Amberlyst-catalyzed reaction of indole: Synthesis of bisindolylalkane

Article abstract of DOI:10.1081/SCC-200054794

Amberlyst was found to be an effective catalyst for the condensation reactions of indoles 2 with aldehydes 3 to afford bisindolylalkanes 1 in good to excellent yields. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200054794

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Amberlyst‐Catalyzed Reaction
of Indole: Synthesis of
Bisindolylalkane
Bowen Ke a , Yong Qin a , Yin Wang a & Fengpeng
Wang a
a Department of Chemistry of Medicinal Natural
Products , West China School of Pharmacy, Sichuan
University , Chengdu, China
Published online: 16 Aug 2006.
To cite this article: Bowen Ke , Yong Qin , Yin Wang & Fengpeng Wang (2005)
Amberlyst‐Catalyzed Reaction of Indole: Synthesis of Bisindolylalkane, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:9, 1209-1212, DOI: 10.1081/SCC-200054794
To link to this article: http://dx.doi.org/10.1081/SCC-200054794
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Synthetic Communicationsw, 35: 1209–1212, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200054794
Amberlyst-Catalyzed Reaction of Indole:
Synthesis of Bisindolylalkane
Bowen Ke, Yong Qin, Yin Wang, and Fengpeng Wang
Department of Chemistry of Medicinal Natural Products, West China
School of Pharmacy, Sichuan University, Chengdu, China
Abstract: Amberlyst was found to be an effective catalyst for the condensation
reactions of indoles 2 with aldehydes 3 to afford bisindolylalkanes 1 in good to
excellent yields.
Keywords: Amberlyst, bisindolylalkane, indole, aldehyde, condensation
INTRODUCTION
Bisindolylalkane 1 is an important class of bioactive metabolite.[1] With the
continuing isolation of structurally more diverted bisindolylalkanes,[2] the
efficient syntheses of bisindolylalkanes becomes of increasing interest in
organic synthesis.[3] Bisindolylalkanes were usually prepared through the
addition reactions of indole with aldehydes catalyzed by a protic acid or a
Lewis acid. Most of these methods suffer from various disadvantages, such
as use of more than stoichiometric amounts of expensive Lewis acids and
preformed reagents. Recently, LiClO4,[4] In(OTf)3,[5] KHSO4,[6] montmorillo-
nite,[7] and idoine[8] were reported to be efficient catalysts to promote the
reaction. In this article, we introduce amberlyst (the strong sulfonic acid
form) as a mild and efficient catalyst for the syntheses of bisindolylalkanes 1.
Received in Japan November 10, 2004
Address correspondence to Yong Qin or Fengpeng Wang, Department of Chemistry
of Medicinal Natural Products, West China School of Pharmacy, Sichuan University,
Chengdu 610041, China. E-mail: yanshuqin@yahoo.com

1210
B. Ke et al.
RESULTS AND DISCUSSION
Our initial study found that p-toluenesulfonic acid promoted the condensation
reaction of indole 2a with benzaldehyde in reflux benzene to afford bisindolyl-
alkane 1 in a moderate yield as well as some decomposed by-products. We
were curious to know whether amberlyst, which has the same functional
group as toluenesulfonic acid, can promote the condensation reaction under
a mild condition (Scheme 1).
After screening the effects of a variety of solvents on the condensation
reaction of indole with benzaldehyde at room temperature in the presence
of amberlyst, acetonitrile was found to be the best choice of solvent. As
shown in Table 1, direct treatment of indole 2a with benzaldehyde in
acetonitrile for 12 h provided bisindolylalkane 1 in almost quantitative yield
at room temperature in the presence of amberlyst (entry 1). Under the
same condition, condensation of indole 2a with a variety of aromatic
aldehydes gave the corresponding indolylalkanes 1 in more then 97% yields
(entries 5, 25, and 26). These reactions were very clean. The exception was
that the electron-rich benzaldehydes, such as 4-methoxyphenylaldehyde and
3,4-dimethoxyphenylaldehyde, showed poor reactivity and longer reaction
time was required to give the satisfied yields (entries 9 and 13). Reaction of
indole 2a with furylaldehyde was very sluggish to give 1 in a good yield
(entry 23). Aliphatic aldehydes, such as pentylaldehyde, isobutylaldehyde,
and 3-phenylpropionaldehyde, also afforded good yields of products but
again required longer reaction time (entries 21, 27, and 28).
The amberlyst-promoted condensation reaction was next extended to sub-
stituted indoles with a substituent at position 2 or position 5. Condensation
reaction of 5-bromoindole 2b with isobutylaldehyde and benzaldehydes pos-
sessing an electron-donating or an electron-withdrawing substituent gave the
corresponding bisindolyalkanes 1 in excellent yields (entries 2, 6, 10, and 14).
For 5-methoxyindole 2c, condensation reactions with butylaldehyde and ben-
zaldehydes required a longer reaction time, compared with the reaction of
2b, to afford products in comparable yields (entries 3, 7, 11, and 15).
2-Methylindole 2d showed similar reactivity compared with 5-bromoindole.
Condensation reactions of 2d with both aromatic aldehydes and aliphatic
Scheme 1. The addition reaction of indole with aldehyde.

Amberlyst-Catalyzed Reaction of Indole
1211
Table 1. Synthesis of bisindolyalkane catalyzed by amberlyst
R
Entry
2
R1
R2
Time
Yielda
Ph
1
2
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2a
2a
2a
H
H
H
Br
MeO
H
12
5
99
99
92
89
98
99
96
96
84
96
84
88
73
91
95
89
74
63
70
91
83
97
78
84
97
99
73
61
3
H
15
12
6
4
Me
H
4-NO2Ph
4-MeOPh
5
H
6
H
Br
MeO
H
4
7
H
10
6
8
Me
H
9
H
18
10
36
15
34
36
48
16
48
48
48
20
10
12
28
10
10
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
H
Br
MeO
H
H
Me
H
3,4-
(MeO)2Ph
H
H
Br
MeO
H
H
Me
H
2-Furyl
iPr
H
H
Br
MeO
H
H
Me
H
H
H
Br
MeO
H
H
Me
H
4-MePh
4-Cl-Ph
Ph(CH2)2
n-Pentyl
H
H
H
H
H
24
48
H
H
aIsolated yield.
aldehydes produced the desired bisindolylalkanes 1 in excellent yields (entries
4, 8, 12, and 16). The electron-rich furylaldehyde showed the poorest reactiv-
ity; condensation of furylaldehyde with four tested indoles (2a–c) as long as
48 h provided the corresponding 1 in only moderate yields (entries 17–19),
whereas the reaction of furylaldehyde with indole 2d needed 20 h to afford
a 91% yield (entry 20).
A typical experimental procedure is described here for the reaction of
indole 2b with benzaldehyde to demonstrate the simplicity of current method:
Indole (1 mmol) and benzaldehyde was stirred with 0.5 g amberlyst (strong
sulfonic acid form) in acetronitrle at room temperature for 4 h. Filtration and
evaporation of the acetonitrile afforded the desired bisindolyalkane,

1212
B. Ke et al.
which was pure enough for analytic purposes. The amberlyst can be recycled
and reactivated for next reaction.
In summary, we have described a highly efficient procedure for the prep-
aration of bisindolyalkane though the amberlyst-promoted condensation
reaction of indole with aldehyde. The procedure offers the advantages of
mild reaction conditions, clean reactions, high yield of product, and a
simple experimental procedure, which makes it a useful, practical method
for the syntheses of bisindolylalkanes.
ACKNOWLEDGMENTS
Support from Ministry of Education (EYTP, RFDP, and SRF for ROCS), the
Excellent Youth Foundation of Sichuan Province (No. 04ZQ026-011), and the
National Natural Science Foundation of China (No. 20372048) are gratefully
acknowledged.
REFERENCES
1. (a) Porter, J. K.; Bacon, C. W.; Robbins, J. D.; Himmelsbach, D. S.; Higman, H. C.
J. Agric. Food Chem. 1977, 88; (b) Osawa, T.; Namiki, M. Tetrahedron Lett. 1983,
4719; (c) Fahy, E.; Potts, B. C.M.; Faulkner, D. J.; Smith, K. J. Nat. Prod. 1991,
564; (d) Bell, R.; Carmell, S.; Sar, N. J. Nat. Prod. 1994, 1587; (e) Bifulco, G.;
Bruno, I.; Riccio, R.; Lavayre, J.; Bourdy, G. J. Nat. Prod. 1995, 1254.
2. (a) Garbe, T. R.; Kobayashi, M.; Shimizu, N.; Takesue, N.; Ozawa, M.;
Yukawa, H. J. Nat. Prod. 2000, 596; (b) Veluri, R.; Oka, I.; Wagner-Dobler, I.;
Laatsch, H. J. Nat. Prod. 2003, 1520.
3. (a) Chen, D.; Yu, L.; Wang, P. Tetrahedron Lett. 1996, 37, 4467; (b) Coenia, M.;
Capacchi, S.; Pogetto, M.; Pelosi, G.; Fava, G. G. Tetrahedron: Asymmetry 1997,
8, 2905; (c) Ji, Sh. J.; Zhou, M. F.; Gu, D. G.; Wang, Sh. Y.; Loh, T. P. Synlett
2003, 2077; (d) Mahadevan, A.; Sard, H.; Gonzalez, M.; McKew, J. C. Tetrahe-
dron Lett. 2003, 4589; (e) Reddy, A. V.; Ravinder, K.; Reddy, V. L. N.;
Goud, T. V.; Ravikanth, V.; Venkateswarlu, Y. Synth. Comm. 2003, 3687;
(f) Kumar, S.; Kumar, V.; Chimni, S. Tetrahedron Lett. 2003, 44, 2101;
(g) Li, J.; Guang, B.; Wang, L.; Li, B.; Zhang, G. Heterocycles 2003, 60, 1307;
(h) Li, J.; Zhou, M.; Li, B. G.; Zhang, G. L. Synth. Comm. 2004, 275;
(i) Chakrabarty, M.; Basak, R.; Ghosh, N.; Harigaya, Y. Tetrahedron 2004, 60,
1941.
4. Yadav, J. S.; Reddy, B. V.S.; Murthy, Ch. V.S.R.; Kumar, G. M.; Madan, Ch.
Synthesis 2001, 783.
5. Nagarajan, R.; Perumal, P. T. Tetrahedron 2002, 1229.
6. Nagarajan, R.; Perumal, P. T. Chem. Lett. 2004, 288.
7. Chakrabarty, M.; Ghosh, N.; Basak, R.; Harigaya, Y. Tetrahedron Lett. 2002,
4075.
8. (a) Bandgar, B. P.; Shaikh, K. A. Tetrahedron Lett. 2003, 1959; (b) Ji, Sh. J.;
Wang, Sh. Y.; Zhang, Y.; Loh, T. P. Tetrahedron 2004, 2051.