Synthesis of new chiral ionic liquids from natural acids and their applications in enantioselective Michael addition

Article abstract of DOI:10.1016/j.tetlet.2005.04.134

Two kinds of novel chiral ionic liquids based on imidazolium have been synthesized from chiral pool by a simple and straightforward procedure in good overall yields (44-60%). The application of CILs as reaction media in the enantioselective Michael additi

Full text of DOI:10.1016/j.tetlet.2005.04.134

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4657–4660
Synthesis of new chiral ionic liquids from natural acids and
their applications in enantioselective Michael addition
a
Zhiming Wang, Qiang Wang, Yu Zhang and Weiliang Bao
a,b
a
a,
*
a
Zhejiang University, Xi Xi Campus, Department of Chemistry, Hangzhou, Zhejiang 310028, China
b
Ningbo University, Department of Chemistry, Ningbo, Zhejiang 315211, China
Received 28 October 2004; revised 25 April 2005; accepted 27 April 2005
Available online 23 May 2005
Abstract—Two kinds of novel chiral ionic liquids based on imidazolium have been synthesized from chiral pool by a simple and
straightforward procedure in good overall yields (44–60%). The application of CILs as reaction media in the enantioselective
Michael addition of diethyl malonate to 1,3-diphenyl-prop-2-en-1-one has also been studied (yield 90–96%, 10–25% ee).
Ó 2005 Elsevier Ltd. All rights reserved.
Room temperature ionic liquids (RTILs) are novel and
promising materials for a variety of chemical applica-
tions. Because of their unique physical and chemical
tion of CILs in asymmetric synthesis is not only an
1
c
opportunity but also a challenge for researchers. It is
interesting, meaningful, and necessary to synthesize dif-
ferent kinds of CILs from different starting materials,
especially from the chiral pool. Herein, we wish to re-
port the synthesis of new CILs based on imidazolium
salt in which the core of positive charge is attached on
the carbon adjacent to the chiral center.
1
properties, RTILs have been widely applied in organic
reactions as Ôgreen solventsÕ for they can accelerate reac-
tion rates, improve selectivities, and facilitate catalyst
1
,2
recovery, etc. In view of the emerging importance of
ILs as reaction media in organic synthesis, several
groups have recently focused on the synthesis of chiral
ionic liquids (CILs Fig. 1) for their particularly potential
applications to chiral discrimination, including asym-
Good chemical stability, especially configurational sta-
bility, is one of the most important criteria for synthesis
of CILs and a necessary property for their application to
chiral discrimination. Noteworthy, the results of Mikami
et al. indicated that the presence of a nitrogen cation
adjacent to chiral center (a secondary carbon) makes
3
–9
metric synthesis and optical resolution of racemates.
For example, Seddon et al. prepared the chiral lactate
salt of 1-butyl-3-methyl imidazolium (I) and investigated
Diels–Alder reactions therein (however, <5% ee were
3
9
obtained). Wasserscheid and co-workers synthesized
the racemization of the CILs possible. However, most
1
9
CIL as chiral shift reagent in F NMR for rac-MosherÕs
acid sodium salt. More recently, the use of CILs as
of CILs, particularly CILs from the chiral pool, have
the structural unit that the core of positive charge is di-
rectly resided at the chiral center. Therefore, we plan to
synthesize the CILs with ÔbetterÕ configurational stability
from chiral pool to overcome this drawback.
4
reaction media in the asymmetric Baylis–Hillman reac-
tion was reported and significant enantiomeric excesses
1
0
were obtained (20–44% ee). The study of the applica-
OH
X
Br
O
O
BETI
CH OH
2
N
N
N
N
N
N
N
N
OEt
Bu
Et
O
R
I
II
III
IV
Figure 1. Examples of chiral ionic liquids.
*
0
Corresponding author. Tel./fax: +86 571 88911554; e-mail: wbao@hzcnc.com
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.134

4658
Z. Wang et al. / Tetrahedron Letters 46 (2005) 4657–4660
Firstly, we used the commercially available and inexpen-
sive L-(+)-diethyl tartarate (1a) as the starting material.
According to JohnsonÕs work on O-benzylation of ethyl
in five steps from chiral pool in 51% overall yield
(Scheme 1).
1
1
(
S)-lactate, O-benzylation of 1a with sodium hydride
and benzyl bromide in THF/DMF afforded the ester
Compared with common ILs (mp <100 °C), the melting
point of the interesting imidazolium salt 6a with C sym-
2
20
(
2a) in 80% yield, and ½aꢀ +79.0 (neat 1 dm) was re-
metry axis is high (182–183 °C). For further investiga-
tion, we also chose the commercially available and
inexpensive L-(ꢁ)-ethyl lactate as the starting material
to synthesize the CIL and hoped to get a low melting
point one. CIL 6b was obtained in five steps from chiral
pool in 60% overall yield, according to the route of
Scheme 2. Encouragingly, the new CIL 6b has a low
melting point (57–58 °C) and no racemization was
detected in a basic (1 M NaOH) or acidic (1 M HCl)
condition, even when heated. It has a good solubility
in water, acetone, DMSO, and even in CHCl3.
D
corded. Compared with the methods of Seebach and
Yamamoto et al., severe and high price reagents, such
as thallium alkoxide and 18-crown-6, were avoided.
The diol 3a was obtained by the reduction of 2a with
1
2,13
20
LiAlH in >99% optical purity (yield 89%, ½aꢀ +13.1
4
D
ethanol, c 4.9)) (lit. +13.2). Ditosylate 4a was pre-
1
2
(
pared under standard conditions in a yield of 88%.
1
4
When we followed K u¨ ndigÕs procedure to transform
4
1
a to 5a, the reaction rate was very slow (Table 1, entry
). We also examined the reaction in acetone and even
longer reaction time was needed (Table 1, entry 2). Since
some recent reports have indicated that ILs not only can
Anion exchange was performed to get salts 7–8a and
7–8b (Scheme 3). The melting point of the CIL 8b
(41–42 °C) is the lowest compared with the CILs 7a
(88–90 °C), 8a (129–130 °C), and 7b (92–93 °C). The
CILs 7a and 7b are both hydrophobic and immiscible
with ether, therefore, the traces of organic or inorganic
impurities can be removed by extraction with water or
ether. There is another merit in the synthetic pathway:
both the anion exchange reactions were completed in
less than 0.5 h and the reaction yields were rather high.
It is beneficial to synthesize CILs in large scale for fur-
ther investigations.
1
5,16
be used as the excellent reaction reagents
the efficient promoting reaction solvents in nucleophilic
but also as
1
7,18
substitution reactions,
we tried the reaction in ILs
and excellent results were obtained. Especially, when
conducted in [bmim]Br, the reaction finished after only
1
h with rather high yield (Table 1, entry 4). Herein,
bmim]Br was used both as excellent ÔgreenÕ reagent
and solvent. The IL can be successfully recycled and
[
1
6
reused following NguyenÕs process (Table 1, entry 5).
Finally, the target molecule 6a was obtained by the
quarternization reaction of 5a and 1-methylimidazole
in acetone. Thus, the imidazolium salt 6a was prepared
Activities on asymmetric induction of CIL 8b as Ôchiral
induction solventÕ were evaluated by Michael addition
of diethyl malonate to 1,3-diphenylprop-2-en-1-one
and the results were summarized in Table 2. Since low
reaction temperature is needed to enhance the chiral
induction and the melting points of the CILs are more
than 40 °C, the co-solvent is necessary to let the reaction
mixture stir smoothly. Compared with DMSO and
DMF, better results were obtained (yield 95%, 24% ee)
when toluene was used as the co-solvent (Table 2, entries
Table 1. Synthesis of dibromide 5a from ditosylate 4a in different
solvents
a
c
Entry
Solvent
Temp (°C)
Time (h)
Yield (%)
1
2
3
DMSO
60
60
80
80
80
20
48
2
89
85
90
Acetone
[bmim]BF
[bmim]Br
4
b
d
4
b
1
93
d
e
5
[bmim]Br
1
92
1
different co-solvents. When anion Br was used instead
–3), perhaps owing to different solubilities of the CIL in
a
All the reactions were run with ditosylate 4a (2 mmol) and LiBr
4 mmol) in solvent (5 mL), unless specified.
ꢁ
(
ꢁ
b
of BF4 , a slight increase of ee was detected. On the
other hand, when anion PF6 was used, a slight decrease
The reaction was run with ditosylate 4a (2 mmol) and [bmim]Br
5 mL).
Isolated yield based on ditosylate 4a.
ꢁ
(
c
d
e
of ee was detected. At the same time, when the CIL with
C symmetry axis (7a) was used in the reaction system,
only 10% ee was obtained. It seems that different anions
20
D
13
½
aꢀ +11.4 (CHCl
3
, c 5.8) (lit. +11.72).
The ionic liquid was recycled and reused following NguyenÕs process.
2
CO Et
CO Et
CH2OH
OBz
H
CH2OTs
OBz
2
2
H
HO
OH
H
a
H
BzO
OBz
H
b
H
BzO
c
H
BzO
H
CO Et
CO Et
CH2OH
CH2OTs
2
2
1
a
2a
3a
4a
Br-
CH Br
N
2
OBz
d
H
BzO
OBz
H
e
N
N
Br-
BzO
CH Br
N
2
5
a
6a [α]D20 = -31.0 (c 2.0, ethanol)
, Et O, 89%; (c) TsCl, pyridine, 88%; (d) 1-butyl-3-
Scheme 1. Reagents and conditions: (a) BzBr, NaH, THF/DMF (1:1), 80%; (b) LiAlH
methylimidazolium bromide, 80 °C, 96%; (e) 1-methylimidazole, acetone, reflux, 85%.
4
2

Z. Wang et al. / Tetrahedron Letters 46 (2005) 4657–4660
Me
Me
4659
Me
Me
a
b
c
H
OH
H
OBz
H
OBz
H
OBz
CO Et
CO Et
CH OH
CH OTs
2
2
2
2
1b
2b
3b
4b
Me
d
e
N
N
H
OBz
Br-
CH Br
BzO
6b[α]D20 = +29.5 (c 2.0, ethanol)
2
5b
Scheme 2. Reagents and conditions: (a) BzBr, NaH, THF/DMF (2:1), 89%; (b) LiAlH
methylimidazolium bromide, 80 °C, 96%; (e) 1-methylimidazole, acetone, reflux, 86%.
4
2
, Et O, 90%; (c) TsCl, pyridine, 91%; (d) 1-butyl-3-
PF -
6
OBz
N
N
N
NH PF / H O (92%)
PF -
6
4
6
2
BzO
Br-
N
OBz
N
7a[α] 20
= -36.3 (c 2.0, acetone)
BF -
N
D
N
Br-
BzO
OBz
N
4
N
NaBF / Acetone (90%)
4
N
6
a
N
BF -
BzO
4
N
8
a[α] 20 = -10.1 (c 2.0, acetone)
D
-N
N
NH PF / H O (90%)
4
6
2
PF6
BzO
b[α]D20 = +30.5 (c 2.0, CH Cl )
N
N
7
Br-
2
2
BzO
6b
NaBF / Acetone (87%)
-N
N
4
BF4
BzO
b[α] 20 = +19.9 (c 2.0, acetone)
8
D
Scheme 3. Anion exchange.
Table 2. Enantioselective Michael addition of diethyl malonate to 1,3-diphenylprop-2-en-1-one in CIL
EtOOC
O
COOEt
O
COOEt
CIL/co-Solvent
+
H2C
COOEt
K2CO3
*
9
10
a
b
c
25
½aꢀD
Entry
CIL
Co-solvent
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
8b
8b
8b
6b
7b
7a
Toluene
DMSO
DMF
10
6
95
90
91
96
93
95
24
17
16
25
23
10
+1.50
+1.10
+1.00
+1.60
+1.46
+0.64
7
Toluene
Toluene
Toluene
10
10
12
a
Reaction conditions: diethyl malonate (1.2 mmol), 1,3-diphenylprop-2-en-1-one (1.0 mmol), K
1 mL) at rt.
Isolated yields based on 9.
2 3
CO (3.0 mmol) in CILs (10 mmol) and co-solvent
(
b
c
19
Enantiomeric excesses were determined from optical rotations.
or cations in CILs have the different effects on the
enantioselectivity of the reaction.
from the chiral pool by a simple and straightforward
procedure in good overall yields (44–60%, selected
data are listed in Ref. 20). And the application of
CILs as reaction media and chiral reagent for the
enantioselective Michael addition of diethyl malonate
In summary, two kinds of new imidazolium CILs with
ÔbetterÕ configurational stability have been prepared

4660
Z. Wang et al. / Tetrahedron Letters 46 (2005) 4657–4660
to 1,3-diphenyl-prop-2-en-1-one has also been studied.
Although the enantiomeric excesses are moderate at
present, the results of this work have provided meaning-
ful insights in the understanding of the use of CILs in
asymmetric induction. Applications of chiral ILs as
green media for other asymmetric syn-thesis and cataly-
sis are actively investigated in our laboratory.
10. P e´ got, B.; Vo-Thanh, G.; Gori, D.; Lopy, A. Tetrahedron
Lett. 2004, 45, 6425.
1
1
1. Varelis, P.; Johnson, B. L. Aust. J. Chem. 1995, 48, 1775.
2. Kalinowski, H. O.; Crass, G.; Seebach, D. Chem. Ber.
1
981, 114, 477.
3. Nemoto, H.; Takamatsu, S.; Yamamoto, Y. J. Org. Chem.
991, 56, 1322.
4. Cunningham, A. F.; K u¨ ndig, E. P. J. Org. Chem. 1988, 53,
823.
5. Lancaster, N. L.; Salter, P. A.; Welton, T.; Young, G. B.
J. Org. Chem. 2002, 67, 8855.
6. Nguyen, H. P.; Matondo, H.; Baboulene, M. Green Chem.
1
1
1
1
1
1
Acknowledgments
This work was financially supported by the Natural Sci-
ence Foundation of China (No. 20372058).
2
003, 5, 303.
17. Kim, D. W.; Song, C. E.; Chi, D. Y. J. Org. Chem. 2003,
8, 4281.
6
1
1
2
8. Wheeler, C.; West, K. N.; Liotta, C. L.; Eckert, C. A.
Chem. Commun. 2001, 887.
9. Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1996,
Supplementary data
37, 6343.
0. All compounds reported here were duly characterized.
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
20
D
Selected data: 7a: mp 88–90 °C; ½aꢀ ꢁ36.3 (c 2.0,
2
005.04.134.
1
acetone); H NMR (DMSO-d ) d 3.80 (s, 6H), 4.04 (d,
6
J = 9.20 Hz, 2H), 4.28–4.34 (m, 4H), 4.46–4.61 (m, 4H),
7
.12–7.15 (m, 4H), 7.31–7.32 (m, 6H), 7.60–7.63 (m, 4H),
1
3
References and notes
. (a) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis;
Wiley-VCH: Weinheim, 2003; (b) Rogers, R. D.; Seddon,
K. R.; Volkov, S. Green Industrial Applications of Ionic
Liquids; Kluwer Academic: Dordrecht, 2002; (c) Baude-
quin, C.; Baudoux, J.; Levillain, J.; Cahard, D.; Gau-
montb, A. C.; Plaqueventa, J. C. Tetrahedron: Asymmetry
9.02 (s, 2H); C NMR (DMSO-d ) d 36.23, 49.19, 72.98,
6
7
6.72, 123.30, 123.95, 128.45, 128.55, 128.82, 137.64,
ꢁ
1
1
137.67; IR 3474, 3184, 3131, 1596 cm ; Anal. Calcd for
: C, 43.22; H, 4.46; N, 7.75. Found: C,
26 32 12 4 2 2
C H F N O P
2
0
43.12; H, 4.73; N, 7.55. 8a: mp 129–130 °C; ½aꢀ ꢁ10.1 (c
D
1
6
2.0, acetone); H NMR (DMSO-d ) d 3.79 (s, 6H), 4.05 (d,
J = 8.80 Hz, 2H), 4.29–4.35 (m, 4H), 4.46–4.61 (m, 4H),
7.13–7.15 (m, 4H), 7.29–7.32 (m, 6H), 7.60–7.63 (m, 4H),
1
9.03 (s, 2H); C NMR (DMSO-d
3
2003, 14, 3081; (d) Marsh, K. N.; Boxall, J. A.; Lichtent-
) d 36.26, 49.36, 73.04,
6
haler, R. Fluid Phase Equilibria 2004, 219, 93; (e) Aslanov,
L. A.; Anisimov, A. V. Petroleum Chem. 2004, 44, 65; (f)
Stalcup, A. M.; Cabovska, B. J. Liquid Chromatogr. Relat.
Technol. 2004, 27, 1443.
. (a) Welton, T. Chem. Rev. 1999, 99, 2071; (b) Freemantal,
M. Chem. Eng. News 2000, 15, 37; (c) Wasserschied, P.;
Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772; (d)
Sheldon, R. Chem. Commun. 2001, 2399.
76.82, 123.34, 123.99, 128.46, 128.59, 128.86, 137.73; IR
ꢁ
1
3463, 3155, 3101, 1685, 1574 cm ; Anal. Calcd for
: C, 51.52; H, 5.32; N, 9.24. Found: C,
C H B F N O
26 32 2 8 4 2
2
D
0
51.46; H, 5.47; N, 9.14. 7b: mp 92–93 °C; ½aꢀ +30.5 (c 2.0,
1
2
2 2 6
CH Cl ); H NMR (DMSO-d ) d 1.15 (d, J = 5.60 Hz,
3H), 3.78– 3.85 (m, 4H, CH
3
, CH), 4.14 (dd, J = 14.20 Hz,
0
0
J = 7.40 Hz, 1H), 4.33 (dd, J = 14.00 Hz, J = 3.20 Hz,
1H), 4.37 (d, J = 12.00 Hz, 1H), 4.54 (d, J = 12.40 Hz,
1H), 7.16–7.19 (m, 2H), 7.28–7.31 (m, 3H), 7.63–7.64 (m,
3
4
5
6
. Earle, M. J.; McCormac, P. B.; Seddon, K. R. Green
Chem. 1999, 1, 23.
1
3
2H), 9.01 (s, 1H); C NMR (DMSO-d
6
) d 16.96, 36.16,
. Wasserscheid, P.; Boesmann, A.; Bolm, C. Chem. Com-
mun. 2002, 200.
. Ishida, Y.; Miyauchi, H.; Saigo, K. Chem. Commun. 2002,
53.72, 70.09, 72.88, 123.51, 123.68, 127.93, 127.95, 128.67,
ꢁ
1
137.42, 138.56; IR 3454, 3183, 1632 cm ; Anal. Calcd for
14 19 6 2
C H F N OP: C, 44.69; H, 5.09; N, 7.44. Found: C,
2
0
2240.
44.50; H, 5.28; N, 7.33. 8b: mp 41–42 °C; ½aꢀ +19.9 (c 2.0,
D
1
. (a) Fukumoto, K.; Yoshizawa, M.; Ohno, H. J. Am.
Chem. Soc. 2005, 127, 2398; (b) Bao, W.; Wang, Z.; Li, Y.
J. Org. Chem. 2003, 68, 591.
acetone); H NMR (DMSO-d ) d 1.16 (d, J = 6.40 Hz,
6
3
3H), 3.78–3.85 (m, 4H, CH , CH), 4.12–4.17 (m, 1H),
4.32–4.39 (m, 2H), 4.55 (d, J = 12.40 Hz, 1H), 7.17–7.19
(m, 2H), 7.29–7.32 (m, 3H), 7.62–7.63 (m, 2H), 8.99 (s,
7
8
9
. Levillain, J.; Dubant, G.; Abrunhosa, I.; Gulea, M.;
Gaumont, A. C. Chem. Commun. 2003, 2914.
. Thanh, G. V.; Pegot, B.; Loupy, A. Eur. J. Org. Chem.
1
1H); C NMR (DMSO-d
3
6
) d 17.05, 36.21, 53.79, 70.18,
72.98, 123.56, 123.73, 128.04, 128.75, 137.46, 138.64; IR
ꢁ
1
3443, 3155,1635 cm ; Anal. Calcd for C14
2004, 1112.
4 2
H19BF N O: C,
. Jodry, J. J.; Mikami, K. Tetrahedron Lett. 2004, 45, 4429.
52.86; H, 6.02; N, 8.81. Found: C, 52.74; H, 6.15; N, 8.78.