
1
1
00%); H: l 1.35 (9H, t, J 7.2 Hz, N-CH CH ), 4.05
The authors sincerely thank the Director, Bose Institute
for providing laboratory facilities and an Institute fel-
lowship to S.S., Professor D. E. Games, University of
Wales, Swansea, UK and Mr. B. Majumdar, NMR
Laboratory, Bose Institute for recording the mass and
NMR spectra.
2
3
(
6H, q, J 7.2 Hz, N-CH CH ), 6.15 (1H, s, Ar CH), 6.70
2 3 3
(3H, s, H-2), 6.96 (3H, t, J 7.2 Hz, H-5), 7.16 (3H, t, J 7.2
Hz, H-6), 7.31 (3H, d, J 8 Hz, H-7), 7.47 (3H, d, J 8 Hz,
13
H-4); C: l 136.8, 128.2, 118.5 (all C), 126.8, 121.3,
120.8, 118.6, 118.5, 109.4, 31.6 (all CH), 41.1 (CH ), 15.9
CH3).
5. 4c: 58 mg (23%); red prisms, mp 222–224°C; IR: 3406
2
(
1
−
1
+
(
NH), 1459, 1348, 740 cm ; MS: m/z 417 (M ; 100%);
H: l 1.35 (6H, t, J 7.2 Hz, N-CH CH ), 4.05 (4H, q, J
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