Ionic liquid-supported proline as catalyst in direct asymmetric aldol reaction

Article abstract of DOI:10.1134/S1070428008120154

Ionic-liquid-supported proline derivative was synthesized starting from L-proline and was used to catalyze direct asymmetric aldol reaction of acetone with aldehydes. The yield and optical purity of the condensation products, the corresponding β-hydroxy carbonyl compounds were comparable with those obtained under homogeneous conditions. Moreover, the catalyst can be reused for at least four times.

Full text of DOI:10.1134/S1070428008120154

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 12, pp. 1807–1810. © Pleiades Publishing, Ltd., 2008.
Published in Russian in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 12, pp. 1834–1837.
Ionic Liquid-Supported Proline as Catalyst in Direct Asymmetric
Aldol Reaction*
Chen Zhuoa, Li Yongb, Xie Huia, Hu Chang-ganga, and Dong Xiana
a School of Physics and Chemistry, Guizhou Normal University, Guiyang, 550001 China
e-mail: chenzhuo@gznu.edu.cn
b School of Chemistry and Environmental Science, Guizhou University for Ethnic Minorities,
Guiyang, 550004 China
Received April 9, 2007
Abstract—Ionic-liquid-supported proline derivative was synthesized starting from L-proline and was used to
catalyze direct asymmetric aldol reaction of acetone with aldehydes. The yield and optical purity of the con-
densation products, the corresponding β-hydroxy carbonyl compounds were comparable with those obtained
under homogeneous conditions. Moreover, the catalyst can be reused for at least four times.
DOI: 10.1134/S1070428008120154
Asymmetric aldol reaction is one of the most
important carbon–carbon bond-forming processes in
organic synthesis [1]. Among these, the most efficient
and attractive from the viewpoint of atom economy is
direct asymmetric aldol reaction between an aldehyde
and unmodified ketone [2]. L-Proline was recently
used to catalyze direct asymmetric aldol reaction with
formation of the corresponding β-hydroxy carbonyl
compounds with moderate to excellent ee (enantio-
meric excess) values [3–5]. The use of proline as cata-
lyst is advantageous, for the procedure requires no
metal derivatives and the catalyst is cheap and acces-
sible in both enantiomerically pure forms. However,
the reaction was carried out in an organic solvent
(dimethyl sulfoxide, dimethylformamide, chloroform,
tetrahydrofuran, or acetonitrile) whose toxic and/or
hazardous properties restrict large-scale application of
this procedure. Furthermore, it is rather difficult to
reuse chiral catalyst.
In the recent years, ionic liquids have attracted con-
siderable interest as environmentally benign reaction
media due to their fascinating and intriguing prop-
erties, such as high thermal and chemical stabilities,
negligible vapor pressure, nonflammability, friction
reduction, antiwear performance, and high loading ca-
pacity [6]. Ionic liquids are also widely used as media
for electrochemical technologies [7], chemical extrac-
tion [8], and other industrial processes [9]. In most
cases, ionic liquids are readily regenerated and can be
recycled. An attractive feature of ionic liquids is that
their solubility can be tuned easily, so that they can be
separated from both organic and aqueous phases, de-
pending on the choice of cation and anion. The sub-
strate solubility can also be controlled [10]. Therefore,
such low molecular weight ionic liquids may serve as
soluble supports for organic synthesis. Phase separa-
tion between ionic liquid phase, organic phase, and
aqueous phase ensures isolation and purification of
Scheme 1.
(1) BrCH2CH2OH
(2) NaBF4, acetone
Boc-Pro-OH, DCC, DMAP
Pro-Boc
BF4
OH
BF4
O
N
N
N
N
N
N
Me
Me
Me
I
II
III
CF3COOH
Pro-H
O
N
N
Me
CF3COO
IV
* The text was submitted by the authors in English.
1807

CHEN ZHUO et al.
1808
Scheme 2.
products [11]. Ionic liquids were recently used to carry
out aldol condensations [12, 13].
O
O
OH
O
IV (10 mol %)
+
*
In the present study we examined the catalytic ac-
tivity of new ionic liquid-supported proline derivative
in direct asymmetric aldol reaction of acetone with
some aldehydes, as well as the possibility for recycl-
ing. To the best of our knowledge, this is the first
example of direct asymmetric aldol condensation cata-
lyzed by ionic liquid-supported proline.
R
H
Me
Me
R
Me
Va–Vg
R = Ph (a), 4-O2NC6H4 (b), 2-O2NC6H4 (c), 4-BrC6H4 (d),
4-MeC6H4 (e), i-Pr (f), 3-O2NC6H4 (g).
reaction of 1-(2-hydroxyethyl)-1-methylimidazolium
tetrafluoroborate (II) with Boc-L-proline and subse-
quent deprotection of proline derivative III by the
action of trifluoroacetic acid (Scheme 1). Compound
IV was then used to catalyze aldol condensation of
acetone with some aromatic and aliphatic aldehydes
(Scheme 2). The reactions were carried out with
10 mol % of the catalyst and 10 ml of acetone. In all
cases, we isolated the expected aldol condensation
products in good yields and with moderate to excellent
ee values (Table 1).
Initially we prepared ionic liquid-supported proline
IV according to the procedure described in [14], by
Table 1. Asymmetric aldol condensation of acetone with
aldehydes in the presence of L-proline derivative IV
Enantiomeric excess
Compound no.
Yield,a %
ee,b %
70
Va
Vb
Vc
Vd
Ve
Vf
54
75
89
74
69
71
73
85
Next we examined the effect of the amount of the
catalyst in the reaction with o-nitrobenzaldehyde. No
reaction occurred in the absence of ionic liquid-sup-
ported proline IV. Comparable results were obtained in
the presence of 10 and 30 mol % of the catalyst (reac-
tion time 36 and 24 h, respectively). At 5 mol % of the
catalyst, the product yield decreased insignificantly,
whereas in the presence of 1 mol % of IV (48 h) the
yield was almost twice as low. In all cases, the enan-
tioselectivity remained fairly high (82–85%; Table 2).
67
68
92
a
Here and in Tables 2 and 3, yield of the product isolated by
chromatography is given.
Here and in Tables 2 and 3, ee was determined by chiral HPLC.
b
Table 2. Effect of the amount of catalyst IV on the yield and
optical purity of hydroxy ketone Vc in the aldolization of
acetone with o-nitrobenzaldehyde
We then continued our study by exploring the
recyclability of the catalyst, which is important from
the viewpoint of large-scale processes, especially with
expensive catalyst. As model reaction we used the con-
densation of acetone with o-nitrobenzaldehyde in the
presence of ionic-liquid-supported proline IV. When
the reaction was complete, the mixture was concen-
trated by removal of acetone and extracted with diethyl
ether (3×20 ml). The residue was proline derivative
Сatalyst,
mol %
Reaction
time, h
Enantiomeric
excess ee, %
Yield, %
00
01
05
10
10
30
24
48
36
24
36
24
00
41
76
89
90
92
–
82
85
85
85
84
1
IV; according to the H NMR data, it contained no
aldol condensation product. The catalyst was dried for
30 min under reduced pressure and reused. This proce-
dure was repeated four times (Table 3). We observed
only a slight decrease of the chemical yield and enan-
tioselectivity, in keeping with the results obtained in
the reaction in DMSO [4] and with bmimPF6 [12];
however, ee values were lower than under homogene-
ous conditions [4].
Table 3. Recycling of ionic liquid-supported proline IV in
the asymmetric aldol condensation of acetone with o-nitro-
benzaldehyde
Enantiomeric excess
Cycle no.
Yield, %
ee, %
1
2
3
4
89
92
88
86
85
86
We have no reasonable explanation for the ob-
served drop in stereoselectivity. Even if ee values were
slightly higher, the yields were lower, and they con-
85
84
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

IONIC LIQUID-SUPPORTED PROLINE AS CATALYST
1809
siderably decreased after four cycles. Moreover, it
should be remembered that the reaction with o-nitro-
benzaldehyde was performed in toxic solvents such as
dimethylformamide.
were combined with the organic phase and concentrat-
ed under reduced pressure. The residue was washed
with diethyl ether (3×20 ml) and dissolved in methyl-
ene chloride, and the solution was washed with
2 N hydrochloric acid (3×10 ml). The organic phase
was dried over Na2SO4 and evaporated. Yield 1.85 g
(90%), pale yellow oil.
Our results demonstrate that ionic liquid-supported
proline as catalyst provides a convenient approach to
phase separation and isolation of the products, which
may be used in other fields of organic synthesis. Ionic
liquid-supported proline turned out to be a convenient
catalyst for direct asymmetric aldol reaction. In most
cases, no elimination products were detected, or they
were formed in insignificant amounts. The ionic liquid
catalyst may be reused at least four times without
appreciable loss in efficiency and enantioselectivity.
The results of our study indicate that further research
in this line is fairly promising.
1-Methyl-3-{2-[(2S)-pyrrolidine-2-carbonyloxy]-
ethyl}-1H-imidazol-3-ium trifluoroacetate (IV).
Compound III, 1.0 g (2.4 mmol), was dissolved in
10 ml of methylene chloride, 10 ml of trifluoroacetic
acid was added, and the mixture was stirred for 30 min
at room temperature under nitrogen. The mixture was
evaporated under reduced pressure, and the residue
was washed with two portions of diethyl ether and
dried under reduced pressure. Yield 0.7 g (93%), pale
1
yellow oil. H NMR spectrum (acetone-d6), δ, ppm:
EXPERIMENTAL
9.20 s (0.55H), 9.12 s (0.45H), 7.83 s (1H), 7.68 d
(1H), 5.46–5.34 m (0.45H), 4.75–4.58 m (4H), 4.25–
4.15 m (0.55H), 4.05 s (3H), 3.58–3.29 m (2H), 2.50–
2.45 m (2H), 1.09–1.06 m (2H). 13C NMR spectrum
(acetone-d6), δC, ppm: 168.4, 161.2 (0.45C), 161.1
(0.55C), 137.8, 124.0 (0.45C), 123.7 (0.55C), 117.8
(0.45C), 116.1 (0.55C), 64.9, 59.8, 48.5 (0.45C), 47.8
(0.55C), 35.8, 27.8, 23.8 (0.45C), 23.5 (0.55C).
1
The H NMR spectra were recorded on Inova-400
(400 MHz; compounds Va–Vg, CDCl3) and Jeol ECX
Delta 2 spectrometers (500 MHz, salt IV) using tetra-
methylsilane as internal reference. The optical purities
(ee values) were determined by high-performance
liquid chromatography (HPLC) according to the proce-
dure described in [15] on an Agilent Technologies 1100
instrument equipped with a UV detector (λ 254 nm);
Daicel Chiralpak AS-H column; eluent hexane–pro-
pan-2-ol, 70:30, flow rate 1.0 ml/min. Products of
the reaction of acetone with o-nitrobenzaldehyde were
analyzed using Daicel Chiralcel OD column; eluent
hexane–propan-2-ol, 85:15.
All commercially available reagents were used
without additional purification. 1-(2-Hydroxyethyl)-1-
methylimidazolium tetrafluoroborate (II) was synthe-
sized from 1-methyl-1H-imidazole (I) and 2-bromo-
ethanol in the presence of NaBF4, following the proce-
dure reported in [16] (Scheme 1); yield 92%, colorless
liquid.
General procedure for direct aldol condensation
of acetone with aldehydes. A mixture of 10 mol % of
compound IV, 10 ml of acetone, and 1 mmol of the
corresponding aldehyde was stirred for 25 h at room
temperature. The mixture was then extracted with di-
ethyl ether (5×20 ml), and the catalyst was recovered.
The extracts were combined and evaporated, and the
aldol condensation product was isolated from the resi-
due by flash chromatography on silica gel using hex-
ane–ethyl acetate (6:1) as eluent. The catalyst was
kept under reduced pressure to remove residual diethyl
ether or acetone before reuse.
1
4-Hydroxy-4-phenylbutan-2-one (Va). H NMR
1-{2-[(2S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-
carbonyloxy]ethyl}-3-methyl-1H-imidazol-3-ium
tetrafluoroborate (III). A 1 M solution of N,N′-di-
cyclohexylcarbodiimide (DCC) in methylene chloride,
10 ml, was added to a mixture of 1.07 g (5 mmol) of
1-(2-hydroxyethyl)-1-methylimidazolium tetrafluoro-
borate (II), 2.15 g (10 mmol) of Boc-L-proline, and
0.25 g (2 mmol) of 4-dimethylaminopyridine (DMAP)
in 25 ml of anhydrous acetonitrile. The mixture was
vigorously stirred for 18 h at room temperature under
nitrogen and passed through a layer of Celite. The
Celite layer was washed with acetonitrile, the washings
spectrum, δ, ppm: 2.19 s (3H, COCH3), 2.80–2.82 m
(2H, CH2), 3.32 br.s (1H, OH), 5.12 d.d (1H, CH, J =
9.2, 3.1 Hz), 7.16–8.25 m (5H, Harom).
4-Hydroxy-4-(4-nitrophenyl)butan-2-one (Vb).
1H NMR spectrum, δ, ppm: 2.23 s (3H, COCH3), 2.84–
2.87 m (2H, CH2), 3.57 br.s (1H, OH), 5.26–5.28 m
(1H, CH), 7.55 d (2H, Harom, J = 8.1 Hz), 8.22 d (2H,
Harom, J = 8.1 Hz).
4-Hydroxy-4-(2-nitrophenyl)butan-2-one (Vc).
1H NMR spectrum, δ, ppm: 2.23 s (3H, COCH3),
2.75 d.d (1H, CH2, J = 17.2, 9.6 Hz), 3.09 d (1H, CH2,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

CHEN ZHUO et al.
1810
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9.6 Hz), 7.42–7.93 m (4H, Harom).
4-(4-Bromophenyl)-4-hydroxybutan-2-one (Vd).
1H NMR spectrum, δ, ppm: 2.21 s (3H, COCH3), 2.82–
2.84 m (2H, CH2), 3.37 d (1H, OH, J = 2.8 Hz), 5.10–
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(3H, C6H4CH3), 2.77–2.92 m (2H, CH2), 3.26 br.s (1H,
OH), 5.12 d.d (1H, CH, J = 9.2, 3.1 Hz), 7.16 d (2H,
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3.46 br.s (1H, OH), 5.12 d.d (1H, CH, J = 9.2, 3.1 Hz).
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1H NMR spectrum, δ, ppm: 2.23 s (3H, COCH3), 2.88–
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This work was supported by the Natural Science
Foundation of China (grant no. 20862004), by the Key
Project of Science and Technology of Guizhou prov-
ince (grant no. 2007-2022), and by the Special Scien-
tific Research Foundation of Guizhou (grant no. TZJF-
2006.25).
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