First application of chiral ionic liquids in asymmetric Baylis-Hillman reaction

Article abstract of DOI:10.1016/j.tetlet.2004.06.134

The first example of the use of chiral ionic liquids as reaction media in the asymmetric Baylis-Hillman reaction was described using N-alkyl-N- methylephedrinium salts. Good yields and significant enantiomeric excesses were obtained. The first example of

Full text of DOI:10.1016/j.tetlet.2004.06.134

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6425–6428
First application of chiral ionic liquids in asymmetric
Baylis–Hillman reaction
*
´ ´
Bruce Pegot, Giang Vo-Thanh, Didier Gori and Andre Loupy
´ ´ ´
Laboratoire des Reactions Selectives sur Supports, ICMMO, CNRS UMR 8615, Universite Paris-Sud 91405 Orsay Cedex, France
Received 19 May 2004; revised 29 June 2004; accepted 30 June 2004
Available online 19 July 2004
Abstract—The first example of the use of chiral ionic liquids as reaction media in the asymmetric Baylis–Hillman reaction was
described using N-alkyl-N-methylephedrinium salts. Good yields and significant enantiomeric excesses were obtained.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Ionic liquids (ILs), or room temperature molten salts,
have attracted much attention as new clean media for
green chemistry, especially in synthetic and catalytic
transformations.1 Among them, chiral ILs are particu-
larly attractive for their potential applications to chiral
discrimination, including asymmetric synthesis and opti-
cal resolution of racemates. However, very few chiral
ILs have been reported2 and their use as reaction media
in asymmetric transformations has been very limited. To
the best of our knowledge, no significant enantioselectiv-
ity was observed so far.3
O
O
OH
O
1
DABCO, IL*2
OMe
*
Ar
H
Ar
OMe
R
N
R: C4H9, C8H17, C10H21, C16H33
Z: OH, OAc
IL*2 :
X
Z
X: OTf, PF6
Ph
Scheme 1. Asymmetric Baylis–Hillman reaction in the presence of
chiral ILs as reaction media.
For our studies (Scheme 1, Ar=Ph), an asymmetric ver-
sion of the Baylis–Hillman can be in principle carried
out with a chiral source in any one of the two essential
components either catalyst or solvent. In fact, several
efforts have been made in using various asymmetric cat-
alysts.6 However, the enantioselectivities were found to
be poor to moderate. Noticeable enhancements in both
reaction rate and enantiomeric excess (ee) were observed
under high-pressure conditions.7 A highly enantioselec-
tive asymmetric Baylis–Hillman of aromatic aldehydes
and imines has been achieved by Hatakeyama and co-
workers.8 using b-isocupreidine (b-ICD, cinchona alka-
loid derivatives) as a chiral amine catalyst. Recently,
Chen and co-workers.9 described for the first time the
use of novel camphor-derived dimerized ligands for chi-
ral Lewis acid catalyzed asymmetric Baylis–Hillman
reaction. Good enantioselectivities were obtained. In
all cases, the use of aprotic polar solvent (DMF,
CH3CN) was necessary. On the other hand, no chiral
solvent was reported in the literature for this transfor-
mation. Our aim was therefore to study the use of chiral
ILs as reaction media in asymmetric Baylis–Hillman
reaction, especially the transfer of chirality of these sol-
vents due to their high degree of organization.
In connection with our studies on chiral ILs and our
ongoing project on the asymmetric synthesis, we have
recently reported the synthesis of chiral ILs possessing
a chiral ephedrinium cation4 using solvent-free reaction
and microwave activation under green chemistry condi-
tions.5 In this communication, we describe the use of
chiral ILs as reaction media for the first time in the
asymmetric Baylis–Hillman reaction between benzalde-
hyde (Ar=Ph) and methyl acrylate (Scheme 1).
The Baylis–Hillman reaction has attracted considera-
ble interest due to the fascinating tandem Michael-aldol
sequence catalyzed by a Lewis base (such as a tertiary
amine) or a Lewis acid and the promising utility of the
multifunctional products. Recent literature continues
to record impressive progress in rate acceleration as well
as asymmetric induction based on imaginative ideas.6
Keywords: Ionic liquids; Chirality; Baylis–Hillman reaction; Asym-
metric synthesis.
*
Corresponding author. Tel.: +33-1-69-15-76-50; fax: +33-1-69-15-46-
79; e-mail: gvothanh@icmo.u-psud.fr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.134

´
B. Pegot et al. / Tetrahedron Letters 45 (2004) 6425–6428
6426
Table 1. Asymmetric Baylis–Hillman reaction in the presence of chiral
ILs 2 (R=C8H17, X=OTf, Z=OH)
It should be pointed out that the use of chiral solvents in
asymmetric syntheses was already reported in the litera-
ture.10 However, low enantioselectivities were obtained
and the difficult preparation of chiral solvents as well
as their high cost often precluded their use. With regard
to chiral ILs, due to their ease of synthesis, recyclability
and their peculiar properties, these new chiral solvents
should be highly more attractive than classical chiral sol-
vents for asymmetric induction.
Entry
ILs 2
(equiv)
Conversion
(%)a
Yield
(%)a
(R)-1 ee
(%)b
1
0.5
85
1.5
3
86
76
20
21
3
78 (374)
2
85
65
83
75
60
88
73
45
28
32
24c
4
5
1
67
c
6
3
52(50)
30
60
32
7
3
24c,d
The use of achiral ILs as reaction media for the Baylis–
Hillman reaction was described in the literature. How-
ever, low yields were obtained when the reaction was
conducted in the presence of an imidazolium-based ionic
liquid due to direct addition of the deprotonated imid-
azolium salt to aldehyde.11 On the other hand, this reac-
tion has been found to be accelerated in the presence of
a catalytic amount of an imidazolium-based ionic liq-
uid.12 A moderate acceleration was observed when the
above-mentioned ionic liquid was used in combination
with Lewis acid. Kumar and Pawar13 have shown that
the DABCO-catalyzed Baylis–Hillman reaction has
been shown to be improved in the chloroaluminate
room temperature ionic liquids. The authors noted that
these solvents could be recovered and reused with-
out loss of efficiency. Recently, Chu and co-workers14
described the use of butyldimethylimidazolium hexa-
fluorophosphate ([bdmim][PF6]) as solvent for this reac-
tion. Unlike the commonly used [bmim][PF6] that
evidently reacts with electrophilic aldehyde under basic
conditions, ionic liquid [bdmim][PF6] is inert and the
Baylis–Hillman reaction in this solvent proceeds
smoothly with better yield.
8
3
44e
Conditions=benzaldehyde–methyl acrylate–DABCO=1:1:1. Temper-
ature=30ꢁC. Time=4days.
a Conversion and yield estimated by GC using an internal standard,
isolated yields are given in brackets.
b ee determined by chiral HPLC15 and configuration (R)-1 determined
by comparison of optical rotation with the literature value.16
c Benzaldehyde–methyl acrylate–DABCO=1:3:0.3.
d Temperature=50ꢁC.
e Time=7days.
rality of these new chiral solvents in asymmetric trans-
formations. Thus, a series of different alkyl chain
lengths (R=C4H9, C8H17, C10H21, C16H33) was tested
on this reaction model. However, no effect on the enan-
tioselectivity was observed. On the other hand, a slight
À
decrease of ee was detected when anion PF6 was used
instead of OTfÀ (Table 2, entries 1 and 2), perhaps ow-
ing to more decomposition of the chiral IL 2 (R=C8H17,
X=PF6) as already mentioned in the literature.17
It is important to note that the presence of the hydroxyl
function on chiral ILs is propitious for the transfer of
chirality. Thus, when the hydroxyl group was replaced
by an acetyl group, only 6% ee was obtained (Table 2,
entry 3). This was in fact already observed by Colonna
and co-workers18 in asymmetric induction in the boro-
hydride reduction of carbonyl compounds by means of
a chiral phase transfer catalyst. The noticeable influence
of OH group is presumably connected to the interven-
tion of a hydrogen bond with a carbonyl function (from
either benzaldehyde or methyl acrylate) which implies a
fixing point for chiral IL on reactants. It results in an
In our initial studies, we attempt to optimize the reac-
tion conditions for the Baylis–Hillman reaction between
benzaldehyde and methyl acrylate using DABCO as Le-
wis base and in the presence of chiral ILs 2, easily ob-
tained in Ôtwo-step sequenceÕ reaction from (À)-N-
methylephedrine.5 Good yields and moderate enantio-
meric excesses15 were obtained. The main results are
given in Table 1.
As illustrated in Table 1, the excess of chiral ILs leads to
a noticeable enhancement in enantioselectivity (entries 1
and 4). However, low yields and considerable loss of
benzaldehyde were observed when 3equiv of chiral ILs
were used, possibly owing to the instability of the benz-
aldehyde under these conditions. In fact, the low yields
obtained in the presence of a large excess of ionic liquid
are presumably due to the reaction between benzalde-
hyde and the alkoxy group resulting from the deproto-
nation of the hydroxy function on chiral ILs under
basic conditions as already reported by Aggarwal
et al.11 A large excess of methyl acrylate (3equiv for
entry 6 and 1equiv for entry 4) in the presence of a cat-
alytic amount of DABCO (0.3equiv) gave the same ee.
On the other hand, the best enantioselectivity was
obtained (44%) when the reaction was performed for
7days (entry 8).
Table 2. Asymmetric Baylis–Hillman reaction in the presence of chiral
ILs 2 (R=C8H17)
Entry
Chiral source 2
Conversion
(%)a
Yield
(%)a
(R)-1 ee
(%)b
1
2
3
4
2, OTf, OH
2, PF6, OH
2, OTf, OAc
(À)-NME
85
87
89
78
78 (75)c
74
77
23 (24)c
2 0
6
9d
75
Conditions=benzaldehyde–methyl acrylate–DABCO–2=1:1:1:1. Tem-
perature=30ꢁC. Time=4days.
a Conversion and yield estimated by GC using an internal standard.
b ee determined by chiral HPLC15 with a margin of error about 1%.
Configuration (R)-1 was determined by comparison of optical rota-
tion with the literature value.16
c Yield and ee obtained by reaction with recycled chiral IL is given in
brackets.
d (À)-N-Methylephedrine was used as a chiral source.
One of the major points of our work that has received
considerable attention is the study of the transfer of chi-

´
B. Pegot et al. / Tetrahedron Letters 45 (2004) 6425–6428
6427
inflexible system and the origin for possible stereoselec-
tivity.18,19
IL 2 (1mmol) was stirred for a period of time and tem-
perature (see Tables 1 and 2). The mixture was extracted
with Et2O (1mL·3). After evaporation of solvent, the
crude product was purified by flash chromatography
or analyzed by GC. The ionic liquid was diluted in
dichloromethane (20mL) and then recycled by washing
with water (10mL·2). The organic phase was dried over
anhydrous MgSO4, filtered and evaporated in vacuo to
In order to show the efficacy of chiral ILs, especially
their particular properties due to their high degree of
organization, (À)-N-methylephedrine was used as a chi-
ral catalyst for this study. A poor ee (only 9%) was de-
tected in the similar reaction conditions (Table 2, entries
1 and 4). The use of recycled chiral ILs led to the same
ee proving thus the possibility of reuse without loss of
efficiency (Table 2, entry 1). As expected, when the
(+)-ephedrinium salt 2 was used instead of the (À)-2,
the direction of stereoselectivity was reversed to give
(S)-1 as a major product with comparable yield and
ee. The main results were summarized in Table 2.
1
afford the recycled ionic liquid. Spectra data (IR, H
and 13C) were identical to the initial ionic liquid sample.
This chiral IL was reused without loss of efficiency
(Table 2, entry 1).
References and notes
Next, attempts were carried out to extend the use of chi-
ral ILs in the transfer of chirality. Thus, some others
aldehydes were tested under similar conditions. All reac-
tions were performed in the presence of 1equiv of chiral
ILs 2 (R=C8H17, X=OTf, Z=OH). A very low enantio-
selectivity was observed in the case of p-nitrobenzalde-
hyde and pyridine-3-carboxaldehyde (Table 3, entries 4
and 5) probably due to the formation of a hydrogen
bond between the OH group of 2 with the NO2 function
or with the lone pair on N atom, respectively. A slight
increase of ee (not optimized value) was detected when
p-methoxybenzaldehyde, which is less reactive than
benzaldehyde, was used (Table 3, entries 1 and 2).
On the other hand, with the Cl group in para-position,
lower ee was observed (Table 3, entries 1 and 3). The re-
sults obtained are given in Table 3.
1. (a) Welton, T. Chem. Rev. 1999, 99, 2071–2083; (b)
Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000,
39, 3772–3789; (c) Sheldon, R. Chem. Commun. 2001,
2399–2407; (d) Ionic Liquids in Synthesis; Wasserscheid,
P., Welton, T., Eds.; Wiley-VCH, 2002; (e) Ionic Liquids
Industrial Applications to Green Chemistry. Rogers, R. D.;
Seddon, K. R. Eds.; ACS, Symposium Series 818,
2001.
2. For a review on the chiral ionic liquids, see: Baudequin,
C.; Baudoux, J.; Levillain, J.; Cahard, D.; Gaumont,
A.-C.; Plaquevent, J.-C. Tetrahedron: Asymmetry 2003,
14, 3081–3093.
3. (a) Earle, M. J.; McCormac, P. B.; Seddon, K. R. Green
Chem. 1999, 1, 23–25; (b) Howarth, J.; Hanlon, K.; Fayne,
D.; McCormac, P. Tetrahedron Lett. 1997, 38, 3097–3100.
4. Wasserscheid, P.; Bo¨smann, A.; Bolm, C. Chem. Commun.
2002, 200–201.
´
5. Vo-Thanh, G.; Pegot, B.; Loupy, A. Eur. J. Org. Chem.
2004, 5, 1112–1116.
6. Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811–891.
In conclusion, we have taken advantage for the first time
of the use of chiral ILs as reaction media in the enantio-
selective version of Baylis–Hillman reaction. Although
the enantiomeric excesses are moderate at present, sev-
eral important parameters have been studied and the re-
sults of this work have provided useful insights into the
understanding of the use of chiral ILs in asymmetric
induction. Based on these observations, the construction
of novel chiral ILs, which should afford higher levels of
enantioselectivities, is currently being investigated in our
laboratory. The results of these studies will be communi-
cated in due course.
´
7. (a) Marko, I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron
1997, 53, 1015–1024; (b) Oishi, T.; Oguri, H.; Hirama, M.
Tetrahedron: Asymmetry 1995, 6, 1241–1244.
8. (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hata-
keyama, S. J. Am. Chem. Soc. 1999, 121, 10219–10220; (b)
Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Org. Lett. 2003, 5, 3103–3105.
9. Yang, K.-S.; Lee, W.-D.; Pan, J.-F.; Chen, K. J. Org.
Chem. 2003, 68, 915–919.
10. (a) Seebach, D.; Oei, H. Angew. Chem., Int. Ed. Engl.
1975, 14, 634–636; (b) March, J.; Smith, M. B. Advanced
Organic Chemistry; Wiley-Interscience, 2001; p 150; (c)
Typical procedure: a mixture of benzaldehyde (1mmol),
methyl acrylate (1mmol), DABCO (1mmol) and chiral
´
Ulbert, O.; Szarka, A.; Halasi, S.; Somogyi, B.; Belafi-
Bako, K.; Gubicza, L. Biotechnol. Tech. 1999, 13,
´
299–302.
11. Aggarwal, V. K.; Emme, I.; Mereu, A. Chem. Commun.
2002, 1612–1613.
12. Kim, E. J.; Ko, S. Y.; Song, C. E. Helv. Chim. Acta 2003,
86, 894–899.
13. Kumar, A.; Pawar, S. S. J. Mol. Catal. A 2004, 211, 43–47.
14. Hsu, J.-C.; Yen, Y.-H.; Chu, Y.-H. Tetrahedron Lett.
2004, 45, 4673–4676.
15. The ee value was determined by chiral HPLC analysis of 1
(Ar=Ph). Separation conditions: (S,S)-Whelk-01 column
4.6mm·250mm (thermostatted column 0–1ꢁC); elution
with a mixture of hexane/ethanol 99/1; flow rate 1mL/min;
retention time 28min for (R)-1 and 33min for (S)-1
enantiomer.
Table 3. Asymmetric Baylis–Hillman reaction in the presence of chiral
ILs 2 (R=C8H17, Z=OH, X=OTf)
Entry Ar
Conversion (%)a Yield (%)a 1 ee (%)b
1
2
3
4
Ph
85
50
93
95
78
36
2
30
3
p-MeOPh
p-ClPh
p-NO2 Ph
8216
87
1
6
5
95
83
N
Conditions=aldehyde–methyl acrylate–DABCO–2=1:1:1:1. Temper-
ature=30ꢁC. Time=4days.
a Conversions and yields determined after flash chromatography.
b ee determined by chiral HPLC with a margin of error about 1%.
16. Drewes, S. E.; Emslie, N. D.; Field, J. S.; Kahn, A. A.;
Ramesar, N. Tetrahedron: Asymmetry 1992, 3, 255–260.

´
B. Pegot et al. / Tetrahedron Letters 45 (2004) 6425–6428
6428
17. Swatloski, R. P.; Holbrey, J. D.; Roger, R. D. Green
Chem. 2003, 5, 361–363.
18. (a) Balcells, J.; Colonna, S.; Fornasier, R. Synthesis 1976,
266–267; (b) Colonna, S.; Fornasier, R. J. C. S. Perkin
Trans. 1 1978, 371–373.
19. (a) Loupy, A.; Zaparucha, A. Tetrahedron Lett. 1993, 34,
473–476; (b) Diez-Barra, E.; de la Hoz, A. In Handbook of
Phase Transfer Catalysis; Diez-Barra Sasson, Y., Ed.;
Blackie Academic and Professional: London, 1997; pp
276–316.