Efficient asymmetric aldol reaction catalyzed by polyvinylidene chloride-supported ionic liquid/l-proline catalyst system

Article abstract of DOI:10.1016/j.tetasy.2012.03.023

A series of polyvinylidene chloride (PVDC)-supported ionic liquids were derived from 4-dimethylaminopyridine and used together with l-proline in water as efficient asymmetric organocatalysts for direct asymmetric aldol reactions between cyclohexanone and

Full text of DOI:10.1016/j.tetasy.2012.03.023

Tetrahedron: Asymmetry 23 (2012) 468–473
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Tetrahedron: Asymmetry
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Efficient asymmetric aldol reaction catalyzed by polyvinylidene chloride-sup-
ported ionic liquid/L-proline catalyst system
Xuan Zhang a, Wenshan Zhao b, Chengke Qu b, Lili Yang b, Yuanchen Cui a,
⇑
a Key Laboratory of Ministry of Education for Special Functional Materials, Henan University, Kaifeng 475004, China
b College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 February 2012
Accepted 28 March 2012
A series of polyvinylidene chloride (PVDC)-supported ionic liquids were derived from 4-dimethylamino-
pyridine and used together with -proline in water as efficient asymmetric organocatalysts for direct
asymmetric aldol reactions between cyclohexanone and a variety of aromatic aldehydes at room temper-
ature. These PVDC-supported ionic liquids/ -proline catalyst systems have been used as asymmetric organ-
L
L
ocatalysts to afford the corresponding aldol products with a moderate to high isolated yield of up to 99%,
with diastereoselectivity of up to 6:94, and excellent enantioselectivity of up to 98%. Furthermore, they
could be easily recycled and showed only a slight reduction in selectivity after seven recycles.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
decrease in the ee and yield is observed in some cases during the
recycling and reuse of the catalyst system. Moreover, some func-
The asymmetric aldol reaction is an important C–C bond-form-
ing reaction in synthetic chemistry and in Nature;1 the catalytic
asymmetric aldol reaction is the subject of intense research, due
to the synthetic utility of enantioenriched b-hydroxyl carbonyl enti-
ties produced by enantioselective aldol reactions.2 In particular,
catalytic enantioselective reactions with water as the solvent pos-
sess the advantages of being inexpensive, safe and environmentally
benign and hence have attracted a great deal of attention.3 In recent
years, asymmetric direct aldol reactions have received much atten-
tion, and many chiral catalysts including biocatalysts,4 transition-
metal complexes,5 and organocatalysts6 have been investigated.
Of the various recyclable catalysts, polymer-supported proline,
prolineamides, diarylprolinols, MacMillan imidazolidinones, and
cinchona-derivatives, as well as ionic liquid-supported organic cat-
alysts and inorganic material-supported organocatalysts have been
highly focused on.7
tionalized ionic liquids can be used for a variety of purposes and
are sometimes referred to as task specific ionic liquids.12 Recently
some supported liquid/L-proline catalyst systems have also been
reported for catalyzing asymmetric reactions.13
With all of this in mind, we herein report a new class of ionic
liquids supported by polyvinylidene chloride (PVDC) and use them
together with
asymmetric aldol reactions of ketones catalyzed by the synthesized
PVDC-supported ionic liquid/ -proline have yielded aromatic
L-proline for asymmetric aldol reactions. Herein, the
L
aldehydes under mild and environmentally benign conditions.
2. Results and discussion
A number of PVDC resin supported ionic liquids were prepared
according to the synthetic routes shown in Scheme 1.
The catalyst system’s activity of compounds a, b, and c together
In order to obtain better selectivities and reaction rates, some
researchers have conducted proline-catalyzed aldol reactions under
high pressure8 or in the presence of 1–10 equiv of water.9 The mod-
ification of the structure of proline has also been attempted.10 Sev-
eral room temperature ionic liquids have also been tested as
reaction media in order to investigate the recycling and reuse of pro-
line-based catalysts for asymmetric aldol reactions;11 it has been
found that good yields and enantioselectivities, in comparison to
those obtained from the reactions in dimethyl sulphoxide (DMSO),
can be obtained in the first run of the reactions, but an obvious
with L-proline was evaluated by conducting the direct asymmetric
aldol reaction of 4-nitrobenzaldehyde with cyclohexanone at room
temperature. The relevant results are summarized in Table 1.
Initially, we tested the catalyst system under various conditions.
While screening the catalyst system for the reaction, we found that
the aldol reaction proceeded smoothly at room temperature in the
presence of compound a/L-proline, b/L-proline, and c/L-proline
under neat reaction conditions or in an aqueous medium, to gener-
ate the corresponding products with moderate to high yields and
enantioselectivities. Compounds a/L-prolineand b/L-proline showed
good catalytic performances under all conditions (Table 1, entries 1
and 2 as well as 4 and 5; yield 94–99%; ee 97–98%); while the com-
pound c/L-proline catalyst system showed better performances
⇑
Corresponding author. Tel./fax: +86 378 3881358.
E-mail addresses: yuanchencui@126.com, yccui@henu.edu.cn (Y. Cui).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.023

X. Zhang et al. / Tetrahedron: Asymmetry 23 (2012) 468–473
469
H
H
toluene, 80oC
N
Cl-
N+
HO
HO
H
H
+
Cl Cl
PVDC
n
Cl
N
N
a
Cl
N
N
n
toluene, 80oC
N+
Cl-
+
Cl Cl
PVDC
n
N
b
Cl
80oC
+
n
N+
Cl Cl
PVDC
n
N
Cl-
c
Scheme 1.
Table 1
Screening compounds for the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehydea
O
O
OH
ionic liquid
compound/
L-proline
OHC
+
solvent, r.t.
NO2
NO2
drc (syn/anti)
Entry
Ionic liquid compound
Solvent
Time (d)
Yieldb (%)
Eec (%) (anti)
1
2
3
4
5
6
7
a
b
c
a
b
c
H2O
H2O
H2O
Neat
Neat
Neat
H2O
2
2
2
2
2
2
2
99
99
36
95
94
94
97
10:90
6:94
6.94
8:92
8:92
8:92
6:94
98
98
97
97
98
98
81
d
a
Reaction was performed on a 0.22 mmol scale of aldehyde, 10 equiv of cyclohexanone in the presence of 100
12 mol % of -proline.
l
L H2O, 18 mol % of the compound and
L
b
Isolated yield.
c
Determined by chiral high-performance liquid chromatography (HPLC; Chiralpak AD-H).
under neat reaction conditions (Table 1, entry 6; yield 94%, dr 8:92,
ee 98%) than in water (Table 1, entry 3; yield 36%, dr 6:94, ee 97%).
The resin-free ionic liquid compound d/ -proline (Scheme 2), gave
low ee values (Table 1, entry 7; yield 97%, dr 6:94, ee 81%), compared
with ionic liquid compound b/ -proline (Table 1, entry 2; yield 99%,
dr 6:94, ee 98%). Thus it can be concluded that compound b/ -proline
systems tested, while water helps to increase the dr value of the
asymmetric aldol reaction catalyzed by compound b/ -proline.
Next, we mixed different amounts of compound b with differ-
ent amounts of water and -proline, and examined the catalytic
performance of the resulting mixtures for the aforementioned
asymmetric aldol reaction. The corresponding results are shown
in Table 2. When 18 mol % of compound b and 0.1 mL of water
were used, the yield increased with the increase of the amount
L
L
L
L
L
possessed the best catalytic performance among the three catalyst
of L-proline (Table 2, entries 2–4; yield 57–99%, ee up to 98%, dr
6:94). When the amount of water was increased, the yield
decreased sharply (Table 2, entries 3, 5 and 6). When the amount
of catalysts and L-proline was reduced by 50%, the yield also
reduced by nearly 50% (Table 2, entries 2 and 7). This indicates that
the enantioselectivity and activity of the catalyst system highly
depends on the amount of both the ionic liquid compound and
N
80oC
Cl-
Cl
+
N+
N
Cl
Cl
N
Scheme 2.
water used. When 18 mol % of compound b, 12 mol % of L-proline

470
X. Zhang et al. / Tetrahedron: Asymmetry 23 (2012) 468–473
Table 2
Screening amounts of catalyst and solvent for the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehydea
ionic liquid
compound b/
L-aproline
O
O
OH
OHC
+
H2O, r.t.
NO2
NO2
Entry
Compound b (mol %)
Solvent (mL)
Time (d)
Yieldb (%)
drc (syn/anti)
Eec (%) (anti)
L
-Proline (mol %)
1
2
3
4
5
6
7
8
22
18
18
18
18
18
9
25
18
12
6
12
12
6
0.1
0.1
0.1
0.1
0.5
1.0
0.1
0.1
2
2
2
2
2
2
2
7
92
99
99
57
22
20
50
Trace
6:94
8:92
6:94
8:92
21:79
33:67
7:93
—
96
96
98
95
41
53
95
—
—
20
a
Reaction was performed on a 0.22 mmol scale of aldehyde, 10 equiv of ketone in the presence of different amounts of compound b,
water.
L-proline and
b
Isolated yield.
Determined by chiral HPLC analysis (Chiralpak AD-H).
c
Table 3
Effect of the amount of cyclohexanone on the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde
catalyzed by compound b/L-prolinea
O
O
OH
ionic liquid
compound b/
L-proline
OHC
+
0.1 mL of H2O, r.t.
NO2
NO2
Entry
Cyclohexanone (equiv)
Yieldb (%)
drc (syn/anti)
Eec (%) (anti)
1
2
3
4
5
6
12
10
8
6
4
99
99
99
99
98
96
9:91
6:94
7:93
6:94
6:94
6:94
97
98
98
98
98
98
2
a
Reaction was performed on a 0.22 mmol scale of aldehyde and different equivalent of ketone in the presence of
18 mol % of compound b, 12 mol % of
L
-proline and 0.1 mL of water at room temperature for 2 days.
b
Isolated yield.
c
Determined by chiral HPLC analysis (Chiralpak AD-H).
and 0.1 mL of water were used, the best reaction conditions were
achieved (Table 2, entry 3; yield 99%, dr 7:94, ee 98%). However,
when only L-proline was used as the catalyst, only trace amounts
enantioselectivities and diastereoselectivities (Table 4, entries 1–
3 and 9–11), while weak electron-withdrawing groups attached
to the benzene ring slightly slowed down the asymmetric aldol
reaction (Table 4, entries 4-6). When 4-methoxybenzaldehyde
was used, the reaction did not take place (Table 4, entry 7). Cyclo-
pentanone reacted with 4-nitrobenzaldehyde to give the product
in a high yield and with better enantioselectivity [Table 4, entry
8; yield 97%, dr 73:27, ee (anti) 91%, ee (syn) 80%]. When cyclohex-
anone was replaced by acetone, the yields decreased slightly, while
enantioselectivities were moderate. When 3-nitrobenzaldehyde
was used as the aldol donor and acetone as the acceptor, good yield
and enantioselectivity were obtained (Table 4, entry 11; yield 90%,
ee 95%). 2-Butanone was also used and gave high yield and moder-
ate selectivity (Table 4, entry 16; yield 92%, dr 42:58, ee 78%).
of the desired product were isolated (Table 2, entry 8).
In order to optimize the reaction conditions, we also examined
the effect of the amount of cyclohexanone on the aldol reaction un-
der investigation. As shown in Table 3, when the amount of cyclo-
hexanone was reduced from 12 to 6 equiv, the catalyst system
exhibited good activity and high enantioselectivity (Table 3, entry
4; yield 99%, dr 6:94, ee 98%). When decreasing the amount of
cyclohexanone, the yield also decreased. The optimized reaction
conditions for the aldol reaction between cyclohexanone and 4-
nitrobenzaldehyde catalyzed by compound b/L-proline were sug-
gested as 18 mol % of compound b, 12 mol % of
L-proline, 0.1 mL
of water, and 6 equiv of cyclohexanone at room temperature for
2 days. The highest yield and stereoselectivity were obtained under
these optimized reaction conditions.
Under these optimized reaction conditions, a series of alde-
hydes and ketones were tested in order to examine the scope of
the substrates (Table 4). It was found that substituted benzalde-
hydes with strong electron-withdrawing groups attached to the
benzene ring accelerated the reaction and afforded good yields,
The recyclability of the compound b/L-proline catalyst system
for the aldol reaction between 4-nitrobenzaldehyde and cyclohex-
anone was also investigated with the relevant results shown in Ta-
ble 5. Good yield and high stereoselectivities were retained even
after six cycles of the catalyst system. This indicates that the pre-
pared PVDC-supported ionic liquid/L-proline catalyst systems
show promising applications as efficient catalysts for the asym-
metric aldol reaction between ketones and aromatic aldehydes.

X. Zhang et al. / Tetrahedron: Asymmetry 23 (2012) 468–473
471
Table 4
Asymmetric aldol reactions catalyzed by compound b/L-prolinea
O
O
OH
ionic liquid
compound b/
L-proline
OHC
R1
R1
+
R
R2
R
R2
01. mL of H2O, r.t.
Entry
Aldehyde
4-NO2
2,4-Dinitro
4-CN
4-F
4-Cl
Ketone
Yieldb (%)
drd (anti/syn)
Eec (%)
1
2
3
4
5
6
7
8
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclopentanone
Acetone
Acetone
Acetone
Acetone
Acetone
99
99
99
96
96
94
Trace
97
89
87
90
90
78
82
75
74
92
6:94
7:93
7:93
29:71
12:88
12:88
—
73:27
—
—
—
—
—
—
—
—
42:58
98
98
87
91
96
97
—
4-Br
4-CH3O-
4-NO2
4-NO2
2-NO2
3- NO2
2,4-Dinitro
4-CN
4-F
4-Cl
4-Br
4-NO2
91 (anti) 80 (syn)
9d
10d
11d
12d
13d
14d
15d
16d
17e
71
87
95
67
69
67
72
73
78
Acetone
Acetone
Acetone
Butanone-2
a
A mixture of aldehyde (0.22 mmol), water (0.1 mL), cyclohexanone (6 equiv) or acetone (0.5 mL), catalyst system (containing
18 mol % of compound b and 12 mol % of
L
-proline) was stirred at room temperature for 2 days.
b
Isolated yield.
c
Determined by chiral HPLC analysis (Chiralpak AD-H or AS-H).
Acetone was used as the aldol acceptor.
0.5 mL of butanone-2 was used.
d
e
Table 5
Recovery and reuse of recoverable compound b/L-prolinea
O
OH
O
ionic liquid
OHC
compound b/
L-proline
+
NO2
0.1 mL H2O, r.t.
NO2
Eec (%; anti)
Cycle
Yieldb (%)
drc (syn/anti)
0
1
2
3
4
5
6
99
99
99
99
99
99
99
7:93
9:91
9:91
10:90
11:89
7:93
98
98
98
97
98
98
98
11:89
a
Reaction was performed on a 0.22 mmol scale of aldehyde, 6 equiv of cyclohexanone in the presence of 18 mol %
of compound b, 12 mol % of
L
-proline and 0.1 mL of water and was stirred at room temperature for 2 days.
b
Isolated yield.
c
Determined by chiral HPLC analysis (Chiralpak AD-H).
recovered and recycled while retaining good activity and enantiose-
lectivity even after six cycles of recovery, thus showing promising
application as an efficient organocatalyst system for asymmetric
aldol reactions between ketones and aromatic aldehydes.
3. Conclusion
In conclusion, we have developed a series of PVDC-immobilized
ionic liquid compound/ -proline systems by making use of simple
L
synthetic procedures. These catalyst systems as novel, highly stere-
oselective and recyclable organocatalysts for the asymmetric aldol
reaction between ketones and aromatic aldehydes possess good cat-
alytic performance. The PVDC-supported N,N-dimethylpyridin-4-
4. Experimental
4.1. General
amine/L-proline system is able to catalyze the asymmetric aldol
PVDC powder (type #2051-2) was purchased from Kureha Cor-
poration. Aromatic aldehydes, 4-dimethylaminopyridine (DMAP),
reaction between cyclohexanone and a variety of aromatic alde-
hydes with high yields (up to 99%) as well as excellent diastereose-
lectivities (dr >6:94) and enantioselectivities (ee >98%). Further
cinchonine (CN) and
L-proline were purchased from the commercial
supplier Alfa Aesar. Ketones and pyridine (PD) were purchased from
more, the compound b/L-proline catalyst system can be readily

472
X. Zhang et al. / Tetrahedron: Asymmetry 23 (2012) 468–473
Sinopharm Chemical Reagent Co., Ltd. Other common solvents and
reagents were purchased from common markets. All the reagents
and solvents were used without further purification. Thin layer
chromatography (TLC) analysis was carried out with GF254 silica
gel plates. Infrared spectra were recorded with an Avatar 360 Fou-
rier transform infrared spectrometer (FTIR; Nicolet Company,
USA). Nuclear magnetic resonance (NMR) spectra were obtained
with a Bruker Avance 300 M system, and the chemical shifts of 1H
NMR spectra are given in relation to tetramethylsilane (d = 0). Melt-
ing points were measured with an X-6 melting point apparatus.
Ultimate analysis was conducted with a PE 2400-II CHNS/O elemen-
tal analyzer. High performance liquid chromatography (HPLC) anal-
ysis was performed with Agilent 1100 (Daicel Chiralpak AD-H or AS-
H columns) equipped with a diode array ultraviolet (UV) detector
and isopropanol or n-hexane as the eluent.
ether–ethyl acetate (2.5:1) as the eluent, to afford the correspond-
ing pure aldol adducts. The resulting pure products were weighed
to calculate the yield, ee and dr values based on HPLC analysis.
4.4.1. 2-[Hydroxyl(4-nitrophenyl)methyl]cyclohexan-1-one14
[Daicel Chiralpak AD-H column, n-hexane/isopropanol = 92:8;
flow rate in first 10 min is 1.0 mL minꢁ1, then it is gradually
increased to 1.5 mL minꢁ1 in another 10 min. k = 268 nm;
tR (anti) = 32.05 min (major) and 25.04 min, tR (syn) = 22.49 min
and 20.58 min]; 1H NMR (300 MHz, CDCl3) d: 8.20–8.26 (m, 2H),
7.47–7.54 (m, 2H), 4.93 (d, J = 8.1 Hz, 1H), 4.09 (s, 1H), 2.32–2.67
(m, 3H), 2.06–2.17 (m, 1H), 1.81–1.88 (m, 1H), 1.36–1.75 (m, 4H).
4.4.2. 2-[Hydroxyl(2,4-dinitrophenyl)methyl]cyclohexan-1-one
1414a
[Daicel Chiralpak AD-H column, n-hexane/isopropanol = 92:8,
4.2. Preparation of PVDC resin-supported ionic liquids a–c
flow rate 1.2 mL minꢁ1
, k = 254 nm; tR (anti) = 43.57 min and
38.81 min (major), tR (syn) = 29.26 min and 24.70 min (major)]; 1H
NMR (400 MHz, CDCl3) d: 1.61–1.68 (m, 1H), 1.69–1.79 (m, 1H),
1.79–1.82 (m, 1H), 1.82–1.88 (m, 1H), 2.04–2.14 (m, 1H), 2.11–
2.33 (m, 1H), 2.44–2.47 (m, 1H), 2.73–2.77 (m, 1H), 5.51–5.53 (br
s, 1H), 6.05–6.06 (d, J = 1.9 Hz, 1H), 8.06–8.08 (d, J = 8.7 Hz, 1H),
8.45–8.49 (d, J = 2.4, 8.7 Hz, 1H), 8.74–8.75 (d, J = 2.3 Hz, 1H).
4.2.1. Synthesis of PVDC-CN (compound a)
Into a round-bottomed flask charged with 25 mL of toluene
were added 1.0 g of PVDC and 1 g of cinchonine. The reaction mix-
ture was left at 80 °C for 3 h, after which ethanol was added to give
a crude product. The crude product was filtered, washed with
ethanol, and dried in vacuo, to generate brown PVDC-CN (com-
pound a) as a brown powder. Elemental analysis showed that cat-
alyst a has a cinchonine unit loading of 0.82 mmol/g (based on
4.4.3. 2-[Hydroxyl(4-cyanophenyl)methyl]cyclohexan-1-one14
[Daicel Chiralpak AD-H column, n-hexane/isopropanol = 92:8, flow
rate 1.0 mL minꢁ1, k = 268 nm; tR (anti) = 38.34 min (major) and
29.32 min, tR (syn) = 25.89 min and 22.12 min]; 1H NMR (300 MHz,
CDCl3) d: 1.32–1.41 (m, 1H), 1.49–1.73 (m, 3H), 1.81–1.83 (m, 1H),
2.08–2.15 (m, 1H), 2.31–2.41 (m, 1H), 2.47–2.62 (m, 2H), 4.07 (s,
1H), 4.84 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz,
2H).
nitrogen element). Catalyst a was used together with L-proline as
a novel catalyst for the direct asymmetric aldol reaction.
4.2.2. Synthesis of PVDC-DMAP (compound b) and PVDC-PD
(compound c)
PVDC-DMAP (compound b) and PVDC-PD (compound c) were
synthesized using the same procedures for preparing catalyst a.
Elemental analysis showed that compound b has a DMAP unit
loading of 1.71 mmol/g (based on nitrogen element) while com-
pound c has a pyridine unit loading of 1.14 mmol/g (based on
nitrogen element).
4.4.4. 2-[Hydroxyl(4-fluorophenyl)methyl]cyclohexan-1-one15
[Daicel Chiralpak AD-H column, n-hexane/isopropanol = 90:10,
flow rate 0.3 mL minꢁ1; k = 224 nm; tR (anti) = 48.73 min (major)
and 44.39 min, tR (syn) = 33.31 min and 29.35 min]; 1H NMR
(300 MHz, CDCl3) d: 1.41–1.87 (m, 5H), 1.91–2.21 (m, 1H),
2.26–2.49 (m, 3H), 3.01–3.20 (br s, 1H), 3.88–3.92 (br s, 1H),
4.70–4.73 (d, J = 9.0 Hz, 1H), 5.29 (s, 1H), 6.96–7.00 (m, 2H),
7.20–7.23 (br s, 2H).
4.2.3. Synthesis of EC-DMAP (compound e)
Into a round-bottomed flask charged with 10 mL of ethylidene
chloride were added 0.25 g of DMAP. The reaction mixture was left
at 80 °C for 3 h, after which ethyl ether was added to give a crude
product. The crude product was filtered, washed with ethyl ether,
and dried in vacuo to give EC-CN (compound e, 0.43 g, yield 95%) as
a white powder.
4.4.5. 2-[Hydroxyl(4-chlorophenyl)methyl]cyclohexan-1-one15
[Daicel Chiralpak AD-H column, n-hexane/isopropanol = 90:10,
flow rate 0.3 mL minꢁ1; k = 224 nm; tR (anti) = 52.57 min (major)
and 46.33 min, tR (syn) = 35.05 min and 30.43 min]; 1H NMR
(300 MHz, CDCl3) d: 1.55–1.87 (m, 5H), 1.98–2.09 (m, 1H), 2.33–2.55
(m, 3H), 3.00 (br s, 1H), 3.91 (br s, 1H), 4.71–4.74 (d, J = 9.0 Hz, 1H),
5.33 (s, 1H), 7.20–7.30 (m, 4H).
4.3. Recyclability of PVDC supported ionic liquid/L-proline
After the reaction was complete, 5 mL of tetrahydrofuran (THF)
were added into the reaction system, followed by stirring for
2 min, filtering, and washing with THF (2 ꢀ 5 mL), giving the recov-
ered catalysts after drying in a vacuum oven. These recovered cat-
alysts were reused directly without further purification.
4.4.6. 2-[Hydroxyl(4-bromophenyl)methyl]cyclohexan-1-one15
[Daicel Chiralpak AD-H column, n-hexane/isopropanol = 90:10,
flow rate 0.3 mL minꢁ1; k = 224 nm; tR (anti) = 56.72 min (major)
and 49.43 min, tR (syn) = 36.57 min and 31.13 min]; 1H NMR
(300 MHz, CDCl3) d: 1.50–1.87 (m, 5H), 2.05–2.11 (m, 1H), 2.33–2.57
(m, 3H), 3.05 (br s, 1H), 3.93 (br s, 1H), 4.70–4.73 (d, J = 9.0 Hz, 1H),
5.30 (br s, 1H), 7.14–7.18 (m, 2H), 7.42–7.46 (m, 2H).
4.4. General procedure for the aldol reactions
Into a solution of the aldehyde acceptor (0.22 mmol) and the
ketone donor (cyclohexanone 6 equiv or acetone 0.5 mL) were
added 0.1 mL of water, 18 mol % of compound b and 12 mol % of
4.4.7. 2-[Hydroxyl(4-bromophenyl)methyl]cyclopentan-1-one
[Daicel Chiralpak AD-H column, n-hexane/isopropanol = 92:8,
flow rate 0.8 mL minꢁ1; k = 254 nm; tR (anti) = 33.85 min (major)
and 33.00 min, tR (syn) = 24.42 min and 18.09 min (major)]; 1H
NMR (300 MHz, CDCl3) d: 1.60–2.73 (m, 7H), 4.84 (d, J = 4.6 Hz,
1H), 5.42 (d, J = 3.6 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 8.20 (d,
J = 8.4 Hz, 2H).
L-proline. The resulting reaction system was stirred at room tem-
perature for a pre-set time. At the end of the reaction, THF was
added into the reaction system, followed by filtering, washing with
THF, drying over anhydrous Na2SO4, and concentration to give
crude products. The crude products were then separated and puri-
fied using a silica gel chromatographic column with petroleum

X. Zhang et al. / Tetrahedron: Asymmetry 23 (2012) 468–473
473
4.4.8. 4-Hydroxy-3-methyl-4-(4-nitrophenyl)-butan-2-one
12.91 min]; 1H NMR (300 MHz, CDCl3) d: 2.10 (s, 3H), 2.67 (m,
2H), 3.55 (br s, 1H), 5.10 (dd, J = 5.0, 7.0 Hz, 1H), 7.20 (d,
J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H).
[Daicel Chiralpak AS-H column, n-hexane/isopropanol = 70:30,
flow rate 1.0 mL minꢁ1
, k = 254 nm; tR (anti) = 11.78 min and
11.14 min (major) and tR (syn) = 9.91 min]; 1H NMR (300 MHz,
CDCl3) d: 1.07 (t, 3H), 2.49 (q, J = 7.5, 3H), 2.86 (m, 1H), 5.63 (m,
1H), 7.51–8.92 (m, 4H).
4.4.16. 4-Hydroxyl-4-(40-bromophenyl)-butan-2-one16
[Daicel Chiralpak AS-H column, n-hexane/isopropanol = 85:15,
flow rate 1.0 mL minꢁ1, k = 254 nm; tR = 11.12 min (major) and
12.91 min]; 1H NMR (300 MHz, CDCl3) d: 2.20 (s, 3H), 2.70–2.80
(m, 2H), 3.38 (br s, 1H), 5.08 (dd, J = 5.6, 7.8 Hz, 1H), 7.22 (d,
J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H).
4.4.9. 4-Hydroxyl-4-(40-nitrophenyl)-butan-2-one16
[Daicel Chiralpak AS-H column, n-hexane/isopropanol = 70:30,
flow rate 1.0 mL minꢁ1, k = 254 nm; tR = 15.39 min and 12.08 min
(major)]; 1H NMR (300 MHz, CDCl3) d: 2.21 (s, 3H), 2.80–2.85 (m,
2H), 3.56 (br s, 1H), 5.20–5.30 (m, 1H), 7.52 (d, J = 7.0 Hz, 2H),
8.20 (d, J = 7.0 Hz, 2H).
References
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4.4.10. 4-Hydroxyl-4-(20-nitrophenyl)-butan-2-one16
[Daicel Chiralpak AS-H column, n-hexane/isopropanol = 70:30,
flow rate 1.0 mL minꢁ1, k = 254 nm; tR = 12.87 min and 11.09 min
(major)]; 1H NMR (300 MHz, CDCl3) d: 2.24 (s, 3H), 2.70–2.85 (m,
2H), 3.70–3.76 (br s, 1H), 5.70 (dd, J = 9.3 Hz, 1H), 7.71 (dt, J = 1.2,
8.1 Hz, 1H), 7.44 (dt, J = 1.2, 8.1 Hz, 1H), 7.91 (dd, J = 1.2, 8.1 Hz,
1H), 7.96 (dd, J = 1.2, 8.1 Hz, 1H).
4.4.11. 4-Hydroxyl-4-(30-nitrophenyl)-butan-2-one16
[Daicel Chiralpak AS-H column, n-hexane/isopropanol = 70:30,
flow rate 1.0 mL minꢁ1, k = 254 nm; tR = 11.37 min and 9.74 min
(major)]; 1H NMR (300 MHz, CDCl3) d: 2.23 (s, 3H), 2.82 (m, 2H),
3.50 (br s, 1H), 5.15–5.27 (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.71
(d, J = 7.5 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.24 (s, 1H).
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4.4.12. 4-(20,40-Dinitrophenyl)-4-hydroxylbutan-2-one
[Daicel Chiralpak AS-H column, n-hexane/isopropanol = 70:30,
flow rate 1.0 mL minꢁ1, k = 254 nm; tR = 16.77 min (major) and
11.29 min]; 1H NMR (300 MHz, CDCl3) d: 2.13 (s, 3H), 2.79–3.06
(m, 2H), 3.65 (br s, 1H), 4.73 (dd, J = 9.3 Hz, 1H), 7.88 (dt, J = 1.2,
8.1 Hz, 1H), 8.53 (dd, J = 1.2, 8.1 Hz, 1H), 8.84 (dd, J = 1.2 Hz, 1H).
4.4.13. 4-Hydroxyl-4-(40-cyanophenyl)-butan-2-one16
[Daicel Chiralpak AS-H column, n-hexane/isopropanol = 85:15,
flow rate 1.0 mL minꢁ1, k = 254 nm; tR = 17.68 min and 10.70 min
(major)]; 1H NMR (300 MHz, CDCl3) d: 2.21 (s, 3H), 2.82 (m, 2H),
3.32 (br s, 1H), 5.20 (m, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.64 (d,
J = 8.1 Hz, 2H).
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4.4.14. 4-Hydroxyl-4-(40-fluorophenyl)-butan-2-one16
[Daicel Chiralpak AS-H column, n-hexane/isopropanol = 85:15,
flow rate 1.0 mL minꢁ1, k = 254 nm; tR = 11.12 min (major) and
12.91 min]; 1H NMR (300 MHz, CDCl3) d: 2.23 (s, 3H), 2.87
(m, 2H), 3.35 (br s, 1H), 5.16 (dd, J = 4.6, 6.6 Hz, 1H), 7.09
(d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H).
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4.4.15. 4-Hydroxyl-4-(40-chlorophenyl)-butan-2-one16
[Daicel Chiralpak AS-H column, n-hexane/isopropanol = 85:15,
flow rate 1.0 mL minꢁ1, k = 254 nm; tR = 11.12 min (major) and