Influence of ionic liquids on the phase transfer-catalysed enantioselective Michael reaction

Article abstract of DOI:10.1016/S0040-4039(03)01198-5

The enantioselective Michael addition of dimethyl malonate to 1,3-diphenylprop-2-en-1-one promoted by a quaternary derived ammonium salt from quinine as a phase transfer catalyst in different ionic liquids, 1-butyl-3-methyl imidazolium hexafluorophosphate, [bmim]PF₆, 1-butyl-3-methyl pyridinium tetrafluoroborate, [bpy]BF₄, 1-butyl-3-methyl imidazolium tetrafluoroborate [bmim]BF₄ as well as in conventional organic solvents was studied.

Full text of DOI:10.1016/S0040-4039(03)01198-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5351–5353
Influence of ionic liquids on the phase transfer-catalysed
enantioselective Michael reaction
Ravindra T. Dere, Ravindra R. Pal, Prashant S. Patil and Manikrao M. Salunkhe*
Department of Chemistry, The Institute of Science, 15-Madam Cama Road, Mumbai 400 032, India
Received 20 February 2003; revised 29 April 2003; accepted 9 May 2003
Abstract—The enantioselective Michael addition of dimethyl malonate to 1,3-diphenylprop-2-en-1-one promoted by a quaternary
derived ammonium salt from quinine as a phase transfer catalyst in different ionic liquids, 1-butyl-3-methyl imidazolium
hexafluorophosphate, [bmim]PF , 1-butyl-3-methyl pyridinium tetrafluoroborate, [bpy]BF , 1-butyl-3-methyl imidazolium tetra-
6
4
fluoroborate [bmim]BF as well as in conventional organic solvents was studied. © 2003 Elsevier Science Ltd. All rights reserved.
4
The development of catalytic asymmetric car-
as a phase transfer catalyst. The introduction of a bulky
subunit at the bridge head nitrogen leads to a quater-
nary ammonium salt, which enhances the stereoselectiv-
ity in catalytic phase transfer reactions. Also, the
introduction of an electron withdrawing group at the
bonꢀcarbon bond forming reactions is one of the most
1
challenging aspects of organic synthesis. Over the past
5
two decades many successes involving molecular cata-
lysts in which well-designed chiral ligands and transi-
tion metals have played an important role have been
4-position on the phenyl ring of the N-benzyl unit is
1
,2
6
reported. Phase transfer catalysts (PTC) possessing
many advantages such as mild reaction conditions,
safety, operational simplicity, and selectivity, have been
widely accepted as one of the most powerful reagents in
industry. Efforts towards achieving asymmetric conju-
gate addition of malonates to chalcones in the presence
of chiral catalysts have been the subject of several
reports. Recently, the field of chemistry in ionic liquids
has been escalating at an overwhelming rate. These
liquids have captivated us for quite some time owing to
their remarkable properties. In continuation of our
quite effective. PTCs including electron withdrawing
groups on the phenyl ring afforded the desired product
with higher enantiomeric excess. During our research
work in order to develop a more effective cinchona-
alkaloid derived phase transfer catalyst, we quaternised
the bridgehead nitrogen of quinine with a bulky group
10
in order to give quininium bromide 1.
3
quest to explore different reactions in ionic liquids, we
thought it would be worthwhile to employ these liquids
as solvents in the asymmetric conjugate addition of
dimethyl malonate to 1,3-diphenylprop-2-en-1-one
using quinine, as a chiral catalyst. The reaction of
dimethyl malonate with 1,3-diphenylprop-2-en-1-one 2
using K CO in the presence of catalytic quinine, in an
2
3
ionic liquid, at room temperature, afforded the Michael
adduct 3 in good yield but with low enantioselectivity.
We have carried out the asymmetric conjugate addition
of dimethyl malonate to 1,3-diphenylprop-2-en-1-one
using quininium bromide 1 in ionic liquids and organic
solvents.
There have been many successful applications of cata-
lytic asymmetric synthesis using cinchona-alkaloid
4
derived quaternary ammonium salts. Hence, we
In this communication, we report for the first time, the
enantioselective Michael reaction in an ionic liquid as
the reaction media employing a novel chiral phase
transfer catalyst. The ionic liquids employed for the
decided to use a quaternary ammonium salt of quinine
*
Corresponding author. Tel.: 91-22-22816750; fax: 91-22-22816750;
e-mail: mmsalunkhe@hotmail.com
current
study
are
1-butyl-3-pyridinium
tetra-
fluoroborate, [bpy]BF , 1-butyl-3-methylimidazolium
4
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01198-5

5
352
R. T. Dere et al. / Tetrahedron Letters 44 (2003) 5351–5353
Table 1. Catalytic enantioselective Michael addition of dimethyl malonate to 1,3-diphenylprop-2-en-1-one in ionic liquids
and organic solvents
Yield (%)a
ee (%)b
[h]
26
D
Entry
Solvents
Temp. (°C)
Time (h)
1
2
3
4
5
6
DMSO
Toluene
DCM
[bmim]PF6
[bmim]BF4
[bpy]BF4
28
28
0
28
28
28
6
8
6
3
4
4
96
92
94
99
97
97
61
56
46
50
44
42
+20.31
+18.64
+15.31
−16.64
−14.65
+13.98
a
Isolated yields are shown.
Enantiomeric excesses were determined from optical rotations.
b
hexafluorophosphate
methylimidazolium
These liquids are distinctly different in their properties
in two senses: the [bmim]BF4 and [bpy]BF4 are
hydrophilic and [bmim]PF is highly hydrophobic in
[bmim]PF6
tetrafluoroborate,
and
1-butyl-3-
[bmim]BF4.
medium. We observed that the rate of the reaction is
much better in [bmim]PF than in [bpy]BF , [bmim]BF
4
6
4
8
and other organic solvents. The reaction time is also
reduced drastically even under ambient conditions, in
9
contrast to reported procedures with an excellent yield
6
nature. To study the influence of this novel reaction
media on the rate as well as on the enantioselectivity of
the reaction, we investigated the asymmetric Michael
addition of dimethyl malonate to 1,3-diphenylprop-2-
of product 3. Phase transfer catalysts are a commer-
cially viable option for asymmetric synthesis, however,
if the phase transfer catalyst-containing medium were
recyclable then it would be an added advantage. We
carried out several experiments where quininium bro-
mide 1 was taken in [bmim]PF6 and charged with
substrate 2 and dimethyl malonate. Similarly, the recy-
clability of the medium containing the quininium bro-
mide 1 was studied for three consecutive runs. Thus,
ionic liquids can act as a medium for phase transfer
catalysed asymmetric synthesis. There are four advan-
tages of the use of ionic liquids as the reaction medium
rather than the corresponding organic solvents: (1) the
reaction is fast, (2) good enantioselectivity and yields,
(3) easy work up of the reaction and (4) recyclability of
the ionic liquid (Table 2).
en-1-one in the presence of K CO3 in ionic liquids
2
[
bmim]PF , [bmim]BF and [bpy]BF at room tempera-
6 4 4
ture. As expected the reactions worked well in these
liquids and the results are shown in Table 1. The
reactions in ionic liquids afforded excellent yields of the
product in relatively short periods of time but interest-
ingly and to our surprise, the enantioselectivity was
reversed in the reactions in [bmim]BF and [bmim]PF ,
4
6
whereas it remained the same in [bpy]BF as was the
4
case for the conventional organic solvents under inves-
tigation. In order to ascertain the factor responsible for
the reversal of enantioselectivity, we carried out the
Michael addition of dimethyl malonate to 1,3-diphenyl-
prop-2-en-1-one in the presence of K CO by employ-
2
3
2
6
Table 2. Recyclability of the Michael reaction in
ing quinine (yield 97%, 21% ee), (c 2, CHCl ) ([h]
3
D
[bmim]PF6
−7.062) and a chiral quaternary ammonium salt, N-(4-
nitrobenzyl) quininium bromide (yield 95%, 32% ee), (c
Cycle
Time (h)
Yield (%)
2
3 D
6
2, CHCl ), ([h] −10.64) in ionic liquids. However,
results indicated that the reversal of enantioselectivity
was not due to the PTC but can be attributed to the
cation associated with the anion of the ionic liquid.
Recently, several groups have investigated lipase-
catalysed transesterification of chiral substrates in ionic
liquids and have reported that rates and enantioselec-
tivity were dependent on both the anion and the alkyl
1
2
3
3
3
3
97
95
94
In conclusion, we have developed a new class of asym-
metric phase transfer catalyst, which shows good enan-
tioselectivity in the Michael reaction of dimethyl
malonate to 1,3-diphenylprop-2-en-1-one in both
organic solvents and ionic liquids. Work on further
development of these catalyst systems and investigating
their applicability to other asymmetric phase transfer
processes is underway.
7
group in the 1-methyl-3-alkyl imidazolium cation.
11
The ionic liquid [bmim]PF being polar due to its ionic
6
nature, is hydrophobic and it is unlike common polar
organic solvents. This feature of [bmim]PF made us
6
inquisitive about the behaviour of PTC in such a

R. T. Dere et al. / Tetrahedron Letters 44 (2003) 5351–5353
5353
Acknowledgements
7. Sheldon, R. A.; Lau, R. M.; Sorgedrayer, M. J.;
Rantwijk, F. V.; Seddon, K. R. Green Chem. 2002, 4,
147–151.
The support of the University Grants Commission,
New Delhi for this research is gratefully acknowledged.
8. Catalysed by 1 (10 mol%), dimethyl malonate reacted
with 1,3-diphenylprop-2-en-1-one in the presence of
K CO , at room temperature, to afford the Michael
2
3
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