Silica gel supported pyrrolidine-based chiral ionic liquid as recyclable organocatalyst for asymmetric Michael addition to nitrostyrenes

Article abstract of DOI:10.1016/j.tet.2008.05.039

A novel silica gel supported pyrrolidine-based chiral ionic liquid 6a has been developed and found to be a highly effective catalyst for the Michael addition reaction of ketones with nitrostyrenes. The reactions generated the corresponding products in good yields (up to 94%), excellent enantioselectivities (up to >99% ee), and high diastereoselectivities (up to >99:1 dr). In addition, the catalyst 6a can be reused at least five times without a significant loss of catalytic activity and stereoselectivity.

Full text of DOI:10.1016/j.tet.2008.05.039

Tetrahedron 64 (2008) 7633–7638
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Silica gel supported pyrrolidine-based chiral ionic liquid as recyclable
organocatalyst for asymmetric Michael addition to nitrostyrenes
a
a
,
c
,
a
b,
*
*
Pinhua Li , Lei Wang
, Yicheng Zhang , Guanwu Wang
a
Department of Chemistry, Huaibei Coal Teachers College, Huaibei, Anhui 235000, PR China
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, PR China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel silica gel supported pyrrolidine-based chiral ionic liquid 6a has been developed and found to be
a highly effective catalyst for the Michael addition reaction of ketones with nitrostyrenes. The reactions
generated the corresponding products in good yields (up to 94%), excellent enantioselectivities (up to
Received 18 February 2008
Received in revised form 5 May 2008
Accepted 9 May 2008
>
99% ee), and high diastereoselectivities (up to >99:1 dr). In addition, the catalyst 6a can be reused at
least five times without a significant loss of catalytic activity and stereoselectivity.
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 14 May 2008
Keywords:
Supported chiral ionic liquids
Asymmetric Michael addition
Organocatalysts
Nitrostyrenes
Recyclable
1
. Introduction
associated with chemical processes have encouraged the de-
velopment of more environmentally friendly methodology for or-
ganic reactions. In recent years, immobilizing chiral organocatalyst
has received considerable interest. A great deal of efforts has gone
into the development of asymmetric organic reactions catalyzed by
The development of non-metallic asymmetric catalysis has
drawn much attention in recent years. Among all the organo-
molecules catalyzed reactions, asymmetric conjugate addition has
received much more attentions because it is one of the most im-
12
supported organocatalyst. Silica gel, polymer, ionic liquid sup-
1
13
portant C–C bond-forming reactions in organic chemistry. The
ported L-proline has been successfully used in aldol reactions.
asymmetric Michael addition reactions of nucleophiles to electron
deficient nitroalkenes are particularly useful because the products,
optically active nitroalkanes, are versatile building blocks for agri-
Recently, some recyclable organocatalysts for asymmetric Michael
addition of ketone or aldehydes with nitroolefins have also been
14
developed, such as fluorous pyrrolidine sulfonamide, ionic liquid
2
15
cultural and pharmaceutical research. In the past decades, various
supported pyrrolidine-based catalyst, polymer supported pyrro-
16
17
enantioselective processes have been developed for the addition of
lidine, polymer supported thiourea catalyst, etc. Herein we wish
to report a novel silica gel supported pyrrolidine-based organo-
3
ketones to nitroalkenes. Chiral metal–ligand complexes and
metal-free chiral organocatalysts have been achieved. The orga-
nocatalytic asymmetric Michael addition of ketone with nitro-
olefins was pioneered by List and Barbas, independently. Since
then, the interest in the field of asymmetric Michael addition has
catalyst, which was easily prepared from (S)-Boc-L-proline as
shown in Scheme 1, that catalyzes the reaction of ketones with
arylnitroolefins smoothly in excellent yields with high diaster-
eoselectivities and excellent enantioselectivities (up to 94% of yield,
up to >99% ee and up to >99:1 dr).
4
5
increased intensively and various effective organocatalysts have
6
been widely developed, such as modified
L
-proline, pyrrolidine-
based diamine,7 chiral diaime, chiral guanidine, cinchona alka-
8
9
2. Results and discussion
1
0
loids-based bifunctional organocatalyst,
urea(thiourea)-based
etc. Environmental concerns
11
bifunctional organocatalysts,
Initially, various solvents and additives were examined at room
temperature by using 6a and 6b as catalysts, as shown in Table 1.
Both silica gel supported catalysts, 6a and 6b, were effective to the
addition of cyclohexanone with trans-b-nitrostyrene, and a slight
difference was observed on both activity and selectivity. It was
*
Corresponding authors. Tel.: þ86 561 380 2069; fax: þ86 561 309 0518 (L.W.).
E-mail addresses: leiwang@hbcnc.edu.cn (L. Wang), gwang@ustc.edu.cn
(
G. Wang).
obvious that 6a is slightly superior to 6b not only in activity, but
0
040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.039

7634
P. Li et al. / Tetrahedron 64 (2008) 7633–7638
Cl3Si
CH2Cl
OH
OH
OH
O
O Si
O
CH2Cl
Toluene, 120 °C
1
OH
OH
OH
O
O Si
O
(
H3CO)3Si
Cl
Cl
Toluene, 120 °C
2
O
.
NaBH4, BF3 OEt2
IPAc, 0 °C to rt
1. TsCl/ Pyrridine
OH 2. Imidazole/NaH
N
N
N
OH
N
N
Boc
3
Boc
4
Boc
5
O
O Si
O
Cl
N
N
6a
NH
1. 1 or 2
5
2. HCl/C2H5OH
O
Cl
O Si
O
N
N
NH
6b
O
Ar
O
Yield: up to 96%
ee: up to >99%
dr: up to >99:1
NO2
6
a (10 mol-%)
NO2
+
Ar
Solvent-free, r.t., 36h
Scheme 1. Synthesis of silica gel supported pyrrolidine-based chiral ionic liquid and its application in asymmetric Michael addition to nitrostyrenes.
ꢀ
completed in 36 h with 10 mol % of 6a at room temperature (25 C)
also in selectivity (entry 1 vs 2, entry 3 vs 4, entry 5 vs 6, and entry
2 vs 13, Table 1). As shown in Table 1, the reactions were carried
out with 10 mol % of 6a in a variety of solvents (entries 1, 3, 5, and
–11, Table 1). In polar solvents, such as EtOH, DMF, CH Cl , H O,
1
(entries 15 and 16, Table 1). The reaction time, as expected, was
inversely proportional to the temperature. Room temperature
ꢀ
7
2
2
2
(25 C) was found to be optimal. Thus, the optimized reaction
the Michael addition reactions proceeded smoothly to give the
corresponding products in moderate to good yields with excellent
enantioselectivities and diastereoselectivities (entries 1, 3, 5, and 7,
conditions for this Michael reaction are 6a (10 mol %) in neat re-
action conditions at room temperature (25 C) for 36 h.
ꢀ
Under the optimized reaction conditions, a variety of nitro-
olefins with different substituents were investigated, and the re-
sults are summarized in Table 2. Various styrene-type nitroolefins
reacted smoothly with cyclohexanone in good yields, high dia-
stereoselectivities, and excellent enantioselectivities (entries 1–12,
Table 2). Generally, substituents on aryl groups slightly influenced
the diastereoselectivities and enantioselectivities as well as the
yields. For example, nitroolefins with aryl rings bearing both
electron-withdrawing and electron-donating groups gave the de-
sired products with high selectivity (dr up to >99:1 and ee up to
>99%) in excellent yields (up 94% of yield). Moreover, the Michael
reactions were evaluated with other ketones and found that tet-
rahydrothiopyran-4-one and tetrahydro-4H-pyran-4-one were
also suitable substrates as Michael donors (entries 13 and 14,
Table 2). However, acetone and cyclopentanone served as efficient
Michael donor to produce the desired adducts with excellent
yields, but moderate to good enantioselectivities (entries 15 and
16, Table 2).
Table 1), whereas using Et
yields and similar enantioselectivities and diastereoselectivities
entries 8 and 9, Table 1). In non-polar solvents, such as toluene and
2
O and THF as solvents resulted in poor
(
hexane, the Michael addition reactions also proceeded smoothly to
give the desired products in good yields with excellent enantiose-
lectivities and diastereoselectivities (entries 10 and 11, Table 1). To
our delight, under solventless reaction conditions, higher isolated
yields and similar enantioselectivities and diastereoselectivities
were observed (entries 12 and 13, Table 1). Moreover, slightly
higher enantioselectivity and diastereoselectivity were observed
when the reaction temperature was down from room temperature
ꢀ
ꢀ
(
(
25 C) to 10 C without a significant decrease of the reaction rate
entry 17, Table 1). It is noteworthy that the addition of a catalytic
amount of organic acids could decrease dramatically the reaction
rate without a loss of enantiomeric excess and diastereoselectivity
(
entry 14, Table 1). To avoid the use of volatile solvents, reduce the
environmental pollution, and enhance activity and selectivity, all
the Michael reactions were performed under solvent-free reaction
conditions.
During the course of our further optimization of the reaction
conditions, we observed that the reactions were generally
In addition, the recyclability of the supported pyrrolidine 6a
was investigated. After carrying out the reaction, the catalyst was
filtered using a sintered-glass funnel and washed with ethyl ac-
etate (3 mL) and dichloromethane (3 mL), respectively. After

P. Li et al. / Tetrahedron 64 (2008) 7633–7638
7635
Table 1
Table 2 (continued)
a
Optimization of the reaction conditions
Entry
Product
Yieldb (%)
94
eec (%)
97
drd
O
Ph
O
_
_
O
O
C6H4 4 F
NO2
Ph
NO2
Catalyst 6 (10 mol%)
+
7
8
98:2
r. t., solvent, 36 h
NO2
7g
Entry
Catalyst
Solvent
Yieldb (%)
eec (%)
drd
_ _
C6H4 4 Cl
NO2
1
2
3
4
5
6
7
8
9
6a
6b
6a
6b
6a
6b
6a
6a
6a
6a
6a
6a
6b
6a
6a
6a
6a
EtOH
EtOH
DMF
DMF
71
68
76
72
61
56
51
32
35
72
78
91
87
76
69
68
73
98
97
99:1
99:1
98:2
98:2
98:2
98:2
98:2
98:2
98:2
98:2
98:2
99:1
98:2
98:2
99:1
99:1
99:1
92
86
99
98
99:1
98
98
98
96
98
98
98
98
99
99
98
98
98
98
>99
7h
CH
CH
2
Cl
Cl
2
O
O
2
2
2
H O
THF
Et
9
O
O
98:2
2
O
NO2
1
0
Hexane
Toluene
Neat
Neat
Neat
Neat
Neat
Neat
1
1
7i
1
2
1
3
e
f
1
4
O
1
5
g
1
6
10
85
>99
99:1
NO2
7j
h
17
a
Nitrostyrene (0.5 mmol), cyclohexanone (1.0 mmol under solvent conditions or
0
.4 mL under neat conditions), and catalyst 6 (contains 0.05 mmol of active loading)
ꢀ
in solvent (2.0 mL) at room temperature (25 C) for 36 h.
b
Isolated yields.
c
Determined by HPLC using chiralpak AD-H column.
d
Diasteromeric ratio, dr (syn/anti), determined by 1H NMR spectroscopy.
e
TFA (5 mol %) was added at room temperature for 48 h.
The reaction time was 12 h.
Catalyst 6a (5 mol %) was added.
f
O
11
87
>99
>99:1
g
NO2
h
ꢀ
The reaction temperature was 10 C.
7k
Table 2
Michael additions of ketones and aldehyde to trans-
b
-nitrostyrenes catalyzed by 6aa
Ar
O
O
O
O
1
2
84
98
98:2
Ar
6
a (10 mol-%)
NO2
NO2
+
R1
R1
Solventless, r.t., 36h
NO2
R2
R2
7l
6 5
C H
Entry
1
Product
Yieldb (%)
eec (%)
98
drd
NO2
13
88
85
92
87
95
93
52
41
95:5
96:4
d
O
C6H5
7m
NO2
O
O
91
93
88
90
89
99:1
99:1
99:1
99:1
98:2
7a
C6H5
C6H5
NO2
14
_
_
O
C6H4 4 Me
NO2
7n
2
3
4
5
99
99
98
96
S
7b
O
15
NO2
_
_
O
C6H4 4 OMe
NO2
7o
7
c
O
C6H5
16
NO2
75:25
_
_
O
O
C6H4 4 Br
NO2
7p
a
Nitroolefin (0.5 mmol), ketone (0.4 mL), and 6a (contains 0.05 mmol of active
loading) under solvent-free reaction conditions at room temperature (25 C) for
7d
ꢀ
36 h.
_
_
C6H4 3 Br
NO2
b
Isolated yields.
c
Determined by HPLC using chiralpak AD-H or AS-H column.
d
Diastereomeric ratio, dr (syn/anti), determined by 1H NMR spectroscopy.
7e
_
_
O
C6H4 2 Br
NO2
being dried, 6a was reused directly without further purification,
and it was recovered and reused for six consecutive trials without
significant loss of activity and enantioselectivity (entries 1–6,
Table 3).
6
88
98
99:1
7f

7636
P. Li et al. / Tetrahedron 64 (2008) 7633–7638
Table 3
The propylchloride functionalized silica (2) was prepared
a
Successive trials by using recoverable organocatalyst 6a
according to the above procedure and (3-chloropropyl)trimethoxy-
silane was used instead of trichloro[4-(chloromethyl)phenyl]-
silane in the procedure. The loading of the propylchloride
functionalized silica was readily quantified via CHN microanalysis
O
O
Ph
Ph
NO2
Reused 6a (10 mol%)
+
NO2
Solventless, r.t., 24h
ꢁ
1
and found to be 0.78 mmol g based on carbon percentage.
Run
Yieldb (%)
eec (%)
drd
4
.2.2. Preparation of silica gel supported pyrrolidine-based chiral
ionic liquids
Preparation of 5. Imidazole (680 mg,10 mmol) and NaH (480 mg,
1
2
3
4
5
6
91
89
90
88
81
85
98
98
97
98
98
98
98:2
98:2
98:2
98:2
98:2
97:3
purity 60%, 12 mmol) were added in 30 mL of anhydrous acetoni-
trile and stirred at room temperature for 0.5 h, then (S)-N-(tert-
butoxycarbonyl)prolinol p-toluenesulfonate (1.78 g, 5 mmol) was
added. The mixture was heated at reflux for 5 h under nitrogen
atmosphere and then cooled to room temperature. Solvent was
removed under vacuo and the residue was diluted with 10 mL of
water. The resulted mixture was extracted with chloroform
a
Nitrostyrene (0.5 mmol), cyclohexanone (0.4 mL), and reused 6a (contains
.05 mmol of active loading) under solvent-free reaction conditions at room tem-
0
ꢀ
perature (25 C) for 36 h.
b
Isolated yields.
c
Determined by HPLC using chiralpak AD-H column.
d
Diasteromeric ratio, dr (syn/anti), determined by 1H NMR spectroscopy.
(
20 mLꢂ3). The combined organic layer was dried over anhydrous
Na SO and concentrated in vacuo. The residue was purified by
2
4
flash chromatograph on silica gel (eluant, EtOAc/EtOH¼5:1, v/v) to
give the desired product 5 as colorless crystal (1.08 g, 86% of yield).
Preparation of 6a and 6b. Under nitrogen atmosphere, 5 (0.75 g,
3
. Conclusion
In summary, we have developed a novel silica gel supported
3
.0 mmol) and 1 (2.0 g) or 2 (3.0 g) were mixed in toluene (15 mL).
pyrrolidine-based chiral ionic liquids, which are capable of cata-
lyzing Michael addition reaction of ketones with nitrostyrenes in
good yields, excellent enantioselectivities and high diaster-
eoselectivities. The method is operationally simple, the catalyst can
be easily recycled, and reused six times without a significant loss of
catalytic activity and stereoselectivity. Further investigation on the
application of this supported organocatalyst in asymmetric catal-
ysis is still underway in our laboratory.
ꢀ
The solution was kept at 70 C and stirred for 24 h. Then the solu-
tion was filtered and the solid was washed with chloroform,
methanol, and ethyl ether, respectively, and dried under vacuo at
ꢀ
6
0 C, the Boc-protected supported chiral ionic liquid was obtained
as pale yellow solid. Then the pale yellow solid was deprotected by
using 5 M HCl in ethanol solution (20 mL) with vigorously stirring
at room temperature for 4 h, and the solution was filtered and
3
subsequently neutralized with NEt (5 mL). The solution was fil-
tered and the solid was washed with ethanol and ethyl ether, re-
spectively, and dried under vacuo at room temperature. Catalyst 6a
4
4
. Experimental
was readily quantified via CHN microanalysis and found to be
.1. Physical measurements and materials
All 1H and 13C NMR spectra were recorded on a Varian Inova
ꢁ1
0
.92 mmol g of pyrrolidine-based imidazole, and 6b was readily
ꢁ
1
quantified via CHN microanalysis and found to be 0.61 mmol g of
pyrrolidine-based imidazole based on nitrogen percentage.
1
13
3
00 MHz FT-NMR spectrometer (300 and 75 MHz, for H and
C
NMR, respectively). Chemical shifts were given as
d
value with
4.3. Typical experimental procedure for Michael addition
reference to tetramethylsilane (TMS) as the internal standard. HPLC
analysis was performed on Agilent 1100 using a Chiralpak AD-H or
AS-H column purchased from Daicel Chemical Industries, Ltd.
Products were purified by flash column chromatography on 230–
reaction
The supported catalyst 6a (54 mg, containing pyrrolidine-based
organocatalyst 0.05 mmol), trans- -nitrostyrene (75 mg,
.5 mmol), and cyclohexanone (0.4 mL) were added to a 5 mL of
b
4
00 mesh silica gel, SiO
The chemicals were purchased from commercial suppliers
Aldrich, USA and Shanghai Chemical Company, China) and were
2
.
0
round-bottom flask, the mixture was stirred at room temperature
(
ꢀ
(
25 C) for 36 h, then washed with ethyl acetate (3 mLꢂ3) and the
used without purificationprior to use. All reactions unless otherwise
noted were carried outdirectlyunderair. Nitroolefins wereprepared
combined ethyl acetate was concentrated. Flash chromatography
(
g
hexane/ethyl acetate¼3:1, v/v) furnished the corresponding
18
according to the literature procedures.
(S)-N-(tert-Butoxy-
-nitroketone as a colorless crystal (112.3 mg, 91% yield).
carbonyl)prolinol (4) and (S)-N-(tert-butoxycarbonyl)prolinol
19
p-toluenesulfonate were prepared according to the literature.
7b
4
.3.1. (S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone 7a
1
3
H NMR (300 MHz, CDCl ): d 7.35–7.23 (m, 3H), 7.19–7.16 (m,
4
.2. Preparation of silica gel supported pyrrolidine-based
2H), 4.97 (dd, J¼4.5, 12.0 Hz, 1H), 4.64 (dd, J¼9.9, 12.3 Hz, 1H), 3.76
chiral ionic liquids
(dt, J¼4.5, 9.9 Hz, 1H), 2.68 (ddd, J¼7.8, 8.4, 11.7 Hz, 1H), 2.49–2.33
1
3
(m, 2H), 2.10–2.04 (m, 1H), 1.80–1.52 (m, 4H), 1.29–1.15 (m, 1H);
C
4
.2.1. Preparation of benzyl chloride functionalized silica (1)
A 100 mL of round-bottom flask were introduced successively
0 mL of anhydrous toluene, 5.0 g of activated silica, and 2.0 g of
NMR (75 MHz, CDCl
43.9, 42.7, 33.2, 28.5, 25.0. syn/anti¼99:1; ee¼98%; HPLC (Chiralcel
AD-H, i-propanol/hexane¼10:90, flow rate 1.0 mL/min, ¼254 nm):
minor¼10.0 min, tmajor¼12.8 min.
3
): d 211.8, 137.7, 128.9, 128.1, 127.7, 78.9, 52.5,
3
l
trichloro[4-(chloromethyl)phenyl]silane. The solution was refluxed
for 24 h at 120 C under an inert atmosphere. The solution was fil-
t
ꢀ
tered and the solid was washed subsequently with toluene,
dichloromethane, and methanol, and dried under reduced pressure
at 80 C for 10 h. The benzyl chloride functionalized silica was
4.3.2. (S)-2-((R)-1-(4-Methylphenyl)-2-nitroethyl)cyclo-
hexanone 7b
14b
ꢀ
1H NMR (300 MHz, CDCl
J¼8.1 Hz, 2H), 4.89 (dd, J¼4.8, 12.3 Hz, 1H), 4.57 (dd, J¼9.6, 12.3 Hz,
1H), 3.69 (dt, J¼4.8, 9.9 Hz,1H), 2.66–2.58 (m,1H), 2.45–2.28 (m, 2H),
2.26 (s, 3H), 2.10–1.99 (m, 1H), 1.78–1.50 (m, 4H), 1.27–1.14 (m, 1H);
3
):
d
7.10 (d, J¼8.1 Hz, 2H), 7.01 (d,
obtained (5.81 g). The loading of the modified silica was readily
ꢁ1
quantified via CHN microanalysis and found to be 1.12 mmol g
based on carbon percentage.

P. Li et al. / Tetrahedron 64 (2008) 7633–7638
7637
13C NMR (75 MHz, CDCl
3.6, 42.6, 33.2,28.5, 25.0, 21.0. syn/anti¼99:1;ee¼99%;[
.2, CH
Cl); HPLC (Chiralpak AD-H, i-propanol/hexane¼10:90, flow
rate 1.0 mL/min,
¼254 nm): tminor¼8.48 min, tmajor¼10.68 min.
2.05 (m,1H),1.83–1.56 (m, 4H),1.29–1.15 (m,1H); 13C NMR (75 MHz,
CDCl ): 211.6, 136.3,133.5, 129.6,129.1, 122.9, 78.5, 52.4, 43.4, 42.6,
33.2, 29.5, 28.3, 25.1. syn/anti¼99:1; ee¼99%; [
CH
Cl); HPLC (Chiralpak AD-H, i-propanol/hexane¼10:90, flow rate
.0 mL/min,
¼254 nm): tminor¼15.29 min, tmajor¼18.60 min.
3
): d 212.0,137.4,134.6,129.7,128.0, 79.0, 52.6,
25
4
1
a]
D
ꢁ26.3(c
3
d
2
5
3
a
]
D
ꢁ29.8 (c 1.0,
l
3
1
l
4
.3.3. (S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclo-
7a
hexanone 7c
4.3.9. (S)-2-((R)-1-(Benzo[d][1,3]dioxol-5-yl)-2-nitroethyl)-
1H NMR (300 MHz, CDCl
11f
3
):
d
7.08 (d, J¼8.7 Hz, 2H), 6.84 (d,
cyclohexanone 7i
1
J¼8.7 Hz, 2H), 4.93 (dd, J¼4.5, 12.3 Hz, 1H), 4.58 (dd, J¼9.9, 12.0 Hz,
H NMR (300 MHz, CDCl
3
):
d
6.75 (d, J¼7.8 Hz, 1H), 6.66 (s, 2H),
1
2
(
H), 3.78 (s, 3H), 3.72 (dt, J¼4.5, 9.9 Hz, 1H), 2.68–2.60 (m, 1H),
6.64–6.58 (m, 2H), 5.96 (s, 2H), 4.92 (dd, J¼4.5, 12.3 Hz, 1H), 4.56
(dd, J¼4.5, 9.9 Hz, 1H), 3.67 (dt, J¼4.5, 9.9 Hz, 1H), 2.68–2.56 (m,
1H), 2.51–2.33 (m, 2H), 2.15–2.07 (m, 1H), 1.83–1.61 (m, 4H), 1.31–
.52–2.32 (m, 2H), 2.12–2.03 (m, 1H), 1.82–1.51 (m, 4H), 1.30–1.16
m, 1H); 13C NMR (75 MHz, CDCl
):
d 212.1, 137.4, 134.6, 129.6, 128.0,
3
13
7
9.0, 52.6, 43.6, 42.7, 33.2, 28.5, 25.0, 21.0. syn/anti¼99:1; ee¼99%;
3
1.25 (m, 1H); C NMR (75 MHz, CDCl ): d 211.7, 148.0, 147.1, 131.2,
2
5
[
a
]
D
ꢁ19.2 (c 1.2, CH
3
Cl); HPLC (Chiralpak AD-H, i-propanol/
¼254 nm): ¼
121.6, 108.5, 108.0, 101.2, 78.9, 52.5, 43.6, 42.6, 33.2, 28.3, 25.1. syn/
anti¼98:2; ee¼98%; HPLC (Chiralpak AD-H, i-propanol/
hexane¼10:90, flow rate 1.0 mL/min,
l
t
minor
13.22 min, tmajor¼16.41 min.
hexane¼10:90, flow rate 1.0 mL/min,
l¼254 nm): tminor¼17.49 min,
t
major¼18.70 min.
4
.3.4. (S)-2-((R)-1-(4-Bromophenyl)-2-nitroethyl)cyclo-
15a
7b
hexanone 7d
4.3.10. (S)-2-((S)-1-(Furan-2-yl)-2-nitroethyl)cyclohexanone 7j
1H NMR (300 MHz, CDCl
):
d
7.45 (d, J¼8.7 Hz, 2H), 7.06 (d,
1
H NMR (300 MHz, CDCl
):
d
7.36 (d, J¼1.2 Hz, 1H), 6.29 (dd,
3
3
J¼8.4 Hz, 2H), 4.92 (dd, J¼4.5, 12.6 Hz, 1H), 4.60 (dd, J¼9.9, 12.6 Hz,
J¼1.8, 3.3 Hz, 1H), 6.16 (d, J¼3.3 Hz, 1H), 4.81–4.62 (m, 2H), 3.99 (dt,
J¼4.8, 9.3 Hz, 1H), 2.79–2.71 (m, 1H), 2.51–2.32 (m, 2H), 2.16–2.07
1
H), 3.74 (dt, J¼4.5, 9.9 Hz, 1H), 2.69–2.59 (m, 1H), 2.52–2.32 (m,
13
13
2
H), 2.15–2.05 (m, 1H), 1.83–1.54 (m, 4H), 1.30–1.17 (m, 1H);
): 210.9, 148.5, 140.1, 134.8, 129.9, 122.9, 78.0,
2.2, 43.6, 42.7, 33.2, 28.3, 25.0. syn/anti¼99:1; ee¼98%; HPLC
Chiralpak AD-H, i-propanol/hexane¼10:90, flow rate 1.0 mL/min,
¼254 nm): tminor¼11.92 min, tmajor¼18.65 min.
C
(m, 1H), 1.92–1.56 (m, 4H), 1.35–1.23 (m, 1H); C NMR (75 MHz,
NMR (75 MHz, CDCl
5
(
l
3
d
CDCl
28.2, 25.0. syn/anti¼99:1; ee>99%; [
(Chiralpak AD-H, i-propanol/hexane¼10:90, flow rate 1.0 mL/min,
¼254 nm): tmajor¼10.53 min, tminor¼12.86 min.
3
): d 210.9, 150.8, 142.3, 110.3, 108.9, 76.6, 51.0, 42.5, 37.5, 32.4,
2
5
a]
D
ꢁ15.2 (c 1.5, CH
3
Cl); HPLC
l
4
.3.5. (S)-2-((R)-1-(3-Bromophenyl)-2-nitroethyl)cyclo-
4.3.11. (S)-2-((R)-2-(Naphthalen-1-yl)-2-nitroethyl)cyclo-
hexanone 7k
11g
7d
hexanone 7e
1HNMR(300 MHz,CDCl
d
7.40(d, J¼7.8 Hz,1H), 7.33(s,1H), 7.21
1H NMR (300 MHz, CDCl
):
d
7.84–7.79 (m, 3H), 7.63 (d, J¼1.2 Hz,
3
):
3
(
t, J¼7.8 Hz, 1H), 7.10 (d, J¼7.5 Hz, 1H), 4.93 (dd, J¼4.5, 12.9 Hz, 1H),
1H), 7.49–7.46 (m, 2H), 7.30–7.26 (m, 1H), 5.02 (dd, J¼4.5, 12.6 Hz,
1H), 4.73 (dd, J¼9.9, 12.3 Hz, 1H), 3.99–3.92 (m, 1H), 2.78–2.75 (m,
4
2
1
.62 (dd, J¼9.9, 12.6 Hz, 1H), 3.77–3.68 (m, 1H), 2.65–2.62 (m, 1H),
.50–2.38 (m, 2H), 2.11–2.05 (m,1H),1.79–1.57 (m, 4H),1.30–1.20 (m,
1H), 2.50–2.47 (m, 2H), 2.42–2.39 (m, 1H), 1.76–1.58 (m, 4H), 1.29–
13
13
H); C NMR (75 MHz, CDCl
22.8, 78.3, 52.2, 43.6, 42.7, 33.1, 28.4, 25.0. syn/anti¼98:2;
ee¼96%; HPLC (Chiralpak AD-H, i-propanol/hexane¼10:90, flow rate
.0 mL/min,
¼254 nm): tminor¼10.86 min, tmajor¼12.21 min.
3
):
d
211.2,140.1,131.2,130.9,130.4,126.9,
1.25 (m, 1H); C NMR (75 MHz, CDCl
3
):
d
211.8, 135.1, 133.4, 132.8,
1
128.9, 127.9, 127.7, 126.5, 126.2, 125.2, 78.8, 76.6, 52.5, 44.1, 42.8,
2
5
33.3, 28.5, 25.0. syn/anti>99:1; ee>99%; [
HPLC (Chiralpak AD-H, i-propanol/hexane¼30:70, flow rate 1.0 mL/
min,
¼254 nm): tminor¼8.83 min, tmajor¼14.45 min.
a
]
D
ꢁ69.2 (c 1.1, CH
3
Cl);
1
l
l
4.3.6. (S)-2-((R)-1-(2-Bromophenyl)-2-nitroethyl)cyclo-
11f
hexanone 7f
4.3.12. (S)-2-((R)-1-(Naphthalen-1-yl)-2-nitroethyl)cyclo-
1H NMR (300 MHz, CDCl
11f
3
):
d
7.57 (d, J¼8.1 Hz, 1H), 7.32–7.21 (m,
hexanone 7l
2
1
H), 7.15–7.10 (m, 1H), 4.90 (d, J¼8.1 Hz, 2H), 4.32 (dd, J¼6.3, 6.6 Hz,
1H NMR (300 MHz, CDCl
3
):
d
8.17 (s, 1H), 7.86 (d, J¼7.8 Hz, 1H),
H), 2.91–2.88 (m, 1H), 2.45–2.34 (m, 2H), 2.12–2.08 (m, 1H), 1.84–
7.75 (d, J¼8.1 Hz,1H), 7.60–7.35 (m, 4H), 5.06 (dd, J¼4.5,12.6 Hz,1H),
13
1
1
.53 (m, 4H), 1.40–1.20 (m, 1H); C NMR (75 MHz, CDCl
37.2, 133.6, 129.0, 127.9, 77.3, 52.1, 43.0, 42.6, 41.9, 32.9, 28.5, 25.2.
syn/anti¼99:1; ee¼98%; HPLC (Chiralpak AD-H, i-propanol/
3
):
d
211.6,
4.91–4.88 (m, 1H), 4.76 (s, 1H), 2.65 (br s, 1H), 2.45–2.38 (m, 2H),
13
2.09–2.04 (m, 1H), 1.69–1.47 (m, 4H), 1.29–1.20 (m, 1H); C NMR
(75 MHz, CDCl ): 212.1,134.5,128.9,128.1,126.3,125.7,125.1,123.5,
3
d
hexane¼10:90, flow rate 1.0 mL/min,
l¼254 nm):
t
minor
¼
122.4, 78.6, 53.5, 42.7, 36.5, 33.1, 28.5, 25.1. syn/anti¼98:2; ee¼
98%; HPLC (Chiralpak AS-H, i-propanol/hexane¼30:70, flow rate
10.00 min, tmajor¼15.90 min.
1.0 mL/min,
l¼254 nm): tminor¼10.60 min, tmajor¼15.61 min.
4
.3.7. (S)-2-((R)-1-(4-Fluorophenyl)-2-nitroethyl)cyclo-
11g
hexanone 7g
4.3.13. (R)-Tetrahydro-3-((R)-2-nitro-1-phenylethyl)pyran-
1
14b
H
NMR (300 Hz, CDCl
3
):
d
7.16 (d, J¼8.1 Hz, 2H), 7.02
4-one 7m
(
1
d, J¼8.4 Hz, 2H), 4.94 (dd, J¼4.5, 12.6 Hz, 1H), 4.59 (dd, J¼10.2,
1H NMR (300 MHz, CDCl
3
): d 7.39–7.27 (m, 3H), 7.24–7.17 (m,
2.6 Hz, 1H), 3.81–3.73 (m, 1H), 2.69–2.61 (m, 1H), 2.50–2.32 (m,
2H), 4.78–4.62 (m, 2H), 4.11–4.02 (m, 1H), 3.87–3.75 (m, 2H), 3.70
13
2
H), 2.12–2.05 (m, 1H), 1.88–1.51 (m, 4H), 1.30–1.15 (m, 1H);
): 211.7, 133.4, 129.7, 129.5, 124.6, 124.4,
16.0, 115.7, 78.8, 52.4, 43.2, 42.7, 33.2, 28.4, 25.0. syn/anti¼98:2;
ee¼97%; HPLC (Chiralpak AD-H, i-propanol/hexane¼10:90, flow
rate 1.0 mL/min,
¼254 nm): tminor¼11.69 min, tmajor¼15.79 min.
C
(dd, J¼4.8, 11.7 Hz, 1H), 3.29 (dd, J¼9.6, 11.4 Hz, 1H), 2.93–2.85 (m,
13
NMR (75 MHz, CDCl
3
d
1H), 2.73–2.62 (m, 1H), 2.58–2.49 (m, 1H); C NMR (75 MHz,
1
CDCl
31.7. syn/anti¼95:5; ee¼95%; HPLC (Chiralpak AS-H, i-propanol/
hexane¼30:70, flow rate 1.0 mL/min, ¼254 nm): tminor¼11.63 min,
major¼16.93 min.
3
): d 209.3, 136.3, 129.2, 128.3, 128.0, 78.6, 54.7, 44.6, 43.5, 35.2,
l
l
t
4.3.8. (S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)cyclo-
11g
hexanone 7h
4.3.14. (R)-Tetrahydro-3-((R)-2-nitro-1-phenylethyl)thiopyran-4-
1H NMR (300 MHz, CDCl
14b
3
):
d
7.31 (d, J¼8.4 Hz, 2H), 7.16 (d,
one 7n
J¼8.4 Hz, 2H), 4.93 (dd, J¼4.5, 12.6 Hz, 1H), 4.60 (dd, J¼9.9, 12.6 Hz,
H), 3.78–3.70 (m, 1H), 2.68–2.60 (m, 1H), 2.50–2.32 (m, 2H), 2.12–
1H NMR (300 MHz, CDCl
3
):
d 7.38–7.28 (m, 3H), 7.23–7.17 (m,
1
2H), 4.75 (dd, J¼4.8, 12.6 Hz, 1H), 4.65 (dd, J¼9.6, 12.3 Hz, 1H), 4.01

7
638
P. Li et al. / Tetrahedron 64 (2008) 7633–7638
2. (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877; (b)
(
1
dt, J¼4.5, 10.2 Hz, 1H), 3.10–2.77 (m, 5H), 2.62 (ddd, J¼1.5, 4.2,
13
Kranse, N.; Hoffmaan-Roder, A. Synthesis 2001, 171.
3.8 Hz, 1H), 2.46 (dd, J¼9.6, 13.8 Hz, 1H); C NMR (75 MHz,
3
. For selected examples, see: (a) Ji, J.; Barnes, D. M.; Zhang, J. S.; King, A.; Wit-
temberg, S. J.; Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215; (b) Luchaco-
Cullis, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192; (c) Alexakis, A.;
Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262; (d)
Rimkus, A.; Sewald, N. Org. Lett. 2003, 5, 79; (e) Watanabe, M.; Ikagawa, A.;
Wang, H.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2004, 126, 11148; (f) Evans, D.
A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958; (g) Janka, M.; He, W.; Haedicke,
I. E.; Fronczek, F. R.; Frontier, A. J.; Eisenberg, R. J. Am. Chem. Soc. 2006, 128,
3
CDCl ): d 208.6, 136.7, 129.4, 128.6, 127.9, 78.8, 71.9, 69.3, 53.5, 43.0,
4
1.5. syn/anti¼96:4; ee¼93%; HPLC (Chiralpak AS-H, i-propanol/
hexane¼30:70, flow rate 1.0 mL/min,
l
¼254 nm): tminor¼11.85 min,
tmajor¼17.63 min.
15a
4
.3.15. (R)-5-Nitro-4-phenylpentan-2-one 7o
5
312.
1
H NMR (300 MHz, CDCl
H), 4.05–4.00 (m, 1H), 2.94 (d, J¼6.6 Hz, 2H), 2.14 (s, 3H); C NMR
): 205.5, 138.8, 129.1, 127.9, 127.4, 79.5, 64.4, 46.1,
9.0, 30.4, 25.3. ee¼52%; HPLC (Chiralpak AD-H, i-propanol/
¼254 nm): tminor¼11.74 min,
3
): d 7.35–7.22 (m, 5H), 4.75–4.51 (m,
4
. List, B.; Pojarlier, P.; Martin, H. J. Org. Lett. 2001, 3, 2423.
5. Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C. F., III. Tetrahedron
Lett. 2001, 42, 4441.
13
2
(
75 MHz, CDCl
3
d
6. Gu, L. Q.; Zhao, G. Adv. Synth. Catal. 2007, 349, 1629.
3
7. (a) Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126,
hexane¼10:90, flow rate 1.0 mL/min,
l
9558; (b) Cobb, A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Com-
mun. 2004, 1808; (c) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 4966; (d) Pansare, S. V.; Pandya, K.
J. Am. Chem. Soc. 2006, 128, 9624; (e) Vishnumaya; Singh, V. Org. Lett. 2007, 9,
1117.
tmajor¼12.79 min.
7
d
4
.3.16. (S)-2-((R)-2-Nitro-1-phenylethyl)cyclopentanone 7p
1
H NMR (300 MHz, CDCl
3
):
d
7.28–7.20 (m, 3H), 7.13–7.08 (m,
8. (a) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559; (b) Mosse,
S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Org. Lett. 2006, 8, 2559.
2
1
H), 5.30–5.23 (m, 1H), 4.95 (dd, J¼9.9, 12.6 Hz, 1H), 3.67–3.60 (m,
9
. Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454.
0. (a) Li, H. M.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906; (b) Ye,
J. X.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481.
H), 2.34–2.25 (m, 2H), 2.10–2.06 (m, 1H), 1.87–1.78 (m, 2H), 1.72–
1
1
3
1
.65 (m, 1H), 1.53–1.37 (m, 1H); C NMR (75 MHz, CDCl
37.7, 137.4, 128.9, 128.5, 127.9, 78.3, 50.5, 44.2, 38.7, 28.3, 25.0. syn/
anti¼75:25; ee¼41%; HPLC (Chiralpak AD-H, i-propanol/
hexane¼10:90, flow rate 1.0 mL/min, ¼254 nm): tminor¼8.83 min,
major¼14.45 min.
3
): d 218.5,
1
1. (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672; (b)
Wang, J.; Li, H.; Duan, W. H.; Zu, L. S.; Wang, W. Org. Lett. 2005, 7, 4713; (c)
Tsogoeva, S. B.; Wei, S. W. Chem. Commun. 2006, 1451; (d) Lalonde, M. P.; Chen,
Y. G.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366; (e) Huang, H. B.;
Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170; (f) Cao, C. L.; Ye, M. C.; Sun, X.
L.; Tang, Y. Org. Lett. 2006, 8, 2901; (g) Cao, Y. J.; Lu, H. H.; Lai, Y. Y.; Lu, L. Q.;
Xiao, W. J. Synthesis 2006, 3795.
1
l
t
1
2. (a) Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103, 3401; (b) Cozzi, F.
Adv. Synth. Catal. 2006, 348, 1367.
Acknowledgements
13. (a) Benaglia, M.; Celentano, G.; Cozzi, F. Adv. Synth. Catal. 2001, 343, 171; (b)
We gratefully acknowledge financial support by the National
Natural Science Foundation of China (No. 20772043, 20572031) and
the Key Project of Science and Technology of the Department of
Education, Anhui Province, China (No. ZD2007005-1).
Benaglia, M.; Cinquini, M.; Puglisi, A.; Cozzi, F.; Celentano, G. Adv. Synth. Catal.
2
002, 344, 533; (c) Calderon, F.; Fernandez, R.; Sanchez, F.; Mayoralas, A. F. Adv.
Synth. Catal. 2005, 347, 1395; (d) Miao, W. S.; Chan, T. H. Adv. Synth. Catal. 2006,
48, 1711.
3
14. (a) Zu, L. S.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077; (b) Wang, J.; Li,
H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem.dEur. J. 2006, 12, 4321.
1
5. (a) Luo, S. Z.; Mi, X. L.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J. P. Angew. Chem., Int. Ed.
2006, 45, 3093; (b) Ni, B. K.; Zhang, Q. Y.; Headley, A. D. Green Chem. 2007, 9,
37; (c) Ni, B. K.; Zhang, Q. Y.; Headley, A. D. Tetrahedron Lett. 2008, 49, 1249; (d)
Siyutkin, D. E.; Kucherenko, A. S.; Struchkova, M. I.; Zlotin, S. G. Tetrahedron Lett.
008, 49, 1212.
6. (a) Alza, E.; Cambeiro, X. C.; Jimeno, C.; Peric a` s, M. A. Org. Lett. 2007, 9, 3717; (b)
Miao, T.; Wang, L. Tetrahedron Lett. 2008, 49, 2173.
7. Miyabe, H.; Tuchida, S.; Yamauchi, M.; Takemoto, Y. Synthesis 2006, 3295.
8. Jang, Y. J.; Shih, Y. K.; Liu, J. Y.; Kuo, W. Y.; Yao, C. F. Chem.dEur. J. 2003, 9, 2123.
9. (a) Zhao, D.; Kuethe, J. T.; Journet, M.; Peng, Z.; Humphrey, G. R. J. Org. Chem.
006, 71, 9111; (b) Bartoli, G.; Bosco, M.; Giuliani, A.; Mecozzi, T.; Sambri, L.;
Torregiani, E.; Marcantoni, E. J. Org. Chem. 2002, 67, 4336.
References and notes
7
1. (a) Blaser, S. U.; Schmidt, E. Asymmetric Catalysis on Industrial Scale: Challenges,
2
Approaches and Solutions; Wiley-VCH: Weinheim, Germany, 2004; (b) Berkes-
sel, A.; Gr o¨ ger, H. Asymmetric Organocatalysis: From Biomimetic Concepts to
Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim, Germany, 2005;
1
1
1
1
(
c) Dalko, P. L.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (d) Almasi, D.;
Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299; (e) Acc. Chem.
Res. 2004, 37, 487, special issue on organocatalysis; (f) Tetrahedron 2006, 62,
2
243, Organocatalysis in Organic Synthesis; (g) Tsogoeva, S. B. Eur. J. Org. Chem.
2007, 1701.