Pyrrolidine-based chiral quaternary alkylammonium ionic liquids as organocatalysts for asymmetric Michael additions

Article abstract of DOI:10.1007/s10562-011-0649-4

A series of chiral pyrrolidine-type quaternary alkylammonium ionic liquids were synthesized and served as efficient catalysts for asymmetric Michael additions of aldehydes and ketones to nitroolefins, and the corresponding adducts were obtained in excelle

Full text of DOI:10.1007/s10562-011-0649-4

Catal Lett (2011) 141:1324–1331
DOI 10.1007/s10562-011-0649-4
Pyrrolidine-Based Chiral Quaternary Alkylammonium Ionic
Liquids as Organocatalysts for Asymmetric Michael Additions
•
•
•
Ge Wang Huichao Sun Xiaohui Cao
Ligong Chen
Received: 12 April 2011 / Accepted: 11 June 2011 / Published online: 25 June 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of chiral pyrrolidine-type quaternary
alkylammonium ionic liquids were synthesized and served
as efficient catalysts for asymmetric Michael additions of
aldehydes and ketones to nitroolefins, and the corre-
sponding adducts were obtained in excellent enantioselec-
tivities ([99% ee) and diastereoselectivities ([99% dr)
under solvent-free reaction conditions. Furthermore, the
catalyst 7c could be recovered for next run of the reaction
with similar yield and selectivity.
Therefore, several groups introduced quaternary ammonium
groups into chiral catalysts [25–43]. Thereinto, pyrrolidine-
type imidazolium ILs, DABCO ILs and pyridinium ILs all
produced encouraging results for the Michael additions of
ketones or aldehydes to nitroolefins.
Herein, we designed and synthesized several novel
pyrrolidine-based quaternary alkylammonium ILs. And
structure of these ionic liquids could be easily adjusted to
obtain better catalytic capability by changing each of the
alkyl groups. Then all of them were used as organocatalysts
in the asymmetric Michael additions of cyclohexanone to
nitroalkenes. And the results are summarized and reported
here.
Keywords Ionic liquids Á Chiral catalyst Á Asymmetric
Michael additions Á Solvent-free reaction
1 Introduction
2 Experimental
Michael addition is one of the most important organic
reactions to form C–C bonds, and asymmetric Michael
addition catalyzed by chiral catalyst is a very significative
strategy for organic synthesis [1–7]. Since L-proline was
reported as a chiral catalyst in Michael addition by List at
2001 [8], lots of pyrrolidine derivatives have been used for
the asymmetric Michael additions of ketones or aldehydes
to nitroolefins [9–19]. Most of them yielded high enanti-
oselectivity and diastereoselectivity. But it is difficult for
them to be recovered and reused.
2.1 General Information
Commercial reagents were used without purification except
for otherwise explanation. Analytical thin layer chroma-
tography was performed on 0.20 mm silica gel plates and
silica gel (200–300 mesh) was used for flash chromatog-
raphy both purchased from Qingdao Haiyang Chemistry
1
Company. H and 13C NMR were recorded on Varian-500
instruments. Chemical shifts were reported in ppm down
field from internal Me4Si. All the multiplet patterns
assigned the first-order splitting patterns. Mass spectra
were recorded using electrospray ionization (ESI) on LCQ
Advanted MAX Mass instruments. Optical rotations were
tested on a WZZ-3 polarimeter using 10 mL cell with a
1 dm path length and Autopol II polarimete using 1 mL
cell with a 1 dm path length. HPLC analysis was measured
using ChiralPak AS-H column at 254 nm.
Normally, room temperature ionic liquids (RTILs) can be
easily separated from organic reaction systems [20–24].
G. Wang Á H. Sun Á X. Cao Á L. Chen (&)
School of Chemical Engineering and Technology, Tianjin
University, Tianjin 300072, People’s Republic of China
e-mail: lgchen@tju.edu.cn
123

Pyrrolidine-Based Chiral Quaternary Alkylammonium Ionic Liquids
1325
2.2 (S)-Benzyl 2-(hydroxymethyl)pyrrolidine-1-
carboxylate (2)
solution of Me2NH (7.8 g, 0.18 mol) in water (16 g). After
sealing the bottle by a rubber plug, the reaction mixture was
stirred for 18 h at 55 °C. Then MeOH was removed in
vacuo. The residuary mixture was extracted with EA
(20 mL 9 3). The combined organic layer was washed with
water (30 mL 9 2) and brine (30 mL 9 2), then dried over
anhydrous MgSO4 and concentrated in vacuo. The residue
was purified by flash chromatography (MeOH:CH2Cl2 =
1:20) on silica gel to give the compound 5, a colorless oil.
The compound 2 was obtained following literature proce-
dure [44].
2.3 (S)-Benzyl 2-((methylsulfonyloxy) methyl)-
pyrrolidine-1-carboxylate (3)
1
To a stirred solution of compound 2 (5.5 g, 0.023 mol) in
CH2Cl2 (60 mL), (Et)3N (3.0 g, 0.030 mol) was dropped at
0 °C [45, 46]. Then a solution of methanesulfonyl chloride
(3.2 g, 0.028 mol) in CH2Cl2 (20 mL) was dropped into the
above reaction solution. After naturally increasing the
reaction temperature to r. t., the reaction mixture was stirred
for 18 h. The mixture was diluted with water (50 mL), and
then the resulted mixture was extracted with CH2Cl2
(20 mL 9 3). The combined organic layer was washed with
1 M HCl solution (25 mL 9 2) and brine (20 mL 9 2),
then dried over anhydrous Na2SO4 and concentrated in
vacuo to give the compound 3 as colorless oil. Yield: 99%;
1H NMR (500 MHz, CDCl3): d = 1.84–2.02 (4H, m), 2.93
(3H, s), 3.42–3.49 (2H, m), 4.09–4.22 (1H, m), 4.27–4.38
(2H, m), 5.12–5.18 (2H, m), 7.26–7.40 (5H, m); 13C NMR
(500 MHz, CDCl3): d = 155.22, 137.71, 136.89, 128.97,
128.88, 128.83, 128.76, 128.64, 128.55, 128.31, 128.13,
69.75, 69.61, 67.49, 67.12, 56.54, 55.87, 47.41, 47.09,
37.22, 37.13, 28.83, 27.99, 24.04, 23.17.
Yield: 86%; H NMR (500 MHz, CDCl3): d = 1.86–1.97
(4H, m), 2.19–2.54 (8H, m), 3.41–3.43 (2H, m), 3.92–4.00
(1H, m), 5.10–5.19 (2H, m), 7.28–7.38 (5H, m).
2.6 General Procedure for the Preparation
of Compounds 6a–6e
Under N2 protection, compound 5 (1.3 g, 5.0 mmol) and
MeCN (10 mL) was added to a 100 mL single neck bottle
[47]. After compound 5 dissolved, corresponding alkyl
bromide (0.019 mol) was added into the solution. The
reaction mixture was stirred under refluxing until compound
5 disappeared by analytical thin layer chromatography
(EA:PE = 1:1), and MeCN was removed away in vacuo.
The mixture was diluted with 10 mL EA, and then the
resulted mixture was extracted with water (10 mL 9 3). The
combined water layer was washed with EA (15 mL 9 3) and
concentrated in vacuo. The residue was purified by flash
chromatography (MeOH:CH2Cl2 = 1:10) on silica gel to
give the corresponding quaternary ammonium 6.
2.4 (S)-Benzyl 2-(bromomethyl)pyrrolidine-1-
carboxylate (4)
2.6.1 (S)-N-((1-(Benzyloxycarbonyl)pyrrolidin-2-
yl)methyl)-N,N-dimethylethanaminium bromide (6a)
Under N2 protection, compound 3 (3.1 g, 0.01 mol) and
THF (30 mL) was added to a 100 mL single neck bottle
[45, 46]. After compound 3 dissolved, LiBr.H2O (3.2 g,
0.03 mol) was added to the solution. The reaction mixture
was stirred for 16 h under refluxing, and THF was removed
away in vacuo. The mixture was diluted with water
(10 mL), and the resulted mixture was extracted with
CH2Cl2 (10 mL 9 3). The combined organic layer was
washed with water (10 mL 9 2) and brine (20 mL 9 2),
then dried over anhydrous MgSO4 and concentrated in
vacuo. The residue was purified by flash chromatography
(EA:PE = 1:4) on silica gel to give the compound 4, a
1
Colorless oil. Yield: 44%; H NMR (500 MHz, CD3OD):
d = 1.17–1.40 (3H, m), 1.95–2.01 (3H, m), 2.20–2.24 (1H,
m), 2.92–2.93 (2H, m), 3.00–3.01 (2H, m), 3.17–3.57
(10H, m), 4.41 (1H, s), 5.15 (2H, s), 7.31–7.48 (5H, m).
2.6.2 (S)-N-((1-(Benzyloxycarbonyl)pyrrolidin-2-
yl)methyl)-N,N-dimethylpropan-1-aminium bromide
(6b)
1
Colorless oil. Yield: 99%; H NMR (500 MHz, CD3OD):
d = 0.87–1.01 (3H, m), 1.63–2.01 (5H, m), 2.18–2.26 (1H,
m),2.92–3.00 (2H, m), 3.17 (3H, s), 3.20 (3H, s), 3.45–3.55
(4H, m), 4.41 (1H, s), 5.15 (2H, s), 7.31–7.46 (5H, m).
1
colorless oil. Yield: 81%; H NMR (500 MHz, CDCl3):
d = 1.81–2.01 (4H, m), 3.27–3.67 (4H, m), 4.10–4.14 (1H,
m), 5.11–5.21 (2H, m), 7.32–7.37 (5H, m).
2.6.3 (S)-N-((1-(Benzyloxycarbonyl)pyrrolidin-2-
yl)methyl)-N,N-dimethylbutan-1-aminium bromide
(6c)
2.5 (S)-Benzyl 2-((dimethylamino) methyl)pyrrolidine-
1-carboxylate (5)
1
Colorless oil. Yield: 99%; H NMR (500 MHz, CD3OD):
In a 250 mL single neck bottle, compound 4 (17 g,
0.058 mol) in MeOH (114 mL) was added to a stirred
d = 0.94–1.03 (3H, m), 1.24–1.41 (2H, m), 1.59–1.82 (2H,
123

1326
G. Wang et al.
2.7.2 (S)-N,N-Dimethyl-N-(pyrrolidin-2-ylmethyl) propan-
1-aminium bromide (7b)
m), 1.91–2.01 (3H, m), 2.18–2.25 (1H, m), 2.92 (1H, s),
3.01 (1H, s), 3.17 (3H, s), 3.20 (3H, s), 3.40–3.56 (4H, m),
4.41 (1H, s), 5.15 (2H, s), 7.31–7.46 (5H, m).
1
White solid. Yield: 72%; H NMR (500 MHz, CD3OD):
d = 1.00 (3H, t, J = 7 Hz), 1.38–1.42 (1H, m), 1.68–1.73
(1H, m),1.78–1.86 (3H, m), 2.07–2.12 (1H, m), 2.87–2.99
(2H, m), 3.15 (3H, s), 3.16 (3H, s), 3.27–3.40 (4H, m),
3.59–3.64 (1H, m); 13C NMR (500 MHz, CD3OD):
2.6.4 (S)-N-((1-(Benzyloxycarbonyl)pyrrolidin-2-
yl)methyl)-N,N-dimethyloctan-1-aminium bromide
(6d)
1
Colorless oil. Yield: 99%; H NMR (500 MHz, CD3OD):
d = 68.10, 66.82, 53.35, (50.80, 50.76, 50.72, 50.69),
= ?12.8
t.
46.71, 31.37, 25.14, 15.94, 9.67; [a]Dr.
(c = 0.97, MeOH); MS (ESI) m/z: calcd. for C10H23N2
d = 0.90–0.91 (3H, m), 1.32–1.77 (12H, m), 1.80–2.02
(3H, m),2.19–2.23 (1H, m), 2.90 (1H, s), 2.98 (1H, s),
3.10–3.19 (4H, m), 3.35–3.55 (7H, m), 4.40 (1H, s), 5.15
(2H, s), 7.31–7.45 (5H, m).
171.30 (positive ion), found 171.2 (positive ion).
2.7.3 (S)-N,N-Dimethyl-N-(pyrrolidin-2-ylmethyl)
butan-1-aminium bromide (7c)
2.6.5 (S)-1-(1-(Benzyloxycarbonyl)pyrrolidin-2-yl)-N,N,N-
trimethylmethanaminium bromide (6e)
1
White solid. Yield: 65%; H NMR (500 MHz, CD3OD):
d = 1.01 (3H, t, J = 7.5 Hz), 1.39–1.47 (3H, m),
1.70–1.87 (4H, m), 2.09–2.15 (1H, m), 2.90–3.01 (2H, m),
3.16 (3H, s), 3.17 (3H, s), 3.31–3.46 (4H, m), 3.63–3.66
(1H, m); 13C NMR (500 MHz, CD3OD): d = 68.02, 65.36,
53.39, 50.77, 46.71, 31.37, 25.11, 24.41, 19.54, 12.75; [a]Dr.
A solution of NaOH (11 g, 0.27 mol) in water (12 mL) was
dropped to Me3N.HCl (20 g, 0.21 mol) to produce Me3N
[48]. The Me3N was bubbled to a solution of compound 4
(3.3 g, 0.011 mol) in EA (20 mL) at 0 °C. After Me3N (9.6 g,
0.16 mol) was absorbed, the reaction mixture was sealed by a
rubber plug and stirred at r.t. for 168 h. The mixture was
filtrated, andthefiltercakewaswashedbyEA (20 mL) to give
the product 6e, a white solid. Yield: 89%; 1H NMR
(500 MHz, CD3OD): d = 1.93–2.01 (3H, m), 2.18–2.25 (1H,
m), 3.02–3.04 (3H, m), 3.24–3.26 (6H, m), 3.42–3.55 (4H, m),
4.39 (1H, s), 5.15 (2H, s), 7.31–7.47 (5H, m).
t.
= ?8.5 (c = 0.98, MeOH); MS (ESI) m/z: calcd. for
C11H25N2 185.33 (positive ion), found 185.2 (positive ion).
Recycled 7c: Light yellow solid. Recycled yield:
90–95%; 1H NMR (500 MHz, D2O): d = 1.02 (3H, t,
J = 7.5 Hz), 1.31–1.32 (1H, m), 1.40–1.40 (2H, m),
1.61–1.64 (1H, m),1.72–1.85 (3H, m), 1.93–1.99 (1H,
m),2.04–2.09 (1H, m), 2.29–2.38 (2H, m), 3.11–3.20 (6H,
m), 3.24–3.35 (2H, m), 3.43–3.46 (2H, m), 3.71–3.81 (1H,
m), 4.05–4.06 (1H, m), 7.25–7.32 (1H, m).
2.7 General Procedure for the Preparation
of Compounds 7a–7e
2.7.4 (S)-N,N-Dimethyl-N-(pyrrolidin-2-ylmethyl)
octan-1-aminium bromide (7d)
To the solution of corresponding compound 6 (3.9 mmol)
in EtOH (30 mL) [49], 10% Pd/C (0.15 g) was added. The
reaction mixture was stirred at r. t. under 1 atm H2 over-
night. After filtrating the Pd/C, the solution was concen-
trated in vacuo to give the crude product. Adding EA
(5 mL) to the crude product and vibrating by ultrasonic
wave, the product was solidified. The corresponding cata-
lyst 7 was obtained by filtration.
1
White solid. Yield: 60%; H NMR (500 MHz, CD3OD):
d = 0.90 (3H, t, J = 7.5 Hz), 1.33–1.46 (11H, m),
1.69–1.87 (4H, m), 2.08–2.14 (1H, m), 2.89–3.00 (2H, m),
3.16 (3H, s), 3.18 (3H, s), 3.31–3.48 (4H, m), 3.60–3.67
(1H, m); 13C NMR (500 MHz, CD3OD): d = 67.93, 65.55,
53.41, 50.77, 46.71, 31.71, 31.37, 29.05, 29.02, 26.22,
t.
25.08, 22.50, 22.48, 13.25; [a]rD. = ?14.0 (c = 1.01,
2.7.1 (S)-N,N-Dimethyl-N-(pyrrolidin-2-ylmethyl)
ethanaminium bromide (7a)
MeOH); MS (ESI) m/z: calcd. for C15H33N2 241.44
(positive ion), found 241.3 (positive ion).
1
White solid. Yield: 85%; H NMR (500 MHz, CD3OD):
2.7.5 (S)-N,N,N-Trimethyl-1-(pyrrolidin-2-yl)
methanaminium bromide (7e)
d = 1.38 (3H, t, J = 7.5 Hz), 1.45–1.53 (1H, m),
1.72–1.81 (1H, m),1.84–1.91 (1H, m), 2.13–2.19 (1H, m),
2.95–3.05 (2H, m), 3.17 (3H, s), 3.18 (3H, s), 3.39–3.49
(2H, m), 3.59 (2H, q, J = 7 Hz), 3.71–3.75 (1H, m); 13C
NMR (500 MHz, CD3OD): d = 67.22, 60.98, 53.50, 50.37,
1
White solid. Yield: 89%; H NMR (500 MHz, CD3OD):
d = 1.75–1.81 (1H, m), 1.90–1.96 (1H, m), 1.98–2.06 (1H,
m),2.34–2.40 (1H, m), 3.14 (9H, s), 3.29–3.32 (2H, m),
3.75–3.84 (2H, m), 4.04–4.09 (1H, m); 13C NMR
(500 MHz, CD3OD): d = 71.45, 71.43, 54.78, 54.53,
t.
46.70, 31.39, 24.94, 7.63; [a]rD. = ?14.1 (c = 0.99,
MeOH); MS (ESI) m/z: calcd. for C9H21N2 157.28 (posi-
tive ion), found 157.4 (positive ion).
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Pyrrolidine-Based Chiral Quaternary Alkylammonium Ionic Liquids
t.
= ?7.8
1327
54.50, 47.80, 32.42, 26.28, 24.19; [a]Dr.
2.68–2.72 (1H, m), 3.72–3.80 (1H, m), 4.62–4.66 (1H, m),
4.93–4.96 (1H, m), 7.16–7.34 (5H, m).
(c = 0.95, MeOH); MS (ESI) m/z: calcd. for C8H19N2
143.25 (positive ion), found 143.1 (positive ion).
2.9.2 (S)-2-((R)-2-Nitro-1-(2-
nitrophenyl)ethyl)cyclohexanone (9b)
2.8 (S)-N,N-Dimethyl-N-(pyrrolidin-2-ylmethyl)butan-
1-aminium fluoroboric acid (8) [32]
1H NMR (500 MHz, CDCl3): d = 1.24–1.32 (1H, m),
1.43–1.73 (3H, m), 1.81–1.84 (1H, m), 2.04–2.14 (1H, m),
2.37–2.39 (1H, m), 2.40–2.51 (1H, m), 2.72–2.77 (1H, m),
3.92–3.96 (1H, m), 4.68–4.73 (1H, m), 5.00–5.03 (1H, m),
7.51–7.68 (2H, m), 8.08–8.16 (2H, m).
To the solution of corresponding compound 7 (1.7 mmol)
in MeCN (33 mL) and acetone (4 mL), NaBF4 (0.95 g,
8.7 mmol) was added. The reaction mixture was stirred at
r.t. for 72 h. After filtrating the insoluble solid, a saturated
solution of AgBF4 in MeCN was dropped into the solution
above until no precipitate produced. After filtrating the
insoluble solid, the solution was concentrated in vacuo to
give the corresponding product 8.
2.9.3 (S)-2-((R)-1-(4-Methoxyphenyl)-2-
nitroethyl)cyclohexanone (9c)
Orange solid. Yield: 68%; 1H NMR (500 MHz,
CD3OD): d = 1.02 (3H, t, J = 7.5 Hz), 1.39–1.47 (2H, m),
1.62–1.70 (1H, m),1.74–1.83 (2H, m), 1.89–1.95 (1H, m),
1.96–2.02 (1H, m), 2.27–2.34 (1H, m), 3.11–3.22 (8H, m),
3.38–3.44 (2H, m), 3.52–3.62 (2H, m), 3.85–3.91 (1H, m);
13C NMR (500 MHz, CD3OD): d = 65.70, 65.36, 57.16,
50.41, 50.19, 46.34, 30.91, 24.31, 23.46, 19.40, 12.70; [a]Dr.
1H NMR (500 MHz, CDCl3): d = 1.19–1.28 (1H, m),
1.57–1.82 (4H, m), 2.05–2.11 (1H, m), 2.36–2.42 (1H, m),
2.46–2.50 (1H, m), 2.62–2.68 (1H, m), 3.69–3.74 (1H, m),
3.79 (3H, s), 4.57–4.61 (1H, m), 4.90–4.93 (1H, m), 6.84
(2H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.5 Hz).
2.9.4 (S)-2-((R)-1-(4-Chlorophenyl)-2-
nitroethyl)cyclohexanone (9d)
t.
= ?6.7 (c = 1.03, MeOH); MS (ESI) m/z: calcd. for
C15H33N2 185.33 (positive ion), found 185.2 (positive ion).
1H NMR (500 MHz, CDCl3): d = 1.19–1.28 (1H, m),
1.57–1.83 (4H, m), 2.08–2.13 (1H, m), 2.35–2.42 (1H, m),
2.46–2.51 (1H, m), 2.63–2.68 (1H, m), 3.74–3.79 (1H, m),
4.59–4.63 (1H, m), 4.92–4.96 (1H, m), 7.11–7.14 (2H, m),
7.29–7.32 (2H, m).
2.9 General Experimental Procedure for the Michael
addition of Cyclohexanone to Nitroalkene
by Chiral Catalyst
To a solution of the chiral catalyst (0.075 mmol) in cyclo-
hexanone (1 g, 10 mmol), TFA (2.85 mg, 0.025 mmol) was
dropped in. After stirring for 1 h, the nitroalkene
(0.5 mmol) was added, and the solution was stirred at r.t. for
72 h except for otherwise explanation. The solution was
diluted with 5 mL of water, and the resulted mixture was
extracted with EA (2 mL 9 3). The combined organic layer
was washed with water (3 mL 9 2) and brine (3 mL 9 2),
then dried over anhydrous MgSO4 and concentrated in
vacuo to give the crude product. Adding PE (3 mL) to the
crude product and vibrating by ultrasonic wave for 1 h. The
corresponding product was obtained by filtration.
2.9.5 (S)-2-((R)-1-(2,4-Dichlorophenyl)-2-
nitroethyl)cyclohexanone (9e)
1H NMR (500 MHz, CDCl3): d = 1.30–1.38 (1H, m),
1.60–1.86 (4H, m), 2.10–2.15 (1H, m), 2.35–2.42 (1H, m),
2.46–2.51 (1H, m), 2.84–2.92 (1H, m), 4.11–4.24 (1H, m),
4.86–4.92 (2H, m), 7.17 (1H, d, J = 8.0 Hz), 7.23 (1H, dd,
J1 = 8.0 Hz, J2 = 2.0 Hz), 7.41 (1H, d, J = 2.0 Hz).
2.9.6 (S)-2-((R)-1-(2-Chlorophenyl)-2-
nitroethyl)cyclohexanone (9f)
The relative configurations of the products (syn and
anti) were determined by comparison of HPLC data with
those reported in the literature [13]. The absolute con-
figurations of the product (e.e) were determined by
comparison of HPLC retention times catalyzed by the
racemic proline [8].
1H NMR (500 MHz, CDCl3): d = 1.30–1.38 (1H, m),
1.59–1.85 (4H, m), 2.09–2.14 (1H, m), 2.37–2.43 (1H, m),
2.47–2.51 (1H, m), 2.90–2.97 (1H, m), 4.27–4.31 (1H, m),
4.87–4.94 (2H, m), 7.20–7.25 (3H, m), 7.38–7.39 (1H, m).
2.9.7 (S)-2-((R)-2-Nitro-1-p-tolylethyl)cyclohexanone (9g)
2.9.1 (S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone (9a)
1H NMR (500 MHz, CDCl3): d = 1.20–1.28 (1H, m),
1.57–1.81 (4H, m), 2.03–2.11 (1H, m), 2.32 (3H, s),
2.36–2.42 (1H, m), 2.46–2.50 (1H, m), 2.64–2.70 (1H, m),
1H NMR (500 MHz, CDCl3): d = 1.20–1.28 (1H, m),
1.27–1.82 (4H, m), 2.06–2.11 (1H, m),2.37–2.51 (2H, m),
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G. Wang et al.
3.70–3.75 (1H, m), 4.59–4.63 (1H, m), 4.90–4.94 (1H, m),
As shown in Table 1, it is obvious that the ratio of
cyclohexanone to trans-nitrostyrene played an important
role to the model addition. When the ratio was about 20:1,
the product was obtained in the highest yield (80%),
excellent enantioselectivity (99%) and diastereoselectivity
(99:1). Then, the analogs of 7c were also investigated as
the organocatalysts for the model addition. The Michael
additions of cyclohexanone to trans-nitrostyrene in the
presence of these catalysts afforded similar enantioselec-
tivity and diastereoselectivity, but lower yields (Entries
6–10). These results showed that alkyl length and anion of
ionic liquids exhibited little impact on the stereoselectivity,
but much impact on the reaction yield and time. A plau-
sible reason was that the solubility of 7a–7e and 8 in
cyclohexanone was closed related to their structures. While
7c could dissolve in cyclohexanone, 7e, 7b and 8 could not
absolutely dissolve under the same condition.
7.04 (2H, d, J = 8.0 Hz), 7.12 (2H, d, J = 8.0 Hz).
2.9.8 (2R,3S)-2-Ethyl-4-nitro-3-phenylbutanal (9i)
1H NMR (500 MHz, CDCl3): d = 0.82–0.91 (3H, m),
1.48–1.55 (2H, m), 2.66–2.72 (1H, m),3.77–3.82 (1H, m),
4.61–4.75 (2H, m), 7.18–7.22 (2H, m), 7.29–7.37 (2H, m),
9.73 (1H, d, J = 2.5 Hz).
3 Results and Discussion
In order to improve the stereoselectivity and yield of
asymmetric Michael additions, we designed and prepared
pyrrolidine-based chiral quaternary alkylammonium ionic
liquids 7a–7e and 8. At first, the simplest pyrrolidine-based
quaternary alkylammonium ionic liquid 7e was designed.
Then 7a–7d was designed to study the impact of alkyl
length of ionic liquids on catalytic activity. For studying
the effect of anion, compound 8 was designed. All of them
were easily prepared from the commercially available (S)-
(2-hydroxy-methyl)pyrrolidine 1 in six or seven steps, and
the synthetic route were shown in Scheme 1. Then all these
ionic liquids were used as organocatalysts for asymmetric
Michael additions of cyclohexanone to trans-nitrostyrene,
and the representative results are summarized in Table 1.
A plausible transition state was proposed to explain the
stereochemical results (Scheme 2). In this state, the alkyl
chains of the ILs moiety would hinder nitroolefins to
approach the si-face of enamine. Perhaps the ionic attrac-
tion between the quaternary alkylammonium cation and the
nitro group of the nitroolefins would increase the stere-
oselectivity too [26].
For IL 7c showed the best catalytic activity among the ILs
above when catalyzed the Michael addition of cyclohexa-
none to trans-nitrostyrene, it was selected as the organo-
catalyst for the following studies. Next, the recyclability of
Scheme 1 Synthesis of several chiral ILs
123

Pyrrolidine-Based Chiral Quaternary Alkylammonium Ionic Liquids
1329
Table 1 Michael additions of cyclohexanone to trans-nitrostyrene
Table 2 The effects of acidic additives and solvents
Entry Cat. Cyclohexanone Time Yielda syn/
ee (syn)c
(%)
Entrya Solvent Acids/
(mol %)
Time Yieldb syn/
ee
antib
(h)
(%)
antic (syn)c
(%)
(eq)
(h)
(%)
1
7c
7c
7c
7c
7c
7a
7b
7d
7e
8
10
15
20
30
40
20
20
20
20
20
20
20
48
46
60
80
60
67
56
42
65
60
74
76
70
98/2
98/2
99/1
99/1
99/1
99/1
99/1
99/1
99/1
94/6
99/1
96/4
99
98
99
99
99
99
99
99
99
96
98
96
1
2
3
4
5
6
7
8
9
10
a
MeOH
DMSO
DMF
TFA/5
TFA/5
TFA/5
142
142
144
312
288
288
48
51
56
82
73
74
40
48
39
80
98/2 97
99/1 99
99/1 99
96/4 98
95/5 96
96/4 99
99/1 76
96/4 78
97/3 98
99/1 99
2
72
72
3
4
72
CH2Cl2 TFA/5
5
72
THF
EA
TFA/5
TFA/5
6
144
144
144
96
7
Neat
Neat
Neat
Neat
CH3SO3H/5 168
8
p-TsOH/5
AcOH/5
neat
168
72
9
10
11d
12e
a
216
72
216
7c
7c
480
20 equiv of ketone
b
c
Isolated yield
Isolated yield
b
Determined by chiral HPLC
Determined by chiral HPLC; Column: ChiralPak AS-H; Flowing
phase: 2-propanol/hexane = 10/90; Flowing rate: 0.7 mL/min
c
Determined by chiral HPLC
Interestingly, the Michael reaction could proceed slowly
without acidic additive to afford similar results (entry 10).
The reasons why acidic additives exhibited important
impacts may be explained as follows. As shown in
Scheme 2 (state B), there was enamine structure in the
transition state. A proper acidity was helpful to form the
enamine. When TFA was used as an acidic additive, the
reaction system could attain more appropriate acidity than
CH3SO3H, p-TsOH, and without acidic additive. When
AcOH was used as an additive, it would form a salt with
catalyst 7c which could not absolutely dissolve in cyclo-
hexanone, so the catalytic activity of 7c descended. So
TFA was a better acidic additive than CH3SO3H, p-TsOH,
AcOH and without acidic additive. Then TFA was selected
as the acidic additive for the following studies.
d
Second cycle of catalyst 7c
e
Third cycle of catalyst 7c
Scheme 2 Plausible transition state
catalyst 7c was studied. The result showed that 7c could be
easily recovered from the reaction mixture only by filtration
after ethyl ether was added to the reaction mixture in
90–95% yield. And the Michael addition in the presence of
the recovered 7c obtained similar results but required longer
As shown in Table 2, the impact of solvents on asym-
metric Michael reaction was not significant. The reactions
proceeded in different solvents showed similar stereose-
lectivity, but different reaction yields (entries 1–6). A
plausible reason was that when a strong polar solvent, such
as MeOH, DMSO and DMF, was used, the reaction was
accelerated and the by-product was increased. Then the
reaction time and yield was decreased.
1
reaction time (entries 11–12). The H NMR data of the
recycled 7c showed that the purity of 7c descended. The
descended purity and the loss of the catalyst 7c in recycled
process, perhaps, reduced the catalytic activity of the recy-
cled 7c.
Encouraged by the results described above, the effects
of acidic additives and solvents to the reaction were
investigated, and the results are shown in Table 2. It is
clear that acidic additives exhibited important impact on
the yield and enantioselectivity of the reaction. Better
enantioselectivity was obtained in the presence of TFA or
AcOH rather than CH3SO3H and p-TsOH (entries 7–9).
TFA afforded the best yield among those protonic acids.
Finally, IL 7c was applied to several Michael reactions
for a variety of aldehydes, ketones and nitroolefins. The
results summarized in Table 3 indicated that different
substituents on nitroolefins would yield different results.
While Cl or CH3 substituted aryl nitroolefins gave the
corresponding products with moderate yields, excellent
stereoselectivity (entries 3–6), CH3O substituted indicated
123

1330
G. Wang et al.
Table 3 Asymmetric Michael addition of ketones and aldehydes to trans-nitrostyrenes catalyzed by 7c
Entrya
R1
R2
R3
Time
(h)
Product
Yield
(%)b
Flowing phase
Flowing
rate
(mL/min)
syn/
antic
ee
(%)c
1
2
3
4
5
6
7
8
a
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
2-NO2-Ph
4-OMe-Ph
4-Cl-Ph
2,4-Cl-Ph
2-Cl-Ph
4-Me-Ph
Ph
144
144
168
168
168
72
9b
9c
9d
9e
9f
55
76
85
68
88
73
–
2-propanol:hexane = 7:93
2-propanol:hexane = 10:90
2-propanol:hexane = 10:90
2-propanol:hexane = 10:90
2-propanol:hexane = 10:90
2-propanol:hexane = 10:90
2-propanol:hexane = 10:90
2-propanol:hexane = 1:99
0.7
2
97:3
99:1
97:3
99:1
99:1
99:1
–
96
78
94
99
96
94
–
0.7
0.7
0.7
0.7
0.7
1.0
9g
9h
9i
Me
H
H
72
Et
Ph
72
88
99:1
74
20 equiv of ketone
Isolated yield
b
c
Determined by Chiral HPLC
lower enantioselectivies (entry 2) and NO2 substituted gave
lower yield (entry 1). Furthermore, 1-butyraldehyde was
found to be a suitable Michael donor with high yield
(88%), diastereoselectivities (99:1) and enantioselectivies
(74%). But acetone exhibited low activity, after stirring
240 h under the same reaction conditions, no correspond-
ing adduct was detected (Entries 7, 9). The reasons why the
reaction yield and stereoselectivity was different may be
explained as follows. One plausible reason was the electron
cloud density of the benzyl position of substituted nitro-
olefins was different. One was the space hindrance of the
substituent group on phenyl group of substituted nitroole-
fins was dissimilar. The other was the activity and structure
of aldehydes and ketones were different. The electron-
deficient substituent on phenyl group of nitroolefin would
decrease the electron cloud density of the benzyl position,
which was of benefit to Michael reaction. So 9d and 9f
were obtained with higher reaction yield and stereoselec-
tivity than 9c and 9g (entries 2, 3, 5, 6). The large sub-
stituent group on phenyl group of nitroolefin would hinder
the nitroolefin to approach the enamine structure. So 9b
and 9e were obtained with lower reaction yield (entries 1,
4). The activity and structure of aldehydes and ketones
were important factors too. The activity to form enamine
structure of acetone was too low to obtain Michael product
(entry 8). 1-butyraldehyde could form enamine structure
with catalyst 7c, but this enamine could not hinder nitro-
olefin to approach the si-face of enamine perfectly because
the space hindrance of this enamine was much less than
enamine formed by cyclohexanone and 7c. So 9i was
obtained with higher reaction yield and lower enantiose-
lectivies (entry 7).
4 Conclusions
In conclusion, a series of chiral pyrrolidine-type quaternary
alkylammonium ILs have been developed, which can be
used to promote highly efficient for the asymmetric
Michael addition reactions of cyclohexanone to nitroole-
fins. These chiral ILs catalysts could be easily synthesized
from (S)-(2-hydroxy-methyl)pyrrolidine in six or seven
steps. IL 7c is easily recovered and reused. Further inves-
tigation on the applications of these ILs to other asym-
metric reactions and the structure activity relationship of
catalysts, are presently underway in our lab.
Acknowledgment We are most grateful to Prof. Wan for technical
assistance.
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