Highly enantioselective michael addition of ketones and an aldehyde to nitroalkenes catalyzed by a binaphthyl sulfonimide in water

Article abstract of DOI:10.1055/s-0030-1260464

A binaphthyl sulfonimide organocatalyst was used to promote highly enantioselective and diastereoselective Michael addition reactions of ketones to nitroalkenes in water. In most cases, the products were obtained in good yields with excellent enantioselec

Full text of DOI:10.1055/s-0030-1260464

1968
PAPER
Highly Enantioselective Michael Addition of Ketones and an Aldehyde to
Nitroalkenes Catalyzed by a Binaphthyl Sulfonimide in Water
Catalytic Michae
h
A
ddition
R
u
eactionsof
N
n
itroalkene
s
hua Luo, Da-Ming Du*
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, P. R. of China
E-mail: dudm@bit.edu.cn
Received 17 March 2011
metric Michael addition. Singh hypothesized that when
Abstract: A binaphthyl sulfonimide organocatalyst was used to
promote highly enantioselective and diastereoselective Michael ad-
dition reactions of ketones to nitroalkenes in water. In most cases,
the products were obtained in good yields with excellent enantiose-
the reaction is performed in an aqueous medium, hydro-
phobic hydration should be enhanced by a binaphthyl
group and, because of the aromatic nature of this group,
lectivities and diastereoselectivities (93–97% ee, up to >99:1 dr). that this should also work in an organic medium.4b We
The catalyst could also be used in an asymmetric Michael addition
of isobutyraldehyde to nitroalkenes to give the desired products in
therefore hypothesized that catalysts 1a–d should also act
as water-soluble organocatalysts, and we attempted to ap-
moderate yields and moderate enantioselectivities (up to 83% ee).
ply them in catalyzing the Michael addition of ketones to
Key words: asymmetric catalysis, organocatalysis, Michael addi-
tions, nitroalkenes, sulfonimides
nitroalkenes in water.
O
O
S
Asymmetric organocatalysis of Michael addition reaction
is, without doubt, one of the most general and versatile
methods for the construction of C–C bonds in organic
synthesis.1 As a result, this reaction has attracted the inter-
est of many organic chemists who have produced some
good results.2 Recently, asymmetric Michael reactions
that take place in environmentally clean, safe, and cheap
solvents, such as water,3 brine,4 or ionic liquids,5 have
been the subject of considerable development. Compared
with typical organic solvents, water as a solvent for this
reaction has many advantages in that it is nontoxic, envi-
ronmentally benign, cheap, and can be safely handled. Or-
ganic reactions in aqueous media have been reviewed by
Li, with particular attention to the formation of C–C
bonds.6 Despite the excellent results reported in this area,
the design and development of organocatalytic enantiose-
lective reactions that take place in water remain as major
challenges.
N
H
N
S
O
O
O
O
S
N
H
1a
N
H
H
N
H
N
S
O
O
1b
O
O
S
N
H
N
S
O
O
O
O
O
S
N
1c
N
H
H
H
H
N
N
S
We recently prepared the L-proline-based binaphthyl sul-
fonimides and sulfonamides 1a–d (Figure 1) as highly ef-
ficient and stereoselective organocatalysts for the
O
1d
asymmetric Michael addition of ketones to nitroalkenes in Figure 1 Binaphthyl sulfonimide and sulfonamide organocatalysts
the presence of benzoic acid in organic solvents.7 With re-
1a–d
gard to asymmetric organocatalysis of Michael addition
reaction in aqueous media, Lin has reported several new
types of organocatalysts bearing sulfide or sulfone func-
tions that are suitable for highly stereoselective Michael
addition of ketones to nitroalkenes in water.3e He specu-
lated that the oxygen of the sulfone functionality in com-
bination with a protic solvent, such as water, provides a
hydrogen-bonding interaction that leads to an improve-
ment in both reactivity and stereoselectivity in the asym-
To our surprise, the (R)-1,1¢-binaphthyl-derived catalyst
1a showed interesting results in the catalytic asymmetric
Michael addition of cyclohexanone (2) with [(E)-2-nitro-
vinyl]benzene (3a) in water. Cyclohexanone (2) (1.0
mmol) reacted with [(E)-2-nitrovinyl]benzene (3a) (0.2
mmol) in the presence of the catalyst 1a (10 mol%) in wa-
ter (0.2 mL at room temperature to give the desired adduct
4a in 95% yield with 95% ee and 99:1 dr within 12 hours
(Table 1, entry 1).
SYNTHESIS 2011, No. 12, pp 1968–1973
Advanced online publication: 13.05.2011
DOI: 10.1055/s-0030-1260464; Art ID: C30311SS
x
x.
x
x
.
2
0
1
1
Encouraged by these results, we attempted to optimize the
reaction conditions. With the catalyst 1a–d in hand, the
© Georg Thieme Verlag Stuttgart · New York

PAPER
Catalytic Michael Addition Reactions of Nitroalkenes
1969
effects of the solvent, additive, and reaction time on the lectivities. A slight influence on the reactivity was ob-
outcome of the reaction were thoroughly investigated, and served in the reactions of cyclohexanone (2) and
the results are summarized in Table 1. Initially, the reac- nitroalkenes with a para-oriented electron-withdrawing
tion was performed by using 10 mol% of 1a in water or or electron-donating substituents on the aromatic rings,
brine. It has been reported that the addition of an acid to such as 3f, which afforded the corresponding adduct 4f
the Michael reaction system can improve chemical yields within 48 hours. Interestingly, the rate and enantioselec-
by accelerating the formation of the enamine.8 However, tivity of this this reaction were better in water than in or-
the reaction rate, yield, and enantiomeric excess were de- ganic solvents.7
creased when acids such as 2-nitrobenzoic acid (entry 7;
The reactions of other ketones (cyclopentanone, 1-tetra-
93% ee, 98:2 dr), 4-toluenesulfonic acid (entry 3; 91% ee,
lone, indan-1-one, and acetone) were also carried out in
97:3 dr), or benzoic acid (entry 4; 93% ee, 98:2 dr) was
the presence of catalyst 1c (Scheme 1). The reaction of
cyclopentanone with [(E)-2-nitrovinyl]benzene (3a) in
water gave the corresponding product 6 in a higher yield
added. No product was obtained in the presence of tri-
fluoroacetic acid (entry 2). Furthermore, the results of the
reaction were not improved by using brine instead of wa-
ter (entries 1 and 6). Therefore, the other chiral catalysts
Ph
O
O
1b–d were screened by using water as solvent without an
additive (entries 8–10). Catalysts 1a–d facilitated the
asymmetric Michael addition reaction with good-to-
excellent stereoselectivities and yields. Sulfonimides 1a
and 1c produced slight higher enantioselectivities than did
sulfonamides 1b and 1d. Catalyst 1c gave the best results,
with a 96% yield and 96% ee (entry 9) of the syn diaste-
reomer (99:1 dr).
1c (10 mol%)
NO2
NO2
+
Ph
H2O, r.t., 48 h
5
3a
6
60% yield, syn/anti = 67:33,
88% ee (syn), 92% ee (anti)
O
O
or
The excellent catalytic ability of the organocatalyst 1c
was confirmed by further studies, and the results are sum-
marized in Table 2. They show that various aromatic ni-
troalkenes 3a–l react smoothly with cyclohexanone (2) in
the presence of catalyst 1c (10 mol%) in water, leading to
the corresponding adducts 4a–l in moderate-to-excellent
yields and excellent diastereoselectivities and enantiose-
7
8
1c (10 mol%)
no reaction
+
H2O, r.t., 48 h
NO2
Ph
3a
Scheme 1 Further studies on the scope of substrates for the Michael
addition of ketones to (E)-2-nitrovinyl]benzene (3a)
Table 1 Optimization of Solvents, Additives, and Catalysts
O
O
Ph
NO2
1 (10 mol%)
NO2
+
Ph
additive (10 mol%)
H2O or brine, r.t.
2
3a
4a
Entrya
Catalyst
1a
Additive
–
Solvent
H2O
H2O
H2O
H2O
brine
brine
H2O
H2O
H2O
H2O
Time (h)
12
Yieldb (%)
drc (syn/anti) eed (%)
1
2
95
0
99:1
–
95
–
1a
CF3CO2H
TsOH
PhCO2H
PhCO2H
–
24
3
1a
12
90
94
94
90
93
92
96
90
97:3
98:2
98:2
97:3
98:2
97:3
99:1
98:2
91
93
93
93
93
92
96
94
4
1a
12
5
1a
12
6
1a
12
7
1a
2-O2NC6H4CO2H
12
8
1b
–
–
–
12
9
1c
12
10
1d
12
a All reactions were carried out by using cyclohexanone (2; 98 mg, 1.0 mmol), the additive (10 mol%), and catalyst 1 (10 mol%) in H2O or brine
(0.2 mL). The mixture were stirred at r.t. for 15 min, then [(E)-2-nitrovinyl]benzene (3a; 29.8 mg, 0.20 mmol) was added.
b Yield of the isolated product after chromatography on silica gel.
c Determined by chiral HPLC on a Chiracel AS-H column with hexane and i-PrOH as eluents.
d Determined by chiral HPLC analysis.
Synthesis 2011, No. 12, 1968–1973 © Thieme Stuttgart · New York

1970
C. Luo, D.-M. Du
PAPER
shown in Figure 2. The pyrrolidine ring first reacts with
the carbonyl compound to form an enamine. Subsequent-
ly, the oxygen atom of the sulfonimide group, through a
hydrogen bond with water, directs the nitro group so that
the enamine attacks the nitroalkene from the Re face op-
posite the binaphthyl group of 1c to give the product with
a high enantio- and diastereoselectivity.
Table 2 Catalytic Asymmetric Michael Addition of Cyclohexanone
to Nitroalkenes
O
R
O
NO2
1c (10 mol%)
NO2
+
R
H2O, r.t.
2
3
4
Entrya
R
Time Product Yieldb drc
eed
In an attempt to extend the application of the catalyst, we
next examined the Michael addition of an aldehyde to ni-
troalkenes under the optimized conditions. As expected,
the catalyst can also be applied to enolizable aldehydes,
such as isobutyraldehyde, and the results are summarized
in Table 3. Isobutyraldehyde gave the desired products 10
in moderate yields (63–86%) and moderate enantioselec-
tivities (55–83% ee). In these cases, catalyst 1c showed a
similar reactivity and selectivity for a range of nitroal-
kenes.
(h)
12
24
24
24
24
48
24
24
24
(%)
96
94
91
88
80
85
90
85
85
60
65
68
(syn/anti) (%)
1
2
Ph
4a
4b
4c
4d
4e
4f
99:1
96:4
96
95
97
96
97
97
95
97
96
93
94
95
2-MeOC6H4
2-ClC6H4
4-ClC6H4
4-FC6H4
3
>99:1
>99:1
98:2
4
5
6
4-MeC6H4
4-BrC6H4
3-O2NC6H4
3-BrC6H4
>99:1
99:1
In conclusion, we used the water-soluble L-proline-based
binaphthyl sulfonimides and sulfonamides 1a–d as highly
efficient and stereoselective organocatalysts in the asym-
7
4g
4h
4i
8
98:2
Table 3 Catalytic Asymmetric Michael Addition of Isobutyralde-
hyde to Nitroalkenes
9
97:3
10
11
12
3,4-(MeO)2C6H3 48
4j
98:2
O
R
O
1c (10 mol%)
NO2
NO2
+
2-thienyl
2-furyl
48
48
4k
>99:1
98:2
H
H
R
H2O, r.t.
4l
9
3
10
a All the reactions were carried out by using cyclohexanone (2; 100
mg, 1.0 mmol) and catalyst 1c (10 mol%) in H2O (0.2 mL). The mix-
ture was stirred at r.t. for 15 min, then nitroalkene 3 (0.20 mmol) was
added.
Entrya
R
Time (h) Product Yieldb (%) eec (%)
1
2
3
4
5
6
Ph
4-FC6H4
72
48
48
48
96
48
10a
10b
10c
10d
10e
10f
80
73
76
63
67
86
83
67
69
72
55
79
b Yield of the isolated product after chromatography on silica gel.
c Determined by chiral HPLC.
d Determined by chiral HPLC analysis; the configuration was as-
signed according to the literature.2
4-ClC6H4
4-BrC6H4
4-Tol
(60%) and better enantioselectivity (88% ee) than in
dichloromethane (21% yield and 73% ee).7 Unfortunately,
as shown in Scheme 1, the reactions of 1-tetralone, indan-
1-one, and acetone with [(E)-2-nitrovinyl]benzene (3a) in
water failed to give the corresponding products.
3-O2NC6H4
a All reactions were carried out by using aldehyde 9 (72 mg, 1.0
mmol) and catalyst 1c (10 mol%) in H2O (0.2 mL). The mixture was
stirred at r.t. for 15 min, then nitroalkene 3 (0.20 mmol) was added.
b Yield of the isolated product after chromatography on silica gel.
c Determined by chiral HPLC analysis; the configuration was as-
signed according to the literature.8
On the basis of the configuration of the product, we pro-
pose the putative transition state for the 1c-catalyzed
asymmetric Michael addition of a ketone to a nitroalkene
O
S
O
O
H
H
N
O
O
S
N
O
O
S
O
N
H
O
S
N
N
O
O
O
O
N
O
H
Re
H
H
Figure 2 A proposed transition state
Synthesis 2011, No. 12, 1968–1973 © Thieme Stuttgart · New York

PAPER
Catalytic Michael Addition Reactions of Nitroalkenes
1971
(2S)-2-[(1R)-1-(4-Chlorophenyl)-2-nitroethyl]cyclohexanone
(4d)
metric Michael addition of cyclohexanone to nitroalk-
enes. The corresponding products were obtained in good
yields and excellent enantioselectivities and diastereose-
lectivities (93–97% ee, up to >99:1 dr). The catalyst 1c
was also effective in the asymmetric Michael addition of
isobutyraldehyde to nitroalkenes, and the desired products
were obtained in moderate yields and enantioselectivities
(up to 83% ee). Syntheses of derivatives of these organo-
catalysts as well as studies on their applications in other
organic reactions are currently under way in our group.
White solid; yield: 88%; mp 93–95 °C; [a]D20 –34.4 (c 1.0, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.16 (dd, J = 5.2, 8.8 Hz, 2 H),
6.99–7.03 (m, 2 H), 4.96 (dd, J = 4.8, 12.8 Hz, 1 H), 4.60 (dd,
J = 10.4, 12.8 Hz, 1 H), 3.78 (dt, J = 4.4, 10.0 Hz, 1 H), 2.62–2.70
(m, 1 H), 2.33–2.48 (m, 2 H), 2.06–2.11 (m, 1 H), 1.55–1.81 (m, 4
H), 1.17–1.27 (m, 1 H).
HPLC [Chiralpak AS-H, hexane–i-PrOH (85:15), flow rate 1 mL/
min, detection at 230 nm]: tR (minor) = 13.9 min, tR (major) = 24.8
min; syn/anti = 99:1, 96% ee.
(2S)-2-[(1R)-1-(4-Fluorophenyl)-2-nitroethyl]cyclohexanone
(4e)
Commercially available compounds were used without further pu-
rification. Column chromatography was carried out on silica gel
(200–300 mesh). Melting points were measured with a XT-4 melt-
ing point apparatus. The 1H NMR spectra were recorded on a Varian
Mercury-plus 400 M spectrometer. Optical rotations were measured
with a WZZ–3 polarimeter. The enantiomeric excesses of the prod-
ucts were determined by chiral HPLC analysis using an Agilent HP
1200 instrument with hexane–i-PrOH as the eluent.
White solid; yield: 80%; mp 64–65 °C; [a]D20 –34.0 (c 0.5, CH2Cl2).
1H NMR (CDCl3, 400 MHz): d = 7.16 (dd, J = 5.2 and 8.8 Hz, 2 H),
6.99–7.03 (m, 2 H), 4.96 (dd, J = 4.8, 12.8 Hz, 1 H), 4.60 (dd,
J = 10.4, 12.8 Hz, 1 H), 3.79 (dt, J = 4.4, 10.0 Hz, 1 H), 2.62–2.75
(m, 1 H), 2.37–2.48 (m, 2 H), 2.07–2.11 (m, 1 H), 1.58–1.81 (m, 4
H), 1.17–1.27 (m, 1 H).
HPLC [Chiralpak AS H, hexane–i-PrOH (90:10), flow rate 1.0 mL/
min, detection at 254 nm]: tR (minor) = 21.6 min, tR (major) = 36.6
min; syn/anti = 98:2, 97% ee.
(2S)-2-[(1R)-2-Nitro-1-phenylethyl]cyclohexanone (4a); Typi-
cal Procedure
The organocatalyst 1c (9.8 mg, 0.02 mmol) was added to cyclohex-
anone (2; 98 mg, 1.0 mmol) in H2O (0.2 mL) at r.t. Nitroalkene 3a
(29.8 mg, 0.2 mmol) was added, and the resulting mixture was
stirred at r.t. until the reaction was complete (TLC). The product
was isolated by flash chromatography (silica gel, PE–EtOAc) as a
(2S)-2-[(1R)-1-(4-Methylphenyl)-2-nitroethyl]cyclohexanone
(4f)
20
White solid; yield: 85%; mp 124–126 °C; [a]D –14.0 (c 1.0,
CH2Cl2).
20
white solid; yield: 96%; mp 122–124 °C; [a]D –18.0 (c 0.5,
1H NMR (CDCl3, 400 MHz): d = 7.12 (d, J = 8.0 Hz, 2 H), 7.04 (d,
J = 8.0 Hz, 2 H), 4.92 (dd, J = 4.4, 12.4 Hz, 1 H), 4.60 (dd,
J = 10.0, 12.0 Hz, 1 H), 3.72 (dt, J = 4.4, 10.0 Hz, 1 H), 2.63–2.70
(m, 1 H), 2.34–2.49 (m, 2 H), 2.31 (s, 3 H), 2.05–2.10 (m, 1 H),
1.55–1.80 (m, 4 H), 1.18–1.27 (m, 1 H).
CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.27–7.34 (m, 3 H), 7.18 (d,
J = 8.0 Hz, 2 H), 4.95 (dd, J = 4.4, 12.8 Hz, 1 H), 4.64 (dd,
J = 10.4, 12.4 Hz, 1 H), 3.76 (dt, J = 4.4, 10.0 Hz, 1 H), 2.66–2.73
(m, 1 H), 2.36–2.51 (m, 2 H), 2.07–2.11 (m, 1 H), 1.67–1.81 (m, 2
H), 1.55–1.62 (m, 2 H), 1.22–1.29 (m, 1 H).
HPLC [Chiralpak AS-H, hexane–i-PrOH (90:10), flow rate 1.0 mL/
min, detection at 230 nm]: tR (minor) = 10.5 min, tR (major) = 17.5
min; syn/anti = > 99:1, 97% ee.
HPLC [Chiralpak AS-H, hexane–i-PrOH (85:15), flow rate 1 mL/
min, detection at 230 nm]: tR (minor) = 13.5 min, tR (major) = 21.1
min; syn/anti = 99:1, 96% ee.
(2S)-2-[(1R)-1-(4-Bromophenyl)-2-nitroethyl]cyclohexanone
Compounds 4b–l and 6 were similarly prepared.
(4g)
20
White solid; yield: 90%; mp 119–121 °C; [a]D –33.6 (c 0.5,
CH2Cl2).
(2S)-2-[(1R)-1-(2-Methoxyphenyl)-2-nitroethyl]cyclohexanone
(4b)
1H NMR (400 MHz, CDCl3): d = 7.44 (d, J = 6.0, 8.4 Hz, 2 H), 7.15
(d, J = 8.4 Hz, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 4.94 (dd, J = 4.4,
12.4 Hz, 1 H), 4.59 (dd, J = 10.4, 12.8 Hz, 1 H), 3.75 (dt, J = 4.4,
10.0 Hz, 1 H), 2.61–2.73 (m, 1 H), 2.34–2.47 (m, 2 H), 2.02–2.10
(m, 1 H), 1.54-1.76 (m, 4 H), 1.17–1.27 (m, 1 H).
White solid; yield: 94%; mp 96–99 °C; [a]D20 –34.0 (c 0.5, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.22–7.27 (m, 1 H), 7.08 (dd,
J = 1.2, 7.2 Hz, 1 H), 6.88 (t, J = 7.2 Hz, 2 H), 4.82–4.85 (m, 2 H),
3.93–4.00 (m, 1 H), 3.84 (s, 3 H), 2.95–3.02 (m, 1 H), 2.38–2.45 (m,
2 H), 2.06–2.10 (m, 1 H), 1.74–1.79 (m, 1 H), 1.55–1.69 (m, 3 H),
1.15–1.25 (m, 1 H).
HPLC [Chiralpak AS-H, hexane–i-PrOH (90:10), flow rate = 1.0
mL/min, detection at 254 nm]: tR (minor) = 19.0 min, tR
(major) = 35.9 min; syn/anti = 99:1, 95% ee.
HPLC [Chiralpak AS-H, hexane–i-PrOH (85:15), flow rate 1 mL/
min, detection at 230 nm]: tR (minor) = 16.2 min, tR (major) = 19.0
min; syn/anti = >96:4, 95% ee.
(2S)-2-[(1R)-2-Nitro-1-(3-nitrophenyl)ethyl]cyclohexanone (4h)
Colorless oil; yield: 85%; [a]D20 –30.2 (c 1.0, CH2Cl2).
(2S)-2-[(1R)-1-(2-Chlorophenyl)-2-nitroethyl]cyclohexanone
(4c)
1H NMR (CDCl3, 400 MHz): d = 8.10–8.17 (m, 2 H), 7.52–7.60 (m,
2 H), 5.03 (dd, J = 4.4, 13.2 Hz, 1 H), 4.71 (dd, J = 10.4, 13.2 Hz,
1 H), 3.95 (dt, J = 4.4, 9.6 Hz, 1 H), 2.73–2.88 (m, 1 H), 2.40–2.51
(m, 2 H), 2.11–2.15 (m, 1 H), 1.60–1.73 (m, 4 H), 1.24–1.33 (m, 1
H).
Colorless oil; yield: 91%; [a]D20 –42.0 (c 1.0, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.36–7.39 (m, 1 H), 7.19–7.25 (m,
3 H), 4.89 (d, J = 7.2 Hz, 2 H), 4.27–4.33 (m, 1 H), 2.88–2.96 (m,
1 H), 2.35–2.50 (m, 2 H), 2.08–2.13 (m, 1 H), 1.79–1.83 (m, 1 H),
1.55–1.75 (m, 3 H), 1.25–1.38 (m, 1 H).
HPLC [Chiralpak IA, hexane–i-PrOH (98:2), flow rate = 1.0 mL/
min, detection at 254 nm]: tR (minor) = 60.7 min, tR (major) = 74.0
min; syn/anti = 98:2, 97% ee.
HPLC [Chiralpak IA, hexane–i-PrOH (90:10), flow rate 1 mL/min,
detection at 254 nm]: tR (minor) = 8.0 min, tR (major) = 10.5 min;
syn/anti = > 99:1, 97% ee.
Synthesis 2011, No. 12, 1968–1973 © Thieme Stuttgart · New York

1972
C. Luo, D.-M. Du
PAPER
Sulfonimide 1c-Catalyzed Asymmetric Michael Addition of
(2S)-2-[(1R)-1-(3-bromophenyl)-2-nitroethyl]cyclohexanone
(4i)
Isobutyraldehyde to Nitroalkenes; General Procedure
Organocatalyst 1c (9.8 mg, 0.02 mmol) was added to isobutyralde-
hyde (9) (72 mg, 1.0 mmol) in H2O (0.2 mL) at r.t. Nitroalkene 3
(0.2 mmol) was then added and the resulting mixture was stirred at
r.t. until the reaction was complete (TLC). The product was isolated
by flash chromatography (silica gel, PE–EtOAc).
Colorless oil; yield: 85%; [a]D20 –28.8 (c 0.5, CH2Cl2).
1H NMR (CDCl3, 400 MHz): d = 7.33–7.41 (m, 2 H), 7.11–7.22 (m,
2 H), 4.95 (dd, J = 4.4, 12.8 Hz, 1 H), 4.60 (dd, J = 10.0, 12.8 Hz,
1 H), 3.75 (dt, J = 4.4, 9.6 Hz, 1 H), 2.62–2.75 (m, 1 H), 2.37–2.46
(m, 2 H), 2.08–2.11 (m, 1 H), 1.60–1.73 (m, 4 H), 1.22–1.29 (m, 1
H).
(3R)-2,2-Dimethyl-4-nitro-3-phenylbutanal (10a)
Colorless oil; yield: 80%; [a]D20 +9.6 (c 0.5, CHCl3).
1H NMR (CDCl3, 400 MHz): d = 9.53 (s, 1 H), 7.26–7.35 (m, 3 H),
7.19–7.21 (m, 2 H), 4.86 (dd, J = 11.2, 13.2 Hz, 1 H), 4.69 (dd,
J = 4.4, 13.2 Hz, 1 H), 3.78 (dd, J = 4.4, 11.2 Hz, 1 H), 1.13 (s, 3
H), 1.00 (s, 3 H).
HPLC [Chiralpak AS-H, hexane–i-PrOH (90:10), flow rate 1.0
mL/min, detection at 230 nm]: tR (minor) = 21.1 min, tR
(major) = 41.7 min; syn/anti = 97:3, 96% ee.
(2S)-2-[(1R)-1-(3,4-Dimethoxyphenyl)-2-nitroethyl]cyclohex-
anone (4j)
White solid; yield: 60%; mp 133–135 °C; [a]D –13.6 (c 0.5,
CH2Cl2).
1H NMR (CDCl3, 400 MHz): d = 6.81 (d, J = 8.4 Hz, 1 H), 6.71 (dd,
J = 62.0, 8.4 Hz, 1 H), 6.66 (d, J = 2.0 Hz, 1 H), 4.91 (dd, J = 4.8,
12.4 Hz, 1 H), 4.62 (dd, J = 10.0, 12.0 Hz, 1 H), 3.87 (s, 3 H), 3.86
(s, 3 H), 3.71 (dt, J = 4.8, 10.0 Hz, 1 H), 2.62–2.69 (m, 1 H), 2.35–
2.50 (m, 2 H), 2.07–2.11 (m, 1 H), 1.59–1.82 (m, 4 H), 1.20–1.29
(m, 1 H).
20
HPLC [Chiralpak IB, hexane–i-PrOH (80:20), flow rate 0.8 mL/
min, detection at 254 nm]: tR (major) = 11.6 min, tR (minor) = 14.8
min; 83% ee.
(3R)-3-(4-Fluorophenyl)-2,2-dimethyl-4-nitrobutanal (10b)
Brown oil; yield: 73%; [a]D20 +1.2 (c 0.48, CHCl3).
1H NMR (CDCl3, 400 MHz): d = 9.5 (s, 1 H), 7.17–7.21 (m, 2 H),
7.01–7.05 (m, 2 H), 4.83 (dd, J = 11.4, 13.0 Hz, 1 H), 4.69 (dd,
J = 4.2, 13.0 Hz, 1 H), 3.77 (dd, J = 4.2, 11.4 Hz, 1 H), 1.12 (s, 3
H), 1.01 (s, 3 H).
HPLC [Chiralpak AS-H, hexane–i-PrOH (75:25), flow rate 1.0 mL/
min, detection at 230 nm]: tR (minor) = 17.5 min, tR (major) = 38.9
min; syn/anti = 98:2, 93% ee.
HPLC [Chiralpak IB, hexane–i-PrOH (85:15), flow rate 0.8 mL/
min, detection at 254 nm]: tR (major) = 10.5 min, tR (minor) = 16.0
min; 67% ee.
(2S)-2-[(1S)-2-Nitro-1-(2-thienyl)ethyl]cyclohexanone (4k)
Brown solid; yield: 65%; mp 82–84 °C; [a]D –30.4 (c 0.5,
CH2Cl2).
1H NMR (CDCl3, 400 MHz): d = 7.23 (d, J = 4.8 Hz, 1 H), 6.93 (dd,
J = 3.6, 5.2 Hz, 1 H), 6.87 (d, J = 3.6 Hz, 1 H), 4.89 (dd, J = 4.4,
12.4 Hz, 1 H), 4.65 (dd, J = 9.6, 12.4 Hz, 1 H), 4.13 (dt, J = 4.4, 8.8
Hz, 1 H), 2.65–2.72 (m, 1 H), 2.37–2.47 (m, 2 H), 2.08–2.13 (m, 1
H), 1.83–1.93 (m, 2 H), 1.60–1.70 (m, 2 H), 1.30–1.34 (m, 1 H).
20
(3R)-3-(4-Chlorophenyl)-2,2-dimethyl-4-nitrobutanal (10c)
Brown oil; yield: 76%; [a]D20 +1.7 (c 0.45, CHCl3).
1H NMR (CDCl3, 400 MHz): d = 9.50 (s, 1 H), 7.31 (d, J = 8.4 Hz,
2 H), 7.15 (J = 8.4 Hz, 2 H), 4.82 (dd, J = 11.6, 13.2 Hz, 1 H), 4.69
(dd, J = 4.0, 13.2 Hz, 1 H), 3.77 (dd, J = 4.0, 11.6 Hz, 1 H), 1.12 (s,
3 H), 1.01 (s, 3 H).
HPLC [Chiralpak IA, hexane–i-PrOH (98:2), flow rate 1.0 mL/min,
detection at 230 nm]: tR (minor) = 26.3 min, tR (major) = 33.9 min;
syn/anti = 99:1, 94% ee.
HPLC [Chiralpak IB, hexane–i-PrOH (80:20), flow rate 0.8 mL/
min, detection at 254 nm]: tR (major) = 9.9 min, tR (minor) = 13.8
min; 69% ee.
(2S)-2-[(1S)-1-(2-Furyl)-2-nitroethyl]cyclohexanone (4l)
Brown oil; yield: 68%; [a]D20 –12.8 (c 0.5, CH2Cl2).
(3R)-3-(4-Bromophenyl)-2,2-dimethyl-4-nitrobutanal (10d)
Brown oil; yield: 63%; [a]D20 +1.1 (c 0.42, CHCl3).
1H NMR (CDCl3, 400 MHz): d = 9.50 (s, 1 H), 7.47 (d, J = 8.4 Hz,
2 H), 7.09 (d, J = 8.4 Hz, 2 H), 4.82 (dd, J = 11.6, 13.2 Hz, 1 H),
4.69 (dd, J = 4.0, 13.2 Hz, 1 H), 3.76 (dd, J = 4.0, 11.6 Hz, 1 H),
1.12 (s, 3 H), 1.01 (s, 3 H).
1H NMR (CDCl3, 400 MHz): d = 7.35 (d, J = 2.0 Hz, 1 H), 6.29 (dd,
J = 2.0, 3.2 Hz, 1 H), 6.18 (d, J = 3.2 Hz, 1 H), 4.79 (dd, J = 4.8,
12.4 Hz, 1 H), 4.67 (dd, J = 9.6, 12.4 Hz, 1 H), 3.98 (dt, J = 4.8, 9.2
Hz, 1 H), 2.72–2.79 (m, 1 H), 2.33–2.48 (m, 2 H), 2.08–2.13 (m, 1
H), 1.72–1.86 (m, 2 H), 1.62–1.67 (m, 2 H), 1.26–1.30 (m, 1 H).
HPLC [Chiralpak IB, hexane–i-PrOH (80:20), flow rate 0.8 mL/
min, detection at 230 nm]: tR (major) = 13.4 min, tR (minor) =
17.8 min; 72% ee.
HPLC [Chiralpak AS-H, hexane–i-PrOH (85:15), flow rate 1.0 mL/
min, detection at 230 nm]: tR (minor) = 15.6 min, tR (major) = 18.2
min; syn/anti = 98:2, 95% ee.
(R)-2,2-Dimethyl-3-(4-methylphenyl)-4-nitrobutanal (10e)
Colorless oil; yield: 67%; [a]D20 +2.5 (c 0.38, CHCl3).
1H NMR (CDCl3, 400 MHz): d = 9.53 (s, 1 H), 7.13 (d, J = 8.0 Hz,
1 H), 7.07 (d, J = 8.0 Hz, 1 H), 4.82 (dd, J = 11.2, 12.8 Hz, 1 H),
4.67 (dd, J = 4.2, 12.8 Hz, 1 H), 3.74 (dd, J = 4.2, 11.2 Hz, 1 H),
2.32 (s, 3 H), 1.12 (s, 3 H), 1.00 (s, 3 H).
(2S)-2-[(1R)-2-Nitro-1-phenylethyl]cyclopentanone (6)
White solid; yield: 60%; mp 115–117 °C; [a]D –16.6 (c 1.0,
CH2Cl2).
1H NMR (CDCl3, 400 MHz): d = 7.29–7.32 (m, 3 H), 7.15–7.18 (m,
2 H), 5.34 (dd, J = 5.6, 12.8 Hz, 1 H), 4.71 (dd, J = 9.9, 12.8 Hz, 1
H), 3.66–3.74 (m, 1 H), 2.31–2.44 (m, 2 H), 2.08–2.20 (m, 1 H),
1.84–1.94 (m, 2 H), 1.64–1.76 (m, 1 H), 1.48–1.56 (m, 1 H).
20
HPLC [Chiralpak IB, hexane–i-PrOH (80:20), flow rate 0.8 mL/
min, detection at 230 nm]: tR (major) = 10.0 min, tR (minor) = 12.6
min; 55% ee.
HPLC [Chiralpak IA, hexane–i-PrOH (95:5), flow rate 1.0 mL/min,
detection at 230 nm]: tR (major, anti) = 10.8 min, tR (minor,
anti) = 12.5 min, tR(minor, syn) = 13.6 min, tR (major, syn) = 19.8
min; syn/anti = 67:33, 88% ee (syn), 92% ee (anti).
(R)-2,2-Dimethyl-4-nitro-3-(3-nitrophenyl)butanal (10f)
Brown oil; yield: 86%; [a]D20 +4.4 (c 0.55, CHCl3).
1H NMR (CDCl3, 400 MHz): d = 9.51 (s, 1 H), 8.13–8.21 (m, 2 H),
7.53–7.61 (m, 2 H), 4.93 (dd, J = 11.4, 13.4 Hz, 1 H), 4.77 (dd,
Synthesis 2011, No. 12, 1968–1973 © Thieme Stuttgart · New York

PAPER
Catalytic Michael Addition Reactions of Nitroalkenes
1973
J = 3.8, 13.4 Hz, 1 H), 3.94 (dd, J = 3.8, 11.4 Hz, 1 H), 1.18 (s, 3
H), 1.06 (s, 3 H).
Chem. 2008, 1157. (g) Tan, B.; Zeng, X. F.; Lu, Y. P.; Chua,
P. J.; Zhong, G. F. Org. Lett. 2009, 11, 1927. (h) Belot, S.;
Quintard, A.; Krause, N.; Alexakis, A. Adv. Synth. Catal.
2010, 352, 667. (i) Lu, A. D.; Wu, R. H.; Wang, Y. M.;
Zhou, Z. H.; Wu, G. P.; Fang, J. X.; Tang, C. C. Eur. J. Org.
Chem. 2010, 2057. (j) Lv, G. H.; Jin, R. H.; Mai, W. P.; Gao,
L. X. Tetrahedron: Asymmetry 2008, 19, 2568. (k) Sato, A.;
Yoshida, M.; Hara, S. Chem. Commun. 2008, 6242.
(3) For asymmetric Michael reactions in water, see: (a)Luo, S.;
Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P. Chem. Commun. 2006,
3687. (b) Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006,
8, 3077. (c) Yan, Z.-Y.; Niu, Y.-N.; Wei, H.-L.; Wu, L.-Y.;
Zhao, Y.-B.; Liang, Y.-M. Tetrahedron: Asymmetry 2006,
17, 3288. (d) Cao, Y.-J.; Lai, Y.-Y.; Wang, X.; Li, Y.-J.;
Xiao, W.-J. Tetrahedron Lett. 2007, 48, 21. (e) Syu, S.-E.;
Kao, T.-T.; Lin, W. Tetrahedron 2010, 66, 891. (f) Palomo,
C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.; Vera, S.
Angew. Chem. Int. Ed. 2007, 46, 8431. (g) Zhu, S.; Yu, S.;
Ma, D. Angew. Chem. Int. Ed. 2008, 47, 545. (h) Alza, E.;
Cambeiro, X. C.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2007,
9, 3717.
HPLC [Chiralpak AS-H, hexane–i-PrOH (90:10), flow rate = 1.0
mL/min, detection at 254 nm]: tR (minor) = 49.2 min, tR
(major) = 53.4 min; 79% ee.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (Grant No. 21072020), the Major Pro-
jects Cultivating Special Program in Technology Innovation
Program (Grant No. 2011CX01008), and the Development Program
for Distinguished Young and Middle-Aged Teachers of Beijing In-
stitute of Technology.
References
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Synthesis 2011, No. 12, 1968–1973 © Thieme Stuttgart · New York