Design and synthesis of bistereogenic chiral ionic liquids and their use as solvents for asymmetric Baylis-Hillman reactions

Article abstract of DOI:10.1039/b808502a

Three novel chiral ionic liquids (CILs) containing two chiral centers in the side chain bonded to the 2-position of the imidazolium cation and different anions have been synthesized, characterized and used as chiral solvents for asymmetric Baylis-Hillman (BH) reactions; good yields and fair enantioselectivities were obtained.

Full text of DOI:10.1039/b808502a

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Design and synthesis of bistereogenic chiral ionic liquids and their use as
solvents for asymmetric Baylis–Hillman reactions†
Satish Garre, Erica Parker, Bukuo Ni* and Allan D. Headley*
Received 20th May 2008, Accepted 11th July 2008
First published as an Advance Article on the web 21st July 2008
DOI: 10.1039/b808502a
Three novel chiral ionic liquids (CILs) containing two
chiral centers in the side chain bonded to the 2-position
of the imidazolium cation and different anions have been
synthesized, characterized and used as chiral solvents for
asymmetric Baylis–Hillman (BH) reactions; good yields and
fair enantioselectivities were obtained.
for asymmetric reactions. Herein, we wish to report the synthesis
of bistereogenic CILs and their use as solvents for asymmetric BH
reactions.
The BH reaction has attracted much attention as a useful C–C
bond formation reaction in organic synthesis, mainly because it
efficiently converts simple starting materials into highly function-
alized products. Recently, a highly enantioselective asymmetric
BH reaction of acrylates and aldehydes has been achieved by the
use of chiral Brønsted acids,9 chiral lanthanide Lewis acids,10 and
quinidine-derived chiral nucleophilic amine catalysts.11 In all these
cases, a volatile organic solvent, such as THF, DMF, or CH3CN
was necessary. Recent research on the BH reaction, in which
nonvolatile achiral ILs were used as solvents, has demonstrated
that such IL media can accelerate the reaction rate.12 However,
low yields were obtained when the reaction was conducted in
the presence of imidazolium-based ILs under basic conditions,
due to the deprotonation that occurs in the C-2 position of the
imidazolium cation, which results in undesired side products.13
Owing to the versatility in the design of chiral ionic liquids to
accomplish various tasks and to explore the use of imidazolium
type CILs in the BH reaction, we have chosen to design a new
type of CIL that contains the imidazolium cation as well as a side
chain that contains two chiral centers, which is bonded to the 2-
position of the imidazolium cation.14 An important feature in the
design is that there is not an acidic hydrogen at the C-2 position
of the imidazolium ring. In addition, the hydroxyl and NH groups
are present, which are propitious for the transfer of chirality via
hydrogen bonding.
The synthesis is similar to that reported earlier;14 the imidazole
precursor was synthesized from commercially available 1-methyl-
2-imidazole carboxaldehyde and (1S,2R)-norephedrine by a con-
densation reaction, and the intermediate imine was reduced by
sodium borohydride, quenched with hydrochloric acid, followed
by neutralization to form product 1. The alkylation reaction is
carried out under reflux using toluene for 12 hours to form
the imidazolium bromide salt 2 in good yields and high purity.
The syntheses of the corresponding bistereogenic CILs with
different anions were carried out using anion exchange of the
bromide anion with BF4 and NTf2 anions to form CILs 3, and
4 respectively, which were purified with flash chromatography
with a suitable solvent system (Scheme 1). The CIL 4 with
NTf2 as anion was a good liquid at room temperature and was
found to be very soluble in common solvents, such as alcohols,
CH2Cl2, ethyl acetate, DMF, and DMSO, but was immiscible
with ether, hexane, and H2O. The CILs 2 and 3 were highly
viscous liquids at room temperature and were found to be only
soluble in high polarity solvents, such as alcohols, DMF, H2O and
DMSO.
The toxic and volatile nature of many organic solvents that are
widely used in organic synthesis has posed a serious threat to
the environment. Efforts aimed at replacing these volatile organic
solvents with environmentally friendly ones as reaction media have
been pursued in recent years. Performing organic reactions in ionic
liquids (ILs) has received considerable attention owing to the in-
triguing properties of ILs, which include lack of measurable vapor
pressure, high chemical and thermal stability, noncombustibility,
and high ionic conductivity, compared to typical organic solvents.1
Moreover, the solubility of ILs can be tuned readily by modifying
their cations and anions so that they can be separated easily from
organic solvents as well as aqueous media. As a result, numerous
important organic reactions have been successfully conducted in
ILs. Recently, chiral ionic liquids (CILs) have been the focus
of attention, especially their effect on asymmetric reactions.2,3
To date, there are only a few CILs that have been designed,
synthesized, and used effectively as solvents and catalysts for
asymmetric reactions; examples of reactions include the Baylis–
Hillman (BH) reaction,4 Michael addition,5 aldol reactions,6 and
many other reactions.7 A review of the literature reveals that most
CILs that have been successfully used to influence asymmetric
reactions contain one chiral center, and only a limited number
contain two chiral centers. Such bistereogenic CILs have been
successfully used for chiral discrimination and other applications
in asymmetric synthesis;4,5a,8 examples of bistereogenic chiral ionic
liquids are shown in Fig. 1. This ‘designer’ feature of ionic liquids
opens up new areas of research for their design and use as solvents
Fig. 1 Examples of known bistereogenic CILs.
Department of Chemistry, Texas A & M-University-Commerce, Commerce,
TX, 75429-3001, USA. E-mail: bukuo_ni@tamu-commerce.edu, allan_
headley@tamu-commerce.edu
† Electronic supplementary information (ESI) available: Experimental and
NMR spectra. See DOI: 10.1039/b808502a
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Org. Biomol. Chem., 2008, 6, 3041–3043 | 3041
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Scheme 1 The synthesis of bistereogenic CILs.
Optimization of asymmetric induction reaction conditions of
CILs as chiral solvents was examined by using the BH reaction
of benzaldehyde and methyl acrylate and DABCO was used as a
Lewis base; the results are summarized in Table 1. Using CIL 4
with THF or toluene as co-solvents, the reaction gave the desired
product 6a in moderate yields and fair enantioselectivities with
80–85% CIL recovery (Table 1, entries 1–2). While using CH2Cl2
as co-solvent with CIL 4, no enantioselectivity was observed
(Table 1, entry 3). When protic solvents MeOH and H2O were
used as co-solvents with CILs 2, 3, and 4, only minimal to no
enantioselectivity was observed, although CILs 2 and 3 have good
solubility in water (Table 1, entries 4–7). One possible explanation
for the low or no enantiomeric excess in the presence of H2O
and MeOH is that there is a competition for hydrogen bonding
with the substrate and such interactions are stronger with the
substrate molecules, compared to those with the chiral ionic
liquid, which in turn affect the stereoselectivity. However, when
the CIL 4 was used as the solvent without a co-solvent, the desired
adduct was obtained in 80% yield and 19% ee (Table 1, entry 8).
The enantioselectivity was further increased to 25% ee when the
reaction temperature was lowered to 4 ◦C without reduction in
the reaction rate (Table 1, entry 9). Interestingly, using one chiral
center ionic liquid 5 only resulted in 5% ee (Table 1, entry 10). The
absolute configuration of 6a was determined to be S, by comparing
the specific rotation of 6a with that reported elsewhere.15 Although
the research on chiral ionic liquids as solvents for asymmetric
reactions is still at a preliminary stage and the enatioselectivities
are often poor and even zero,2 the results obtained for these
bistereogenic chiral ionic liquids are promising.
Next, investigations on asymmetric induction of CIL 4 as
chiral solvent were carried out by using the BH reaction with
a series of aldehydes and acrylates under the optimized reaction
conditions of entry 9 (Table 1) and the results are summarized in
Table 2. As shown in Table 2, all reactions occurred smoothly
in the presence of CIL 4 under these standard conditions,
giving the corresponding products 6a–g in moderate to high
yields. Typically, substituents on the aromatic aldehydes and
acrylates influenced the enantioselectivities as well as the yields.
For example, the reaction of the more steric t-butyl acrylate
with benzaldehyde afforded adduct 6b with a decreased yield
and enantioselectivity compared to the methyl acrylate (Table 2,
entries 1–2). Low enantioselectivities were observed in the cases
of 4-chlorobenzaldehde and 4-nitrobenzaldehyde (Table 2, entries
3–4). While the reaction of 4-methoxybenzaldehyde with methyl
acrylate gave adduct 6e with a slightly increased ee, the reaction
rate was slow (Table 2, entry 5). When the aliphatic aldehydes were
used as substrates, very low enantioselectivities were observed,
although the yields were high (Table 2, entries 6–7).
Table 1 Optimization of asymmetric BH reaction of benzaldehyde and
methyl acrylatea
The enantioselectivities observed in the BH reactions could be
explained by the presence of the hydroxyl and NH groups, which
play an important role in the transfer of chirality via hydrogen
Table 2 BH reactions of aldehydes and acrylates using CIL 4 as solvent16
Entry CIL Co-solvent T/d Yield (%)b Ee (%)c
CIL-recovery
1
2
3
4
5
6
7
8
9d
4
4
4
4
2
3
4
4
4
5
THF
7
7
7
7
2
2
7
7
7
6
50
50
45
78
80
20
< 5
80
82
80
14
14
80%
85%
Toluene
CH2Cl2
MeOH
H2O
H2O
H2O
None
None
None
Racemic 97%
Racemic 91%
5
3
Entry R1
R2
Product Yield (%)a Ee (%)b CIL-recovery
96%
55%
1c
2
3
4
5
6
7
Ph
Ph
4-Cl-C6H4
4-NO2-C6H4 Me 6d
4-MeO-C6H4 Me 6e
Me 6a
t-Bu 6b
Me 6c
80
60
97
80
38
91
90
24
7
12
18
23
3
95%
98%
98%
95%
95%
97%
95%
Racemic 95%
19
25
5
96%
97%
98%
10
i-Pr
PhCH2CH2
Me 6f
a Reaction conditions: benzaldehyde (0.5 mmol), methyl acrylate
(1.5 mmol), DABCO (1.0 mmol), CIL (4.0 mmol), co-solvent (0.5 mL).
b Isolated yield. c Determined by HPLC (chiralpak AS-H). d The reaction
temperature at 4 ◦C.
d
6g
2
a Isolated yield. b Determined by HPLC (chiralpak AS-H). c The recycled
CIL 4 was used as solvent. d Cyclohexenone was used.
3042 | Org. Biomol. Chem., 2008, 6, 3041–3043
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bonding with the aldehyde substrate in a manner such that C–C
bond formation would take place by the zwitterionic intermediate
addition to the less hindered Re face of the aldehyde. A depiction
of the bifurcated hydrogen bonding that is expected to stabilize
the transition state and make the selectivity possible is shown in
Fig. 2.
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Fig. 2 Proposed mechanism for BH reaction using bistereogenic CIL as
solvent.
In conclusion, three novel chiral ionic liquids have been designed
and synthesized. These CILs were assembled by incorporating
chiral side chains on the C-2 position of the imidazolium
cation rings; this avoids the shortcomings of their traditional
counterparts that can participate in deprotonation side reactions
on their C-2 positions. Application of these new CILs as green
media for asymmetric Baylis–Hillman reaction has been studied
and afforded moderate to high yields (up to 97%) with fair
enantioselectivities (up to 25% ee). Based on these preliminary
results, the design of novel CILs, which is expected to afford higher
levels of enantioselectivities for asymmetric reactions, is currently
being investigated in our laboratory.
Acknowledgements
We are grateful to the Robert A. Welch Foundation (T-1460) for
financial support of this research.
15 S. E. Drewes, N. D. Emslie, J. S. Field, A. A. Khan and N. Ramesar,
Tetrahedron: Asymmetry, 1992, 3, 255. The rotation for 6a is [a]D20
+27.9◦ (c = 0.77, MeOH).
=
16 Typical procedure for BH reaction: A mixture of aldehyde (1 mmol),
acrylate (3 mmol), DABCO (1.5 mmol) and CIL 4 (4 mmol) was stirred
for a period of time at the required temperature. The mixture was
extracted with ether (2 mL × 3), concentrated and purified by flash
chromatography and analyzed with 1H-NMR. The ether insoluble CIL
4 was diluted in dichloromethane (15 mL) and washed with water
(5 mL × 2). The organic layer was dried with anhydrous CaCl2, filtered
and evaporated in vacuum to afford the recycled CIL 4. The CIL 4 was
tested for its purity with spectral data and was found to be identical
with the initial one. The recycled CIL was reused without significant
loss of efficiency (Table 2, entry 1).
Notes and references
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This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3041–3043 | 3043
©