An ionic liquid containing L-proline moiety as highly efficient and recyclable chiral organocatalyst for Michael addition

Article abstract of DOI:10.1002/bkcs.10848

A novel chiral ionic liquid containing proline moiety was synthesized. It can be used as a highly efficient and recyclable chiral organocatalyst for Michael addition of cyclohexanone with (E)-β-nitroalkenes in methanol at room temperature. The Michael add

Full text of DOI:10.1002/bkcs.10848

Article
DOI: 10.1002/bkcs.10848
BULLETIN OF THE
J. Li et al.
KOREAN CHEMICAL SOCIETY
An Ionic Liquid Containing L-Proline Moiety as Highly Efficient
and Recyclable Chiral Organocatalyst for Michael Addition
†
†
†
†
†,
Jiang Li,†,‡, Xia Bing Li, Sha Sha Ma, Juan Liu, Ben Hao Li, and Bao Lin Li
*
*
†Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical
Chemistry, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710062,
China. *E-mail: lijiang_1218@163.com; baolinli@snnu.edu.cn
‡Department of Medical Chemistry, School of Basic Medical Science, Ningxia Medical University,
Yinchuan 750004, China
Received February 24, 2016, Accepted May 25, 2016
A novel chiral ionic liquid containing proline moiety was synthesized. It can be used as a highly efficient
and recyclable chiral organocatalyst for Michael addition of cyclohexanone with (E)-β-nitroalkenes in
methanol at room temperature. The Michael addition affords the corresponding products in satisfactory
yields of isolated products (78–98%) with high diastereoselectivities and excellent enantioselectivities
(up to 98% dr and up to 99% ee). The catalyst can be recycled up to five times without any decrease in
yields and stereoselectivities.
Keywords: Michael addition, Chiral catalysis, Chiral ionic liquid, β-Nitroalkenes, L-Proline
Introduction
reactions.29 Recently, it was reported that the ionic liquid-
supported proline or pyrrolidine derivatives were success-
fully used in the Michael addition of ketones and aldehydes
to nitroolefins,30–36 affording the products in high yields
and excellent stereoselectivities. These supported catalysts
can be recovered by magnetic field or precipitation with
diethyl ether. The reactions catalyzed by recovered catalysts
showed no decrease in both yield and enantioselectivity.
Although the excellent yields and stereoselectivities could
be obtained by using this series of ionic liquid-supported
catalysts,37,38 the weak ester bonds for linking between the
ionic liquid and proline or pyrrolidine can be easily hydro-
lyzed under the strong external conditions, resulting in the
difficulties of the recovery of the catalysts. Lombardo’s
group used more stable amide bond instead of ester bond to
improve the linking between ionic liquid and proline, and
the obtained ion-tagged 4-hydroxy-proline was then used
successfully as a robust and efficient catalyst to the asym-
metric Aldol reaction.39 Inspired by this work, we herein
developed a novel chiral ionic liquid (1, Figure 1), which is
formed by using an aliphatic chain containing three carbon
atoms and a nitrogen atom to link imidazole ring and
L-proline units. This chiral ionic liquid was used as a
recyclable and effective organocatalyst for the asymmetric
Michael additions.
Michael addition is one of the most powerful methods for
the formation of C–C bonds.1 The application of catalytic
amount of chiral catalyst could significantly induce the
enantioselectivity or distereoselectivity of the reaction.2–7
Early in 2001, the first example of enantioselective Michael
addition of cyclohexanone to β-nitrostyrene catalyzed by
L-proline was reported by List et al.8 Since then, this reaction
has always been taken as a model to explore more efficient
organocatalysts.9–12 Among the catalysts, proline and
pyrrolidine-based derivatives were used as effective chiral
catalysts for the Michael addition of aldehydes and ketones
to nitroolefins.13–18 However, these organocatalysts still
have some disadvantages. For example, a high catalyst
loading (up to 30 mol%) is generally required or they are
difficulty to be recycled. These problems limit the wide-
spread application of the catalysts. Thus, the development
of environment-friendly, metal-free, and recyclable chiral
organocatalysts for asymmetric Michael addition with high
stereoselectivity is a challenging task.
Recently, supported chiral organocatalysts including pro-
line and proline derivatives on various materials to improve
its recyclability have been the subject of some reviews.19,20
Usually, these materials, such as polymer,21,22 silica,23
ionic liquid,24 magnetite nanoparticles,25 dendrimer,26 and
cyclodextrin,27 were considered as supports for the immobi-
lization of proline and proline derivatives. In these sup-
ports, ionic liquids have attracted considerable attention
based on its high thermal stability, negligible vapor pres-
sure, high loading capacity, and easy recyclability.28 Espe-
cially, some ionic liquids as simple recyclable chiral
catalyst have opened an access for highly enantioselective
Experimental
General Methods. All chemicals were purchased from
Sinopharm Chemical Reagent Co. (Shanghai, China) at rea-
gent grade and used without further purification. All reac-
tions were carried out under nitrogen atmosphere. Silica gel
used in analytical thin layer chromatography and flash
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Article
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KOREAN CHEMICAL SOCIETY
4 M HCl/MeOH solution (10 mL) for 12 h under nitrogen
atmosphere at 0ꢀC to deprotect the Boc group and hydro-
lyse the ester group. Then the reaction mixture was concen-
trated under vacuo to give the hydrochloride of 1, which
was subsequently neutralized with saturated sodium bicar-
bonate solution (50 mL). The aqueous solution was evapo-
rated to dryness under vacuo and the residue was extracted
with chloroform (20 mL × 6). The combined organic layer
was concentrated in vacuo to give 1.31 g chiral ionic liquid
N
N
NH
Cl
COOH
N
H
1
Figure 1. Structure of chiral ionic liquid 1.
rt
1 as pale yellow viscous liquid (90% yield). [α]D = −14.4ꢀ
chromatography was purchased from Qingdao Haiyang
Chemistry Company (Qingdao, China). All samples were
dried thoroughly under vacuum prior to analytical measure-
ments to remove strongly adhering solvent molecules.
1H and 13C NMR spectra were recorded using CDCl3 or
DMSO-d6 as a solvent on a Bruker Avance 400 or
600 MHz spectrometer (Billerica, MA, USA). The IR spec-
tra were recorded with a Nicolet Avatar 360E.S.P. FT-IR
spectrometer (Madison, WI, USA) using KBr pellets. The
optical rotations of chiral ionic liquid and Michael adducts
were measured in methanol or chloroform on Rudolph
Research Analytical Autopol IV with a 2 cm cuvette. ESI
MS was performed by the MS service of the Bruker Dal-
tonics microTOF-Q III. Chiral HPLC analysis was carried
out on a LC-2010A HT instrument (Shimadzu Ltd, Kyoto,
Japan) with a CHIRALPAK IB00CE-KL011 column
(0.46 cm ϕ × 25 cm) (Daicel Corporation, Japan).
1
(c = 1.1, MeOH); H NMR (400 MHz, D2O) δ: 8.69 (s,
1H), 7.43 (s, 1H), 7.36 (s, 1H), 4.47 (dd, J = 10.0, 8.0 Hz,
1H), 4.24 (t, J = 7.0 Hz, 2H), 4.13 (dd, J = 15.0, 7.5 Hz,
1H), 3.84 (dt, J = 15.0, 8.0 Hz, 1H), 3.79 (s, 3H), 3.77 (d,
J = 8.0 Hz, 1H), 3.57–3.54 (m, 1H), 3.15–3.10 (m, 2H),
2.94 (dt, J = 15.0, 5.0 Hz, 1H), 2.33–2.20 (m, 3H). 13C
NMR (100 MHz, D2O) δ 170.3, 136.2, 124.0, 122.1, 59.0,
55.2, 46.3, 46.2, 44.0, 35.9, 30.6, 26.5. FT-IR (KBr): 3317,
2976, 2478, 1699, 1404, 1161, 1115, 899, 770 cm−1;
MS(ESI) m/z: calcd. for C12H21N4O2(M+) 253.1659, found
253.1657.
Typical Experimental Procedure for the Asymmetric
Michael Addition of Cyclohexanone to Nitroolefin. To a
mixture of nitroolefin (1 mmol), catalyst 1 (0.1 mmol),
triethylamine (0.15 mmol), and dry methanol (freshly dis-
tilled in the presence of Mg) (2 mL) was added cyclohexa-
none (2 mmol). The mixture was stirred at room
temperature until completion of the reaction monitoring by
TLC. The reaction mixture was diluted with diethyl ether to
precipitate the catalyst. The supernatant was separated, con-
centrated and purified by Flash chromatography (hexane/
ethyl acetate = 4/1, v/v) to give the Michael adduct. The
Procedure for the Synthesis of Chiral Ionic Liquid 1.
(2S,4S)-1-tert-Butoxycarbonyl-4-aminoproline methyl ester
3 was obtained from 2 in 86% yield following the literature
procedure.40
A mixture of 10 mmol of compound 3, 15 mmol of
anhydrous potassium carbonate and 15 mmol of 1-bromo-
3-chloropropane were added to 20 mL of N,N-
dimethylformamide (DMF) and stirred for 12 h under
nitrogen atmosphere at 30ꢀC. The mixture was then filtered,
and the solvent was evaporated to give a residue, which
was then dissolved in dichloromethane (DCM) and washed
with saturated sodium bicarbonate solution. The organic
layer was dried with anhydrous sodium sulfate. After filtra-
tion, the solvent was evaporated in vacuo. Purification of
the residue by column chromatography (DCM/ethyl acetate =
2/1, v/v) afforded product 4 as off-white crystal (2.95 g,
1
syn/anti ratio of adduct was determined by H-NMR, and
the ee of syn isomer was determined by chiral HPLC analy-
sis. The absolute configuration of the major isomer was
1
determined by comparison with H-NMR data and optical
rotation values of known isomer.
Products 6a,14 6b,14 6c,41 6d,41 6e,10 6f,42 6 g,9 6h10 are
known compounds.
(S)-2-[(R)-1-(3,4,5-Trimethoxylphenyl)-2-nitroethyl] cyclohexa-
rt
1
none (6i). White solid. [α]D = −12.6ꢀ(c = 1.0, CHCl3); H
NMR (400 MHz, CDCl3) δ: 6.32 (s, 2H), 4.86 (dd,
J = 12.6, 4.5 Hz, 1H), 4.61 (dd, J = 12.6, 9.9 Hz, 1H),
3.80 (s, 6H), 3.78 (s, 3H), 3.65 (dd, J = 9.9, 4.5 Hz, 1H),
2.65–2.57 (m, 1H), 2.44 (dt, J = 11.9, 3.4 Hz, 1H), 2.35
(td, J = 11.9, 6.3 Hz, 1H), 1.81–1.50 (m, 6H). 13C NMR
(100 MHz, CDCl3) δ: 207.6, 149.2, 133.2, 129.1, 100.9,
74.4, 56.5, 51.9, 48.5, 40.0, 38.5, 28.9, 24.3, 20.8 ppm. FT-
IR (KBr): 3693, 2957, 1699, 1551, 1460, 1248, 1132, 1005,
822, 660 cm−1. MS (ESI) m/z: calcd. for C17H23NO6Na ([M
+Na]+) 360.1423, found 360.1418. HPLC analysis
(CHIRALPAK IB00CE-KL011 column, hexane:2-propa-
nol = 85:15, flow rate = 1.0 mL/min, wavelength = 254
nm): tR (major) = 13.7 min, tR (minor) = 22.5 min.
rt
92% yield). [α]D = −28.9ꢀ(c = 1.0, CHCl3); FT-IR (KBr):
3317, 2976, 2478, 1699, 1404, 1161, 1115, 899, 770 cm−1;
MS (ESI) m/z: calcd. for C14H26ClN2O4 ([M+H]+)
321.1581, found 321.1582.
A
mixture of compound 4 (5.5 mmol) and 1-
methylimidazol (5 mmol) in toluene (0.3 mL) was irra-
diated by microwave at 85ꢀC for 30 min. The reaction mix-
ture was brought to room temperature and washed with
ethyl acetate and ethyl ether. Solvent was evaporated to
yield a light brown viscous liquid 5 (1.75 g, 79% yield).
rt
[α]D = −17.6ꢀ(c = 1.2, MeOH); FT-IR (KBr): 3439, 2959,
2704, 1742, 1684, 1560, 1263, 1169, 1013, 760, 621 cm−1;
MS (ESI) m/z: calcd. for C18H31N4O4 (M+) 367.2340,
found 367.2331. The obtained compound 5 was stirred in
(S)-2-[(R)-1-(3,4-Dibenzyloxyphenyl)-2-nitroethyl]cyclo-
rt
hexanone (6j). White solid. [α]D = −8.8ꢀ (c = 1.0, CHCl3);
Bull. Korean Chem. Soc. 2016
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2

Chiral Ionic Liquid Containing L-Proline Moiety as an
Organocatalyst for Asymmetric Michael Addition
BULLETIN OF THE
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1H NMR (600 MHz, CDCl3) δ: 7.47–7.27 (m, 10H), 6.86
(d, J = 8.0 Hz, 1H), 6.68 (dd, J = 6.0, 5.0 Hz, 2H),
5.18–5.10 (m, 4H), 4.84 (dd, J = 12.0, 5.0 Hz, 1H), 4.52
(dd, J = 12.0, 10.0 Hz, 1H), 3.63 (td, J = 10.0, 5.0 Hz,
1H), 2.55–2.48 (m, 1H), 2.44 (dt, J = 13.0, 3.0 Hz, 1H),
2.33 (td, J = 13.0, 6.0 Hz, 1H), 2.09–2.01 (m, 1H),
1.75–1.68 (m, 1H), 1.61–1.57 (m, 2H), 1.51–1.43 (m, 1H),
1.10 (m, 1H) ppm. 13C NMR (150 MHz, CDCl3) δ: 212.1,
148.9, 148.8, 137.3, 137.2, 130.9, 128.7, 128.6, 128.0,
127.9, 127.7, 127.5, 121.6, 116.0, 115.1, 79.0, 71.8, 71.4,
52.8, 43.5, 42.8, 33.1, 28.6, 25.1 ppm. FT-IR (KBr): 3701,
2949, 1699, 1551, 1269, 1028, 731, 652 cm−1. MS (ESI)
m/z: calcd. for C28H29NO5Na ([M+Na]+) 482.1943, found
482.1938. HPLC analysis (CHIRALPAK IB00CE-KL011
column, hexane:2-propanol = 90:10, flow rate = 1.0 mL/
min , wavelength = 254 nm): tR (major) = 17.4 min, tR
(minor) = 26.9 min.
HO
H2N
Cl
NH
a,b,c
d
COOMe
COOMe
N
N
COOMe
N
Boc
Boc
Boc
4
2
3
N
N
N
N
NH
NH
e
Cl
f
Cl
COOMe
COOH
N
N
Boc
H
1
5
Scheme 1. The synthetic route of chiral ionic liquid anchored L-
proline unit. a: TsCl, pyridine, rt, 12 h, 92%; b: NaN3, DMF,
50ꢀC, overnight, 95%; c: Ph3P, THF/H2O, 20 h, 98%; d:1-bromo-
3-chloropropane, K2CO3, DMF, 30ꢀC, 12 h, 92%; e: 1-methylimi-
dazole, microwave, 80ꢀC, 30 min, 79%; f: HCl(q), MeOH, 90%.
should tolerate the hydrolytic condition in the presence of
acid or base. 1 was synthesized by a six step procedure
from commercially available starting material (2S,4R)-N-
Boc-4-hydroxy-proline methylester (2) in total yield 56%
(Scheme 1). The procedure included the amination of
4-hydroxyl group of compound 2,42 alkylation of 3 with
1-bromo-3-chloropropane, followed by the connection of
proline unit with 1-methylimidazole through nucleophilic
substitution, and finally the deprotection of Boc and the
hydrolysis of ester.
For the evaluation of the catalytic property of this chiral
ionic liquid, Michael addition of cyclohexanone with trans-
nitrostyrene was selected as a model reaction (Scheme 2).
Initially, considering trans-nitrostyrene is soluble in cyclo-
hexanone, the mixture of two reactants, nitrostyrene
(1.0 mmol) and cyclohexanone (2.0 mmol), was stirred in
the presence of 20 mol% catalyst 1 at room temperature for
36 h. The target product 6a was obtained in 33% yield with
good enantioselectivity (83% ee) of major diastereoisomer
(entry 1 in Table 1). It was thought that the polarity of the
solvent may affect the yield of the reaction. In this case, a
variety of solvents was screened under the same condition.
The results were summarized in Table 1. When the reaction
mixture was stirred in toluene or hexane for 36 h, no prod-
uct was found due to the insolubility of the synthesized cat-
alyst (entry 2 and 3). Though the catalyst can be dissolved
in water, the insolubility of the reactants, nitrostyrene and
cyclohexanone, in water led to the low yield (25%) of iso-
lated product (entry 4). In other organic solvent, the reac-
tion gave a low to moderate yield except alcohol (entries
5–8). A high yield (82%) with excellent stereoslectivity
(92/8 dr and 95% ee) was achieved in methanol as the sol-
vent at room temperature for 24 h (entry 9). It may benefit
(S)-2-[(R)-1-(4-Hydroxy-3-methoxyphenyl)-2-nitroethyl]
rt
cyclohexanone (6k). White solid. [α]D = −4.8ꢀ (c = 1.0,
CHCl3); 1H NMR (600 MHz, CDCl3) δ: 6.83 (d,
J = 8.0 Hz, 1H), 6.63 (d, J = 9.0 Hz, 2H), 5.71 (s, 1H),
4.88 (dd, J = 12.0, 4.5 Hz, 1H), 4.61–4.54 (m, 1H), 3.83
(s, 3H), 3.67 (td, J = 10.0, 4.5 Hz, 1H), 2.62 (td, J = 11.0,
4.5 Hz, 1H), 2.46–2.31 (m, 2H), 2.09–2.00 (m, 1H),
1.85–1.70 (m, 2H), 1.70–1.44 (m, 2H), 1.28–1.16 (m, 1H)
ppm. 13C NMR (150 MHz, CDCl3) δ: 206.9, 141.5, 139.9,
124.3, 115.3, 109.5, 105.9, 73.8, 50.7, 47.5, 38.5, 37.5,
27.9, 23.3, 19.8 ppm. FT-IR (KBr): 3472, 3115, 1607,
1489, 1296, 1213, 1022, 816, 573 cm−1. MS (ESI) m/z:
calcd. for C15H19NO5Na ([M+Na]+) 316.1161, found
316.1169. HPLC analysis (CHIRALPAK IB00CE-KL011
column, hexane:2-propanol = 85:15, flow rate = 1.0 mL/
min, wavelength = 254 nm): tR (major) = 20.6 min, tR
(minor) = 29.7 min.
Typical Experimental Procedure for the Recycling Test
of Catalyst. To a mixture of β-nitrostyrene (10.0 mmol),
catalyst 1 (1.0 mmol), triethylamine (1.5 mmol) and dry
methanol (freshly distilled in the presence of Mg) (15 mL)
was added cyclohexanone (20.0 mmol). The mixture was
stirred at room temperature until the completion of the reac-
tion monitoring by TLC. The reaction mixture was diluted
with ethyl ether (20 mL) to precipitate the catalyst. After
centrifugation, the precipitation was separated, washed with
ethyl ether, and dried in vacuo, and then was used as a
recyclable catalyst to the next reaction again. The result
was shown in Table 4. The supernatant was separated, con-
centrated and purified by flash chromatography (hexane/
ethyl acetate = 4/1, v/v) to give the Michael adduct.
Results and Discussion
O
Ph
O
To get a more stable chiral ionic liquid containing proline
moiety, we designed and synthesized a new compound 1.
This chiral ionic liquid catalyst 1 was formed by using an
aliphatic chain containing three carbon atoms and a nitrogen
atom linking imidazole ring and L-proline unit. This linking
NO2
catalyst 1
Ph
+
NO2
6a
Scheme 2. Michael addition of cyclohexanone to β-nitrostyrene.
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Chiral Ionic Liquid Containing L-Proline Moiety as an
Organocatalyst for Asymmetric Michael Addition
BULLETIN OF THE
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Table 1. Screening of solvent for Michael addition of cyclohexanone to β-nitrostyrene catalyzed by 1.a
Entry
Solvent
Cat. 1 (mol %)
T (ꢀC)
Time (h)
Yieldb (%)
Syn/antic
ee of synd (%)
1
2
3
4
5
6
7
8
9
10
a
Free
Toluene
Hexane
H2O
CHCl3
MeCN
THF
DMF
MeOH
EtOH
20
20
20
20
20
20
20
20
20
20
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
36
36
36
36
36
36
36
36
24
24
33
-
-
25
23
65
41
40
82
76
62/38
-
-
58/42
71/29
73/27
83/17
79/21
92/8
87/13
83
-
-
61
66
63
76
78
95
86
Reaction conditions: nitrostyrene (1.0 mmol), cyclohexanone (2.0 mmol), and catalyst 1 (0.20 mmol) in solvent-free or solvent (2.0 mL).
Yield of isolated product.
b
c
d
Determined by 1H NMR of the crude product.
Determined by chiral HPLC using CHIRALPAK IB00CE-KL011 column.
from that methanol has a good dissolubility for both reac-
tants and ionic liquid catalyst 1.
were introduced at room temperature (entries 6–9). The
results suggested that triethylamine (TEA) is the best addi-
tive in all tested additives. When adding 10 mol% TEA to
the mixture of nitrostyrene (1.0 mmol), cyclohexanone
(2.0 mmol), catalyst 1 (0.1 mmol), and methanol (2 mL),
90% yield and high stereoselectivity (97/3 dr and 96% ee)
of the product were obtained (entry 9). Increasing the
amount of TEA to 15 mol% and 20 mol% of nitrostyrene,
the same results, 98% yield, 98/2 dr, and 99% ee, were
obtained (entries 10 and 11). Thus, an optimized reaction
condition was achieved as stirring the mixture of nitrostyr-
ene (1.0 mmol), cyclohexanone (2.0 mmol), catalyst
1 (0.1 mmol), and TEA (0.15 mmol) in methanol (2 mL) at
room temperature for 20 h. This promotive effect of basic
additive suggested the proline moiety of 1 as carboxylate
formation react with cyclohexanone to yield enamine car-
boxylate. Meanwhile it indicated the stereocontrolling tran-
sition state for C C bond formation in the addition of
Encouraged by this initial result, we optimized other
reaction conditions, such as the catalyst loading, tempera-
ture and additive etc, in methanol. As shown in Table 2,
the loading of catalyst 1 was investigated from 5 to 20 mol%
relative to nitrostyrene (entries 1–3). The results indicated
the catalyst loading of 10 mol% is a good choice at
room temperature and it still gave a similar yield and
stereoselectivity compared with the catalyst loading of
20 mol%. Raising the temperature to 60ꢀC gave the prod-
uct in an improved yield of 90%, but this gave decreased
stereoselectivity (78/22 dr and 63% ee, entry 4). When the
temperature was decreased to 4ꢀC, a longer reaction time
was required (entry 5). In the other hand, some acidic or
basic additives can obviously increase the yield and stereo-
selectivity of the reaction catalyzed by proline deriva-
tives.41,43 To further optimize the reaction, some additives
Table 2. Optimization of the condition for Michael addition of cyclohexanone to β-nitrostyrene catalyzed by 1.a
Cat. 1
Entry
(mol %)
Additive
Additive loading (mol %)
T (ꢀC)
Time (h)
Yieldb (%)
Syn/antic
ee of synd (%)
1
2
3
4
5
6
7
8
5
Free
Free
Free
Free
rt
rt
rt
60
4
rt
rt
rt
rt
rt
rt
24
24
24
24
72
24
24
24
24
20
20
53
83
82
90
82
25
23
65
90
98
98
90/10
92/8
92/8
78/22
92/8
58/42
71/29
53/47
97/3
93
95
95
63
96
61
76
53
96
99
99
10
20
10
10
10
10
10
10
10
10
Free
Benzoic acid
Pyridine
KOH
TEA
TEA
TEA
10
10
10
10
15
20
9
10
11
a
98/2
98/2
Reaction conditions: the mixture of nitrostyrene (1.0 mmol), cyclohexanone (2.0 mmol), catalyst 1, and additive was stirred in MeOH (2.0 mL)
at indicated temperature.
Yield of isolated product.
b
c
d
Determined by 1H NMR of crude product.
Determined by chiral HPLC using CHIRALPAK IB00CE-KL011 column.
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Chiral Ionic Liquid Containing L-Proline Moiety as an
Organocatalyst for Asymmetric Michael Addition
BULLETIN OF THE
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Table 3. The scope of the asymmetric Michael addition catalyzed
Table 4. Reusability of catalyst 1.a
by 1.a
O
Ar
O
Entry
Time (h)
Yield (%)b
Syn/antic
ee of syn (%)d
10 mol% cat. 1
NO2
15 mol% TEA
Ar
+
NO2
MeOH, rt
1
2
3
4
5
6
a
20
24
24
24
36
72
98
98
96
96
94
53
98/2
98/2
96/4
96/4
95/5
72/28
99
99
99
98
97
74
6b-6k
Time
(h)
Yieldb
(%)
Syn/
ee of
Entry Product
antic
synd (%)
OCH3
1
48
87
93/7
96
O
Reaction condition: nitrostyrene (10.0 mmol), cyclohexanone
(20.0 mmol), catalyst 1 (1.0 mmol), and TEA (1.5 mmol) in
methanol (15 mL) at room temperature.
Yield of isolated product.
NO2
6b
b
c
d
CH3
2
48
81
92/8
95
Determined by 1H NMR spectroscopy.
Determined by Chiral HPLC.
O
NO2
6c
enamine carboxylate to nitrostyrene may be in anti-face
addition models.43
NO2
NO2
3
4
38
36
92
94
95/5
94/6
95
94
O
With the optimal reaction conditions in hand, the reac-
tion scope of the asymmetric Michael addition catalyzed by
1 was investigated and the results were summarized in
Table 3. The results showed that the reactions proceeded
efficiently with cyclohexanone and nitroolefins bearing
both electron-deficient and electron-rich substituents on the
phenyl ring, affording the corresponding products 6b–6k in
high yields (78–98%) with high diastereoselectivity (dr up
to 97/3) and enantioselectivities of syn isomers (ee up to
96%) (entries 1–10). 2-(2-nitrovinyl)furan was also a suita-
ble Michael acceptor. The corresponding reaction gave
Michael adduct 6h in 88% yield with 96/4 dr and excellent
enantioselectivity of syn isomer (94% ee) (entry 7).
6d
N
O
NO2
6e
Cl
5
6
48
36
92
95
97/3
96/4
95
94
O
NO2
6f
O
O
O
The reusability of catalyst 1 was briefly tested. After
reaction, the catalyst 1 could be easily recycled by precipi-
tation with ethyl ether, centrifugation, washing with ethyl
ether and drying in vacuo. Spectrum data (1H and 13C
NMR) of recycled catalyst were identical to the initial ionic
liquid sample. The recovered catalyst could maintain simi-
lar activity and stereoselectivity after being recycled for five
times (Table 4). The active reduction of catalyst was
observed in the sixth time, resulting from the loss of cata-
lyst mass during the recovery.
NO2
6g
6h
7
8
48
48
88
86
96/4
93/7
94
92
O
O
NO2
OCH3
OCH3
H
3CO
O
NO2
6i
Bn
9
48
48
98
78
97/3
92/8
94
96
O
O
Bn
Conclusion
O
NO2
6j
We have developed a novel chiral ionic liquid containing
L-proline unit as highly efficient and recyclable organocata-
lyst for asymmetric Michael additions of cyclohexanone
with nitroolefins. The asymmetric Michael additions were
carried out in the presence of 10 mol% chiral ionic liquid
and 15 mol% TEA in methanol at room temperature. The
reactions generated the corresponding products with satis-
factory yields of isolated products and high stereoselectiv-
ities. It is noteworthy that the chiral ionic liquid can be
recycled up to five times without any decrease in yields
and stereoselectivities.
OH
10
O
O
NO2
6k
a
Reaction condition: aryl nitroolefin (1.0 mmol), cyclohexanone
(2.0 mmol), triethylamine (0.15 mmol), and catalyst 1 (0.10 mmol)
in MeOH (2.0 mL) at rt.
b
c
d
Yield of isolated product.
Syn/anti ratio was determined by 1H NMR spectroscopy.
Determined by chiral HPLC.
Bull. Korean Chem. Soc. 2016
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
5

Chiral Ionic Liquid Containing L-Proline Moiety as an
Organocatalyst for Asymmetric Michael Addition
BULLETIN OF THE
Article
KOREAN CHEMICAL SOCIETY
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Acknowledgments.
National Natural Science Foundation of China (Grant
No. 21272144) for financial support.
The authors are grateful to the
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© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
6