Enantioselective Michael reaction of malonates and chalcones by phase-transfer catalysis using chiral quaternary ammonium salt

Article abstract of DOI:10.1016/S0040-4039(01)01237-0

The catalytic enantioselective Michael reaction promoted by quaternary ammonium salt from cinchonidine as a phase-transfer catalyst is described. Treatment of malonate with chalcone derivatives under mild reaction conditions afforded the corresponding Michael adducts in good yields with good to moderate enantiomeric excesses.

Full text of DOI:10.1016/S0040-4039(01)01237-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6299–6301
Enantioselective Michael reaction of malonates and chalcones by
phase-transfer catalysis using chiral quaternary ammonium salt
Dae Young Kim,* Sun Chul Huh and Sung Min Kim
Department of Chemistry, Soonchunhyang University, Asan PO Box 97, Chungnam 336-600, South Korea
Received 23 April 2001; revised 4 July 2001; accepted 6 July 2001
Abstract—The catalytic enantioselective Michael reaction promoted by quaternary ammonium salt from cinchonidine as a
phase-transfer catalyst is described. Treatment of malonate with chalcone derivatives under mild reaction conditions afforded the
corresponding Michael adducts in good yields with good to moderate enantiomeric excesses. © 2001 Elsevier Science Ltd. All
rights reserved.
The formation of carbonꢀcarbon bonds by conjugated
addition of appropriate carboanionic reagents to a,b-
unsaturated carbonyl compounds is one of the most
useful methods of remote functionalization in organic
synthesis.1 Therefore, their catalytic asymmetric version
have been studied extensively.2 Efforts toward achiev-
ing asymmetric conjugate addition of malonates to
chalcones in the presence of chiral catalysts have been
the subject of several reports. For example, the reaction
of malonates with chalcones catalyzed by La–BINOL
Phase-transfer catalysis have been increasingly useful in
organic synthesis.8 Recently, there have been successful
applications to catalytic asymmetric synthesis using cin-
chona–alkaloids-derived quaternary ammonium salts.9
The attachment of the bulky substituents to bridgehead
nitrogen leads to a quaternary ammonium structure of
well-defined geometry in which tetrahedral face about
ammonium nitrogen is blocked by bulky subunit. The
introduction of a bulky subunit at the 1-position of
cinchona alkaloids leads to enhance the stereoselectivity
in catalytic phase-transfer reactions.10 As part of our
research program toward the development of a more
effective cinchona–alkaloid-derived phase-transfer cata-
complexes,3 -proline derivatives,4 chiral aminoalcohol–
L
Al complexes,5 pyrrolidylalkyl ammonium hydroxide,6
and chiral ammonium salts.7
ROOC
COOR
O
O
catalyst
CH2(COOR)2
+
Ph
Ph
Ph
Ph
2
3
1
N
N
N
Br
N
N
Br
Br
N
H
H
H
O
O
O
O
5
4
6
Scheme 1.
Keywords: phase transfer; Michael reactions; ammonium salt; asymmetric reactions.
* Corresponding author. Tel.: +82-41-530-1244; fax: +82-41-530-1247; e-mail: dyoung@sch.ac.kr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01237-0

6300
D. Y. Kim et al. / Tetrahedron Letters 42 (2001) 6299–6301
Table 1. Catalytic asymmetric Michael reaction of malonates to chalcone 1a with phase-transfer catalysts
Entry
Malonate 2, R
Catalyst
Base
Solvent
Temp. (°C)
Yield (%)
Eea (%)
1
2
3
4
5
6
7
8
9
Et
Et
Et
Et
4
4
4
4
4
4
4
4
5
6
t-BuOK
KOH
KOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Toluene
Toluene
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
20
20
0
20
0
20
20
20
20
20
3a, 74
3a, 74
3a, 68
3a, 70
3a, 68
3b, 92
3c, 77
3d, 91
3d, 64
3d, 67
35
40
43
46
40
27
55
70
6
Et
Me
i-Pr
Bn
Bn
Bn
10
35
a Enantiopurities of 3a–d were determined by HPLC analysis with Chiralcel AD column (for 3a and 3c) and Chiralcel AS column (for 3b and 3d),
2-propanol–hexane (1:9), 1.2 mL/min, umax=254 nm. It was established by analyses of racemic 3 that the enantiomers were fully resolved.
lyst, we introduced a bulky environment at the 1-posi-
tion by (3,5-di-tert-butyl-4-methoxy)benzyl group. In
this paper, we wish to report herein on the catalytic
asymmetric conjugate addition of malonates 2 to chal-
cones 1 using N-(3,5-di-tert-butyl-4-methoxy)benzyl-
cinchonidinium bromide (4). A new catalyst 4 is derived
in two steps from cinchonidine.11 In order to determine
suitable reaction conditions for the catalytic asymmetric
conjugate addition of malonates 2 to chalcones 1
(Scheme 1), we initially investigated the reaction system
using 10 mol% of catalyst, with malonate as the
Michael donor and chalcone 1a as the Michael acceptor
(Table 1).
investigated catalytic asymmetric Michael reaction of
dibenzyl malonate to chalcone derivatives 1.12 The reac-
tion smoothly proceeded to afford the corresponding
adducts 3 with good enantioselectivities. Reaction of
1.5 equiv. of dibenzyl malonate with chalcone deriva-
tives 1, cinchonidinium salt 4 (10 mol%), and K2CO3 in
toluene at room temperature with stirring for 18–24 h
afforded the Michael adducts 3 (Scheme 2) in good
yields with moderate enantioselectivities (45–70% ee)
(Table 2). In all cases the enantiomeric excesses were
determined by HPLC analysis.
In conclusion, we have developed a new class of asym-
metric phase-transfer catalyst, which shows good enan-
tioselectivity in the Michael reaction of malonates to
chalcones. We are currently involved in the further
development of these catalyst systems and investigating
their applicability to other asymmetric phase-transfer
processes.
Catalyzed by 4 (10 mol%), malonate reacted with chal-
cone in the presence of K2CO3, at room temperature, to
afford the Michael adduct 3a in 70% yield and 46% ee
(Table 1, entry 4). In the presence of other bases such
as KOH or t-BuOK, 3a was obtained in good yield and
low enantioselectivity (entries 1–3). Toluene as solvent
was effective in this reaction. The reaction temperature
is not critical in this reaction (entries 4 and 5). As
increased bulkiness of malonates, the enantioselectivity
was increased in this reaction (entries 6–8). Known
cinchona-type phase-transfer catalysts 5 and 610 were
less effective than catalyst 4 in this reaction (entries 9
and 10). The stirring rate does not appear to influence
the enantioselectivity of this reaction, however it does
affect the rate of reaction and substantially decreased
reaction time can be achieved with high stirring rate.
The absolute configuration of the major enantiomer of
3b was determined to be R from the optical rotation
and chiral HPLC analysis.3
Table 2. Catalytic asymmetric Michael reaction of diben-
zyl malonate to chalcones 1 with phase-transfer catalyst 4
Ar1
Ar2
Ph
Time (h)
18
Yield (%)
Eea (%)
Ph
Ph
Ph
3d, 91
3e, 91
3f, 94
3g, 88
3h, 60
3i, 58
70
47
51
45
67
59
p-OMe, Ph 18
2-Thienyl
18
18
24
24
p-OMe, Ph Ph
2-Naphthyl m-Br, Ph
2-Naphthyl p-Br, Ph
a Enantiopurities of 3d–i were determined by HPLC analysis with
chiral column (Chiralcel AS for 3d–g, OD-H for 3h and 3i),
2-propanol–hexane (1:9), 1.2 mL/min, umax=254 nm. In each case,
it was established by analyses of racemic 3 that the enantiomers
were fully resolved.
Under the optimized reaction conditions described
above (10 mol% of catalyst 4, K2CO3, toluene, rt), we
BnOOC COOBn
O
O
catalyst 4
CH2(COOBn)2
+
Ar2
Ar1
Ar2
Ar1
K2CO3, PhMe. rt
1
2
3
Scheme 2.

D. Y. Kim et al. / Tetrahedron Letters 42 (2001) 6299–6301
6301
Acknowledgements
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This research was supported by research grants from
the Korea Science and Engineering Foundation (2001-
1-12300-006-1).
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12. General procedure for Michael addition of malonate to
chalcones: A mixture of dibenzyl malonate (0.11 mL, 0.45
mmol), K2CO3 (0.16 g, 2.0 mmol), chiral cinchonidinium
salt 4 (18.0 mg, 0.03 mmol), and chalcone (0.3 mmol) in
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