Sustainable conjugate addition of indoles catalyzed by acidic ionic liquid immobilized on silica

Article abstract of DOI:10.1055/s-2008-1032082

A new protocol for 1,4-conjugate addition of indoles to vinyl ketones has been developed, employing Lewis acidic ionic liquid immobilized on silica, ILIS-SO₂Cl, as a catalyst, which exhibited an efficient, mild and recyclable nature. The reacti

Full text of DOI:10.1055/s-2008-1032082

608
LETTER
Sustainable Conjugate Addition of Indoles Catalyzed by Acidic Ionic Liquid
Immobilized on Silica
S
ustainable Conju
i
A
d
s
dition of
a
Chiaki Yokoyamac
a
Graduate School of Science and Technology, Niigata University, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
Fax +81(25)2627368; E-mail: hagiwara@gs.niigata-u.ac.jp
b
Faculty of Engineering, Niigata University, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
c
Institute of Multidisciplinary Research of Advanced Materials, Tohoku University, 2-1-1, Katahira, Aoba-ku, Sendai 980-8577, Japan
Received 20 November 2007
O
Abstract: A new protocol for 1,4-conjugate addition of indoles to
R1
R2
vinyl ketones has been developed, employing Lewis acidic ionic
liquid immobilized on silica, ILIS-SO2Cl, as a catalyst, which ex-
hibited an efficient, mild and recyclable nature. The reaction condi-
tion is applicable to various vinyl ketones and indoles. The mild
nature of the reaction condition showed that the acetoxy or TBDMS
group in indoles was maintained intact. The catalyst was used six
times resulting in 86% average yield.
1
2
R1
O
+
R3
R3
R2
ILIS-SO2Cl
Et2O
r.t.
N
R4
N
R4
3
Key words: catalysis, Michael additions, indoles, ionic liquids,
supported catalysis
+
OMe
O
O
N
N
S
Si
SiO2
SO2X
–
CF3SO3
3-Substituted indoles are important building blocks for
the synthesis of biologically important unnatural and nat-
ural products.1 Among various synthetic methods produc-
ing 3-substituted indoles, conjugate addition of indoles 2
to a,b-unsaturated carbonyl compounds 1 is widely ac-
cepted, in which Bronsted2 or Lewis acidic3 catalysts have
been employed along with thermal4 or high-pressure5 ac-
tivation. In view of an environmentally benign process,
these catalysts should be recycled although most of them
lack such a property due to their homogeneous nature. Use
of metal salts such as Cu, In, Sm and Fe as Lewis acid cat-
alysts is an additional issue.
ILIS-SO2Cl: X = Cl
ILIS-SO3H: X = OH
4
5
Scheme 1 Conjugate addition of indole to vinyl ketone 1 catalyzed
by ILIS-SO2Cl (4)
an efficient and mild procedure for conjugate addition of
indole 2 to vinyl ketone 1 leading to 3-substituted indoles
3 catalyzed by acidic ILIS-SO2Cl (4) (Scheme 1) as a re-
cyclable catalyst.
Optimized reaction conditions were investigated employ-
ing a reaction of but-3-en-2-one (1; R1 = H, R2 = Me) and
indole (2; R3, R4 = H), and the results are shown in
Table 1. Among the solvents investigated, diethyl ether
gave the best result (entry 1) in the reaction catalyzed by
ILIS-SO2Cl (4), when the solvent was evaporated gradu-
ally. For an unknown reason, evaporation of diethyl ether
immediately after mixing substrates and the catalyst did
not give a good yield (entry 4). It is noteworthy that the re-
action proceeded smoothly at ambient temperature. The
product was triturated with diethyl ether, ethyl acetate or
dichloromethane, in which the catalyst was separated by
centrifugation. No aqueous workup was required, which
is an advantage for larger-scale preparation.
We previously demonstrated a mild protocol for conden-
sation of aldehyde with indole catalyzed by Lewis acidic
ionic liquid immobilized on silica (ILIS), that is, ILIS-
SO2Cl (4), leading to bis(indolyl)methane,6 in which cat-
alyst 4 was recycled as a heterogeneous organomolecular
catalyst. In catalyst 4, the ionic liquid residue is connected
to silica as a tether.
Recently, Kobayashi et al. reported conjugate addition of
indoles in water to a,b-unsaturated carbonyl compounds 1
catalyzed by silica-supported sodium sulfate in combina-
tion with an ionic liquid 1-butyl-3-decylimidazolium
hexafluoroantimonate ([dbim]SbF6).7 In the catalyst, ion-
ic liquid exists on the surface of silica to provide hydro-
phobic environment.
While ILIS-SO2Cl (4) and ILIS-SO3H (5) showed similar
catalytic activities (entries 1 and 6), 4 was much better in
terms of general use. Catalytic activities of the ionic liq-
uids IL–SO2Cl (6)7 and SiO2–SO3H (7) (Figure 1) were
not high (entries 11 and 12), although both are recyclable.
Silica itself did not show any catalytic activity (entry 14).
These results suggest that not only silica but also the ionic
liquid residue in the tether played some synergistic roles
for catalytic activity of ILIS-SO2Cl (4), since as shown in
Their work prompted us to report catalytic activity of
ILIS-SO2Cl (4)8 and in this communication, we delineate
SYNLETT 2008, No. 4, pp 0608–0610
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032082; Art ID: U11507ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Sustainable Conjugate Addition of Indoles
609
Table 1 Investigation of Optimum Reaction Conditions in the Re-
Table 2 Reaction of Various Vinyl Ketones 1 with Indole
action of But-3-en-2-one and Indole
Entrya
Olefin 1
Time (h)
Yield (%)b
Entrya Catalyst
Solvent
Et2O
Time (h) Yield (%)b
1
2
3
4
5c
6
1-penten-3-one
2-cyclopentenone
3-penten-2-one
benzalacetone
6
5
92
88
90
72
93
67
1c
2c
ILIS-SO2Cl (4)
4
4
92
83
81
79
75
89
85
82
71
68
62
72
64
3
4
t-BuOMe
THF
5
3c
4
4
5
4c
4
neat
4
dibenzylideneacetone
2-phenylnitroolefin
4
5d
4
MeCN
Et2O
4
24
6d
ILIS-SO3H (5)
4
a Reaction was carried out as described in ref. 9.
b Yield of isolated pure product based on indole (2).
7d
5
CH2Cl2
neat
5
c Monoadduct was obtained.
8c
5
5
9d
5
THF
19
Table 3 Reaction of But-3-en-2-one with Various Indoles 2
10d
11
12c
13
14c
5
aq MeCN 26
Entrya Indole 2
Time (h)
Yield (%)b
IL-SO2Cl (6)
SiO2-SO3H (7)
Et2O
Et2O
4
4
4
4
1
2
3
4
5
6
R3 = Br, R4 = H
6
3
6
3
5
4
88
81
71
88
78
85
R3 = OMe, R4 = H
R3 = OH, R4 = H
R3 = OAc, R4 = H
R3 = OTBS, R4 = H
R3 = H, R4 = Me
IL-SO2Cl (6) + SiO2 Et2O
SiO2 Et2O
a Reaction was carried out as described in ref. 9.
b Yield of isolated pure products based on indole (2).
c Powder of catalyst (0.2 equiv) was used. But-3-en-2-one (5 equiv)
was employed.
a Reaction was carried out as described in ref. 9.
d Pellets of catalyst (0.2 equiv) was used.
b Yield of isolated pure product based on indole 2.
+
OMe
O
O
N
N
Table 4 Recycle of ILIS-SO2Cl (4) in the Reaction of But-3-en-2-
one with Indole
SO3H
Si
SiO2
SO2Cl
–
CF3SO3
IL-SO2Cl
SiO2-SO3H
Cyclea
Time (h)
Yield (%)b
6
7
Figure 1
1
2
3
4
5c
6
4
6
87
85
81
79
90
93
Table 1 (entry 13), catalytic activity of a mixture of SiO2
and the ionic liquid IL–SO2Cl (6) exhibited comparable
yield as IL–SO2Cl (6).
9
Since the shape of LUMO orbitals of methanesulfonyl
chloride is mainly localized on sulfur atom and its energy
is –2.35 eV as determined by MOPAC-AM 1 calculation,
ILIS-SO2Cl (4) may work as a Lewis acid catalyst.10
LUMO energy of typical Lewis acid such as BF3 or AlCl3
is 1.77 eV or –1.07 eV, respectively, whereas methyl
methanesulfonate has LUMO energy of –0.72 eV. Ac-
cording to inspection by wet litmus paper, the diethyl
ether layer was neutral.
12
2
5
a Reaction was carried out as described in ref. 9.
b Yield of isolated pure product based on indole 2.
c Catalyst 4 was treated with thionyl chloride before use.
The powdery ILIS-SO2Cl (4) could be reused up to five
times (Table 4). A decrease in catalytic activity in four-
cycle use was regained by treating the recovered ILIS-
SO2Cl (4) with hot thionyl chloride (cycle 5).
Based on the optimized reaction conditions (Table 1, en-
try 1), the protocol was applied to various electron-defi-
cient olefins. Not only vinyl ketones 1 (Table 2, entries 1–
5) but also nitroolefin provided the desired conjugate ad-
dition product 3 (entry 6).
In summary, we have demonstrated a new protocol for
1,4-conjugate addition of indoles 2 to vinyl ketones 1 cat-
alyzed by Lewis acidic ionic liquid immobilized on silica,
The present protocol was also applicable to various sub-
stituted indoles 2 (Table 3), in which even electron-poor
indole 2 provided the product 3 (entry 1).
Synlett 2008, No. 4, 608–610 © Thieme Stuttgart · New York

610
H. Hagiwara et al.
LETTER
(4) (a) Kusurkar, R. S.; Alkobati, N. A. H.; Gokule, A. S.;
ILIS-SO2Cl (4), which exhibited an efficient, mild, prac-
Chaudhari, P. M.; Waghchaure, P. B. Synth. Commun. 2006,
36, 1075. (b) Mohammadpoor-Baltok, I.; Memarian, H. R.;
Khosropour, A. R.; Nikoofar, K. Heterocycles 2006, 68,
1837. (c) Banik, B. K.; Garcia, I.; Morales, F. R.
Heterocycles 2007, 71, 919; and earlier references cited in
these references.
tical and recyclable nature.
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas (17073007 for H.H. and T.H.) from The
Ministry of Education, Culture, Sports, Science and Technology
(MEXT), Japan. Thanks are also due to Prof. Dr. Bahlul Awen, Al-
fateh University, Libya, for some preliminary experiments.
(5) Harrington, P.; Kerr, M. A. Can. J. Chem. 1998, 76, 1256.
(6) Hagiwara, H.; Sekifuji, M.; Hoshi, T.; Qiao, K.; Yokoyama,
C. Synlett 2007, 1320.
(7) Gu, Y.; Ogawa, C.; Kobayashi, S. Org. Lett. 2007, 9, 175.
(8) Qiao, K.; Hagiwara, H.; Yokoyama, C. J. Mol. Catal. A:
Chem. 2006, 246, 65.
(9) Typical Experimental Procedure: A suspension of but-3-
en-2-one (50 mL, 0.6 mmol), indole (35.3 mg, 0.3 mmol) and
ILIS-SO2Cl (4; 171 mg; loading of sulfonyl chloride: 0.35
mmol/g, 0.06 mmol) in Et2O (0.2 mL) was stirred gently at
ambient temperature for 4 h in open air, resulting in
evaporation of Et2O. The catalyst was washed with Et2O and
separated by centrifugation. After decantation of the Et2O
layer, the catalyst was washed again with EtOAc and then
with CH2Cl2 in a similar manner. The combined organic
layer was evaporated to dryness. Medium pressure LC of the
residue (eluent: EtOAc–n-hexane, 1:1) afforded the
conjugated addition product 3 (51.9 mg, 92% based on
indole 2).
References and Notes
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Synlett 2008, No. 4, 608–610 © Thieme Stuttgart · New York

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