A highly efficient and recyclable ionic liquid anchored pyrrolidine catalyst for enantioselective Michael additions

Article abstract of DOI:10.1055/s-0028-1083223

Highly enantioselective Michael addition of cyclohexanone to aryl nitroolefins in the presence of an ionic liquid anchored pyrrolidine (10 mol%) and TFA (5 mol%) generated the corresponding adducts in high yields (up to 95%) with excellent diastereoselect

Full text of DOI:10.1055/s-0028-1083223

3
828
PAPER
A Highly Efficient and Recyclable Ionic Liquid Anchored Pyrrolidine
Catalyst for Enantioselective Michael Additions
E
T
nantioselective
a
Michae
l
A
o
dditions Miao, Lei Wang,* Pinhua Li, Jincan Yana
a
a,b
a
a
Department of Chemistry, Huaibei Coal Teachers College, Huaibei, Anhui 235000, P. R. of China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
b
Fax +86(561)3090518; E-mail: leiwang@hbcnc.edu.cn
Received 24 July 2008; revised 1 August 2008
merous catalytic reactions. In addition, ionic liquids with
Abstract: Highly enantioselective Michael addition of cyclohex-
anone to aryl nitroolefins in the presence of an ionic liquid anchored
pyrrolidine (10 mol%) and TFA (5 mol%) generated the corre-
sponding adducts in high yields (up to 95%) with excellent diaste-
functional groups [called ‘task-specific’ ionic liquids
9
(
TSILs)] have been further applied as soluble and sup-
portable organocatalysts for asymmetric reaction by at-
reoselectivities (up to >99:1 dr) and enantioselectivities (up to tachment of catalytically active chiral groups onto the side
99% ee). Furthermore, the catalyst could be recycled and reused at chains of ionic liquids. Very recently, some recyclable
least eight times without loss of its catalytic activity.
>
supported organocatalysts for asymmetric reaction have
Key words: chiral ionic liquid, pyrrolidine unit, organocatalyst, been developed with high enantioselectivities. For exam-
1
0
11
12
asymmetric Michael reaction, aryl nitroolefin, cyclohexanone
ple, Luo et al., Headley and co-workers, Xu et al., and
Liang and co-workers13 have independently reported ex-
cellent ionic liquid supported organocatalysts for the
The asymmetric Michael addition reaction is widely rec- asymmetric Michael reaction to nitrostyrenes. Most re-
ognized as one of the most powerful enantioselective car- cently, Wang and co-workers have reported a mild and ef-
bon–carbon bond-forming reactions in synthetic organic ficient procedure for asymmetric Michael additions of
1
chemistry. Due to the growing need for its transformation cyclohexanone to chalcones catalyzed by an amino acid
1
4
to an environment-friendly metal-free catalyzed asym- ionic liquid. These protocols provide unique methodol-
metric synthesis, the development of efficient small- ogy in asymmetric Michael additions. In this context, a
molecule asymmetric organocatalysts have attracted modular and more efficient approach to constructing
considerable attention from a large number of organic chiral ionic liquids (CILs) through ‘click chemistry’,
chemists working in the area of asymmetric synthesis. In which introduces a chiral pyrrolidine moiety into an imi-
2
3
2
001, Barbas and co-workers and List et al. indepen- dazolium ionic liquid, was developed (Scheme 1). Major
dently reported the first organocatalytic addition of ke- advantages of the ionic liquid-anchored pyrrolidine are
tones to trans-b-nitrostyrene with L-proline as the catalyst that they not only serve as organocatalysts, but also are
in good yields, but with very low enantioselectivities (0– easily recovered from reaction mixture, making it a recy-
2
3% ee). Since these preliminary studies, very effective clable green ionic liquid. Chiral ionic liquids (CILs) 3,
catalytic systems, such as pyrrolidine-based catalytic de- were prepared uneventfully from L-proline as shown in
4
5
rivatives, thiourea-amine bifunctional catalysts, cincho- Scheme 1. We were pleased to find that the designed nov-
6
na alkaloid-based bifunctional organocatalyst, chiral el organocatalysts 3a, 3b, and 3c, catalyzed the reaction of
diaime, etc. have been developed for the asymmetric cyclohexanone with aryl nitroolefins smoothly in high
7
Michael reaction of ketones with nitroalkenes, and the yields with excellent diastereoselectivities and enantiose-
process is generally syn-selective. However, these orga- lectivities (Scheme 1).
nocatalysts are generally more complex, and therefore
have to be prepared by multistep synthesis. Furthermore
these organocatalysts could not be recovered and recy-
cled.
Initially, various solvents were examined at room temper-
ature using 3a as a catalyst and trans-nitroolefin as a sub-
strate. The Michael addition of cyclohexanone to
nitrostyrene was chosen as a model reaction. As shown in
In recent years, ionic liquids have become an exciting area Table 1, in polar solvents, such as THF, CHCl , CH Cl ,
3
2
2
of research. Ionic liquids (ILs) are salts and entirely com- MeCN, H O, MeOH, and EtOH, the Michael additions
2
posed of ions, possess attractive properties, for example, proceeded smoothly to give the corresponding product in
negligible volatility, high thermal stability, viscosity, and moderate to excellent conversions with good to high enan-
8
water immiscibility. Therefore ILs have been extensively tioselectivities (Table 1, entries 1–7), whereas in nonpolar
investigated as easily recycled and reused reaction media solvents, such as hexane, only a trace amount of the de-
instead of conventional molecular organic solvents in nu- sired adduct was observed (Table 1, entry 8). It is proba-
bly due to the insolubility of the chiral ionic liquid 3a in
the nonpolar solvent of hexane. Since catalyst 3a proved
to be an efficient catalyst in terms of asymmetric induc-
tion of Michael addition, we then screened different anion
SYNTHESIS 2008, No. 23, pp 3828–3834
x
x.
x
x
.
2
0
0
8
Advanced online publication: 14.11.2008
DOI: 10.1055/s-0028-1083223; Art ID: F16708SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
Enantioselective Michael Additions
3829
The effect of reaction temperature and time on the
Michael reaction was also investigated. The results are
listed in Table 2. At room temperature (25 °C), the reac-
tion took place smoothly with excellent isolated yield,
good enantioselectivity, and high diastereoselectivity
(Table 2, entry 1). An excellent enantioselectivity (>99%
ee) was obtained along with high yield and diastereoselec-
tivity (>99:1 dr) when the reaction was performed at 10 °C
IL
1
.
2
IL
CuI, DIPEA
toluene, EtOH
N3
N
N
N
N
2
. HCl, EtOH
3. NaHCO3 (aq)
N
H
Boc
1
3
a: X = Cl
N
N
IL
3b: X = BF4
3c: X = PF6
(
Table 2, entry 3). Meanwhile, a lower yield was observed
when the reaction was performed at 0 °C (Table 2, entry
). It is interesting to note that isolated yields, both of ee
X–
2
O
Ar
O
and dr values, were maintained up to 95%, >99%, and
>99:1, respectively, when up to 10 mol% of ionic liquid
anchored pyrrolidine 3a was added to the reaction mix-
ture. A lower yield of the Michael addition product was
isolated when less than 10 mol% of 3a loading was used
in the reaction. It was found that the reaction needed more
than 36 hours to complete at 10 °C.
NO2
3
a (10 mol%)
NO2
+
Ar
TFA (5 mol%), 36 h, 10 °C
yield: up to 95%
ee: up to >99%
dr: up to >99:1
Scheme 1 Synthesis of chiral ionic liquids 3a, 3b, and 3c and their
application in the Michael addition
Table 2 Effect of Temperature and Time on the Michael Reactiona
O
O
Ph
–
–
swapped chiral ionic liquid. The exchange of Cl to BF ,
4
NO2
–
–
3
a (10 mol%)
and Cl to PF afforded comparable catalysts, 3b and 3c,
NO2
6
+
Ph
respectively, with slightly detrimental effect on both the
activities and selectivities (Table 1, entries 9 and 10). In
addition, in the absence of TFA, they could not decrease
the reaction rate dramatically and formed the product with
slight loss of enantiomeric excess (Table 1, entry 11).
Entry Temp (°C) Time (h) Yield (%)b ee (%)c
dr (syn/anti)d
99:1
1
2
3
4
5
6e
25
0
36
36
36
24
48
36
36
97
80
95
90
96
82
95
98
>99
>99
>99
>99
>99
>99
>99:1
Table 1 Effect of Catalyst and Solvent on the Michael Reactiona
10
10
10
10
10
>99:1
O
O
Ph
>99:1
NO2
3
(10 mol%)
solvent
NO2
+
>99:1
Ph
>99:1
b
c
dr (syn/anti)d
94:6
Entry Catalyst Solvent
Yield (%) ee (%)
7f
>99:1
1
2
3
4
5
6
7
8
9
0
1
3a
3a
3a
3a
3a
3a
3a
3a
3b
THF
82
85
87
86
72
90
97
10
94
89
87
90
92
91
93
95
96
98
–
a
Reaction conditions: nitrostyrene (1.0 mmol), cyclohexanone (2.0
mmol), catalyst 3a (containing 0.10 mmol of active loading), and
TFA (0.05 mmol) in EtOH (2.0 mL) at the reaction temperature and
time indicated in Table 2.
Isolated yields.
Determined by HPLC using chiral column.
Diastereomeric ratio, determined by H NMR spectroscopy.
In the presence of 3a (0.05 mmol).
In the presence of 3a (0.20 mmol).
CHCl3
97:3
CH Cl
95:5
2
2
b
MeCN
96:4
c
d
e
f
1
H O
98:2
2
MeOH
EtOH
hexane
EtOH
EtOH
EtOH
99:1
99:1
With the optimal conditions in hand, we then examined a
variety of Michael donors and nitroolefins to establish the
general utility of this asymmetric transformation, and the
results are summarized in Table 3. The reactions worked
extremely well with Michael donors and nitroolefins to
generate the corresponding adducts in good yields (85–
–
96
97
93
99:1
1
3c
98:2
3ae
1
98:2
9
5%), high diastereoselectivities (up to >99:1 dr), and ex-
a
Reaction conditions: nitrostyrene (1.0 mmol), cyclohexanone (2.0
mmol), catalyst 3 (containing 0.10 mmol of active loading), and TFA
cellent enantioselectivities (up to >99% ee). Both elec-
tron-rich and electron-deficient nitrostyrenes were
excellent Michael acceptors for cyclohexanone (Table 3,
entries 1–12). Generally, substituent groups on the phenyl
ring slightly influenced the diastereoselectivities and
enantioselectivities; for example, enantioselectivities for
(
0.05 mmol) in solvent (2 mL) at r.t. for 36 h.
Isolated yields.
b
c
d
e
Determined by HPLC using chiral column.
1
Diastereomeric ratio, determined by H NMR spectroscopy.
In the absence of TFA.
Synthesis 2008, No. 23, 3828–3834 © Thieme Stuttgart · New York

3
830
T. Miao et al.
PAPER
aryl nitroalkenes with substitution at the para-position in Table 3 a Ionic Liquid Anchored Pyrrolidine 3a Catalyzed Michael
Addition (continued)
the phenyl ring were very high (Table 3, entries 2–5).
Moving the substituent to the ortho-position led to a de-
crease in the enantioselectivities (Table 3, entries 11 and
R
O
O
1
2). However, 3,4-disubstituted aryl nitroolefins could
also give the desired products with high stereoselectivities
Table 3, entries 7 and 8). The Michael reactions were
NO2
3
a (10 mol%)
NO2
+
TFA (5 mol%)
(
X
R
X
evaluated with other Michael acceptors and donors as
well, and high enantioselectivities and diastereoselectivi-
ties were obtained (Table 3, entries 13–15).
Yield (%)b ee (%)c
dr (syn/anti)d
Entry Product
Cl
The recyclability and reusability of the ionic liquid an-
chored pyrrolidine catalyst was examined for the reaction
of cyclohexanone to aryl nitroolefin with 3a as the repre-
sentative catalyst. It was found that 3a still maintained the
biphasic property of ionic liquids and could be easily re-
cycled by precipitation with simple disposal. As revealed
in Table 4, the catalyst 3a was recycled and reused at least
eight times without loss of catalytic activity.
5
93
92
88
>99
>99:1
>99:1
>99:1
O
NO2
F
Table 3 a Ionic Liquid Anchored Pyrrolidine 3a Catalyzed Michael
6
97
O
Addition
NO2
R
O
O
NO2
OMe
3
a (10 mol%)
NO2
+
OMe
TFA (5 mol%)
X
R
7
>99
X
O
Yield (%)b ee (%)c
dr (syn/anti)d
NO2
Entry Product
O
O
1
95
94
>99
>99
>99:1
>99:1
O
NO2
8
9
85
93
>99
>99
>99:1
>99:1
O
O
NO2
Me
2
O
NO2
NO2
OMe
3
95
94
>99
>99
>99:1
>99:1
O
NO2
10
95
93
>99
>99:1
>99:1
O
O
NO2
CF3
4
O
Cl
NO2
1
1
95
NO2
Synthesis 2008, No. 23, 3828–3834 © Thieme Stuttgart · New York

PAPER
Enantioselective Michael Additions
3831
Table 4 Successive Trials with Recoverable Catalyst 3aa
Table 3 a Ionic Liquid Anchored Pyrrolidine 3a Catalyzed Michael
Addition (continued)
O
O
Ph
NO2
R
reused 3a
NO2
O
+
Ph
O
NO2
3
a (10 mol%)
NO2
dr (syn/anti)d
>99:1
+
Yield (%)b
ee (%)c
dr (syn/anti)d
TFA (5 mol%)
Trial
X
R
X
1
2
3
4
5
6
7
95
94
93
91
92
90
91
90
>99
>99
>99
>99
>99
>99
>99
>99
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
Entry Product
Yield (%)b ee (%)c
O
Br
NO2
1
1
2
3
95
89
98
91
O
O
>99:1
>99:1
8
NO2
NO2
a
Reaction conditions: nitrostyrene (1.0 mmol), cyclohexanone (2.0
mmol), reused catalyst 3a (containing 0.10 mmol of active loading),
and TFA (0.05 mmol) in EtOH (2.0 mL) at 10 °C for 36 h.
b
Isolated yields.
c
O
Determined by HPLC using chiral column.
Diastereomeric ratio, determined by H NMR spectroscopy.
1
4
5
88
92
96
94
d
1
1
100 using a Chiralpak AD-H or AS-H column purchased from
O
O
Daicel Chemical Industries, Ltd. The CHN analyses were per-
formed on a Vario El III elementary analyzer. Products were puri-
fied by flash chromatography on 230–400 mesh silica gel. The
chemicals were purchased from commercial suppliers (Aldrich,
USA and Shanghai Chemical Company, China) and were used
without purification prior to use. All reactions were carried out di-
rectly under air, unless otherwise noted. Nitroolefins were prepared
1
99:1
NO2
S
1
5
according to literature procedures.
a
Reaction conditions: nitroolefin (1.0 mmol), cyclohexanone (2.0
mmol), catalyst 3a (containing 0.10 mmol of active loading), and
Catalyst 3a
TFA (0.05 mmol) in EtOH (2.0 mL) at 10 °C for 36 h.
To a solution of 1 (226 mg, 1.0 mmol) in EtOH (5.0 mL) were added
b
Isolated yields.
Determined by HPLC using chiral column.
Diastereomeric ratio, determined by H NMR spectroscopy.
–
–
2
(X = Cl , 121 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), and
c
DIPEA (170 mL, 2.0 mmol). The mixture was stirred at reflux tem-
perature for 24 h. After removal of the solvent under reduced pres-
sure, the residue was treated with aq HCl (5.0 M)–EtOH mixture (5
mL) to remove the Boc protection group. The obtained solution was
d
1
In summary, we have developed highly efficient imidazo-
lium anchored pyrrolidine type organocatalysts from L-
proline through a click reaction. The catalyst 3a has been
successfully applied to the asymmetric Michael reaction
of ketones with aryl nitroolefins. The remarkably better
catalytic performance was provided by the reactions in
terms of productivities (up to 95%), diastereoselectivities
subsequently treated with aq sat. NaHCO (30 mL) at r.t. After re-
3
moval of the solvent under reduced pressure, the resulting residue
was purified by flash chromatography on silica gel to give 3a as a
pale yellow oil; yield: 180.3 mg (73%).
1
H NMR (400 MHz, DMSO-d ): d = 10.13 (t, J = 1.2 Hz, 2 H), 9.41
s, 1 H), 8.58 (s, 1 H), 7.87 (s, 1 H), 7.75 (s, 1 H), 5.58 (s, 2 H), 5.00–
6
(
4
.94 (m, 1 H), 4.88–4.83 (m, 1 H), 3.87 (s, 3 H), 3.25–3.22 (m, 1 H),
(
up to >99:1 dr), and enantioselectivities (up to >99% ee). 3.12 (d, J = 5.6 Hz, 1 H), 2.15–2.12 (m, 1 H), 1.99–1.96 (m, 1 H),
Moreover, ionic liquid anchored pyrrolidine 3a could be 1.89 (t, J = 4.0 Hz, 1 H), 1.74–1.68 (m, 1 H).
1
3
easily recycled and reused for at least eight times without
loss of its catalytic activity. Further investigation on the 122.5, 58.9, 49.6, 44.6, 43.5, 35.8, 27.9, 22.8.
application of this kind of organocatalysts to the other
C NMR (100 MHz, DMSO-d ): d = 140.0, 136.7, 125.9, 123.7,
6
Anal. Calcd for C H ClN : C, 50.97; H, 6.77; N, 29.72. Found: C,
1
2
19
6
asymmetric reactions is still in progress in our laboratory. 50.81; H, 6.89; N, 29.58.
Catalyst 3b
Melting points were recorded on a WRS-2B melting point apparatus
To a solution of 3a (247.0 mg, 1.00 mmol) in MeCN and acetone
20 mL, 4:1) was added well-sieved NaBF4 (549.08 mg, 5.00
1
13
and are uncorrected. All H NMR and C NMR spectra were re-
corded on 300 or 400 MHz Bruker FT-NMR spectrometer. Chemi-
cal shift are given as d value with reference to TMS as internal
standard. IR spectra were obtained by using a Nicolet NEXUS 470
(
mmol). The mixture was vigorously stirred at r.t. for 2 d. The mix-
ture was filtered to remove the inorganic salts and the filtrate was
triturated with AgBF solution (200 mg in MeCN) until no more
4
Synthesis 2008, No. 23, 3828–3834 © Thieme Stuttgart · New York

3
832
T. Miao et al.
PAPER
precipitate was formed. The filtrate was filtered again and concen-
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
trated. The residue was diluted with CHCl (50 mL) and the insolu-
min, l = 254 nm; t
= 11.97 min, tmajor = 15.30 min; dr (syn/anti)
3
minor
ble was removed by filtration. The clear filtrate was concentrated in
vacuo and the residue was purified by flash chromatography on sil-
ica gel to give 3b as a pale yellow oil; yield: 317.1 mg (95%).
1
>99:1; ee >99%.
1
H NMR (300 MHz, CDCl ): d = 7.10 (d, J = 8.1 Hz, 2 H), 7.01 (d,
3
J = 8.1 Hz, 2 H), 4.89 (dd, J = 4.8, 12.3 Hz, 1 H), 4.57 (dd, J = 9.6,
12.3 Hz, 1 H), 3.69 (dt, J = 4.8, 9.9 Hz, 1 H), 2.66–2.58 (m, 1 H),
2.45–2.28 (m, 2 H), 2.26 (s, 3 H), 2.10–1.99 (m, 1 H), 1.78–1.50 (m,
4 H), 1.27–1.14 (m, 1 H).
H NMR (400 MHz, DMSO-d ): d = 9.95 (t, J = 1.2 Hz, 2 H), 8.45
6
(
s, 1 H), 8.12 (s, 1 H), 7.59 (s, 1 H), 7.25 (s, 1 H), 5.32 (s, 2 H), 4.98–
4
2
1
.90 (m, 1 H), 4.78–4.69 (m, 1 H), 3.80 (s, 3 H), 3.10–2.91 (m, 1 H),
.89 (d, J = 5.8 Hz, 1 H), 2.10–2.07 (m, 1 H), 1.95–1.91 (m, 1 H),
.85 (t, J = 4.4 Hz, 1 H), 1.70–1.64 (m, 1 H).
13
C NMR (75 MHz, CDCl ): d = 212.0, 137.4, 134.6, 129.7, 128.0,
3
7
9.0, 52.6, 43.6, 42.6, 33.2, 28.5, 25.0, 21.0.
1
3
C NMR (100 MHz, DMSO-d ): d = 139.1, 134.9, 125.8, 121.7,
6
1
21.5, 58.9, 49.4, 44.7, 43.5, 35.6, 27.7, 22.8.
(S)-2-[(R)-1-(4-Methoxyphenyl)-2-nitroethyl]cyclohexanone4b
(
[
Table 3, Entry 3)
a]D –19.2 (c 1.2, CHCl3).
Anal. Calcd for C H BF N : C, 43.14; H, 5.69; N, 25.16. Found:
C, 43.29; H, 5.78; N, 25.03.
1
2
19
4
6
25
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
min, l = 254 nm); t = 13.22 min, tmajor = 16.51 min; dr (syn/
minor
Catalyst 3c
To a solution of 3a (247.0 mg, 1.00 mmol) in MeCN and acetone
20 mL, 4:1) was added well-sieved KPF (919.23 mg, 5.00 mmol).
anti) >99:1; ee >99%.
(
1
6
H NMR (300 MHz, CDCl ): d = 7.08 (d, J = 8.7 Hz, 2 H), 6.84 (d,
3
The mixture was vigorously stirred at r.t. for 2 d. The mixture was
filtered to remove the inorganic salts and the filtrate was triturated
J = 8.7 Hz, 2 H), 4.93 (dd, J = 4.5, 12.3 Hz, 1 H), 4.58 (dd, J = 9.9,
1
2
2.0 Hz, 1 H), 3.78 (s, 3 H), 3.72 (dt, J = 4.5, 9.9 Hz, 1 H), 2.68–
.60 (m, 1 H), 2.52–2.32 (m, 2 H), 2.12–2.03 (m, 1 H), 1.82–1.51
with AgPF solution (300 mg in MeCN) till no precipitate was
6
formed. The filtrate was filtered again and concentrated. The resi-
due was diluted with CHCl (50 mL) and the insoluble was removed
by filtration. The clear filtrate was concentrated in vacuo and the
residue was purified by flash chromatography on silica gel to give
(
m, 4 H), 1.30–1.16 (m, 1 H).
3
1
3
C NMR (75 MHz, CDCl ): d = 212.1, 137.4, 134.6, 129.6, 128.0,
3
7
9.0, 52.6, 43.6, 42.7, 33.2, 28.5, 25.0, 21.0.
3
c as a pale yellow oil; yellow: 360.4 mg (92%).
(
S)-2-[(R)-1-(4-Trifluoromethylphenyl)-2-nitroethyl]cyclo-
1
H NMR (400 MHz, DMSO-d ): d = 9.84 (t, J = 1.6 Hz, 2 H), 8.25
s, 1 H), 8.08 (s, 1 H), 7.52 (s, 1 H), 7.21 (s, 1 H), 5.30 (s, 2 H), 4.95–
4d
6
hexanone (Table 3, Entry 4)
(
25
[
a]D –20.1 (c 1.25, CHCl3).
HPLC: Chiralpak AD-H, i-PrOH–hexane (5:95), flow rate 1.0 mL/
= 16.66 min, tmajor = 36.52 min; dr (syn/anti)
4
2
1
.89 (m, 1 H), 4.75–4.68 (m, 1 H), 3.82 (s, 3 H), 3.06–2.91 (m, 1 H),
.88 (d, J = 5.6 Hz, 1 H), 2.07–1.97 (m, 1 H), 1.93–1.90 (m, 1 H),
.84 (t, J = 4.6 Hz, 1 H), 1.68–1.63 (m, 1 H).
min, l = 254 nm; t
minor
>
99:1; ee >99%.
1
3
C NMR (100 MHz, DMSO-d ): d = 137.8, 132.5, 124.3, 120.1,
6
1
H NMR (400 MHz, CDCl ): d = 7.59 (d, J = 8.1 Hz, 2 H), 7.30 (m
1
19.8, 58.4, 49.0, 44.7, 43.1, 35.6, 27.0, 22.2.
3
2
H), 4.98 (dd, J = 12.6, 4.5 Hz, 1 H), 4.67 (dd, J = 12.2, 9.8 Hz, 1
Anal. Calcd for C H PF N : C, 36.74; H, 4.85; N, 21.43. Found:
C, 36.97; H, 4.68; N, 21.59.
12
19
6
6
H), 3.90–3.82 (m, 1 H), 2.72–2.70 (m, 1 H), 2.51–2.47 (m, 1 H),
2
1
.41–2.38 (m, 1 H), 2.11–2.07 (m, 1 H), 1.83–1.57 (m, 4 H), 1.27–
.23 (m, 1 H).
Asymmetric Michael Addition of Cyclohexanone to Nitro-
olefins; (S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanone;16
Typical Procedure (Table 3, Entry 1)
1
3
C NMR (100 MHz, CDCl ): d = 211.7, 149.5, 136.7, 130.4, 121.9,
3
1
21.2, 78.9, 52.9, 43.7, 42.1, 33.6, 27.8, 25.5.
An oven-dried round-bottomed flask was charged with ionic liquid
anchored pyrrolidine 3a (18 mg, containing 0.10 mmol of active
pyrrolidine unit), nitrostyrene (149 mg, 1.0 mmol), cyclohexanone
(
(
[
S)-2-[(R)-1-(4-Chlorophenyl)-2-nitroethyl]cyclohexanone18
Table 3, Entry 5)
2
5
a
]
–
2
9
.
8
(
c
1
.
0
,
C
H
C
l
)
.
(196 mg, 2.0 mmol), TFA (57 mg, 0.05 mmol), and EtOH (2.0 mL).
D
3
The mixture was stirred at 10 °C for 36 h. After completion of the
reaction, the mixture was evaporated under reduced pressure and
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
min, l = 254 nm; t
>99:1; ee >99%.
= 27.54 min, tmajor = 41.96 min; dr (syn/anti)
minor
extracted with Et O (3 × 10 mL). The combined organic layers
2
were dried (Na SO ), filtered, concentrated, and the residue was pu-
2
4
1
H NMR (300 MHz, CDCl ): d = 7.31 (d, J = 8.4 Hz, 2 H), 7.16 (d,
3
rified by flash chromatography on silica gel using EtOAc–hexane as
eluent to afford the desired asymmetric Michael adduct as a white
J = 8.4 Hz, 2 H), 4.93 (dd, J = 4.5, 12.6 Hz, 1 H), 4.60 (dd, J = 9.9,
2
5
12.6 Hz, 1 H), 3.78–3.70 (m, 1 H), 2.68–2.60 (m, 1 H), 2.50–2.32
solid; yield: 235 mg (95%); [a]D –20.9 (c 1.2, CHCl3).
(
m, 2 H), 2.12–2.05 (m, 1 H), 1.83–1.56 (m, 4 H), 1.29–1.15 (m, 1
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
min, l = 254 nm; tminor = 10.03 min, tmajor = 12.66 min; dr (syn/anti)
H).
13
C NMR (75 MHz, CDCl ): d = 211.6, 136.3, 133.5, 129.6, 129.1,
3
>99:1; ee >99%.
1
22.9, 78.5, 52.4, 43.4, 42.6, 33.2, 29.5, 28.3, 25.1.
1
H NMR (300 MHz, CDCl ): d = 7.35–7.23 (m, 3 H), 7.19–7.16 (m,
3
2
H), 4.97 (dd, J = 4.5, 12.0 Hz, 1 H), 4.64 (dd, J = 9.9, 12.3 Hz, 1
S)-2-[(R)-1-(4-Fluorophenyl)-2-nitroethyl]cyclohexanone18
Table 3, Entry 6)
(
(
H), 3.76 (dt, J = 4.5, 9.9 Hz, 1 H), 2.68 (ddd, J = 7.8, 8.4, 11.7 Hz,
1
1
H), 2.49–2.33 (m, 2 H), 2.10–2.04 (m, 1 H), 1.80–1.52 (m, 4 H),
.29–1.15 (m, 1 H).
HPLC: Chiralpak AD-H, i-PrOH–hexane (5:95), flow rate 1.0 mL/
min, l = 254 nm; t
>99:1; ee = 97%.
= 17.08 min, tmajor = 23.36 min; dr (syn/anti)
minor
1
3
C NMR (75 MHz, CDCl ): d = 211.8, 137.7, 128.9, 128.1, 127.7,
3
7
8.9, 52.5, 43.9, 42.7, 33.2, 28.5, 25.0.
1
H NMR (300 Hz, CDCl ): d = 7.16 (d, J = 8.1 Hz, 2 H), 7.02 (d,
3
J = 8.4 Hz, 2 H), 4.94 (dd, J = 4.5, 12.6 Hz, 1 H), 4.59 (dd, J = 10.2,
(
(
[
S)-2-[(R)-1-(4-Methylphenyl)-2-nitroethyl]cyclohexanone17
1
(
2.6 Hz, 1 H), 3.81–3.73 (m, 1 H), 2.69–2.61 (m, 1 H), 2.50–2.32
m, 2 H), 2.12–2.05 (m, 1 H), 1.88–1.51 (m, 4 H), 1.30–1.15 (m, 1
H).
Table 3, Entry 2)
25
a
]
–
2
6
.
3
(
c
1
.
2
,
C
H
C
l
)
.
D
3
Synthesis 2008, No. 23, 3828–3834 © Thieme Stuttgart · New York

PAPER
Enantioselective Michael Additions
3833
1
3
(S)-2-[(R)-1-(2-Chlorophenyl)-2-nitroethyl]cyclohexanone18
(Table 3, Entry 11)
C NMR (75 MHz, CDCl ): d = 211.7, 133.4, 129.7, 129.5, 124.6,
3
1
24.4, 116.0, 115.7, 78.8, 52.4, 43.2, 42.7, 33.2, 28.4, 25.0.
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 0.5 mL/
(
S)-2-[(R)-1-(3,4-Dimethoxyphenyl)-2-nitroethyl]cyclo-
min, l = 254 nm; t
= 23.31 min, tmajor = 39.70 min; dr (syn/anti)
minor
19
hexanone (Table 3, Entry 7)
>99:1; ee = 95%.
25
[
a]D –28.4 (c 1.2, CHCl3).
HPLC: Chiralpak AS-H, i-PrOH–hexane (30:70), flow rate 1.0 mL/
= 12.94 min, tmajor = 24.49 min; dr (syn/anti)
1
H NMR (300 MHz, CDCl ): d = 7.39–7.36 (m, 1 H), 7.24–7.18 (m,
3
3 H), 4.90 (d, J = 1.2 Hz, 1 H), 4.88 (s, 1 H), 4.33–4.25 (dt, J = 6.6,
7.2, 9.9 Hz, 1 H), 2.96–2.87 (m, 1 H), 2.50–2.35 (m, 2 H), 2.14–2.06
(m, 1 H), 1.84–1.53 (m, 4 H), 1.39–1.26 (m, 1 H).
13
min, l = 254 nm; t
minor
>
99:1; ee >99%.
1
H NMR (400 MHz, CDCl ): d = 6.81 (d, J = 8.2 Hz, 1 H), 6.70–
C NMR (75 MHz, CDCl ): d = 211.6, 135.5, 134.5, 130.4, 129.5,
3
3
6
.66 (m, 2 H), 4.91 (dd, J = 7.8, 4.6 Hz, 1 H), 4.60 (dd, J = 9.9, 2.4
128.9, 127.4, 77.2, 51.7, 42.8, 41.0, 33.0, 28.5, 25.3.
Hz, 1 H), 3.87 (s, 6 H), 3.72–3.68 (m, 1 H), 2.66–2.64 (m, 1 H),
2
1
.49–2.45 (m, 1 H), 2.41–2.38 (m, 1 H), 2.07–2.04 (m, 1 H), 1.80–
.60 (m, 4 H), 1.27–1.23 (m, 1 H).
(S)-2-[(R)-1-(2-Bromophenyl)-2-nitroethyl]cyclohexanone5f
(Table 3, Entry 12)
1
3
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
min, l = 254 nm; tminor = 10.81 min, tmajor = 16.32 min; dr (syn/anti)
>99:1; ee = 98%.
C NMR (100 MHz, CDCl ): d = 212.2, 149.2, 148.6, 130.2, 120.5,
3
1
11.5, 79.1, 56.0, 52.7, 43.8, 42.6, 33.3, 28.5, 27.5, 25.1.
1
(
S)-2-[(R)-1-(Benzo[d][1,3]dioxol-5-yl)-2-nitroethyl]cyclo-
H NMR (300 MHz, CDCl ): d = 7.57 (d, J = 8.1 Hz, 1 H), 7.32–
3
5f
hexanone (Table 3, Entry 8)
7.21 (m, 2 H), 7.15–7.10 (m, 1 H), 4.90 (d, J = 8.1 Hz, 2 H), 4.32
(dd, J = 6.3, 6.6Hz, 1 H), 2.91–2.88 (m, 1 H), 2.45–2.34 (m, 2 H),
2
25
[
a]D –43.8 (c 1.5, CHCl3).
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
= 17.43 min, tmajor = 18.74 min; dr (syn/anti)
.12–2.08 (m, 1 H), 1.84–1.53 (m, 4 H), 1.40–1.20 (m, 1 H).
1
3
min, l = 254 nm; t
>
C NMR (75 MHz, CDCl ): d = 211.6, 137.2, 133.6, 129.0, 127.9,
minor
3
99:1; ee >99%.
77.3, 52.1, 43.0, 42.6, 41.9, 32.9, 28.5, 25.2.
1
H NMR (300 Hz, CDCl ): d = 6.75 (d, J = 7.8 Hz, 1 H), 6.66 (s, 2
3
S)-2-[(S)-1-(Furan-2-yl)-2-nitroethyl]cyclohexanone16 (Table
, Entry 13)
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
(
3
H), 6.64–6.58 (m, 2 H), 5.96 (s, 2 H), 4.92 (dd, J = 4.5, 12.3 Hz, 1
H), 4.56 (dd, J = 4.5, 9.9 Hz, 1 H), 3.67 (dt, J = 4.5, 9.9 Hz, 1 H),
2
1
.68–2.56 (m, 1 H), 2.51–2.33 (m, 2 H), 2.15–2.07 (m, 1 H), 1.83–
.61 (m, 4 H), 1.31–1.25 (m, 1 H).
min, l = 254 nm; tmajor = 10.47 min, tminor = 13.27 min; dr (syn/anti)
>99:1; ee = 91%.
1
3
C NMR (75 MHz, CDCl ): d = 211.7, 148.0, 147.1, 131.2, 121.6,
3
1
H NMR (300 Hz, CDCl ): d = 7.36 (d, J = 1.2 Hz, 1 H), 6.29 (dd,
3
1
08.5, 108.0, 101.2, 78.9, 52.5, 43.6, 42.6, 33.2, 28.3, 25.1.
J = 1.8, 3.3 Hz, 1 H), 6.16 (d, J = 3.3 Hz, 1 H), 4.81–4.62 (m, 2 H),
3.99 (dt, J = 4.8, 9.3 Hz, 1 H), 2.79–2.71 (m, 1 H), 2.51–2.32 (m, 2
H), 2.16–2.07 (m, 1 H), 1.92–1.56 (m, 4 H), 1.35–1.23 (m, 1 H).
13
S)-2-[(R)-1-(Naphthalen-1-yl)-2-nitroethyl]cyclohexanone5f
(
(
[
Table 3, Entry 9)
25
a]D –99.8 (c 1.1, CHCl3).
C NMR (75 MHz, CDCl ): d = 210.9, 150.8, 142.3, 110.3, 108.9,
3
7
6.6, 51.0, 42.5, 37.5, 32.4, 28.2, 25.0.
HPLC: Chiralpak AS-H, i-PrOH–hexane (30:70), flow rate 1.0 mL/
= 10.60 min, tmajor = 15.43 min; dr (syn/anti
min, l = 254 nm; t
minor
R)-Tetrahydro-3-[(R)-2-nitro-1-phenylethyl]pyran-4-one17
Table 3, Entry 14)
(
(
>
1
99:1; ee >99%.
H NMR (300 Hz, CDCl ): d = 8.17 (s, 1 H), 7.86 (d, J = 7.8 Hz, 1
3
HPLC: Chiralpak AS-H, i-PrOH–hexane (30:70), flow rate 1.0 mL/
= 14.10 min, tmajor = 17.69 min; dr (syn/anti)
H), 7.75 (d, J = 8.1 Hz, 1 H), 7.60–7.35 (m, 4 H), 5.06 (dd, J = 4.5,
min, l = 254 nm; t
minor
1
2
1
2.6 Hz, 1 H), 4.91–4.88 (m, 1 H), 4.76 (s, 1 H), 2.65 (br s, 1 H),
.45–2.38 (m, 2 H), 2.09–2.04 (m, 1 H), 1.69–1.47 (m, 4 H), 1.29–
.20 (m, 1 H).
>
99:1; ee = 96%.
1
H NMR (300 MHz, CDCl ): d = 7.39–7.27 (m, 3 H), 7.24–7.17 (m,
3
2
H), 4.78–4.62 (m, 2 H), 4.11–4.02 (m, 1 H), 3.87–3.75 (m, 2 H),
1
3
C NMR (75 MHz, CDCl ): d = 212.1, 134.5, 128.9, 128.1, 126.3,
3
3.70 (dd, J = 4.8, 11.7 Hz, 1 H), 3.29 (dd, J = 9.6, 11.4 Hz, 1 H),
1
25.7, 125.1, 123.5, 122.4, 78.6, 53.5, 42.7, 36.5, 33.1, 28.5, 25.1.
2
.93–2.85 (m, 1 H), 2.73–2.62 (m, 1 H), 2.58–2.49 (m, 1 H).
13C NMR (75 MHz, CDCl
): d = 209.3, 136.3, 129.2, 128.3, 128.0,
8.6, 54.7, 44.6, 43.5, 35.2, 31.7.
S)-2-[(R)-2-(Naphthalen-1-yl)-2-nitroethyl)cyclohexanone4d
3
(
(
[
7
Table 3, Entry 10)
25
a]D –69.2 (c 1.1, CHCl3).
R)-Tetrahydro-3-[(R)-2-nitro-1-phenylethyl]thiopyran-4-one17
Table 3, Entry 15)
(
(
HPLC: Chiralpak AD-H, i-PrOH–hexane (30:70), flow rate 1.0 mL/
min, l = 254 nm; tminor = 10.06 min, tmajor = 16.49 min; dr (syn/anti)
>
HPLC: Chiralpak AS-H, i-PrOH–hexane (30:70), flow rate 1.0 mL/
= 9.81 min, tmajor = 11.98 min; dr (syn/
99:1; ee >99%.
min, l = 254 nm; t
minor
1
anti) = 99:1; ee = 94%.
H NMR (300 MHz, CDCl ): d = 7.84–7.79 (m, 3 H), 7.63 (d,
3
J = 1.2 Hz, 1 H), 7.49–7.46 (m, 2 H), 7.30–7.26 (m, 1 H), 5.02 (dd,
J = 4.5, 12.6 Hz, 1 H), 4.73 (dd, J = 9.9, 12.3 Hz, 1 H), 3.99–3.92
(
H), 1.76–1.58 (m, 4 H), 1.29–1.25 (m, 1 H).
1
1
H NMR (300 MHz, CDCl ): d = 7.38–7.28 (m, 3 H), 7.23–7.17 (m,
3
2
H), 4.75 (dd, J = 4.8, 12.6 Hz, 1 H), 4.65 (dd, J = 9.6, 12.3 Hz, 1
H), 4.01 (dt, J = 4.5, 10.2 Hz, 1 H), 3.10–2.77 (m, 5 H), 2.62 (ddd,
J = 1.5, 4.2, 13.8 Hz, 1 H), 2.46 (dd, J = 9.6, 13.8 Hz, 1 H).
m, 1 H), 2.78–2.75 (m, 1 H), 2.50–2.47 (m, 2 H), 2.42–2.39 (m, 1
3
C NMR (75 MHz, CDCl ): d = 211.8, 135.1, 133.4, 132.8, 128.9,
13
3
C NMR (75 MHz, CDCl ): d = 208.6, 136.7, 129.4, 128.6, 127.9,
3
1
2
27.9, 127.7, 126.5, 126.2, 125.2, 78.8, 76.6, 52.5, 44.1, 42.8, 33.3,
8.5, 25.0.
7
8.8, 71.9, 69.3, 53.5, 43.0, 41.5.
Synthesis 2008, No. 23, 3828–3834 © Thieme Stuttgart · New York

3
834
T. Miao et al.
PAPER
Acknowledgment
(6) (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.
We gratefully acknowledge financial support by the National Natu-
ral Science Foundation of China (No. 20572031, 20772043).
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2
003, 5, 2559. (b) Mosse, S.; Laars, M.; Kriis, K.; Kanger,
T.; Alexakis, A. Org. Lett. 2006, 8, 2559.
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Synthesis 2008, No. 23, 3828–3834 © Thieme Stuttgart · New York