Silica-supported sodium sulfonate with ionic liquid: A neutral catalyst system for Michael reactions of indoles in water

Article abstract of DOI:10.1021/ol062446b

(Chemical Equation Presented) A neutral catalytic system for Michael reactions of indoles has been developed by combining silica-supported benzenesulfonic acid sodium salt with hydrophobic ionic liquid in water. An efficient hydrophobic environment could

Full text of DOI:10.1021/ol062446b

ORGANIC
LETTERS
2007
Vol. 9, No. 2
175-178
Silica-Supported Sodium Sulfonate with
Ionic Liquid: A Neutral Catalyst System
for Michael Reactions of Indoles in
Water
Yanlong Gu, Chikako Ogawa, and Shu¯ Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, The HFRE
DiVision, ERATO, Japan Science and Technology Agency (JST), Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
skobayas@mol.f.u-tokyo.ac.jp
Received October 4, 2006
ABSTRACT
A neutral catalytic system for Michael reactions of indoles has been developed by combining silica-supported benzenesulfonic acid sodium
salt with hydrophobic ionic liquid in water. An efficient hydrophobic environment could be created on the surface of the silica sodium material
under the conditions. Various indole derivatives and -unsaturated carbonyl compounds including some acid-labile substrates were successfully
applied to this system with water as the sole solvent to afford the desired Michael adducts in high yields.
−
r,â
The Michael reaction of indoles with R,â-unsaturated car-
bonyl compounds provides easy access to 3-substituted
indoles, which are important building blocks for the synthesis
of biologically important compounds and natural products.
While the reaction proceeds in the presence of either protic1
or Lewis acids in many cases,2 the acid-catalyzed conjugate
addition requires careful control of acidity to prevent side
reactions such as dimerization, isomerization, and polym-
erization, etc. Furthermore, acidic conditions also prevent
the use of acid-labile substrates. Despite recent advances in
this field, no general methods to address these problems have
been reported. As a result, excess amounts of indoles or R,â-
unsaturated carbonyl compounds are required to obtain high
yields in many cases. Therefore a new method to promote
the reactions more efficiently, for example, the reactions with
equimolar amounts of indoles with R,â-unsaturated carbonyl
compounds, is desired.
(2) (a) Firouzabadi, H.; Iranpoor, N.; Nowrouzi, F. Chem. Commun. 2005,
789. (b) Zhan, Z. P.; Yang, R. F.; Lang, K. Tetrahedron Lett. 2005, 46,
3859. (c) Reddy, A. V.; Ravinder, K.; Goud, V.; Kishnaiah, P.; Raju, T.
V.; Venkateswarlu, Y. Tetrahedron Lett. 2003, 44, 6257. (d) Alam, M. M.;
Varala, R.; Adapa, S. R. Tetrahedron Lett. 2003, 44, 5115. (e) Bartoli, G.;
Bartolacci, M.; Bosco, M.; Foglia, G.; Giuliani, A.; Marcantoni, E.; Sambri,
L.; Torregiani, E. J. Org. Chem. 2003, 68, 4594.
(1) (a) Szmuszkovicz, J. J. Am. Chem. Soc. 1975, 79, 2819. (b) Noland,
W. E.; Christensen, G. M.; Sauer, G. L.; Dutton, G. G. S. J. Am. Chem.
Soc. 1955, 77, 456. (c) Iqbal, Z.; Jackson, A. H.; Rao, K. R. N. Tetrahedron
Lett. 1988, 29, 2577.
10.1021/ol062446b CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/21/2006

Table 2. Michael Reactions of Several Indole Derivatives with
MVK in Water
Figure 1. Silica-supported sodium materials.
Recently, we have found that combination of a silica-
supported scandium catalyst with hydrophobic ionic liquid
can create a hydrophobic environment on the surface of silica
in water, which allows many organic reactions to proceed
well with water as a solvent.3 As an extension of this work,
we focused on a combination of silica gel-supported sodium
materials with ionic liquid as a neutral catalyst in water.
Herein we report the combination as a neutral heterogeneous
catalyst system for Michael reactions of indoles with R,â-
unsaturated carbonyl compounds in water.4
Preparation of silica gel-supported sodium materials was
performed according to a modified literature method.5 The
Silica-Na catalysts thus prepared were added to an ethyl
acetate solution of ionic liquid, and the solvent was removed
under reduced pressure to afford powdery and free-flowing
solid, silica gel-supported sodium sulfonate with ionic liquid
(Silica-Na-IL).As shown in Table 1, use of a standard Silica-
Table 1. Silica-Na Catalyzed Michael Reaction of
1-Methylindole with MVKa
a Experiment in a 10 mmol scale.
was also accelerated, but was not complete within 12 h (entry
3). It is noted that the reaction proceeded smoothly without
using any acidic species, and that high yields were obtained
by using 1 equiv of MVK (refer to N-methylindole). We
also examined the effect of solvents (entries 4 and 5). While
the best yield was obtained in water, much lower yields were
observed with other solvents (dichloromethane and toluene).
It was also found that loading amounts of Na influenced the
silica
material
IL loadingd
(wt %)
yield
(%)
entry
solvent
1
2
3
4
5
6
7
8b
9c
Silica-Na 3
Silica-Na 3
Silica-Na 3
Silica-Na 3
Silica-Na 3
Silica-Na 1
Silica-Na 2
Silica
0
H2O
H2O
H2O
CH2Cl2
toluene
H2O
H2O
H2O
10
95
61
31
9
38
73
0
25.0
12.5
25.0
25.0
25.0
25.0
25.0
25.0
(3) Gu, Y.; Ogawa, C.; Kobayashi, J.; Mori, Y.; Kobayashi, S. Angew.
Chem., Int. Ed. 2006, 45, 7217.
(4) Although supported ionic liquid catalysis has been investigated
recently, there has been no example of combination of silica-supported metal
catalysts with ionic liquids before our recent report (ref 3). In the supported
ionic liquid catalysis, it is reported that silica gel-supported ionic liquids
and additional nonsupported ionic liquids form ionic liquid phases on the
surface of silica gel due to interactions between supported and nonsupported
ionic liquids. For supported ionic liquid catalysis see: (a) Mehnert, C. P.;
Cook, R. A.; Dispenziere, N. C.; Afeworki, M. J. Am. Chem. Soc. 2002,
124, 12932. (b) Riisager, A.; Fehrmann, R.; Flicker, S.; van Hal, R.;
Haumann, M.; Wasserscheid, P. Angew. Chem., Int. Ed. 2005, 44, 815. (c)
Hagiwara, H.; Sugawara, Y.; Hoshib, T.; Suzukib, T. Chem. Commun. 2005,
2942. (d) Gruttadauria, M.; Riela, S.; Aprile, C.; Meo, P. L.; D’Anna, F.;
Noto, R. AdV. Synth. Catal. 2006, 348, 82. (e) Mehnert, C. P. Chem. Eur.
J. 2005, 11, 50.
Silica-Na 3
H2O
94
a Reaction conditions: 50 mg of silica material, 0.25 mmol of N-
methylindole, 0.25 mmol of MVK, 0.25 mL of solvent. b The starting silica
gel was used. See the Supporting Information. c Reused in the second run.
d [DBIm]SbF6 was used. [DBIm] ) 1-butyl-3-decylimidazolium.
Na catalyst (Silica-Na 3) alone gave a low yield for Michael
reaction of N-methylindole and methyl vinyl ketone (MVK)
in water (Table 1, entry 1). To our delight, a great
improvement on the yield was observed when 25 wt % of
[DBIm]SbF6 was loaded on the Silica-Na 3 (entry 2). When
half the amount of the ionic liquid was used, the reaction
(5) (a) Jones, C. W.; Tsuji, K.; Davis, M. E. Nature 1998, 393, 52. (b)
Sow, B.; Hamoudi, S.; Zahedi-Niaki, H.; Kaliaguine, S. Miroporous
Mesoporous Mater. 2005, 79, 129. (c) Li, P.-H.; Wang, L. AdV. Synth. Catal.
2006, 348, 681.
176
Org. Lett., Vol. 9, No. 2, 2007

yield (entries 2, 6, and 7), while no reaction occurred by
using the starting silica without Na (entry 8). These results
confirm that the combination of Silica-Na and ionic liquid
is key to render the reaction to completion. With Silica-Na
3/[DBIm]SbF6 the reaction mixture is heterogeneous, and
the catalyst was readily filtered off after extraction of the
product with a mixture of hexane and ethyl acetate (2:1, v/v).
The Silica-Na 3/[DBIm]SbF6 so recovered could be reused
without significant loss of activity (entry 9).
6 and 7). Furthermore, the reaction in a 10 mmol scale was
successfully conducted, and the same level of yield compared
with that in a preparative scale synthesis was obtained (Table
2, entry 8).
The Silica-Na-IL catalyst system does not require the
inclusion of Lewis or Brønsted acid species, which allows
us to use some acid-labile substrates. This is particularly an
issue in cases where substrates or products are sensitive and
decompose under acidic conditions. As shown in Table 4,
A range of other indoles and R,â-unsaturated carbonyl
compounds were then surveyed by using the Silica-Na-IL
catalyst systems in water (Tables 2 and 3). It should be noted
Table 4. Michael Reactions of Acid-Labile Substrates in the
Silica-Na-IL System in Water
Table 3. Michael Reactions of Several R,â-Unsaturated
Carbonyl Compounds with Indole in Water
a 2-Methylindole was used instead of indole. b N-Methylindole and 50
wt % of ionic liquid were used at 50 °C.
that various indoles and R,â-unsaturated carbonyl compounds
reacted smoothly in water to afford the desired Michael
adducts in high yields. While several substituted indoles
worked well, both acyclic and cyclic R,â-unsaturated car-
bonyl compounds are good substrates in the present Michael
reaction. For example, 2-cyclohexen-1-one, which is prone
to overreact with indoles under acidic conditions,6 was found
to be applicable in the Silica-Na-IL catalyst system (Table
3, entry 5). The Michael reactions with nitrostyrenes as
acceptors also proceeded smoothly in water (Table 3, entries
a 30 °C, 20 h. b 30 °C, 12 h. c 50 °C, 20 h. d 50 wt % of ionic liquid
was used.
several indole derivatives with acid-labile functions were all
successfully converted to the corresponding Michael adducts
by using the Silica-Na-IL catalyst in water without any
(6) Paul, H.; Michael, K. Can. J. Chem. 1998. 76, 1256.
Org. Lett., Vol. 9, No. 2, 2007
177

damage of acid-labile functions (entries 1 to 5). The Michael
reactions of 1-methylindole with 2-(2-nitrovinyl)furan and
2-(2-nitrovinyl)thiophene were also examined to give the
corresponding adducts in 80% and 81% yields, respectively
(entries 6 and 7). Furthermore, the Michael reaction of N-(2-
hydroxyethyl)indole with MVK proceeded smoothly without
formation of a ketalization product (entry 8). As shown in
entry 9, an indol with tertiary amine moiety reacted with
MVK in the Silica-Na-IL system to afford the desired
Michael adduct in excellent yield. These results indicated
the usefulness of the Silica-Na-IL as a neutral catalyst for
the title reactions.
In summary, we have developed a novel neutral catalyst
system derived from silica gel-supported sodium sulfonate
with ionic liquid for Michael reactions of indoles with R,â-
unsaturated carbonyl compounds in water. The use of ionic
liquid supports the formation of a hydrophobic environment
on the surface of the silica material. The system can be
readily recycled without appreciable loss of reactivity.
Simplicity of operation as well as the neutral, mild, and
environmentally benign nature of the reaction could enable
expansion to a wide variety of acid-labile substrates, even
to a larger scale reaction.7 This novel concept is expected to
contribute to the development of more benign reactions in
water, and the related work is underway in our group.
Acknowledgment. This work was partially supported by
Grant-in-Aid for Scientific Research from the Japan Society
of the Promotion of Sciences (JSPS).
Supporting Information Available: Preparation of cata-
lysts, experimental details, and characterization of products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL062446B
(7) At this stage, we use organic solvents in workup processes. This is
a drawback as an environmentally benign reaction, and the development
of a novel workup process without using any organic solvents is now in
progress in our laboratory.
178
Org. Lett., Vol. 9, No. 2, 2007