Prolinol sulfinyl ester derivatives: Organocatalytic Michael addition of ketones to nitroolefins under neat conditions

Article abstract of DOI:10.1055/s-0029-1216637

Highly enantioselective and diastereoselective Michael addition of ketones to nitroolefins catalyzed by prolinol sulfinyl ester was achieved in excellent yields under solvent-free conditions at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216637

SPECIAL TOPIC
1545
Prolinol Sulfinyl Ester Derivatives: Organocatalytic Michael Addition of
Ketones to Nitroolefins under Neat Conditions
Organocatalytic
M
i
ichae
l
A
ddition of
o
Ketones to
N
itroolef
e
ins i Zeng, Guofu Zhong*
Division of Chemistry and Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371, Singapore
Fax +65 67911961; E-mail: guofu@ntu.edu.sg
Received 1 February 2009
forcing the nitroolefin acceptors to approach from the
nonshielded side to give the desired Michael adducts in
high enantio- and diastereoselectivity (Figure 1). We de-
scribe herein the application of our new simple organocat-
alyst in asymmetric Michael addition reactions.
Abstract: Highly enantioselective and diastereoselective Michael
addition of ketones to nitroolefins catalyzed by prolinol sulfinyl es-
ter was achieved in excellent yields under solvent-free conditions at
room temperature.
Key words: catalysis, asymmetric synthesis, ketones, sulfinates,
Michael additions, nitro compounds
efficient space-shielding group
The organocatalytic asymmetric Michael reaction of ke-
tones and nitroolefins is one of the fundamental C–C
bond-formation reactions in organic chemistry.1 The nitro
functionality can easily be transferred into, for example, a
nitrile oxide, ketone, amine, or carboxylic acid, providing
a wide range of synthetically interesting compounds. The
synthesis of some important natural products and their
building blocks relies on asymmetric Michael reactions.2
Thus, this reaction has been attracting the interest of many
organic chemists, and some good results have been
achieved in the past years. Recently increasing attention
has been paid to the design and application of organocat-
alysts in many asymmetric organic reactions.3 Among the
various organocatalysts, proline and its derivatives have
been demonstrated to make up a successful class of orga-
nocatalysts in enamine chemistry.1o,4,5 Some of them have
been proven to be good catalysts for the catalytic asym-
metric Michael reaction of ketones with nitroolefins.5a,1f
Furthermore, green solvents such as water,1f brine,1b and
ionic liquids1c,j can be good media for some of the reac-
tions. Chen and co-workers developed functionalized
chiral ionic liquids as efficient organocatalysts for
Michael addition reactions.1c,j Although these catalytic
processes provide a unique methodology in asymmetric
Michael addition reactions, there is still a need for the de-
velopment of new, effective catalysts.
N
H
NO2
H
R
transition state for
asymmetric Michael addition
R = OS(O)t-Bu
Figure 1 Transition state for asymmetric Michael addition
The catalyst (S)-pyrrolidin-2-ylmethyl 2-methylpropane-
2-sulfinate (4) was synthesized by the reaction of N-Boc-
prolinol (1) with 2-methylpropane-2-sulfinyl chloride (2)
under basic conditions,6 followed by deprotection of the
N-Boc-substituted precursor 3 (Scheme 1). The new cata-
lyst was then tested in the asymmetric Michael addition
reaction of cyclohexanone (6) to b-nitrostyrene (5a)
(Table 1).
O
Et3N
S
+
S
O
N
Cl
N
OH
CH2Cl2
O
Boc
Boc
1
2
3
TFA
CH2Cl2
S
S
O
O
N
N
H
O
O
Boc
In our work towards designing highly enantioselective or-
ganocatalysts for the Michael addition reaction of ketones
with nitroolefins, we have devised a new type of chiral
pyrrolidine catalyst with a sulfinate group adjacent to a
stereogenic carbon center. The formation of the enamine
from the ketone precursors in the presence of this catalyst
causes the resulting sulfinate group to be effectively
shielded from one side of an enamine double bond,
3
4
Scheme 1 The synthesis of (S)-pyrrolidin-2-ylmethyl 2-methylpro-
pane-2-sulfinate
We initially screened a series of organocatalysts for the
Michael reaction between cyclohexanone (6) and nitro-
olefin 5a under neat conditions at room temperature
(23 °C). As shown by the results summarized in Table 1,
the Michael addition reactions did not proceed in the pres-
ence of catalyst 4b, 4d, or 4e (entries 3, 5, and 6); this was
surprising. Although the adduct product can be obtained
SYNTHESIS 2009, No. 9, pp 1545–1550
x
x
.
x
x
.2
0
0
9
Advanced online publication: 14.04.2009
DOI: 10.1055/s-0029-1216637; Art ID: C00509SS
© Georg Thieme Verlag Stuttgart · New York

1546
X. Zeng, G. Zhong
SPECIAL TOPIC
future reactions. The reaction also did not proceed when
triethylamine and trifluoroacetic acid were used as addi-
tives (Table 2, entries 5 and 6). The effect of a few sol-
vents and different conditions on the conjugate addition
reaction in the presence of 4 as the catalyst was then ex-
amined. Good results were achieved in dimethyl sulfoxide
and chloroform, giving yields above 80% and enantiomer-
ic excesses above 94% (Table 2, entries 7 and 8). When
the reaction was carried out in tetrahydrofuran, the reac-
tion was slow and the conjugate addition product 7a was
obtained in low yield after 48 hours at room temperature
(entry 9). There was no reaction when the solvent was
changed to a tetrahydrofuran–water mixture (1:1) (entry
10). Thus, the optimized conditions of the addition reac-
tion consisted of the use of three equivalents of cyclohex-
anone and 10 mol% of 4 as catalyst under neat conditions
at room temperature.
Table 1 Effect of Catalyst on the Michael Addition Reaction of
Cyclohexanone (6) and Nitroolefin 5aa
O
O
NO2
catalyst (10 mol%)
neat, r.t.
NO2
+
5
6
7
O
O
S
O
COOH
OH
N
H
N
H
N
H
4
4a
4b
O
O
O
S
O
O
S
O
N
Me
N
N
H
H
N
H
Table 2 The Michael Addition Reaction of Cyclohexanone with
Nitroolefin 5a Catalyzed by 4 under Different Conditionsa
4c
4d
4e
Entry
Catalyst
Time (h) Yieldb,c (%) drd
eee (%)
O
1
2
3
4
5
6
4
24
24
48
48
48
48
97
98:2
97
24
–
O
catalyst (10 mol%)
neat, r.t.
NO2
NO2
+
4a
4b
4c
4d
4e
80
90:10
NR
48
–
5a
6
7a
95:5
86
–
Entry
6
(equiv)
Solvent
Additive Time Yieldb,c eed
(h)
24
24
36
48
48
48
48
48
48
48
(%)
(%)
95
97
90
91
–
NR
NR
–
–
1
2
5
–
–
97
–
a Reagents and conditions: 5a (0.5 mmol, 1.0 equiv), 6 (1.5 mmol, 3.0
equiv), catalyst (10 mol%), neat, r.t.
b Isolated yield.
c NR = no reaction.
d The dr was determined by 1H NMR spectroscopy of the crude mix-
ture.
e The ee was determined by chiral HPLC analysis (Chiralpak AD-H,
hexane–i-PrOH, 90:10).
3
–
–
97
3
2
–
–
76
4
1.2
3
–
–
48
5
–
Et3N
NR
NR
90
6
3
–
TFA
–
7
3
DMSO
CHCl3
THF
–
–
–
–
95
94
90
–
in 80% yield and 90:10 diastereoselectivity with L-proline
(4a) as catalyst (entry 2), the enantiomeric excess is very
poor (24%). When 1,2¢-methylenedipyrrolidine (4c) was
used as the catalyst (entry 4), the adducts were obtained in
relatively high diastereo- and enantioselectivity (95:5 dr
and 86% ee), but the yield was poor even when the reac-
tion time was extended from 24 to 48 hours. The best re-
sult was obtained with catalyst 4, giving the product in up
to 97% yield and excellent diastereo- and enantioselectiv-
ity (98:2 dr and 95% ee) after the reaction was run for 24
hours.
8
3
81
9
3
46
10
3
THF–H2O (1:1)
NR
a Reagents and conditions: 5a (0.5 mmol, 1.0 equiv), 6, catalyst 4 (10
mol%), r.t.
b Isolated yield.
c NR = no reaction.
d The ee was determined by chiral HPLC analysis (Chiralpak AD-H,
hexane–i-PrOH, 90:10).
Encouraged by the results shown in Table 1, we tested the
effect of the amount of cyclohexanone in this reaction. We
found that nearly the same results were obtained when
five equivalents and three equivalents of cyclohexanone
were used (Table 2, entries 1 and 2). However, the reac-
tion rate, yield, and enantiomeric excess were decreased
when the amount of cyclohexanone was reduced to two
equivalents and 1.2 equivalents (Table 2, entries 3 and 4).
Hence, we chose three equivalents of cyclohexanone for
With 4 as the selected catalyst, the scope of the Michael
reaction was briefly explored under the optimized reac-
tion conditions (Table 3). In general, the reaction worked
quite well with cyclohexanone to give the desired Michael
adducts in high yields and excellent diastereoselectivities
and enantioselectivities. Both electron-rich and electron-
deficient b-nitrostyrenes were excellent Michael accep-
tors for cyclohexanone. Just 10 mol% of the catalyst was
Synthesis 2009, No. 9, 1545–1550 © Thieme Stuttgart · New York

SPECIAL TOPIC
Organocatalytic Michael Addition of Ketones to Nitroolefins
1547
O
Table 3 Michael Addition of Cyclohexanone with Various Nitro-
olefins Catalyzed by 4 under Neat Conditions at Room Temperaturea
O
Ph
NO2
O
O
R
NO2
30 h, 80%
O
7p syn/anti = 62:38
4 (cat.)
NO2
69% ee (syn), 66% ee (anti)
O
+
R
neat, r.t.
Ph
NO2
5
6
7
NO2
7q 47% ee
16 h, 95%
Yieldb syn/antic eed
Ph
Entry
R
7
O
Ph
(%)
97
99
99
97
98
93
99
93
97
98
99
95
96
93
96
(%)
97
94
94
94
91
95
99
95
93
94
96
94
94
93
92
O
S
NO2
1
2
Ph
7a
7b
7c
7d
7e
7f
98:2
95:5
>99:1
96:4
98:2
98:2
98:2
98:2
99:1
98:2
99:1
97:3
98:2
95:5
98:2
30 h, 89%
S
Tol
PMP
7r 98:2 dr, 92% ee
3
Scheme 2 The Michael addition of different Michael donors to b-
nitrostyrene catalyzed by 4 under neat conditions at room temperature
4
4-ClC6H4
CH=CHPh
2-MeC6H4
2-ClC6H4
5
NMR spectra were recorded on Bruker Avance DPX 300 and Bruk-
er AMX 400 spectrophotometers (CDCl3 as solvent). Chemical
shifts were recorded relative to TMS (1H NMR: d = 0.0; 13C NMR:
d = 0.0) and CDCl3 (1H NMR: d = 7.2600, s; 13C NMR: d = 77.03,
t). The proportions of diastereomers and geometric isomers were
determined from the integration data of the 1H NMR spectra. Enan-
tioselectivities were determined by HPLC analysis (Daicel Chiracel
AD-H or AS-H column, 25 °C) in comparison with racemic prod-
ucts. Optical rotations of samples in CHCl3 were measured on a
Schmidt & Haensdch polarimeter (Polartronic MH8) with a 10-cm
cell. The absolute configurations of the products were determined
by comparison with compounds previously published. Nitroolefins
were prepared according to literature procedures.1,2
6
7
7g
8
1,3-benzodioxol-5-yl 7h
9
3-MeC6H4
2-furyl
7i
10
11
12
13
14
15
7j
3-furyl
7k
7l
3-MeOC6H4
2-MeOC6H4
2-thienyl
2-naphthyl
7m
7n
7o
Nitro Ketones 7 by Michael Reactions of Nitroolefins with
Ketones under Solvent-Free Conditions; General Procedure
Catalyst 4 (10.5 mg, 0.05 mmol) was added to a mixture of the ni-
troolefin (0.5 mmol) and the ketone or cyclohexanone (148 mg, 1.5
mmol). The reaction mixture was stirred for the indicated time un-
der neat conditions at r.t. After completion of the reaction (moni-
tored by TLC), H2O (10 mL) was added, the mixture was extracted
with EtOAc (3 × 10 mL), and the combined organic extracts were
dried (Na2SO4). The diastereoselectivity was determined by 1H
NMR analysis of the crude Michael product after short column
chromatographic purification, and the ee was determined by chiral
HPLC analysis. Relative and absolute configurations of the prod-
ucts were determined by comparison with the known 1H NMR spec-
troscopy data, chiral HPLC analysis, and optical rotation values.
a Reagents and conditions: 5 (0.5 mmol, 1.0 equiv), 6 (1.5 mmol, 3.0
equiv), catalyst 4 (10 mol%), neat, r.t.
b Isolated yields.
c The syn/anti ratio was determined by 1H NMR spectroscopy of the
crude mixture or by HPLC analysis.
d The ee was determined by chiral HPLC analysis.
sufficient to promote the reactions, giving the desired
Michael adducts in nearly quantitative yields in reason-
able time.
(S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanone (7a)1f
Reaction time: 24 h; yield: 97%; ee determined by HPLC analysis
[Chiralcel AD-H, i-PrOH–hexane, 10:90, 1.0 mL/min, 300 nm; tR
The reactions of other Michael donors such as cyclopen-
tanone, acetone, and tetrahydrothiopyran-4-one were also
carried out in the presence of catalyst 4 (Scheme 2). Sim- (c 1.0, CHCl3); syn/anti = 98:2.
20
(minor) = 9.85 min, tR (major) = 12.39 min]: 97% ee; [a]D –18.0
1H NMR (400 MHz, CDCl3): d = 7.32–7.26 (m, 3 H), 7.16 (d, J =
7.2 Hz, 2 H), 4.94 (dd, J = 4.4, 12.4 Hz, 1 H), 4.63 (dd, J = 9.6, 12.4
Hz, 1 H), 3.76 (dt, J = 4.4, 10.0 Hz, 1 H), 2.68 (ddd, J = 4.8, 8.1,
11.7 Hz, 1 H), 2.49–2.38 (m, 2 H), 2.10–2.06 (m, 1 H), 1.79–1.55
(m, 4 H), 1.32–1.21 (m, 1 H).
ilar to the results reported by other research groups, the
desired Michael addition product was obtained in high
yields but relatively lower enantioselectivities. The abso-
lute configurations of the Michael addition products were
1
determined by H NMR spectroscopy and comparison
13C NMR (100 MHz, CDCl3): d = 212.0, 137.8, 129.0, 128.2, 127.8,
78.9, 52.5, 44.0, 42.8, 33.2, 28.6, 25.1.
with the known products. Therefore, the transition state of
this reaction shown in Figure 1 should be applicable to all
the cases.
(S)-2-[(R)-2-Nitro-1-(4-tolyl)ethyl]cyclohexanone (7b)1k
Reaction time: 16 h; yield: 99%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
Commercial-grade solvents and reagents were used without further
purification, with the following exception: CH2Cl2 was distilled
from CaH2. Flash chromatography was performed over Merck silica
20
(minor) = 8.20 min, tR (major) = 12.59 min]: 94% ee; [a]D –15.3
(c 1.0, CHCl3); syn/anti = 95:5.
1
gel 60, with freshly distilled solvents as eluents. The H and 13C
Synthesis 2009, No. 9, 1545–1550 © Thieme Stuttgart · New York

1548
X. Zeng, G. Zhong
SPECIAL TOPIC
1H NMR (300 MHz, CDCl3): d = 7.12 (d, J = 8.1 Hz, 2 H), 7.04 (d,
J = 8.1 Hz, 2 H), 4.92 (dd, J = 4.5, 12.3 Hz, 1 H), 4.61 (dd, J = 9.6,
12.4 Hz, 1 H), 3.72 (dt, J = 4.5, 9.9 Hz, 1 H), 2.66 (ddd, J = 4.4, 8.0,
12.3 Hz, 1 H), 2.50–2.36 (m, 2 H), 2.31 (s, 3 H), 2.10–2.04 (m, 1 H),
1.77–1.56 (m, 4 H), 1.28–1.21 (m, 1 H).
(S)-2-[(R)-(2-Chlorophenyl)-2-nitroethyl]cyclohexanone (7g)1f
Reaction time: 36 h; yield: 99%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
(minor) = 8.62 min, tR (major) = 12.37 min]: 99% ee; [a]D –47.4
(c 1.0, CHCl3); syn/anti = 95:5.
20
13C NMR (75 MHz, CDCl3): d = 212.0, 137.5, 134.6, 129.6, 128.0,
79.0, 52.6, 43.6, 42.7, 33.2, 28.5, 25.0, 21.1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.16 (m, 4 H), 4.92–4.82 (m,
2 H), 4.29 (dt, J = 4.8, 13.3 Hz, 1 H), 2.65 (ddd, J = 3.2, 8.4, 13.6
Hz, 1 H), 2.46–2.32 (m, 2 H), 2.10–2.05 (m, 1 H), 1.80–1.55 (m, 4
H), 1.36–1.27 (m, 1 H).
(S)-2-[(R)-1-(4-Methoxyphenyl)-2-nitroethyl]cyclohexanone
(7c)1k
Reaction time: 22 h; yield: 99%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
(minor) = 18.61 min, tR (major) = 23.79 min]: 94% ee; [a]D20 –12.9
(c 1.0, CHCl3); syn/anti = 95:5.
13C NMR (100 MHz, CDCl3): d = 211.7, 135.5, 134.6, 130.3, 129.4,
128.9, 127.4, 78.8, 51.5, 42.7, 38.3, 32.8, 28.3, 25.1.
(S)-2-[(S)-1-(1,3-Benzodioxol-5-yl)-2-nitroethyl]cyclohexanone
(7h)1f
1H NMR (400 MHz, CDCl3): d = 7.10 (d, J = 8.4 Hz, 2 H), 6.84 (d,
J = 8.4 Hz, 2 H), 4.92 (dd, J = 6.4, 16.4 Hz, 1 H), 4.60 (dd, J = 13.2,
16.4 Hz, 1 H), 3.80 (s, 3 H), 3.73 (dt, J = 6.0, 13.2 Hz, 1 H), 2.66
(ddd, J = 5.2, 8.4, 14.6 Hz, 1 H), 2.51–2.35 (m, 2 H), 2.10–2.06 (m,
1 H), 1.78–1.56 (m, 4 H), 1.23–1.19 (m, 1 H).
Reaction time: 24 h; yield: 93%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
(minor) = 31.11 min, tR (major) = 37.68 min]: 95% ee; [a]D20 –20.6
(c 1.0, CHCl3); syn/anti = 98:2.
1H NMR (400 MHz, CDCl3): d = 6.76 (d, J = 8.0 Hz, 1 H), 6.67–
6.63 (m, 2 H), 5.97 (s, 1 H), 4.92 (dd, J = 4.4, 12.4 Hz, 1 H), 4.55
(dd, J = 6.0, 9.6 Hz, 1 H), 3.69 (dt, J = 3.2, 8.4 Hz, 1 H), 2.64 (ddd,
J = 2.8, 8.4, 13.2 Hz, 1 H), 2.48–2.39 (m, 2 H), 2.12–2.08 (m, 1 H),
1.84–1.58 (m, 4 H), 1.28–1.25 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 212.1, 159.0, 129.5, 129.2, 114.3,
79.1, 55.2, 52.7, 43.2, 42.7, 33.1, 28.5, 25.0.
(S)-2-[(R)-1-(4-Chlorophenyl)-2-nitroethyl]cyclohexanone
(7d)1f
Reaction time: 30 h; yield: 99%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 230 nm; tR
(minor) = 10.93 min, tR (major) = 16.88 min]: 91% ee; [a]D20 –17.6
(c 1.0, CHCl3); syn/anti = 94:6.
13C NMR (100 MHz, CDCl3): d = 211.9, 148.1, 147.1.4, 131.3,
121.7, 108.6, 108.1, 101.2, 79.1, 52.7, 43.8, 42.8, 29.4, 28.6, 22.7.
(S)-2-[(R)-2-Nitro-1-(3-tolyl)ethyl]cyclohexanone (7i)1f
Reaction time: 25 h; yield: 99%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
20
(minor) = 9.27 min, tR (major) = 12.10 min]: 93% ee; [a]D –30.5
(c 1.0, CHCl3); syn/anti = 99:1.
1H NMR (400 MHz, CDCl3): d = 7.30 (d, J = 11.2 Hz, 2 H), 7.12 (d,
J = 11.2 Hz, 2 H), 4.93 (dd, J = 6.0, 16.4 Hz, 1 H), 4.60 (dd, J = 13.2,
16.8 Hz, 1 H), 3.80 (s, 3 H), 3.76 (dt, J = 6.4, 13.0 Hz, 1 H), 2.66
(ddd, J = 2.4, 6.0, 16.0 Hz, 1 H), 2.54–2.32 (m, 2 H), 2.12–2.05 (m,
1 H), 1.83–1.54 (m, 4 H), 1.30–1.20 (m, 1 H).
1H NMR (400 MHz, CDCl3): d = 7.28–6.97 (m, 4 H), 4.94 (dd, J =
4.4, 12.4 Hz, 1 H), 4.64 (dd, J = 9.6, 12.4 Hz, 1 H), 3.73 (dt, J = 4.4,
9.8 Hz, 1 H), 2.69 (ddd, J = 4.0, 8.4, 13.2 Hz, 1 H), 2.53–2.35 (m, 5
H), 2.12–2.08 (m, 1 H), 1.83–1.55 (m, 4 H), 1.35–1.22 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 211.5, 136.3, 133.7, 129.6, 129.2,
78.6, 52.4, 43.4, 42.8, 33.2, 28.4, 25.1.
13C NMR (100 MHz, CDCl3): d = 212.0, 144.6, 143.2, 129.0, 128.8,
128.6, 125.0, 78.9, 52.6, 43.9, 42.8, 33.3, 28.6, 25.0, 21.5.
(S)-2-[(R,E)-1-(Nitromethyl)-3-phenylprop-2-enyl]cyclohex-
anone (7e)1g
Reaction time: 24 h; yield: 99%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
(S)-2-[(S)-1-(2-Furyl)-2-nitroethyl]cyclohexanone (7j)1d
Reaction time: 16 h; yield: 99%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 230 nm; tR
(minor) = 12.05 min, tR (major) = 13.10 min]: 94% ee; [a]D20 –8.1
(c 1.0, CHCl3); syn/anti = 95:5.
20
(minor) = 9.99 min, tR (major) = 15.48 min]: 91% ee; [a]D –30.1
(c 1.0, CHCl3); syn/anti = 98:2.
1H NMR (300 MHz, CDCl3): d = 7.32–7.23 (m, 5 H), 6.49 (d, J =
16.5 Hz, 1 H), 6.02 (dd, J = 9.6, 15.6 Hz, 1 H), 4.67 (dd, J = 5.1,
11.7 Hz, 1 H), 4.57 (dd, J = 8.4, 12.0 Hz, 1 H), 3.40–3.30 (m, 1 H),
2.59–2.35 (m, 3 H), 2.19–2.04 (m, 2 H), 1.93–1.89 (m, 1 H), 1.71–
1.59 (m, 2 H), 1.48–1.26 (m, 1 H).
1H NMR (400 MHz, CDCl3): d = 7.33–7.30 (m, 1 H), 6.28 (dd, J =
2.0, 3.2 Hz, 1 H), 6.17 (d, J = 3.2 Hz, 1 H), 4. 78 (dd, J = 4.8, 12.4
Hz, 1 H), 4.66 (dd, J = 9.2, 12.4 Hz, 1 H), 3.96 (dt, J = 4.4, 9.0 Hz,
1 H), 2.74 (ddd, J = 2.8, 8.0, 13.2 Hz, 1 H), 2.47–2.31 (m, 2 H),
2.12–2.06 (m, 1 H), 1.85–1.58 (m, 4 H), 1.33–1.24 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 211.3, 136.3, 134.4, 128.6, 127.9,
126.4, 125.7, 78.1, 51.7, 42.6, 41.9, 32.6, 28.1, 25.1.
13C NMR (100 MHz, CDCl3): d = 210.9, 150.9, 142.3, 110.3, 109.0,
77.9, 51.1, 42.6, 37.6, 32.5, 28.2, 25.1.
(S)-2-[(R)-2-Nitro-1-(2-tolyl)ethyl]cyclohexanone (7f)1f
Reaction time: 33 h; yield: 99%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
20
(minor) = 8.41 min, tR (major) = 11.72 min]: 95% ee; [a]D –26.9
(c 1, CHCl3); syn/anti = 97:3.
(S)-2-[(S)-1-(3-Furyl)-2-nitroethyl]cyclohexanone (7k)1d
Reaction time: 16 h; yield: 99%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
(minor) = 15.32 min, tR (major) = 16.66 min]: 96% ee; [a]D20 –15.6
(c 1.0, CHCl3); syn/anti = 99:1.
1H NMR (400 MHz, CDCl3): d = 7.32–6.96 (m, 4 H), 4.99 (dd, J =
6.0, 12.4 Hz, 1 H), 4.58 (dd, J = 12.4, 13.6 Hz, 1 H), 3.93 (dt, J =
4.0, 10.4 Hz, 1 H), 2.65 (ddd, J = 2.8, 8.4, 12.4 Hz, 1 H), 2.47–2.33
(m, 5 H), 2.17–2.03 (m, 1 H), 1.75–1.48 (m, 4 H), 1.27–1.17 (m, 1
H).
1H NMR (300 MHz, CDCl3): d = 7.38 (d, J = 2.1 Hz, 1 H), 7.29 (d,
J = 2.1 Hz, 1 H), 6.26 (s, 1 H), 4.76 (dd, J = 5.1, 16.4 Hz, 1 H), 4.58
(dd, J = 9.0, 12.0 Hz, 1 H), 3.80 (dt, J = 5.1, 10.2 Hz, 1 H), 2.60
(ddd, J = 4.8, 8.1, 13.2 Hz, 1 H), 2.44–2.35 (m, 2 H), 2.11–1.94 (m,
3 H), 1.88–1.60 (m, 2 H), 1.34–1.26 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 212.3, 137.4, 136.5, 131.0, 127.3,
126.7, 125.7, 78.8, 53.4, 42.9, 38.3, 32.9, 28.8, 25.3, 19.9.
13C NMR (75 MHz, CDCl3): d = 211.3, 143.6, 140.8, 121.4, 109.1,
78.3, 51.9, 42.6, 34.6, 32.4, 28.1, 25.0.
Synthesis 2009, No. 9, 1545–1550 © Thieme Stuttgart · New York

SPECIAL TOPIC
Organocatalytic Michael Addition of Ketones to Nitroolefins
1549
(S)-2-[(S)-1-(3-Methoxyphenyl)-2-nitroethyl]cyclohexanone
(7l)1d
Reaction time: 20 h; yield: 95%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
(minor) = 10.53 min, tR (major) = 11.92 min]: 94% ee; [a]D20 –27.9
(c 1.0, CHCl3); syn/anti = 97:3.
(S)-5-Nitro-4-phenylpentan-2-one (7q)1f
Reaction time: 16 h; yield: 95%; ee determined by HPLC analysis
[Chiralcel AD-H, i-PrOH–hexane, 5:95, 1.0 mL/min, 254 nm; tR
(minor) = 21.22 min, tR (major) = 29.00 min]: 45% ee; [a]D20 2.6
(c 1.1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.35–7.22 (m, 5 H), 4.75–4.59 (m,
2 H), 4.07–3.98 (m, 1 H), 2.94 (d, J = 11.2 Hz, 2 H), 2.14 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 6.83–6.73 (m, 3 H), 4.95 (dd, J =
3.2, 8.0 Hz, 1 H), 4.63 (dd, J = 3.6, 8.8 Hz, 1 H), 3.81–3.74 (m, 4
H), 2.68 (ddd, J = 2.4, 7.8, 12.2 Hz, 1 H), 2.50–2.39 (m, 2 H), 2.11–
2.08 (m, 1 H), 1.78–1.57 (m, 4 H), 1.28–1.24 (m, 1 H).
(S)-3-[(S)-2-Nitro-1-phenylethyl]tetrahydrothiopyran-4-one
(7r)1f
Reaction time: 30 h; yield: 89%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
(minor) = 17.61 min, tR (major) = 22.44 min]: 92% ee; [a]D20 –49.1
(c 1.0, CHCl3); syn/anti = 98:2.
13C NMR (100 MHz, CDCl3): d = 212.0, 159.9, 139.4, 130.0, 120.3,
114.5, 112.6, 78.8, 55.2, 52.5, 43.9, 42.8, 33.2, 28.6, 25.1.
(S)-2-[(S)-1-(2-Methoxyphenyl)-2-nitroethyl]cyclohexanone
(7m)1f
Reaction time: 20 h; yield: 96%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
(minor) = 10.53 min, tR (major) = 11.92 min]: 94% ee; [a]D20 –36.9
(c 1.0, CHCl3); syn/anti = 98:2.
1H NMR (400 MHz, CDCl3): d = 7.38–7.19 (m, 5 H), 4.74 (dd, J =
4.8, 13.2 Hz, 1 H), 4.63 (dd, J = 2.1, 11.6 Hz, 1 H), 3.98 (dt, J = 4.8,
10.4 Hz, 1 H), 3.09–2.77 (m, 4 H), 2.65–2.60 (m, 1 H), 2.49–2.43
(m, 1 H).
13C NMR (100 MHz, CDCl3): d = 209.6, 136.58, 129.4, 128.3,
128.2, 78.6, 55.0, 44.6, 43.5, 35.2, 31.6.
1H NMR (400 MHz, CDCl3): d = 7.26–7.22 (m, 1 H), 7.08 (d, J =
7.2 Hz, 1 H), 6.86–6.90 (m, 2 H), 4.84–4.81 (m, 2 H), 3.96, (dt, J =
2.8, 8.4 Hz, 1 H), 3.84 (s, 3 H), 2.67 (ddd, J = 2.8, 8.0, 12.0 Hz, 1
H), 2.48–2.37 (m, 2 H), 2.08–2.05 (m, 1 H), 1.78–1.55 (m, 4 H),
1.25–1.18 (m, 1 H).
Acknowledgment
Research support from the Ministry of Education in Singapore
(ARC12/07, no. T206B3225) is gratefully acknowledged. We ex-
press our many thanks to Prof. T.-P. Loh’s group for their generous
sharing of equipment.
13C NMR (100 MHz, CDCl3): d = 212.6, 157.6, 131.0, 129.0, 125.4,
120.9, 111.0, 77.6, 55.4, 50.2, 42.8, 41.3, 33.3, 28.6, 25.2.
(S)-2-[(R)-2-Nitro-1-(2-thienyl)ethyl]cyclohexanone (7n)1f
Reaction time: 24 h; yield: 93%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
(minor) = 13.74 min, tR (major) = 17.88 min]: 93% ee; [a]D20 –26.1
(c 1.0, CHCl3); syn/anti = 95:5.
References
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic
Reactions; Pergamon: Oxford, 1992. (b) Vishnumaya;
Vinod, K. S. Org. Lett. 2007, 9, 1117. (c) Luo, S.-Z.; Mi,
X.-L.; Liu, S.; Xu, H.; Chen, J.-P. Chem. Commun. 2006,
3687. (d) Svetlana, B. T.; Wei, S.-W. Chem. Commun. 2006,
1451. (e) Xu, Y.; Cordova, A. Chem. Commun. 2006, 460.
(f) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka,
F.; Barbas, C. F. III J. Am. Chem. Soc. 2006, 128, 4966.
(g) Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8,
3077. (h) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006,
128, 9624. (i) Zhu, M.-K.; Cun, L.-F.; Mi, A.-Q.; Jiang,
Y.-Z.; Gong, L.-Z. Tetrahedron: Asymmetry 2006, 17, 491.
(j) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P.
Angew. Chem. Int. Ed. 2006, 45, 3093. (k)Li, H.; Wang, Y.;
Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L.
Angew. Chem. Int. Ed. 2005, 44, 105. (l) Okino, T.; Hoashi,
Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc.
2005, 127, 119. (m) Wang, W.; Wang, J.; Li, H. Angew.
Chem. Int. Ed. 2005, 44, 1369. (n) Tsogoeva, S. B.;
Yalalov, D. A.; Hateley, M. J.; Weckbecker, C.;
1H NMR (400 MHz, CDCl3): d = 7.23 (d, J = 4.8 Hz, 1 H), 6.96–
6.89 (m, 2 H), 4.91 (dd, J = 4.8, 12.0 Hz, 1 H), 4.66 (dd, J = 7.2,
13.2 Hz, 1 H), 4.15 (dt, J = 4.4, 11.2 Hz, 1 H), 2.69 (ddd, J = 3.2,
8.0, 13.2 Hz, 1 H), 2.49–2.38 (m, 2 H), 2.13–2.09 (m, 1 H), 1.94–
1.84 (m, 2 H), 1.71–1.62 (m, 2 H), 1.38–1.27 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 211.3, 140.5, 127.0, 126.7, 125.0,
79.2, 53.4, 42.6, 39.4, 32.8, 28.3, 25.1.
(S)-2-[(S)-1-(2-Naphthyl)-2-nitroethyl]cyclohexanone (7o)1f
Reaction time: 24 h; yield: 96%; ee determined by HPLC analysis
[Chiralcel AS-H, i-PrOH–hexane, 15:85, 1.0 mL/min, 220 nm; tR
(minor) = 13.72 min, tR (major) = 19.22 min]: 92% ee; [a]D20 –79.5
(c 1.0, CHCl3); syn/anti = 98:2.
1H NMR (400 MHz, CDCl3): d = 8.18 (s, 1 H), 8.04–8.02 (m, 2 H),
7.62–7.31 (m, 4 H), 5.26 (dd, J = 4.8, 12.0 Hz, 1 H), 5.00 (dd, J =
5.6, 10.0 Hz, 1 H), 4.98 (s, 1 H), 2.88 (s, 1 H), 2.46–2.33 (m, 2 H),
2.12–2.05 (m, 1 H), 1.86–1.41 (m, 4 H), 1.31–1.22 (m, 1 H).
Huthmacher, K. Eur. J. Org. Chem. 2005, 4995.
2-[(S)-2-Nitro-1-phenylethyl]cyclopentanone (7p)1f
(o) Hayashi, Y.; Gotoh, T.; Hayasji, T.; Shoji, M. Angew.
Chem. Int. Ed. 2005, 44, 4212. (p) Vakulya, B.; Varga, S.;
Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967.
(q) McCooey, S. H.; Connon, S. J. Angew. Chem. Int. Ed.
2005, 44, 6367. (r) Wang, J.; Li, H.; Duan, W.-H.; Zu, L.-S.;
Wang, W. Org. Lett. 2005, 7, 4713. (s) Li, H.; Wang, Y.;
Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906.
(t) Ishii, T.; Fiujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am.
Chem. Soc. 2004, 126, 9558. (u) Cobb, A. J. A.;
Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem.
Commun. 2004, 1808. (v) Mase, N.; Thayumanavan, R.;
Tanaka, F.; Barbas, C. F. III Org. Lett. 2004, 6, 2527.
(w) Kotrusz, P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J.
Org. Chem. 2004, 1577. (x) Andrey, O.; Alexakis, A.;
Bernardinelli, G. Org. Lett. 2003, 5, 2559. (y)Tian, S.; Ran,
Reaction time: 30 h; yield: 80%; ee determined by HPLC analysis
[Chiralcel AD-H, i-PrOH–hexane, 10:90, 1.0 mL/min, 220 nm; tR
(major, anti) = 8.37 min, tR (minor, anti) = 9.35 min; tR (minor,
syn) = 10.00 min, tR (major, syn) = 12.86 min]: 66% ee (anti), 69%
ee (syn); [a]D20 –19.4 (c 1.0, CHCl3); syn/anti = 1:0.6.
1H NMR (400 MHz, CDCl3): d = 7.34–7.26 (m, 5.2 H), 7.20–7.16
(m, 3.1 H), 5.33 (dd, J = 5.6, 12.8 Hz, 1 H), 5.02 (d, J = 8.0 Hz, 1.2
H), 4.72 (dd, J = 2.4, 12.0 Hz, 1 H), 3.83 (dt, J = 4.4, 10.0 Hz, 0.6
H), 3.70 (dt, J = 4.4, 10.0 Hz, 1 H), 2.41–2.08 (m, 4.2 H), 1.95–1.66
(m, 4.8 H), 1.56–1.48 (m, 1.6 H).
13C NMR (100 MHz, CDCl3): d = 218.5, 218.4, 137.7, 137.6, 129.0,
128.9, 128.5, 128.4, 128.0, 127.9, 78.3, 78.2, 51.4, 50.5, 44.2, 44.1,
39.3, 38.7, 28.3, 27.0, 20.6, 20.3.
Synthesis 2009, No. 9, 1545–1550 © Thieme Stuttgart · New York

1550
X. Zeng, G. Zhong
SPECIAL TOPIC
H.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900. (z) List,
B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423.
(2) For reviews, see: (a) Comprehensive Asymmetric Catalysis;
Jacobson, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer:
New York, 1999, Chap. 31. (b) Krause, N.; Hoffmann-
Roder, A. Synthesis 2001, 171.
(5) For examples, see: (a) Xu, D.-Q.; Yue, H.-D.; Luo, S.-P.;
Xia, A.-B.; Zhang, S.; Xu, Z.-Y. Org. Biomol. Chem. 2008,
6, 2054. (b) Zhang, Q.-Y.; Ni, B.-K.; Headley, A. D.
Tetrahedron 2008, 64, 5091. (c) Xu, D.-Q.; Wang, L.-P.;
Luo, S.-P.; Wang, Y.-F.; Zhang, S.; Xu, Z.-Y. Tetrahedron
2008, 64, 1049. (d) Xiong, Y.; Wen, Y.; Wang, F.; Gao, B.;
Liu, X.; Huang, X.; Feng, X.-M. Adv. Synth. Catal. 2007,
349, 2156. (e) Xu, D.-Q.; Luo, S.-P.; Wang, Y.-F.; Xia, A.-
B.; Yue, H.-D.; Wang, L.-P.; Xu, Z.-Y. Chem. Commun.
2007, 4393. (f) Alza, E.; Cambeiro, X. C.; Jimeno, C.;
Pericas, M. A. Org. Lett. 2007, 9, 3717. (g) Cao, C.-L.; Ye,
M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901.
(h) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.;
Xiao, W.-J. Org. Lett. 2005, 7, 4543. (i) Tang, Z.; Yang, Z.-
H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong,
L.-Z. J. Am. Chem. Soc. 2005, 127, 9285. (j) Hayashi, Y.;
Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M.
J. Am. Chem. Soc. 2005, 127, 16028. (k) Itagaki, N.;
Kimura, M.; Sugahara, T.; Iwabuchi, Y. Org. Lett. 2005, 7,
4185. (l) Tokuda, O.; Kano, T.; Gao, W.-G.; Ikemoto, T.;
Maruoka, K. Org. Lett. 2005, 7, 5103. (m) Kano, T.;
Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc.
2005, 127, 16408. (n) Cordova, A.; Zou, W.; Ibrahem, I.;
Reyes, E.; Engqvist, M.; Liao, W.-W. Chem. Commun.
2005, 3586. (o) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G.
Org. Lett. 2005, 7, 5321. (p) Terakado, D.; Takano, M.;
Oriyama, T. Chem. Lett. 2005, 34, 962.
(3) For selected papers and reviews on organocatalytic Michael
addition reactions, see: (a) Tan, B.; Chua, P. J.; Li, Y.;
Zhong, G. Org. Lett. 2008, 10, 2437. (b) Tan, B.; Shi, Z.;
Chua, P. J.; Zhong, G. Org. Lett. 2008, 10, 3425. (c) Tan,
B.; Chua, P. J.; Zeng, X.-F.; Lu, M.; Zhong, G. Org. Lett.
2008, 10, 3489. (d) Svetlana, B. T. Eur. J. Org. Chem. 2007,
1701. (e) Sulzer-Mossé, S.; Alexakis, A. Chem. Commun.
2007, 3123. (f) Seayad, J.; List, B. Org. Biomol. Chem.
2005, 3, 719. (g) List, B. Chem. Commun. 2006, 819.
(h) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43,
5138. (i) Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid,
P.; Deng, L. Acc. Chem. Res. 2004, 37, 621. (j) Ooi, T.;
Maruoka, K. Acc. Chem. Res. 2004, 37, 526. (k) Shi, Y.
Acc. Chem. Res. 2004, 37, 488.
(4) For selected reviews on reactions catalyzed by proline and
its derivatives, see: (a) List, B. Acc. Chem. Res. 2004, 37,
548. (b) Notz, W.; Tanaka, F.; Barbas, C. F. III Acc. Chem.
Res. 2004, 37, 580. (c) Duthaler, R. O. Angew. Chem. Int.
Ed. 2003, 42, 975. (d) List, B. Tetrahedron 2002, 58, 5573.
(e) Groger, H.; Wilken, J. Angew. Chem. Int. Ed. 2001, 40,
529.
(6) Jagusch, T.; Gais, H.-J.; Bondarev, O. J. Org. Chem. 2004,
69, 2731.
Synthesis 2009, No. 9, 1545–1550 © Thieme Stuttgart · New York