Chiral room temperature ionic liquids as enantioselective promoters for the asymmetric aldol reaction

Article abstract of DOI:10.1002/ejoc.201402436

Chiral ionic liquids derived from natural amino acids are shown to be green and efficient media for direct asymmetric aldol reactions at room temperature catalyzed by (S)-proline. The corresponding aldol products were obtained with moderate to good enanti

Full text of DOI:10.1002/ejoc.201402436

FULL PAPER
DOI: 10.1002/ejoc.201402436
Chiral Room Temperature Ionic Liquids as Enantioselective Promoters for
the Asymmetric Aldol Reaction
Laura González,[a] Jorge Escorihuela,[b] Belén Altava,*[a] M. Isabel Burguete,[a] and
Santiago V. Luis*[a]
Keywords: Organocatalysis / Asymmetric catalysis / Ionic liquids / Aldol reactions / Amino acids
Chiral ionic liquids derived from natural amino acids are
shown to be green and efficient media for direct asymmetric
aldol reactions at room temperature catalyzed by (S)-proline.
participation of match/mismatch interactions of the chiral
medium with both enantiomers of proline. Moreover, these
catalytic systems were easily recovered by simple filtration,
The corresponding aldol products were obtained with mod- and studies on their reuse have demonstrated that recycling
erate to good enantioselectivities. A transfer of chirality from
the chiral reaction media has been observed as well as the
is possible for at least four runs with only a slight reduction
in activity.
amide (DMF), are not environmentally friendly and make
recycling of the catalyst difficult.
Introduction
In recent years, organocatalysis has become a very at-
tractive approach for the stereocontrolled preparation of
chiral products, being an efficient alternative to the well-
established asymmetric transformations based on metal-
containing catalysts.[1] This is true even considering that or-
ganic molecules have been used as catalysts from the early
stages of synthetic chemistry.[2] The aldol reaction is one of
the most important carbon–carbon bond-forming reactions
in organic synthesis for the production of enantiomerically
enriched β-hydroxy ketones,[3] which are important building
blocks for the synthesis of polyfunctional compounds and
natural products.[4] Indeed, the β-hydroxy ketone structural
motif is found in several biologically active compounds,
such as macrolide antibiotics and anticancer drugs.
Since List and Barbas III reported the direct aldol reac-
tion catalyzed by (S)-proline,[5] the use of small organic
molecules as catalysts has received increasing attention.[6]
From the toolbox of organocatalysts, proline is by far one
of the most popular because it is inexpensive, readily avail-
able in both enantiomeric forms, and can be used for a wide
range of synthetic transformations, including aldol reac-
tions. However, the organic solvents employed in this reac-
tion, dimethyl sulfoxide (DMSO) and N,N-dimethylform-
Over the last decade, room temperature ionic liquids
(RTILs) have attracted considerable attention as environ-
mentally benign reaction media for “green” synthetic pro-
cedures.[7] Most applications of ILs in catalysis emphasize
recyclability, allowing efficient recovery of the catalyst,
which usually maintains its activity for several cycles. This
observation was reported independently by Toma and Loh
in their pioneering studies of organocatalyzed aldol reac-
tions using ILs in 2002.[8] More recently, the design and the
use of chiral ionic liquids (CILs) as reaction media or as a
catalyst has emerged as a hot research topic in asymmetric
synthesis.[9] Moreover, the use of different types of additives
have been reported to accelerate the aldol reaction rate and
to increase its diastereo- and enantioselectivity,[10] although
the ability of the additives to induce chirality have rarely
been reported.[11]
Our group has recently studied the influence of the na-
ture of several chiral imidazole derivatives as additives for
the aldol reaction catalyzed by (S)-proline.[12] These addi-
tives seem to form supramolecular complexes with the cata-
lyst through the formation of H-bonds, leading to signifi-
cant improvement in both the reaction rates and the selec-
tivity of the reaction.
Considering the excellent results shown with amino
amides 1 in catalytic asymmetric reactions,[13] we decided
to integrate this structure with imidazolium subunits to de-
velop new families of CILs. Initial studies with this family
of CILs made it possible to observe by 1H NMR
spectroscopy how 3-benzyl-1-[(1S)-1-(butylcarbamoyl)-2-
phenylethyl]-1H-imidazol-3-ium triflamide (2) and other
derivatives could efficiently act as chiral shift agents for the
enatiodiscrimination of racemic mandelate and other chiral
[a] Department of Inorganic and Organic Chemistry, Universitat
Jaume I,
Av. de Vicent Sos Baynat s/n, 12071 Castellón, Spain
E-mail: luiss@uji.es
http://www.quimicasostenible.uji.es/
[b] Centro de Reconocimiento Molecular y Desarrollo
Tecnológico, Departamento de Química, Universitat
Politècnica de València,
Camino de Vera s/n, 46071 Valencia, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402436.
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Asymmetric Aldol Reaction in Chiral Ionic Liquids
carboxylate salts.[14] Herein, as a continuation of our work Table 1. Aldol reaction between acetone and p-nitrobenzaldehyde
using (S)-proline as catalyst with different solvents.[a]
with CILs, we report the application of several imidazolium
salts as solvents (cosolvents) or chiral additives for asym-
metric proline-catalyzed aldol reactions. The catalytic sys-
tems could be easily reused with only a slight decrease in
activity.
Entry
Solvent
Conversion [%][b] Selectivity [%][c] ee [%][d]
Results and Discussion
1
2
3
4
5
6
7
8
toluene
DMSO
–
CH2Cl2
H2O
MeOH
BMIM NTf2
CIL 2
99
99
95
98
0
89
90
97
99
–
71
71
71
67
–
The chiral α-amino amides 1 derived from (S)-valine, (S)-
phenylalanine, and (S)-leucine were used as precursors for
the synthesis of CILs 2–4 (Figure 1). Compound 1 was syn-
thesized by following the general synthetic methodology de-
scribed by our group for the preparation of related amino
amides.[15] The imidazole ring was then formed by reacting
1 with formaldehyde, ammonium acetate, and glyoxal. After
alkylation with butyl chloride, the imidazolium salts were
converted into the corresponding bistriflamide CILs 2–4 by
anion exchange using LiNTf2. These compounds were li-
98
99
80
90
99
99
9
62
77
[a] Reaction conditions: RCHO/acetone/cat. = 1:30:0.2, solvent/
acetone = 1:1 v/v, r.t., 6 h. [b] Conversion [%]: determined by 1H
NMR spectroscopic analysis of the crude reaction mixture.
[c] Selectivity [%]: determined by 1H NMR spectroscopic analysis
of the crude reaction mixture. Selectivity refers to the ratio between
quid at room temperature with a melting point of –20, –12, aldol products and dehydration products or formed through side
and –19 °C for CILs 2, 3, and 4, respectively.[14]
reactions. [d] Enantiomeric excess calculated by HPLC analysis for
the enantiomer R (major peak) {ee = [peak area(R) – peak area
(S)]ϫ100/total area (R + S)}.
To understand this process in more detail, a range of
exploratory experiments were performed. Thus, we studied
the effect of using variable quantities of CIL 2 in the reac-
tion media. Given the nature of the reaction conditions,
CIL 2 was used either as a solvent or as an additive under
solvent-free conditions (Table 2). In all cases, selectivities
were in the order of 99%. When CIL 2 was used as solvent
Figure 1. Structure of α-amino amide 1 and chiral ionic liquids
[CIL: (S)-proline, equiv. ratio ca. 30] the conversion was
2–4.
80%, and the ee was 77% (entry 5). Using a moderate ex-
For the studies on catalysis, the aldol reaction of p-
nitrobenzaldehyde with acetone (1:30 molar ratio) at room
temperature was selected as the benchmark reaction, using
(S)-proline as the organocatalyst. Originally, a screening of
different solvents was undertaken to compare results using
the same experimental conditions, a 20% catalyst and a vol-
ume of solvent equal to that of acetone (used in excess).
Thus, the reaction was carried out in toluene, DMSO,
water, MeOH, and CH2Cl2 (Table 1) as well as under sol-
vent-free conditions (entry 3). The use of an excess of acet-
one allowed acetone to act as both reagent and solvent for
the second component (aldehyde). After 6 h, conversions of
up to 95%, with selectivities ranging from 89 to 99% and
enantioselectivities of around 70% for the (R)-product were
obtained when nonprotic solvents were used (entries 1–4),
similar to reported results.[5] For comparison, when the ex-
periment was conducted with the well-known nonchiral
ionic liquid BMIM NTf2 as solvent, the conversion and
selectivity were both more than 99% and the ee was 62%;
lower yields and similar ee values were reported for reac-
tions using different ILs as solvent.[8] Finally, the reaction
was carried out with the chiral ionic liquid (CIL 2) as the
solvent. In this case, 80% conversion and 99% selectivity
were obtained and an increase of enantioselectivity was ob-
served (77%; entry 8).
cess of CIL 2 over the catalyst afforded excellent conver-
sions and selectivities without affecting the enantio-
selectivity (entries 3 and 4). However, reducing the amount
Table 2. Aldol reaction between acetone and p-nitrobenzaldehyde
using proline as catalyst and CIL 2 as solvent or additive.[a]
(S)-Proline
(R)-Proline
CIL 2/Pro Conversion ee
Conversion ee
Entry [equiv.]
[%][b]
[%][c]
[%][b]
[%][c]
1
2
3
4
5
0.4
1
3
8
30
90
92
97
99
80
72 (R)
74 (R)
78 (R)
76 (R)
77 (R)
92
95
94
97
78
71 (S)
72 (S)
66 (S)
67 (S)
70 (S)
[a] Reaction conditions: RCHO/acetone/cat. 1:30:0.2, r.t., 6 h. In
all cases, selectivities were higher than 98%. [b] Conversion [%]:
1
determined by H NMR spectroscopic analysis of the crude reac-
tion mixture. [c] Enantiomeric excess was calculated based on
HPLC analysis of enantiomer R (major peak) {ee = [peak area(R) –
peak area (S)] ϫ100/total area (R + S)}.
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FULL PAPER
of CIL 2 to equimolar or lower quantities (entries 1 and 2) (from 97 to 94%), but a further decrease to 5% caused a
was accompanied by a slight decrease in both the yield and strong reduction in conversion, although the enantio-
the ee values. It must be pointed out that when CIL 2 was selectivity remained unchanged. Finally, the effect of the
used as additive, it also acted as a cosolvent and was essen- reaction temperature was investigated. When the reaction
tial for the solubilization of the catalyst. For example, for a temperature was reduced to –25 °C, the conversion de-
3:1 ratio of CIL 2/proline (entry 3), the composition of the creased dramatically to 16% after 6 h, without an increase
mixture is 23 mg proline, 188 mg CIL 2, 106 mg benzalde- in the enantiomeric excess (entry 6). This indicated that the
hyde, and 1.7 g acetone.
yield of the aldol product was dependent on the tempera-
Similar experiments were carried out by using the analo- ture but that the enantioselectivity was essentially insensi-
gous nonchiral IL BMIM (Table 3). In this case, conver- tive to this parameter.[17]
sions initially increased with the amount of IL used, reach-
ing 99% for a IL/(S)-proline, equiv. ratio of 30, and then
decreased when more than 100 equiv. was used. The
enantioselectivity increased from 68 to 76% when more
than 60 equiv. IL was used.[8] These results suggest the for-
mation of supramolecular species with (S)-proline, with its
nature being important for the enantioselectivity of the re-
action.[16] The formation of IL-proline supramolecular spe-
cies in which the functional group of proline interacts in a
specific way with the cation and/or anion of the IL can
modify both the catalytic activity of proline and the nature
and structure of the corresponding transition states (TSs).
This interaction can involve not only proline but also the
whole supramolecular species, and may lead to changes in
both the activity and the enantioselectivity of the system.
Table 4. Aldol reaction between acetone and p-nitrobenzaldehyde
with different loadings of (S)-proline as the catalyst.[a]
Entry
(S)-Proline
[mol-%]
Conversion
[%][b]
Selectivity
[%][b]
ee
[%][c]
1
–
–
–
–
2
3
4
20
15
10
5
97
97
94
69
16
99
99
99
99
97
78
76
77
77
76
5
6[d]
20
Table 3. Aldol reaction between acetone and p-nitrobenzaldehyde
using proline as catalyst in the presence of variable amounts of
BMIM NTf2.[a]
[a] Reaction conditions: RCHO/acetone = 1:30, CIL 2/(S)-proline
1
3:1, r.t., 6 h. [b] Conversion and selectivity [%]: determined by H
NMR spectroscopic analysis of the crude reaction mixture. [c] En-
antiomeric excess calculated based on HPLC analysis of enantio-
mer R (major peak) {ee = [peak area (R) – peak area (S)] ϫ100/
total area (R + S)}. [d] Performed at –25 °C.
In summary, according to the initial results detailed here,
a (S)-proline catalyst loading of 20 mol-% in conjunction
with a 3:1 ratio of CIL 2/Pro were selected as the standard
conditions for further experiments.
Entry
[BMIM]
NTf2/Pro
[equiv.]
(S)-Proline
Conversion
[%][b]
(R)-Proline
ee
Conversion ee
To investigate the activity of the supramolecular complex
that can be formed between the catalyst and the CIL, the
reaction was carried out in the presence of the non-natural
amino acid (R)-proline. The trends observed were different
to those obtained by using the natural amino acid as the
organocatalyst (see columns on the right in Table 2 and 3).
In general, conversions increased when the amount of CIL
increased until a maximum value, after which conversions
started to decrease. With the use of (R)-proline, slightly
lower ee values (for the opposite enantiomer) were obtained
in the presence of CIL 2, and the enantioselectivities ob-
served did not increase with increased amount of CIL 2 as
with (S)-proline (Table 2). Moreover, in this case, similar
enantioselectivities were observed when a nonchiral IL was
used as cosolvent (Tables 2 and 3). Thus, for example, when
(S)-proline was used in conjunction with CIL 2 (3 equiv.)
[%][c]
[%][b]
[%][c]
1
2
3
4
5
6
7
9
0
0.4
1
95
90
94
94
98
99
99
80
71 (R)
68 (R)
67 (R)
62 (R)
61 (R)
62 (R)
76 (R)
76 (R)
90
82
90
92
93
95
95
87
70 (S)
69 (S)
68 (S)
65 (S)
64 (S)
64 (S)
76 (S)
77 (S)
3
10
30
60
100
[a] Reaction conditions: RCHO/acetone/cat. 1:30:0.2, r.t., 6 h. In
all cases, selectivities were higher than 99%. [b] Conversion [%]:
determined by H NMR spectroscopic analysis of the crude reac-
tion mixture. [c] Enantiomeric excess calculated based on HPLC
analysis. For enantiomer R (major peak) {ee = [peak area (R) –
peak area (S)] ϫ100/total area (R + S)}; for enantiomer S (major
peak) {ee = [peak area (S) – peak area (R)] ϫ100/total area (R +
S)}.
1
The effect of the amount of catalyst was also investigated an increase in ee was observed relative to the use of the
using CIL 2 as an additive [CIL 2/(S)-proline, equiv. ratio nonchiral IL (77 vs. 62%), but this phenomenon was not
3:1]. As shown in Table 4, no activity was found in the ab- observed (66 against 65%) when (R)-proline was used (com-
sence of (S)-proline, confirming that proline was the active pare entries 3 and 4 for Tables 2 and 3, respectively). These
catalyst. The amount of proline could be reduced from 20 results suggest the presence of a match/mismatch effect be-
to 10 mol-% with only a slight decrease in the conversion tween the configuration of the proline and that of CIL 2.
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Asymmetric Aldol Reaction in Chiral Ionic Liquids
Figure 2. Linear effects observed for the aldol reaction between acetone and p-nitrobenzaldehyde using CIL 2 and mixtures of (S)- and
(R)-proline.
To further investigate this possible match/mismatch ef- ics for the formation of the (S)-aldol product and, particu-
fect, the aldol reaction was carried out by using mixtures larly, for the corresponding retroaldol process should be
of enantiomerically enriched (S)- and (R)-proline. The cor- much lower. On the other hand, these results also indicate
relation between the ee of the catalyst and that of the aldol that the CIL 2/(R)-proline combination provides a less
product showed a linear correlation for both proline active catalytic system. The formation of different supra-
enantiomers (Figure 2, see also Table S1 and Table S2 of molecular catalytic complexes between CIL 2 and proline
the Supporting Information). However, the slopes for both enantiomers, in which the one formed between CIL 2 and
enantiomers were clearly different. For a given level of en- (R)-proline is more stable and, as a consequence, less active,
antiomeric enrichment in the catalyst, the observed ee was could be the origin of these observations. Moreover, when
always higher for the mixtures enriched in (S)-proline. Thus, the reaction was carried out using (S)-proline and 3 equiv.
for instance, for 80% enriched (S)- and (R)-proline, the ob- CIL 2 in the presence of 20% benzoic acid, which should
served ee values were 63 and 50%, respectively, for the cor- contribute to destroy the CIL 2/(S)-proline supramolecular
responding aldol products (opposite enantiomers).
complexes, the results were similar to those observed in the
The kinetic analysis of the reaction catalyzed by (S)-pro-
line using CIL 2 (CIL 2/Pro equiv. ratio 3:1, Figure 3, see
Table S3 of the Supporting Information), showed that the
reaction was essentially complete after 2 h. However, more
than 6 h were needed for the (R)-proline catalyzed reaction
to reach completion (Figure 3, see Table S4 of the Support-
ing Information). Therefore, this catalyzed aldol reaction
goes through a transition state that is lower in energy when
the CIL 2/(S)-proline catalytic system is used. Interestingly,
the observed enantiomeric excess decreased dramatically in
the presence of (S)-proline for long reaction times (from the
initial 79 to 57%ee after 24 h) whereas for the (R)-proline
only a slight decrease was observed (from 74 to 70%ee).
Surprisingly, no decrease in the enantioselectivity was ob-
served when same reaction was tested at –25 °C after 24 h.
This reduction in the observed ee values for long reaction
times was smaller when (S)-proline was studied in the ab-
sence of CIL 2 (from 71%ee at 6 h to 66%ee after 24 h at
room temperature). These results suggest that the matched
CIL 2/(S)-proline combination not only activates the prefer-
ential formation of the (R)-aldol product but also the pref-
Figure 3. Kinetic curves for the aldol reaction catalyzed by (S)- and
(R)-proline using CIL 2 as additive. Inset: Evolution with time of
the ee for the aldol product. In all cases, selectivities were more
erential retroaldol process from this enantiomer. The kinet- than 97%.
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FULL PAPER
absence of CIL 2, showing an ee of 72% after 6 h reaction, cessive runs. Until the third run, no decrease in activity or
which decreases to 67% after 24 h. enantioselectivity was observed (Table 6). In the fourth run,
After completion of the aldol reaction of p-nitrobenzal- however, a slight decrease in activity and a larger decrease
dehyde with acetone at room temperature using CIL 2/(S)- in enantioselectivity was observed (Table 6, entry 4).
proline (3:1 ratio), the catalytic complex could be reused.
After extraction of the aldol products (after vacuum evapo-
ration of the excess acetone) with diethyl ether, the remain-
ing residue containing the catalytic complex CIL 2/(S)-pro-
line was reused again for three successive runs with essen-
tially no significant decrease in activity, stereoselectivity or
enantioselectivity being observed (Table 5).
Table 6. CIL 2 reuse for the aldol reaction between acetone and p-
nitrobenzaldehyde.[a]
Table 5. Catalyst complex reuse for the aldol reaction between acet-
one and p-nitrobenzaldehyde.[a]
Entry Cycle
Conversion Selectivity
ee
[%][b]
[%][b]
[%][c]
1
2
3
4
1st
97
98
99
90
99
95
98
94
78
73
77
61
2nd
3rd
4th
[a] Reaction conditions: RCHO/acetone/cat. 1:30:0.2, CIL 2/(S)-
Entry
Cycle
Conversion
[%][b]
Selectivity
[%][b]
ee
proline 3:1, r.t., 6 h. [b] Conversion and selectivity [%]: determined
[%][c]
1
by H NMR spectroscopic analysis of the crude reaction mixture.
[c] Enantiomeric excess calculated based on HPLC analysis for
enantiomer R (major peak) {ee = [peak area (R) – peak area (S)]
ϫ100/total area (R + S)}.
1
2
3
4
1st
97
90
85
84
99
94
95
93
78
77
75
76
2nd
3rd
4th
Additional information on the nature of the CIL 2/pro-
[a] Reaction conditions: RCHO/acetone/cat. 1:30:0.2, CIL 2/(S)-
1
line complex was obtained from H NMR and ATR-FTIR
proline 3:1, r.t., 6 h. [b] Conversion and selectivity [%]: determined
1
experiments. 1H NMR spectroscopic data showed that after
the addition of proline, the signals for the N-H and C2-H
protons of CIL 2 underwent a downfield shift, which indi-
cates their involvement in hydrogen-bond interactions with
by H NMR spectroscopic analysis of the crude reaction mixture.
[c] Enantiomeric excess calculated based on HPLC analysis for
enantiomer R (major peak) {ee = [peak area (R) – peak area (S)]
ϫ100/total area (R + S)}.
The recyclability of the chiral IL was also tested. When the added species (Figure 4). Interestingly, the observed
the solid residue obtained after evaporation of the excess shifts are larger for (R)-proline than for (S)-proline, which
of acetone was washed with water to extract the proline, is consistent with stronger hydrogen-bonding interactions
chromatographic purification of the mixture containing the involving these protons between CIL-2 and (R)-proline.
aldol products and the additive, allowed the recovery of
Additionally, ATR-FTIR experiments confirmed the
CIL 2, which could be reused as the additive for four suc- hydrogen bond interaction between both species. In the
1
Figure 4. H NMR spectra in [D6]DMSO of (a) CIL 2, (b) CIL 2 after (S)-proline addition, and (c) CIL 2 after (R)-proline addition. 3:1
CIL 2/proline ratio in b and c. [CIL 2] = 6 mm.
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Asymmetric Aldol Reaction in Chiral Ionic Liquids
FTIR spectra for a solid mixture of CIL 2/(S)-proline (3:1), ular complexes (see Table S5 in the Supporting Infor-
the C2–H, C=O, and S=O stretching bands for CIL 2 mation). These results are consistent with the mechanism
moved slightly to lower wavenumbers in the presence of proposed by Seebach–Eschenmoser for the Michael reac-
proline (i.e., 3068 against 3074 cm–1 and 1679 against tion when (S)-proline or (S)-prolinate were used as cata-
1684 cm–1 for C2–H and C=O, respectively), indicating the lysts.[18]
participation of these groups in hydrogen-bond interactions
To investigate the generality of the current organocata-
(Figure 5). Interestingly, in the solid state, no variation was lytic process, the aldol reaction using several aldehydes was
observed for the amide N–H stretching bands. In accord- also studied using CIL 2 as the additive under optimal con-
ance with the formation of different diastereomeric supra- ditions. As shown in Table 7, the results followed the ex-
molecular complexes for both enantiomers of proline with pected trends for proline-catalyzed aldol reactions.[5a,5c] For
CIL 2, slight differences were observed in the aromatic C– a 6 h reaction time, conversions decreased significantly for
H stretching bands for the two complexes formed between less electrophilic aldehydes, being lower than 10% for p-
CIL 2 and (R)- or (S)-proline [i.e., for the (R)-proline com- methoxybenzaldehyde and p-hydroxybenzaldehyde. Selec-
plex, the C2–H stretching band increases in intensity and tivities were, in general, excellent (96–99%) except for benz-
appears at slight lower wavenumbers; see Figure S1 in the aldehyde itself (85%), whereas enantioselectivities ranged
Supporting Information].
from good to moderate (88–41%ee). As can be observed in
Table 5, reactions carried out in the presence of CIL 2 pro-
vided better conversions and, in most cases, better enantio-
selectivities than when no additive was used. It must be
noted that the increase in conversion is most likely associ-
ated with an improvement in solubility of proline in the
reaction medium in the presence of CIL 2.
Table 7. Aldol reaction between acetone and different aldehydes
using (S)-proline as catalyst and CIL 2 as additive.[a]
Entry
Ar
Additive CIL 2
Conversion ee
No additive
Conversion ee
[%][b]
[%][c]
[%][b]
[%][c]
Figure 5. Partial FTIR spectra of (R)-proline (grey line). Partial
FTIR spectra for CIL 2 in the absence (dotted line) and presence
of 0.3 equiv. (R)-proline (black line).
1
2
3
4
5
6
Ph
46[d]
97
66
88
78
41
82
–
23
95
44
68
trace
0
68
71
65
80
–
4-NO2Ph
4-ClPh
3-ClPh
4-CH3OPh 10
4-OHPh
For comparison, complex 6 was synthesized by anion in-
77
terchange between CIL
5 and lithium (S)-prolinate
(Scheme 1) and evaluated for the same aldol reaction (room
temperature, 20% catalyst loading, 6 h). Good conversions
and selectivities were obtained but a low enantioselectivity
5
–
–
[a] Reaction conditions: RCHO/acetone/cat. 1:30:0.2, CIL 2/(S)-
proline 3:1, r.t., 6 h. In all cases, selectivities were higher than 96%.
(27%) was observed. Thus, our previous results cannot be [b] Conversion [%]: determined by 1H NMR spectroscopic analysis
of the crude reaction mixture. [c] Enantiomeric excess calculated
attributed to partial formation of the corresponding salts.
based on HPLC analysis for enantiomer R (major peak) {ee =
[peak area (R) – peak area (S)] ϫ100/total area (R + S)}. [d] Selec-
Indeed, when the aldol reaction was run in the presence of
an acid additive (20% benzoic acid), the conversion de-
tivity 85%.
creased to 21% and the ee increased to 67%. When the
reaction with 5 was carried out in the presence of catalytic
amounts of the organic base 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU), the enantioselectivity decreased further to 5%.
Thus, the prolinate species seem to be much less enantiose-
The feasibility of using other ketones as aldol donors
using CIL 2 as additive was also investigated. The aldol
reaction between cyclohexanone and p-nitrobenzaldehyde
using 20% (S)-proline as catalyst in the presence of CIL 2
lective than those associated with the proline supramolec-
[CIL 2/(S)-proline, 3:1] provided good conversion (76%) af-
ter 6 h reaction, moderate diastereoselectivity (79:21,
anti/syn), and good ee values for both enantiomers (77 and
86%, respectively). It must be pointed out that the observed
diastereoselectivity was significantly higher than that re-
ported for the use of (S)-proline under the same solvent-
free experimental conditions (50:50, anti/syn)[12] or using
DMSO as solvent (63:37, anti/syn).[5c] A considerable in-
Scheme 1. Synthesis of complex 6.
Eur. J. Org. Chem. 2014, 5356–5363
crease in the diastereoselectivity and ee has been reported
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5361

L. González, J. Escorihuela, B. Altava, M. I. Burguete, S. V. Luis
FULL PAPER
perature. After filtration to remove LiCl, the solvent was evapo-
rated and catalyst 6 (0.12 g, 98%) was obtained as a yellow oil.
[α]2D5 = –14.3. 1H NMR (500 MHz, CD3OD): δ = 7.81 (s, 1 H), 7.77
(s, 1 H), 7.40–7.32 (m, 5 H), 4.67 (d, J = 9.8 Hz, 1 H), 4.52 (d, J
= 14.7 Hz, 1 H), 4.42 (d, J = 14.6 Hz, 1 H), 4.33 (t, J = 7.3 Hz, 2
H), 3.68–3.62 (m, 1 H), 3.25–3.19 (m, 1 H), 2.91 (dt, J = 10.8,
7.1 Hz, 1 H), 2.58–2.49 (m, 1 H), 2.21 (dd, J = 12.7, 7.7 Hz, 1 H),
1.98–1.91 (m, 3 H), 1.84 (dt, J = 13.2, 6.6 Hz, 2 H), 1.41 (m, J =
14.8, 7.4 Hz, 2 H), 1.10 (d, J = 6.6 Hz, 3 H), 1.05 (t, J = 7.4 Hz, 3
H), 0.92 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (126 MHz, CD3OD):
with the use of chiral or no chiral additives for this aldol
reaction.[10i,10l,12]
Finally, the influence of the steric bulk of the amino acid
residue present in CIL on the catalytic results was investi-
gated under the optimized reaction conditions between
acetone and p-nitrobenzaldehyde. As reported by other au-
thors, the steric bulk around the chiral carbon atom or the
nitrogen atom in chiral ligands derived from amino acids
generally enhances the enantioselectivity of the process.[19]
Thus, CILs derived from (S)-valine, (S)-phenylalanine, and δ = 168.7, 139.2, 129.6, 129.0, 128.6, 123.7, 123.4, 70.1, 62.8, 50.9,
(S)-leucine were used in the model reaction;[14] however, no
significant differences were detected in the enantio-
selectivity (Table S6 in the Supporting Information). This
observation suggests that the nature of the amino acid side
48.8, 47.2, 44.5, 33.2, 33.0, 31.0, 25.7, 20.4, 19.2, 18.7, 13.7 ppm.
MS (ESI+): m/z (%) = 314.0 (100) [M+]. MS (ESI–): m/z (%) =
114.0 (100) [M–]. C24H36N4O3 (428.57): calcd. C 67.26, H 8.47, N
13.07; found C 66.88, H 8.88, N 12.92.
General Procedure for the Aldol Reactions: (S)-Proline (20 mol-%)
and the corresponding CIL were mixed in either acetone or cyclo-
hexanone (30 mmol). After stirring for 10 min, aromatic aldehyde
(1 mmol) was added and the reaction mixture was stirred at room
temperature (25 °C) for 6 h, following the reaction by TLC (EtOAc/
hexane, 33%). After this time, the acetone was evaporated and the
residue was extracted with diethyl ether (3ϫ 3 mL). The remaining
CIL/proline complex was dried under vacuum at 40 °C for 5 h for
use in the next cycle. The collected solvent was evaporated and the
crude material was analyzed to determine conversion and selectiv-
ity, and then purified by chromatography on a silica gel column
(EtOAc/hexane, 33%) to give the aldol product. The ee was deter-
mined by HPLC analysis, using Chiralpak AD (benzaldehyde, 3-
chlorobenzadehyde, 4-chlorobenzaldehyde, 4-nitrobenzaldhyde: cy-
clohexanone products) or Chiralcel OJ (4-nitrobenzaldehyde prod-
uct) columns.
chain has a minor influence in the enantioselectivity of the
final product.
Conclusions
We have found that chiral room temperature ionic liquids
derived from amino acids can be efficiently used as solvents
or additives for direct enantioselective aldol reactions.
These additives seem to form supramolecular complexes
with the catalyst, leading to an improvement in the enantio-
selectivity of the aldol reaction between p-nitrobenzalde-
hyde and acetone (78 against 62% using CIL 2 or
BMIM NTf2 as additives, respectively). Up to four catalytic
cycles were performed without any significant decrease in
activity or selectivity, using the same conditions, with the
same CIL 2/(S)-proline complex, recovered after a simple
workup. A match/mismatch effect between the configura-
tion of CIL 2 and that of proline, has been observed, with
the enantioselectivity observed being higher for the (S)-
proline/CIL 2 complex. Thus, our results provide an attract-
ive alternative method for the efficient enantioselective syn-
thesis of β-hydroxy ketones. The observed transfer of chiral-
ity from the chiral media is encouraging for the develop-
1
4-Hydroxy-4-(4-nitrophenyl)butan-2-one:[12] Yield 94% (0.19 g). H
NMR (500 MHz, CDCl3): δ = 8.21 (d, J = 8.4 Hz, 2 H), 7.54 (d,
J = 8.4 Hz, 2 H), 5.26 (dd, J = 8.0, 4.0 Hz, 1 H), 2.85 (d, J = 7.7 Hz,
2 H), 2.22 (s, 3 H) ppm. The enantioselectivity of the reaction was
determined by HPLC (Chiralcel OJ column; Hex/IPA (90:10); flow:
0.75 mLmin–1; T: 30 °C; λ: 254 nm): tR = 36.2 (R), 41.0 (S) min.
2-[Hydroxy(4-nitrophenyl)methyl]cyclohexan-1-one:[12] Yield 55%
1
(0.14 g); anti isomer. H NMR (500 MHz, CDCl3): δ = 8.13 (d, J
= 8.5 Hz, 1 H), 7.44 (d, J = 8.5 Hz, 2 H), 5.41 (s, 1 H, CH, syn),
ment of other chiral ionic liquids, designed to provide spe- 4.83 (d, J = 8.3 Hz, 1 H, CH, anti), 2.26–2.53 (m, 4 H), 1.32–1.78
(m, 5 H) ppm. The enantioselectivity of the reaction was deter-
mined by HPLC (Chiralpak AD column; Hex/IPA (90:10); flow:
1 mLmin–1; T: 30 °C; λ: 254 nm): tR = 18.2 and 23.1 (syn) min;
24.7 (2S,1ЈR) and 33.6 (2R,1ЈS) (anti) min.
cific interactions with the corresponding organocatalysts.
Experimental Section
4-Hydroxy-4-phenylbutan-2-one:[5c] Yield 34% (55 mg). 1H NMR
(500 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 5.16 (dd, J = 9.1,
3.2 Hz, 1 H), 2.88 (dd, J = 25.6, 16.5 Hz, 2 H), 2.20 (s, 3 H) ppm.
The enantioselectivity of the reaction was determined by HPLC
(Chiralpak AD column; Hex/IPA (95:5); flow: 0.75 mLmin–1; T:
30 °C; λ: 210 nm): tR = 17.3 (R), 19.0 (S) min.
General: All reagents were purchased from commercial suppliers
and used as received. Chiral α-amino amides were synthesized as
described previously;[13] all the N-protected amino acids were com-
mercially available. The synthesis of chiral room temperature ionic
liquids has been described.[14] The NMR spectroscopic experiments
were carried out at 500 or 125 MHz for 1H and 13C NMR, respec-
tively. The chemical shifts are reported using trimethylsilane as the
internal standard. FTIR spectra were acquired with a MIRacle sin-
gle-reflection ATR diamond/ZnSe accessory.
4-Hydroxy-4-(4-chlorophenyl)butan-2-one:[20] Yield 60% (0.12 g).
1H NMR (500 MHz, CDCl3): δ = 7.29 (m, 4 H), 3.63 (s, 1 H), 5.06
(dd, J = 8.4, 3.9 Hz, 1 H), 2.80–2.68 (m, 2 H), 2.12 (s, 3 H) ppm.
The enantioselectivity of the reaction was determined by HPLC
(Chiralpak AD column; Hex/IPA (95:5); flow: 0.75 mLmin–1; T:
30 °C; λ: 210 nm): tR = 17.0 (R), 18.9 (S) min.
Synthesis of Catalyst 6: A solution of LiOH (7.68 mg, 0.3 mmol)
and (S)-proline (0.037 g, 0.3 mmol) in anhydrous MeOH (5 mL)
was stirred for 2 h at room temperature. A solution of CIL 5
(0.122 g, 0.3 mmol; synthesized by following the general synthetic
methodology described by our group for the preparation of related
imidazolium salts[14]) in anhydrous MeOH (5 mL), was added. The
reaction mixture was stirred for 1 h at 0 °C and 20 h at room tem-
4-Hydroxy-4-(3-chlorophenyl)butan-2-one:[21] Yield 70% (0.14 g).
1H NMR (500 MHz, CDCl3): δ = 7.38–7.18 (m, 4 H), 5.07 (dd, J
= 8.4, 3.9 Hz, 1 H), 2.77–2.75 (m, 2 H), 2.13 (s, 3 H) ppm. The
enantioselectivity of the reaction was determined by HPLC (Chi-
5362
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5356–5363

Asymmetric Aldol Reaction in Chiral Ionic Liquids
ralpak AD column; Hex/IPA (95:5); flow: 0.75 mLmin–1; T: 30 °C;
λ: 210 nm): tR = 20.8 (R), 23.2 (S) min.
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Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for catalyst 6, and chiral HPLC
chromatograms.
Acknowledgments
This work was supported by the Spanish Ministerio de Ciencia
e Innovación (MICINN) (grant number CTQ2011-28903-C02-01),
Generalitat Valenciana PROMETEO/2012/020 and accompGV-/
2013/207 and Universitat Jaume I (P11B2013-38).
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Received: April 17, 2014
Published Online: July 17, 2014
Eur. J. Org. Chem. 2014, 5356–5363
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5363