Cinchona-derived prolinamide in Br?nsted acidic ionic liquids: A novel and recyclable catalytic system for asymmetric aldol reaction

Article abstract of DOI:10.1016/j.cattod.2015.10.004

Cinchonine-derived prolinamide in Br?nsted acidic ionic liquids was utilized for the first time as a novel and recyclable catalytic system for the asymmetric direct aldol reaction of acetone with aromatic aldehydes. The effects of the Br?nsted acidity and amount of ionic liquid, co-solvents, catalyst amount, and reaction temperature on the catalytic activity and enantioselectivity were studied in detail. Good to high yields and ee values were achieved for the aldol reaction of various aromatic aldehydes with neat acetone in 1-methylimidazolium tetrafluoroborate ([Hmim]⁺BF₄^-) in the presence of 10 mol% of catalyst at room temperature. [Hmim]⁺BF₄^- was also identified as a Br?nsted acid additive for the reaction and beneficial to the enhancement of catalytic performance. Moreover, the enhanced interaction between prolinamide and acidic ionic liquid facilitated the recoverability and reusability of organocatalyst. The catalyst recycling experiments indicated that there was only a slight loss in activity and enantioselectivity after four runs.

Full text of DOI:10.1016/j.cattod.2015.10.004

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Catalysis Today
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Cinchona-derived prolinamide in Brønsted acidic ionic liquids: A
novel and recyclable catalytic system for asymmetric aldol reaction
Lan-Lan Loua,b, Jiong Zhanga,b, Huanling Dua,b, Bo Zhaoa,b, Shanshan Lia,b, Wenjun Yua,b
,
Kai Yuc, Shuangxi Liua,b,d,∗
a Institute of New Catalytic Materials Science and Key Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), School of Materials
Science and Engineering, Nankai University, Tianjin 300071, China
b National Institute for Advanced Materials, Nankai University, Tianjin 300071, China
c College of Environmental Science and Engineering, Nankai University, Tianjin 300071, China
d Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Cinchonine-derived prolinamide in Brønsted acidic ionic liquids was utilized for the first time as a novel
and recyclable catalytic system for the asymmetric direct aldol reaction of acetone with aromatic alde-
hydes. The effects of the Brønsted acidity and amount of ionic liquid, co-solvents, catalyst amount, and
reaction temperature on the catalytic activity and enantioselectivity were studied in detail. Good to high
yields and ee values were achieved for the aldol reaction of various aromatic aldehydes with neat acetone
in 1-methylimidazolium tetrafluoroborate ([Hmim]+BF4−) in the presence of 10 mol% of catalyst at room
Received 15 May 2015
Received in revised form
11 September 2015
Accepted 10 October 2015
Available online xxx
temperature. [Hmim]+BF4 was also identified as a Brønsted acid additive for the reaction and beneficial
−
Keywords:
to the enhancement of catalytic performance. Moreover, the enhanced interaction between prolinamide
and acidic ionic liquid facilitated the recoverability and reusability of organocatalyst. The catalyst recy-
cling experiments indicated that there was only a slight loss in activity and enantioselectivity after four
Asymmetric aldol reaction
Brønsted acidic ionic liquid
Organocatalysis
runs.
Prolinamide
© 2015 Elsevier B.V. All rights reserved.
1. Introduction
in an attempt to improve the catalytic activity and enantioselec-
tivity [11–17]. For example, Xiao et al. [18] reported a new kind
Organocatalysis, the third pillar in the field of asymmetric catal-
ysis, has recently received extensive attention due to the low cost
and toxicity of organocatalysts, as well as their easy handling
and utilization as compared with enantioselective transition-metal
catalysts [1–3]. The asymmetric direct aldol reaction is one of
the most powerful carbon-carbon bond forming processes for
the synthesis of enantiomerically pure ␤-hydroxy ketones, which
are highly valuable building blocks and intermediates in organic
synthesis and pharmaceutical industry [4–8]. Since the proline-
catalyzed direct aldol reaction was firstly reported by List and
Barbas III [9,10], organocatalyzed aldol reaction has remained an
active research area in the field of asymmetric catalysis. Over the
past few years, a wide variety of organocatalysts, especially proline
derivatives, have been developed for asymmetric aldol reactions
of organocatalysts for the asymmetric direct aldol reactions by
the combination of proline with cinchona alkaloids, and high iso-
lated yields and enantioselectivities were obtained in the presence
of the Brønsted acid additives. However, the difficulties in cata-
lyst recycling and product separation under homogeneous catalytic
system often hinder the practical applications of these organocat-
alysts. Consequently, the development of practical, efficient and
easily recoverable organocatalysts is highly desirable. Considerable
efforts have been spent in the last decade on the immobilization of
proline and its derivatives by using various supports, such as inor-
ganic materials [19–25], organic polymers [26–31] and ionic liquids
[32–37], to achieve a simplified separation of the catalyst from the
product.
More recently, ionic liquids have attracted considerable inter-
est as environmentally benign media in the synthesis and catalysis
owing to their unique properties such as unusual dissolution abil-
ity, enormous diversity, high thermal stability and recyclability
[38–42]. They have also been employed as green and recoverable
solvents for direct asymmetric aldol reactions. Since Loh et al. [43]
and Toma et al. [44] independently reported the use of ionic liquid
∗
Corresponding author at: Institute of New Catalytic Materials Science and Key
Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), School
of Materials Science and Engineering, Nankai University, Tianjin 300071, China.
E-mail address: sxliu@nankai.edu.cn (S. Liu).
http://dx.doi.org/10.1016/j.cattod.2015.10.004
0920-5861/© 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: L.-L. Lou, et al., Cinchona-derived prolinamide in Brønsted acidic ionic liquids: A novel and recyclable
catalytic system for asymmetric aldol reaction, Catal. Today (2015), http://dx.doi.org/10.1016/j.cattod.2015.10.004

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N
N
H
N
N
NH
H2N
HO
1. N-Boc-Proline, DCC
2. TFA/CH2Cl2
O
N
N
N
cinchonine
9-amino epi-cinchonine
1
Scheme 1. Synthesis of cinchonine-derived prolinamide catalyst 1.
[Bmim]+PF6− (Bmim = 1-butyl-3-methylimidazolium) as solvent in
the proline-catalyzed aldol reactions in 2002, some research about
aldol reactions in ionic liquid phases catalyzed by proline and its
derivatives have been documented [45–51]. These organocatalysts
indeed can be recycled and reused for several times, while moder-
ate isolated yields and enantiomer excess (ee) values were usually
achieved.
H
N
N
0-5 oC
L
+
HL
N
N
CH3
CH3
L-: BF4 , CH3COO-, CH3CH(OH)COO-, HSO4 , Cl-
-
-
Herein we wish to explore the use of Brønsted acidic ionic liq-
uids in catalytic asymmetric aldol reaction by cinchonine-derived
prolinamide catalyst. The ionic liquids here not only provided a
recyclable solvent system, but also acted as Brønsted acid additives,
which were known to be of great importance for the activation
of the aldol acceptor in the enamine-based organocatalytic asym-
metric aldol reaction [5,9,14,15,18]. Moreover, the catalyst was
expected to be well confined in ionic liquids in view of the acid–base
interaction between ionic liquid and prolinamide. To the best of our
knowledge, this is the first report on the utilization of chiral proli-
namide catalyst dissolved in Brønsted acidic ionic liquids for aldol
reaction. In the absence of any other acid additives, this catalytic
system was found to be highly efficient and enantioselective for the
asymmetric aldol reaction of acetone with various aromatic alde-
hydes. Furthermore, the catalyst in ionic liquid was very stable and
could be reused four times with only a slight loss in activity and
enantioselectivity.
Scheme 2. Synthesis of Brønsted acidic ionic liquids.
(m, 5H), 4.79 (d, J = 8.1 Hz, 1H), 5.01–5.04 (m, 2H), 5.87 (m, 1H),
7.54–8.36 (m, 5H), 8.91 (d, J = 4.5 Hz, 1H).
A typical procedure for the synthesis of cinchonine-derived pro-
linamide organocatalyst was carried out as follows [18]. To a stirred
solution of N-t-butyloxycarbonyl-d-proline (1.1 g, 5.1 mmol) in
dry dichloromethane (40 mL) at 0 ◦C, DCC (1.05 g, 5.1 mmol) was
added. The reaction mixture was left stirring for 30 min and then,
a solution of 9-amino epi-cinchonine (1.0 g, 3.4 mmol) in dry
dichloromethane (10 mL) was added dropwise. The reaction mix-
ture was warmed to room temperature and left stirring for 12 h.
After filtration, the solvent was evaporated under reduced pressure
and the crude product was purified using column chromatography
on silica gel eluting with ethyl acetate/methanol (4:1) to afford
the product as a white solid. Then, this solid was dissolved in
a mixture of TFA/dichloromethane (1:4, 15 mL) with stirring at
0 ◦C and the reaction solution was allowed to come to room tem-
perature. After 2 h, concentrated aqueous ammonia was added to
quench the reaction and the resulting solution was extracted with
dichloromethane (20 mL 3×). The organic fractions were combined,
dried over anhydrous sodium sulfate, filtered, and the solvent was
evaporated under reduced pressure. The crude product was puri-
fied using column chromatography on silica gel eluting with ethyl
acetate/methanol (2:1). The purified 1 was isolated as a white solid
(1.04 g, 78% yield over two steps). 1H NMR (CDCl3, 300 MHz) ı
(ppm) 0.98–1.04 (m, 1H), 1.25–1.30 (m, 1H), 1.53–1.67 (m, 6H),
1.98–2.05 (m, 1H), 2.25–2.38 (m, 1H), 2.84–2.90 (m, 1H), 2.98–3.06
(m, 5H), 3.17–3.22 (m, 1H), 3.74–3.77 (m, 1H), 5.13–5.18 (m, 2H),
5.46–5.49 (m, 1H), 5.86–5.95 (m, 1H), 7.38 (d, J = 3.6 Hz, 1H), 7.61
(t, J = 5.4 Hz, 1H), 7.74 (t, J = 5.4 Hz, 1H), 8.13 (d, J = 6.3 Hz, 1H),
8.36–8.43 (m, 2H), 8.88 (d, J = 3.6 Hz, 1H).
2. Experimental
2.1. General
N-t-Butyloxycarbonyl-d-proline
(AR),
N,Nꢀ-
dicyclohexylcarbodiimide (DCC, AR), aromatic aldehydes (AR),
trifluoroacetic acid (TFA, AR), 1-methylimidazole (AR) and
tetrafluoroboric acid (AR, 40%) were purchased from Aladdin
Chemistry Co., Ltd. Cinchonine was provided by Shanghai Ruji
Biotechnology Co., Ltd. Dichloromethane and chloroform were
distilled from calcium hydride. Tetrahydrofuran (THF) was dried
over sodium/benzophenone. All other materials were purchased
from common commercial sources and used without further
purification.
1H NMR spectrum was recorded on a Varian Mercury Vx-300
(300 MHz) spectrometer using tetramethylsilane as an internal
reference. The UV–vis absorption spectra were recorded on a
Shimadzu UV-2550 UV–vis spectrophotometer. ee values were
determined by HPLC with a chiral AS-H column, using an Agilent-
1200 chromatograph equipped with a VWD detector.
2.3. Synthesis of Brønsted acidic ionic liquids [Hmim]+L−
The Brønsted acidic ionic liquids were synthesized as shown
in Scheme 2. In a typical process [53,54], a 100 mL three necked,
round-bottom flask was charged with 1-methylimidazole (6.15 g,
75 mmol), which was allowed to cool to 0 ◦C in an ice bath with
stirring. Then 40% aqueous tetrafluoroboric acid (75 mmol) was
added at a rate sufficient to maintain the reaction temperature
at 0–5 ◦C. After continuous stirring for another 2 h, water was
evaporated under reduced pressure to afford the desired prod-
uct 1-methylimidazolium tetrafluoroborate ([Hmim]+BF4−) as a
2.2. Synthesis of cinchonine-derived prolinamide catalyst 1
Firstly, as shown in Scheme 1, 9-amino epi-cinchonine was
synthesized from cinchonine according to the literature [52]. 1H
NMR (CDCl3, 300 MHz): ı (ppm) 0.85–0.99 (m, 1H), 1.08–1.15 (m,
1H), 1.48–1.60 (m, 3H), 2.05 (s, 2H), 2.24–2.26 (m, 1H), 2.90–3.10
Please cite this article in press as: L.-L. Lou, et al., Cinchona-derived prolinamide in Brønsted acidic ionic liquids: A novel and recyclable
catalytic system for asymmetric aldol reaction, Catal. Today (2015), http://dx.doi.org/10.1016/j.cattod.2015.10.004

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Table 1
3
0.6
Calculation of H0 of different Brønsted acidic ionic liquids.
Ionic liquid
ABSmax
[I] (%)
[HI+] (%)
H0
a: blank
a
0.5
0.4
b: [Hmim]+CH3CH(OH)COO-
b
Blank
0.541
0.502
0.473
0.411
0.318
0.252
100
0
7.2
12.6
24.0
41.2
53.4
−
c
[Hmim]+CH3CH(OH)COO−
[Hmim]+CH3COO−
92.8
87.4
76.0
58.8
46.6
2.10
1.83
1.49
1.14
0.93
c: [Hmim]+CH3COO-
d: [Hmim]+BF4-
d
−
[Hmim]+BF4
[Hmim]+Cl−
e: [Hmim]+Cl-
e
f
0.3
0.2
0.1
0.0
−
[Hmim]+HSO4
f: [Hmim]+HSO4-
Table 2
Asymmetric aldol reaction of 4-nitrobenzaldehyde with acetone in different ionic
liquids.a
O
OH
*
O
O
H
1/ionic liquid
+
300
400
500
600
700
800
r.t.
O2N
Entry
Wavelength (nm)
O2N
Yield (%)b
Conv. (%)
ee (%)c
Fig. 1. UV–vis absorption spectra of 4-nitroaniline in different Brønsted acidic ionic
Ionic liquid
[Hmim]+BF4
t (h)
liquids.
−
1
2
3
4
5
36
24
6
48
48
65
74
–
<5
<5
>99
>99
>99
–
51
44
65
–
[Hmim]+CH3CH(OH)COO−
[Hmim]+CH3COO−
[Hmim]+Cl−
colorless liquid. 1H NMR (DMSO, 300 MHz) ı (ppm) 3.82 (s, 3 H),
7.51 (t, 1H), 7.57 (t, 1H), 8.78 (s, 1H).
[Hmim]+HSO4
–
–
−
Other four ionic liquids including [Hmim]+CH3COO−,
a
[Hmim]+CH3CH(OH)COO−, [Hmim]+HSO4
and [Hmim]+Cl−
−
Reactions were performed with 0.3 mmol of 4-nitrobenzaldehyde and 0.5 mL of
acetone and 2.0 mL of ionic liquid in the presence of 10 mol% of 1 at room tempera-
were synthesized by following the same procedure as above
except that acetic acid, lactic acid, sulfuric acid and hydrochloric
acid were utilized, respectively, instead of tetrafluoroboric acid.
ture.
b
Isolated yield.
c
ee % were determined by HPLC. The absolute configuration was S.
2.4. Asymmetric aldol reaction of acetone with aromatic
aldehydes
liquids was calculated. As listed in Table 1, the type of anions has
great effect on the acidities of ionic liquids. [Hmim]+HSO4− exhibits
a stronger Brønsted acidity than the other four ionic liquids, and
the Brønsted acidity of [Hmim]+CH3CH(OH)COO− is relatively
weak. The Brønsted acidity order of the ionic liquids is as follows:
[Hmim]+HSO4− > [Hmim]+Cl− > [Hmim]+BF4− > [Hmim]+CH3COO−
> [Hmim]+CH3CH(OH)COO−.
A typical procedure for the asymmetric aldol reaction was as
follows. To a stirred solution of catalyst 1 (0.03 mmol) in ionic liq-
uid (2.0 mL), acetone (0.5 mL) was added. The reaction mixture was
stirred at room temperature for 30 min. The aldehyde (0.3 mmol)
was then added and the reaction continued at room temperature.
As the reaction was complete as determined by TLC, the reaction
mixture was extracted by diethyl ether (5 mL 3×), and the com-
bined organic layer was concentrated in vacuo and purified using
column chromatography on silica gel eluting with the appropriate
mixture of ethyl acetate/petroleum ether to afford the pure aldol
product. The remaining ionic liquid phase containing catalyst 1 was
dried in vacuo and subjected to the next run.
3.2. Asymmetric aldol reaction with different acidic ionic liquids
The direct aldol reaction of 4-nitrobenzaldehyde with acetone
catalyzed by 1 in different acidic ionic liquids was car−ried out and
the results are listed in Table 2. When [Hmim]+BF4 was used,
the reaction proceeded to completion in 36 h to afford the product
in 65% yield and 51% ee. As compared with [Hmim]+BF4−, higher
catalytic activity while lower enantioselectivity were achieved
for the aldol reaction with ionic liquid [Hmim]+CH3CH(OH)COO−
(Table 2, entry 2). Among the ionic liquids investigated, the
utilization of [Hmim]+CH3COO− led to the best catalytic perfor-
mance. In [Hmim]+CH3COO−, the reaction completed within 6 h
to give the product in 65% ee. Very low catalytic activity was
3. Results and discussion
3.1. Brønsted acidities of ionic liquids
The Brønsted acidities of ionic liquids were evaluated by
determining the Hammett acidity functions (H0) using UV–vis spec-
troscopy [55,56]. The Hammett function (H0) is defined as
produced when the other two ionic liquids, [Hmim]+HSO4 and
−
[Hmim]+Cl−, were used. These results indicate that the catalytic
performance is closely related to the ionic liquid acidity, and that
a suitable Brønsted acidity level has a beneficial effect on the cat-
alytic performance. Higher activity and enantioselectivity can be
achieved when [Hmim]+CH3COO− was employed. And the reac-
tions both in stronger and weaker acidic ionic liquids gave inferior
catalytic performance. However, it should be noted that when
[Hmim]+CH3COO− was employed, the separation of the reaction
products from this ionic liquid phase was unsuccessful by extrac-
tion with various organic solvents. While for other four ionic
liquids, the reaction products could be readily separated by solvent
extraction from the ionic liquid phase and the catalyst 1 retained in
ionic liquids could be reused. With regard to bot−h the catalytic per-
formance and catalyst reusability, [Hmim]+BF4 was identified as
H0 = pK(I)aq + log([I]s/[IH+]s)
where pK(I)aq is the pKa value of the indicator referred to an
aqueous solution, [I]s and [IH+]s are the molar concentrations of
unprotonated and protonated forms of the indicator in the solvent,
respectively.
The Brønsted acidities of different ionic liquids were deter-
mined with 4-nitroaniline (pK(I)aq = 0.99) as indicator and ethanol
as solvent. As shown in Fig. 1, the maximum absorbance of the
unprotonated form of the indicator can be observed at 372 nm
in ethanol, which decreased with the addition of ionic liquids,
indicating that the indicator was partially in the form as [IH+].
Thus the [I]/[IH+] ratio could be determined from the measured
absorbances, and then the Hammett function H0 of different ionic
Please cite this article in press as: L.-L. Lou, et al., Cinchona-derived prolinamide in Brønsted acidic ionic liquids: A novel and recyclable
catalytic system for asymmetric aldol reaction, Catal. Today (2015), http://dx.doi.org/10.1016/j.cattod.2015.10.004

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Table 3
Asymmetric aldol reaction of 4-nitrobenzaldehyde with acetone under different conditions.a
−
Entry
Amount of [Hmim]+BF4 (mL)
T (◦C)
Amount of 1 (mol%)
t (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
1.0
2.0
3.0
1.0
1.0
1.0
1.0
Rt
Rt
Rt
0
40
Rt
Rt
10
10
10
10
10
5
24
36
48
24
24
24
24
66
65
59
22
65
15
68
60
51
51
57
51
54
62
15
a
Reactions were performed with 0.3 mmol of 4-nitrobenzaldehyde and 0.5 mL of acetone.
Table 4
Table 5
Asymmetric aldol reaction of acetone to 4-nitrobenzaldehyde with various co-
Asymmetric aldol reaction of 4-nitrobenzaldehyde with acetone in different
solvents.a
conditions.a
Entry
Co-solvent
Yield (%)
ee (%)
Entry
Ionic liquid
Acid additiveb
Yield (%)
ee (%)
[Hmim]+BF4
–
–
–
–
80
78
39
77
81
75
67
44
45
62
65
65
−
−
1
2
3
4
5
6
7
8
9
Acetone
CH2Cl2
CHCl3
THF
Et2O
DMF
DMSO
CH3CN
MeOH
H2O
80
67
75
80
78
56
49
65
36
70
67
67
59
64
55
62
56
46
62
57
1
2
3
4
5
6
[Bmim]+BF4
−
[Hmim]+BF4−
[Hmim]+BF4−
[Hmim]+BF4
Benzoic acid
Catechol
Acetic acid
a
Reactions were performed with 0.3 mmol of aromatic aldehyde and 1.0 mL of
acetone in 1.0 mL of ionic liquid in the presence of 10 mol% of 1 at room temperature
for 24 h.
10
b
The amount of acid additive was 10 mol%.
a
Reactions were performed with 0.3 mmol of aromatic aldehyde, 0.5 mL of ace-
−
tone and 0.5 mL of co-solvent in 1.0 mL of [Hmim]+BF4 in the presence of 10 mol%
utilization of the co-solvents with relatively low polarity, such as
THF, acetone, Et2O, CHCl3, and CH2Cl2, generally led to the enhance-
ment of isolated yields. For example, an increase in yield from 66%
to 80% was achieved when THF or acetone was used as co-solvent.
Improved ee values were produced with the addition of acetone,
CH2Cl2 and THF, while inferior enantioselectivities were presented
by using Et2O and CHCl3 as co-solvents. The utilization of highly
polar organic solvents showed a negative effect on the catalytic
activities (Table 4, entries 6–9). Among all the co-solvents studied,
polar protic solvent MeOH gave the lowest activity, which may be
due to the detrimental effect of alcoholic solvents on the hydrogen
bonding interaction between the catalyst and the substrate. It could
be also observed that a lower ee of 46% was obtained when CH3CN
was selected. Besides the organic solvents, water as a green solvent
was also applied in the reaction, and a good yield of 70% with an
ee of 57% was achieved. Thus acetone was considered as the most
suitable one among the co-solvents examined with regard to both
the yield and enantioselectivity, and the corresponding reaction
afforded the product in 80% yield and 67% ee.
of 1 at room temperature for 24 h.
the suitable acidic ionic liquid and was selected for further studies
to optimize the reaction conditions.
3.3. Effects of reaction conditions on the asymmetric aldol
reaction
The effect of ionic liquid amount on the catalytic activity and
enantioselectivity for direct aldol reaction was investigated. As
shown in Table 3, with the increase of the amount of [Hmim]+BF4
,
−
the reaction proceeded more slowly, meanwhile, the yield and ee
value decreased gradually, which may be explained by the rel-
atively higher diffusional resistance in the reaction system. An
optimum result with 66% yield and 60% ee was achieved in 24 h
as the reaction was operated using 1.0 mL of ionic liquid.
The effects of reaction temperature and catalyst amount on the
catalytic performance are also displayed in Table 3. It could be found
that the catalytic activity increased remarkably with the increasing
of reaction temperature. A much lower yield of 22% was obtained
as the reaction was carried out at 0 ◦C for 24 h with an ee value of
57%. The reaction at room temperature furnished the aldol product
in 66% yield and 60% ee. A further increase in reaction temperature
to 40 ◦C led to a lower ee of 51%. Thus the following reactions in
the present work were all conducted at room temperature. The
data listed in Table 3 also revealed that the catalyst amount had a
significant effect on the catalytic activity for the asymmetric aldol
reaction. A pronounced increase in yield from 15% to 66% could
be observed when the catalyst amount was increased from 5 mol%
to 10 mol%, while the enantioselectivity was found not to depend
markedly on the catalyst amount. Further increasing the catalyst
amount caused no obvious enhancement in yield as well as in ee
value (Table 3, entry 7). It should be noted that the catalyst amount
of 10 mol% was three times lower with respect to the use of proline
in the previous reports [9,35,36,43,44].
The Brønsted acid additive was considered to be important
to facilitate the enamine-based organocatalytic asymmetric aldol
reaction [5,9,14,15,18]. The ionic liquid [Hmim]+BF4−, as a strong
Brønsted acid, acts here not only as a solvent, but also as a Brønsted
acid additive for the reaction. In order to investigate the effect
of Brønsted acidic ionic liquids on the catalytic performance, the
reaction without any ionic liquids was performed under other-
wise identical conditions. As shown in Table 5, a high yield of 78%
and a low ee of 44% were achieved. This indicates that the asym-
metric aldol reaction between 4-nitrobenzaldehyde and acetone
can occur with relatively low enantioselectivity in the presence
of prolinamide catalyst 1 without any acid additive, which is
in accordance with that reported in the literature [18]. For the
purpose of comparison, a neutral iminazolium-based ionic liquid
[Bmim]+BF4 was also synthesized according to the method we
−
previously reported [57] and applied in the asymmetric aldol reac-
tion of 4-nitrobenzaldehyde with acetone. It could be found that the
reaction in [Bmim]+BF4− proceeded very slowly, and a low yield of
39% along with a relatively low ee of 45% was obtained after 24 h
(Table 5, entry 3). This documented that the introduction of com-
mon ionic liquids had no positive effect on the enantioselectivity
In attempt to further improve the catalytic activity and enan-
tioselectivity, co-solvents were employed. As shown in Table 4, a
variety of co-solvents were screened in the model reaction between
4-nitrobenzaldehyde and acetone. It could be found that the
Please cite this article in press as: L.-L. Lou, et al., Cinchona-derived prolinamide in Brønsted acidic ionic liquids: A novel and recyclable
catalytic system for asymmetric aldol reaction, Catal. Today (2015), http://dx.doi.org/10.1016/j.cattod.2015.10.004

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5
Table 6
Asymmetric aldol reaction of acetone to various aromatic aldehydes.a
Yield
ee
80
O
OH
*
O
+
-
O
H
1/[Hmim] BF4
R
R
+
60
40
20
0
r.t.
Entry
R
Yield (%)
ee (%)c
1
2
3
4
5
6
7
8
9
4-NO2
2-NO2
4-Cl
80
73
78
77
86
61
69
74
72
67
70
71
74
78
76
75
82
84
2-Cl
2,4-Cl2
4-Br
4-F
4-CF3
4-CN
1
2
3
4
a
Reactions were performed with 0.3 mmol of aromatic aldehyde and 1.0 mL of
Run
−
acetone and 1.0 mL of [Hmim]+BF4 in the presence of 10 mol% of 1 at room tem-
perature for 24–120 h.
−
Fig. 2. Recycle studies of 1/[Hmim]+BF4 in the asymmetric aldol reaction of 4-
nitrobenzaldehyde with acetone.
and led to a notable decrease in the catalytic efficiency due mainly
to the mass transfer limitation in ionic liquid system. Comparing
these results with those achieved in [Hmim]+BF4−, it can be con-
cluded that the utilization of Brønsted acidic ionic liquids can not
only increase the product enantioselectivity but also accelerate the
catalytic reaction. In an attempt to get further insight into the role
of [Hmim]+BF4−, the control experiments were carried out by the
use of additional acid additives including benzoic acid, catechol and
acetic acid. The results, given in Table 5, showed that the employ-
ment of these three acid additives had no obviously positive effects
on the enhancement of catalytic performance. The superior activ-
ity and enantioselectivity−were achieved when the reaction was
performed in [Hmim]+BF4 without any other acid additive.
run. While a decrease in yield and ee value was observed in the sub-
sequent fourth−run. This may be probably due to the catalyst system
1/[Hmim]+BF4 being partially extracted into the organic phase
during the recycling procedures. Indeed, about 10% of mass loss
was found for the ionic liquid phase containing catalyst 1 after four
cycles. For the purpose of comp−arison, the catalyst 1 supported in
neutral ionic liquid [Bmim]+BF4 was also studied in the recycling
experiments. It was found that the catalytic activity and enantiose-
lectivity decreased significantly with each recycle. During the first
three recycling runs, the yield declined from 30% to 18% then to
8%, and no reaction was observed after recycling three times. This
indicated the chiral prolinamide catalyst in [Bmim]+BF4 has a
−
greater tendency to be extracted into the organic phase than that
in [Hmim]+BF4−. Thus it could be concluded that the introduction
of acidic ionic liquid can significantly enhance the stability of the
catalyst system due probably to the stronger interaction between
the catalyst and ionic liquid.
3.4. Asymmetric aldol reaction of various aromatic aldehydes
With the optimized reaction conditions in hand, the substrate
scope of the catalytic asymmetric aldol reaction was then explored.
As shown in Table 6, all the aromatic aldehydes examined under-
went reaction with acetone to furnish the corresponding aldol
product in moderate to high yields and ee values with the presence
of 10 mol% of catalyst at room temperature. In general, reactions
of the aromatic aldehydes with ortho substituents afforded prod-
ucts in lower yields but slightly higher ee values than those with
para substituents, which may be due to the greater steric hin-
drance of ortho substituents (Table 6, entries 1 and 3 vs. 2 and
4). 4-Nitrobenzaldehyde gave a better yield and lower ee than
4-halogen aromatic aldehydes. The dichlorine-substituted ben-
zaldehyde was found to be more reactive and enantioselective
than mono-substituted aldehydes (Table 6, entries 3 and 4 vs.
5). 4-(Trifluoromethyl)benzaldehyde was converted to the corre-
sponding ␤-hydroxy ketone in a moderate yield of 74% and a high
ee of 82%. Moreover, the reaction of 4-cyanobenzaldehyde with
acetone provided the best ee value of 84% with a yield of 72%.
4. Conclusion
Brønsted acidic ionic liquids [Hmim]+L− were applied in the
asymmetric direct aldol reaction of acetone with aromatic alde-
hydes catalyzed by the prolinamide or−ganocatalyst 1 derived from
9-amino epi-cinchonine. [Hmim]+BF4 was found to be the most
suitable ionic liquid for the catalytic system, and the superior activ-
ity and enantioselectivity were achieved in 1.0 mL of [Hmim]+BF4
−
with neat acetone in the presence of 10 mol% of 1 at room tempera-
ture. The ionic liquid, as a Brønsted acid additive, was demonstrated
to play a positive effect on the enhancement of catalytic perfor-
mance. Moreover, the catalyst recycling experiments showed that
the application of acidic ionic liquid could effectively improve the
affinity of catalyst 1 to ionic liquid, th−us increasing the catalyst sta-
bility. The catalyst 1 in [Hmim]+BF4 could be reused four times
with only a slight loss of activity and enantioselectivity.
3.5. Catalyst recycling and stability
The recyclability of catalyst system 1/[Hmim]+BF4 was inves-
−
Acknowledgements
tigated in the model reaction of 4-nitrobenzaldehyde and acetone.
On completion of each reaction, the reaction mixture was extracted
by diethyl ether, and the ionic liquid phase containing catalyst 1
was subjected to the next run with a fresh batch of acetone and
aldehyde. As shown in Fig. 2, the catalytic activity and enantios-
electivity remained basically unchanged in the first three runs. A
yield of 78% along with an ee value of 64% was achieved in the third
We gratefully acknowledge the support of this research by
the National Natural Science Foundation of China (Grant No.
21203102), the Tianjin Municipal Natural Science Foundation
(Grant Nos. 14JCQNJC06000 and 14JCZDJC32000), MOE (IRT13R30)
and 111 Project (B12015).
Please cite this article in press as: L.-L. Lou, et al., Cinchona-derived prolinamide in Brønsted acidic ionic liquids: A novel and recyclable
catalytic system for asymmetric aldol reaction, Catal. Today (2015), http://dx.doi.org/10.1016/j.cattod.2015.10.004

G Model
CATTOD-9817; No. of Pages6
ARTICLE IN PRESS
6
L.-L. Lou et al. / Catalysis Today xxx (2015) xxx–xxx
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Please cite this article in press as: L.-L. Lou, et al., Cinchona-derived prolinamide in Brønsted acidic ionic liquids: A novel and recyclable
catalytic system for asymmetric aldol reaction, Catal. Today (2015), http://dx.doi.org/10.1016/j.cattod.2015.10.004