Conjugate addition of indoles and thiols with electron-deficient olefins catalyzed by Bi(OTf)3

Article abstract of DOI:10.1016/S0040-4039(03)01089-X

Conjugate addition of indoles and thiols with a variety of electron-deficient olefins mediated by a catalytic amount of Bi(OTf)₃ at ambient temperature to afford the corresponding Michael adducts in good to excellent yields with high selectivity is reported.

Full text of DOI:10.1016/S0040-4039(03)01089-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5115–5119
Conjugate addition of indoles and thiols with electron-deficient
olefins catalyzed by Bi(OTf)3
M. Mujahid Alam, Ravi Varala and Srinivas R. Adapa*
Inorganic Chemistry Division Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 11 March 2003; revised 16 April 2003; accepted 25 April 2003
Abstract—Conjugate addition of indoles and thiols with a variety of electron-deficient olefins mediated by a catalytic amount of
Bi(OTf) at ambient temperature to afford the corresponding Michael adducts in good to excellent yields with high selectivity is
3
reported. © 2003 Elsevier Science Ltd. All rights reserved.
Addition reactions of indoles and thiols to electron-
deficient olefins have received much interest because a
number of their derivatives occur in nature and pos-
ization. Furthermore, many of these procedures
involve strongly acidic conditions, expensive reagents
and long reaction times, give low yields of products
due to dimerisation of the indoles or polymerization
of the vinyl ketones, and involve cumbersome experi-
mental product isolation procedures. There is a need
for cheaper and more efficient Lewis acid catalysts
for Michael-type addition reactions. In this regard,
bismuth triflate has been found to be useful to
organic chemists.
1
sess a variety of biological activities. Since the 3-
position of indole is the preferred site for electrophilic
substitution reactions, 3-alkyl or acyl indoles are ver-
satile intermediates for the synthesis of a wide range
2
of indole derivatives. A simple and direct method for
the synthesis of 3-alkylated indoles involves the con-
jugate addition of indoles to a,b-unsaturated com-
3
pounds in the presence of either protic or Lewis
4
acids. However, the acid-catalyzed conjugate addition
Recently, bismuth triflate has emerged as a powerful
5
of indoles requires careful control of acidity to pre-
vent side reactions such as dimerisation or polymer-
Lewis acid for various chemical transformations. We
have reported that bismuth triflate can be used as an
Scheme 1.
Keywords: Bi(OTf) ; indoles; thiols; a,b-unsaturated compounds; addition reactions.
3
*
Corresponding author.
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01089-X

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M. M. Alam et al. / Tetrahedron Letters 44 (2003) 5115–5119
excellent catalyst in the Biginelli reaction under mild
conditions. Herein, we describe the remarkable cata-
ence of strong acids. The procedure does not require
any acidic promoters or anhydrous conditions.
6
lytic activity of Bi(OTf) in the conjugate addition of
3
indoles and thiols to a,b-unsaturated compounds
Conjugate addition of thiols to a,b-unsaturated
7
(
Schemes 1 and 2).
ketones catalyzed by Bi(OTf) : the 1,4 addition of
3
thiols to electron deficient olefins to form a car-
bonꢀsulfur bond constitutes a key reaction in biosyn-
thesis as well as in the synthesis of biologically active
We were pleased to find that indole smoothly reacted
with methyl vinyl ketone in the presence of a cata-
9
lytic amount of Bi(OTf) (5 mol%) in acetonitrile to
compounds such as the calcium antagonist diltiazem.
3
give the corresponding 3-alkylated product in 90%
yield after 1.5 h at ambient temperature (entry 4,
Table 1). Encouraged by this result, we carried out
the reaction under different conditions and the results
were satisfactory. The best solvents for this reaction
were found to be dichloromethane, dichloroethane,
water, THF and acetonitrile. Acetonitrile was a much
better solvent in terms of yields than all the other
solvents tested. The use of 5 mol% of bismuth triflate
was sufficient to carry out the reaction. Substituted
and unsubstituted indoles were used in the optimized
procedure. 2-methylindole (entry 2, Table 1) furnished
higher conversions in comparison to other indoles
In the literature, a large number of conjugate addi-
tions based on the activation of thiols by bases have
10
been reported. In contrast, only a few reports on
the addition of thiols by activation of the acceptors
11
with Lewis acids are known. Additions of sulfur
nucleophiles to a,b-unsaturated ketones have now
7
been carried out by the use of Bi(OTf) (Scheme 2).
3
Substituted and unsubstituted aromatic thiols can be
used in the optimized procedure with numerous cyclic
and acyclic ketones. Products were isolated in good
yields after column chromatography and the results
are summarized in Table 2. Benzylmercaptan (entry 3,
Table 2) afforded a higher conversion in comparison
with other thiols (entries 1 and 2, Table 2). In the
case of dibenzylidene acetone, the bis-alkylated
product was observed under these reaction conditions
(entries 10 and 11, Table 2).
(
entries 1 and 3, Table 1).
The reaction seems to occur via a Friedel–Crafts
8
alkylation pathway. It is interesting to compare sev-
eral of the entries from Table 1. Electron-deficient
olefins such as methyl vinyl ketone, phenyl vinyl
ketone, dibenzylidene acetone, afforded the products
in good to excellent yields. Other Michael acceptors
such as vinyl cyanide and methyl acrylate also reacted
In general, thiols reacted faster than indoles with elec-
tron deficient olefins under the present reaction
conditions.
4
a,e
well under these conditions.
In the case of dibenz-
In summary, we have demonstrated Bi(OTf)3 as a
superior Lewis acid for the alkylation of indoles and
thiols with electron-deficient olefins.
ylidene acetone, no bis-alkylated product was
observed (entry 6, Table 1). The treatment of b-
nitrostyrene with indole produced the corresponding
3
-alkylated indole (entry 7, Table 1) in excellent yield.
The NH proton of the indole does not play a signifi-
cant role in the formation of the addition product
Acknowledgements
(
entries 3 and 8, Table 1). The reactions were clean
and the products were obtained in high yields without
the formation of any side products such as dimers or
trimers, which are normally observed under the influ-
M.M.A. and V.R thank Dr. B. M. Choudary, Head
of the Division and the Director, Dr. K. V. Ragha-
van for their constant support throughout the work.
Scheme 2.

M. M. Alam et al. / Tetrahedron Letters 44 (2003) 5115–5119
5117
Table 1. Michael addition of indoles with electron-deficient olefins catalyzed by Bi(OTf)3

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M. M. Alam et al. / Tetrahedron Letters 44 (2003) 5115–5119
Table 2. Michael addition of thiols with electron-deficient olefins catalyzed by Bi(OTf)3
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1
7
. General procedure for the catalytic addition of indoles and
thiols to a,b-unsaturated ketones: A mixture of indole or
thiol (0.45 mmol), a,b-unsaturated carbonyl compound
(
0.3 mmol), and Bi(OTf) (5 mol%) in acetonitrile (5 ml)
3