Iodine-catalyzed highly efficient Michael reaction of indoles under solvent-free condition

Article abstract of DOI:10.1016/j.tetlet.2005.02.044

Michael reaction of indoles with unsaturated ketones has been accomplished in the presence of catalytic amount of iodine under solvent-free condition.

Full text of DOI:10.1016/j.tetlet.2005.02.044

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2479–2482
Iodine-catalyzed highly efficient Michael reaction of
indoles under solvent-free condition
*
Bimal K. Banik, Miguel Fernandez and Clarissa Alvarez
Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78541, USA
Received 1 December 2004;revised 7 February 2005;accepted 8 February 2005
Abstract—Michael reaction of indoles with unsaturated ketones has been accomplished in the presence of catalytic amount of iodine
under solvent-free condition.
Ó 2005 Published by Elsevier Ltd.
Organic and medicinal chemists are paying tremendous
attention for the simplification or improvement of the
existing methods that are widely used in the manufac-
ture of pharmaceutical substances. Reactions under
solid support, chemoenzymatic reactions and micro-
wave-induced reactions have already created an enorm-
ous impact in modern science. Catalytic methods
have also contributed significantly. Of particular interest
is conducting reactions under solvent-free conditions.
These methods proceed with enhanced reaction rates
and give cleaner products in many cases.
research to develop iodine-catalyzed organic transform-
ations, we herein report an extremely convenient
Michael reaction of indoles using solvent-free conditions.
6
We have reported several iodine-catalyzed organic
6
transformations. For example, protection of carbonyl
compounds was achieved as ketals and thioketal by
using catalytic quantities of iodine. In another report,
a facile oxidation of benzylic alcohols was also investi-
gated. In addition, iodine-catalyzed glycosylation of
alcohols with sugar derivatives is also known. These
are acid-induced processes. As Michael reactions are
among the most important acid-mediated reactions,
development of a reaction that uses catalytic quantities
of lowly toxic, readily available, economic reagent with-
out using any solvent should greatly contribute to the
creation of environmentally benign processes. Since,
most of the common acceptors used in this type of reac-
tion are liquids, we hypothesized that the drawbacks of
the catalysts employed in the Michael reaction may be
avoided if we used iodine as a mild reagent in catalytic
amounts under solvent-free conditions.
Michael reaction, a conjugate addition reaction of
nucleophiles to unsaturated carbonyl compounds re-
1
2
quires basic conditions or acidic catalysts. Many of
these methods require stoichiometric amounts of the re-
agents, and therefore, side reactions can occur if the
3
reactive partners are sensitive. Particularly, polymeriza-
tion of the unsaturated acceptor is very common be-
cause of the acid-induced conditions. Recently, a
number of reagents have been developed to overcome
the problem. The main improvement of these reagents
4
is the ability to limit the catalysts used.
Several addition reactions of enones to indoles using
7
We have been engaged in the synthesis of several biologi-
cally active compounds, including anticancer agents, b-
lactams and other heterocyclics. Indoles are well suited
for our current program, as several of their derivatives
are medicinally active. In connection with our ongoing
Lewis and Bronsted acids have been published. Acid-
induced reaction of indoles requires precise control of
the acidity to prevent side reactions, including dimeriza-
5
8
tion and polymerization. Recently, it has been demon-
strated that indium tribromide mediates the conjugate
9
addition of enones to indoles. However, with less elec-
tron-rich indoles, the yield of the products was not
satisfactory. In such cases, indium trichloride was
proved to be very effective. However, these reactions
were done under classical conditions using organic
*
Corresponding author. Tel.: +1 956 380 8741;fax: +1 956 384
006;e-mail: banik@panam.edu
Undergraduate research participants;contributed equally.
5
0
040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.02.044

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B. K. Banik et al. / Tetrahedron Letters 46 (2005) 2479–2482
a
2
Table 1. I -catalyzed Michael reaction of enones with indoles
Entries
Enones
Indoles
Products
Yield
%)
(
O
O
O
Ph
Ph
1
2
85
78
N
Ph
H
N
b
H
1
1b
NC
O
NC
N
H
Ph
N
H
1
1
1
1
1
1
2
O
O
O
O
O
BnO
O
BnO
Ph
Ph
3
4
5
6
7
8
72
69
56
73
64
79
N
Ph
H
N
H
3
BnO
MeO
O
BnO
MeO
Ph
N
H
N
H
4
5
6
7
NC
O
O
NC
N
H
N
H
BnO
MeO
BnO
MeO
N
H
N
H
NC
NC
O
O
NC
N
H
N
H
O
NC
N
H
N
H
1
1
8
9
O
O
9
55
76
71
45
N
H
N
H
NC
O
O
O
NC
O
O
1
1
1
0
1
2
N
H
N
H
2
2
2
0
1
2
BnO
BnO
N
N
H
H
O
N
H
N
H
a
Reaction was completed within 20 min at room temperature.

B. K. Banik et al. / Tetrahedron Letters 46 (2005) 2479–2482
2481
solvent and approximately 10 mol % of the catalyst for
6–24 h. In addition, in some cases, external proton
existing methods, this procedure is simple, rapid, high-
yielding, and convenient.
1
source such as isopropyl alcohol was needed for the suc-
cess of the reaction.
Acknowledgements
Our method of iodine-catalyzed Michael reaction of in-
doles with enones is very simple and efficient (Table 1).
The starting materials (indoles and ketones, 1:1, 1 mmol
scale) are mixed with iodine (1 mol %) and the mixtures
are stirred. After the specified time (10–20 min) at room
temperature, dichloromethane (25 mL) is added to bring
the mass in solution. It is then washed with sodium thio-
sulfate and the solvent is evaporated under reduced
pressure. The crude material in most of the cases is suf-
ficiently pure (80–90%). The pure products are obtained
by a simple filtration through silica gel using ethyl ace-
tate–hexanes (20:80). Unlike the processes described in
earlier reports, this method is totally independent of
solvent choice or external proton source. Even re-
agents that are undistilled or unpurified can be used with
equal success. Additionally, it has been found that the
indoles with wide range of functionalities react very eas-
ily with cyclic and acyclic enones and give products in
high yield at room temperature in the presence of only
We gratefully acknowledge the partial financial support
for this research from The Robert A. Welch Foundation
(BG-0017) departmental grant and The University of
Texas-Pan American.
References and notes
1
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mol % iodine as the catalyst. Specifically, the reactions
are very efficient, and the products are not contaminated
with side products, such as dimers or trimers which are
9
b
normally formed under the influence of strong acids.
In general, the reactions took place at the 3-position
of the indole ring when this position was unoccupied.
When the 3-position was occupied by a methyl group,
1
240;For a review for enantioselective conjugate addition,
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the reaction took place at C positions.
2
8
To expand the method, reaction of imidazole with 3-
methylcyclohex-2-ene and methyl vinyl ketone was per-
formed in the presence of iodine (5 mol %). The yield of
the products was 60–70%. However, the reaction was
not successful with unsaturated ester and unsaturated
aldehyde.
1
2
Chem. 2001, 9, 593;(d) Banik, B. K.;Becker, F. F. Curr.
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The success of iodine-mediated conjugate reactions
prompted us to investigate the mechanistic process. Cata-
lytic amounts (1 mol %) of iodine crystal is necessary for
a complete reaction, an increase in the proportion to
2
523.
6. (a) Mukhopadhyay, C.;Becker, F. F.;Banik, B. K.
J. Chem. Res. 2001, 108;(b) Samajdar, S.;Basu, M. K.;
Becker, F. F. Synlett 2002, 319;(c) Basu, M. K.;
Samajdar, S.;Becker, F. F.;Banik, B. K.
Tetrahedron
1
0% produced comparable yields. The reaction did not
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catalyzed organic reactions, see: (a) Banik, B. K.;
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proceed in the absence of iodine. Since this reaction is
investigated without using inert atmosphere and dry
conditions, iodine can produce hydroiodic acids. There-
fore, a reaction (Table 1, entry 1) was performed in the
presence of hydroiodic acid in various amounts under
solvent-free conditions. It appeared that hydroiodic
acid-mediated reactions produced products in much
lower yields (10%). Most of the experiments under
hydroiodic acid-induced processes remained incomplete
even after 5 h. With catalytic amounts of hydroiodic
acid, reaction did not proceed at all. This result suggests
that there might be a complexation role for molecular
iodine apart from its acidity.
4
714;(b) Banik, B. K.;Manhas, M. S.;Bose, A. K.
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8
9
In conclusion, Michael reaction of indoles and imidaz-
oles with unsaturated carbonyl compounds was success-
fully carried out in the presence of a catalytic amount of
1
1
iodine in the absence of solvent. In contrast to the

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B. K. Banik et al. / Tetrahedron Letters 46 (2005) 2479–2482
1
0. Kobayashi, S.;Kakumoto, K.;Sugiura, M.
002, 4, 1319.
1. A representative procedure is given below: Iodine
5 mol %) was added to a mixture of indole (1 mmol)
Org. Lett.
and ketone (1 mmol). After being stirred for 30 min,
2
the mixture was chromatographed over silica gel
using ethylacetate–hexane (10:90) to afford the pure
product.
1
(