An effective bifunctional thiourea catalyst for highly enantio- and diastereoselective Michael addition of cyclohexanone to nitroolefins

Article abstract of DOI:10.1055/s-2006-950339

A series of new tunable and bifunctional thiourea catalysts have been synthesized and their catalytic activities are evaluated in the direct Michael addition of cyclohexanone to nitroolefins. High isolated yields (up to 97%), enantioselectivities (up to 9

Full text of DOI:10.1055/s-2006-950339

PAPER
3795
An Effective Bifunctional Thiourea Catalyst for Highly Enantio- and
Diastereoselective Michael Addition of Cyclohexanone to Nitroolefins
Michael Addition
o
f
Cycl
-
ohexano
J
ne to Nitr
uoolefins Cao, Hai-Hua Lu, Yuan-Yuan Lai, Liang-Qiu Lu, Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei, 430079, P. R. of China
Fax +86(27)67862041; E-mail: wxiao@mail.ccnu.edu.cn
Received 5 September 2006
S
Abstract: A series of new tunable and bifunctional thiourea cata-
R
lysts have been synthesized and their catalytic activities are evalu-
ated in the direct Michael addition of cyclohexanone to nitroolefins.
High isolated yields (up to 97%), enantioselectivities (up to 98%)
and diastereoselectivities (up to 99:1) were obtained under the opti-
mal conditions.
N
N
O
S
H
H
N
NH HN
H
HN
NH
1
2
2a: R = 1-naphthyl
Key words: Asymmetric catalysis, Michael addition, bifunctional
thiourea catalyst, organocatalysis, nitroolefins
2b: R = 3,5-(CF3)2C6H3
2c: R = c-Hex
O
2d: R = t-Bu
2e: R = 4-MeC6H4
N
N
H
H
N
H
3
Michael addition is one of the most important C–C bond-
forming reactions. In particular, the addition of nucleo-
philes to nitroolefins is very valuable for the generation of
nitrogen-containing building blocks for organic synthe-
sis.1 Considerable efforts have been made in this area.
Elegant examples include reactions catalyzed by metal–
ligand complexes,2 L-proline3 and proline derivatives.4
Since the late 1960s, advances in the development of
metal-based chiral catalysts have provided a wealth of
asymmetric Michael addition; however, relatively few re-
ports have appeared that employed organic molecules as
reaction catalysts despite the attendant potential for sav-
ings in cost, time, energy, operational complexity and
chemical waste in comparison to chiral metal catalysts.
Therefore, the design of new effective organocatalysts for
asymmetric synthesis is of great interest.
O
S
Me
N
t-Bu
S
N
N
Bn
N
N
H
H
H
H
N
O
NH2
H
4 (Tsogoeva's catalyst)
5 (Jacobsen's catalyst)
Figure 1 Novel tunable and bifunctional amine-thiourea catalysts
In our system, one catalyst has two reaction–activation
sites, which can activate both Michael donors and accep-
tors simultaneously. The selectivity and activity can be
obviously tuned by a simple change of the thiourea motif.
The catalytic potential of these catalysts was initially eval-
uated in the reaction of cyclohexanone (6) with b-nitrosty-
rene (7a) (Table 1).
As can be seen from Table 1, the L-prolinamide based cat-
alyst 1 was initially tested, which was prepared according
to our previous procedures.7 It was found that the reaction
proceeded slowly with an excellent diastereoselectivity
but a poor enantioselectivity (entry 1 in Table 1). We then
examined the bifunctional pyrrolidine-thiourea catalysts
2a–e, which were synthesized from N-Boc-2-aminometh-
ylpyrrolidine and isothiocyanate by a two-step procedure.
All of these catalysts could effectively promote the reac-
tion at ambient temperature in the presence of catalytic
amount of acetic or benzoic acids.8 As predicted, the cat-
alytic activity and the selectivity of the reaction were ap-
parently influenced by the thiourea unit of the catalyst
(entries 2–6 in Table 1). If the thiourea moiety was re-
placed by a urea group (catalyst 3), the enantioselectivity
declined remarkably (entry 7 in Table 1) by maintaining
almost the same level of diasteroselectivity. In these cata-
lysts, the CH2 group between the pyrrolidine and thiourea
moiety was very important in order to maximize the reac-
tion efficiency, because the reaction gave the product
nearly in racemic form and a low yield with the use of cat-
Chiral thiourea catalysts have emerged as versatile cata-
lytic systems. This is due to their strong double hydrogen-
bonding effects and many notable results which have been
recently achieved by Jacobsen and Takemoto and co-
workers.5 However, nearly all of these catalysts were just
suitable for 1,3-dicarbonyl compounds and few reports
were about direct Michael additions of cyclohexanone to
nitroolefins.6 Until recently Tsogoeva6f and Jacobsen6h
have developed amine-thiourea catalysts for addition re-
actions of ketones and nitroolefins with moderate to ex-
cellent stereoselectivities. With the interest in designing
new organocatalysts for organic transformations,7 we syn-
thesized a series of readily tunable and bifunctional
(thio)urea catalysts 1–3 (Figure 1) and their catalytic ac-
tivities were evaluated in the direct Michael addition of
cyclohexanone to nitroolefins.
SYNTHESIS 2006, No. 22, pp 3795–3800
x
x
.x
x
.
2
0
0
6
Advanced online publication: 02.11.2006
DOI: 10.1055/s-2006-950339; Art ID: C05306SS
© Georg Thieme Verlag Stuttgart · New York

3796
Y.-J. Cao et al.
PAPER
Table 1 Optimization of Reaction Conditions for the Direct Michael Addition of Cyclohexanone (6) to b-Nitrostyrene (7a)a
O
O
Ph
catalyst/HA
(20 mol%)
NO2
NO2
+
Ph
solvent, r.t.
6
Entry
1
7a
8a
Catalystb
1
Solvent
Time (h)
125
18
Yield (%)c
dr (syn/anti)d
94:6
ee (%)e
5
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Et2O
81
69
61
60
63
66
51
99
91
79
74
93
0
2
2a
2b
2c
92:8
89
3
51
91:9
84
4
41
89:11
95:5
87
5
2d
2e
48
89
6
29
96:4
91
7
3
60
92:8
70
8
2e
23
94:6
89
9
2e
15
95:5
91
10
11
12
13
14f
15g
2e
15
93:7
88
2e
1,4-dioxane
n-hexane
MeOH
23
92:8
88
2e
15
97:3
93
2e
120
72
n.d.
n.d.
95
2e
n-hexane
n-hexane
94
94
97:3
2e
17
96:4
92
a Unless otherwise specified, the reaction was carried out with 0.5 mmol of 7a and 10 equiv of 6 in the presence of 20 mol% of catalyst/HA at
room temperature in 2 mL of the solvent.
b The co-catalyst HA for entries 1–7 was AcOH, and benzoic acid was used in the cases of entries 8–15.
c Isolated yields.
d Determined by chiral HPLC analysis of the mixture of syn/anti products.
e Determined by chiral HPLC.
f 10 mol% of the catalyst was used.
g 10 mol% of the catalyst and 1 mL of n-hexane were used.
alyst 4.6f Among the catalysts screened, 2e exhibits the With the optimal reaction conditions in hand, a variety of
best catalytic performances (entry 6 in Table 1). Further- aromatic nitroolefins were evaluated in the direct Michael
more, when benzoic acid was employed as a co-catalyst addition and results are summarized in Table 2. Not only
instead of acetic acid, the yield of the product could be substituted nitrostyrenes (entries 1–12 in Table 2) but also
further improved to 99% with comparable stereoselectiv- other aromatic nitroolefins (entries 13–15 in Table 2) can
ity (entries 8 vs. 6 in Table 1). The solvent effects were be employed efficiently in Michael addition reactions, af-
also examined for this reaction. The polar solvents result- fording the corresponding nitro compounds with high to
ed in lower yields (entries 10 and 11 in Table 1), and even excellent enantioselectivities (up to 98%) and diastereose-
no reaction occurred when MeOH was used (entry 13 in lectivities (up to 98:2) at an ambient temperature. In the
Table 1). In contrast, the reaction proceeded smoothly in case of 4-hydroxy-b-nitrostyrene, the reaction was slow,
nonpolar solvents, with the best results being obtained but the selectivity was still very good (entry 12 in
when n-hexane was chosen as the solvent (entry 12 in Table 2). The scope of the Michael donors could be ex-
Table 1). Significantly, when the catalyst loading was re- tended to heterocyclic ketones. For instance, the reaction
duced to 10 mol%, the reaction still took place in high of tetrahydro-4H-pyran-4-one with b-nitrostyrene gave
yield with excellent stereoselectivity (entry 14 in the desired product in 92% yield with excellent stereose-
Table 1), though a longer reaction time was needed. How- lectivities (dr: 98:2; ee: 90%) (entry 16 in Table 2). Both
ever, this drawback could be overcome by running the re- diastereo- and enantioselectivities of these Michael addi-
action in high concentration (entry 15 in Table 1).
tion reactions could be further improved when these reac-
tions were conducted at 0 °C (entries 2, 4, 11 and 14 in
Table 2).
Synthesis 2006, No. 22, 3795–3800 © Thieme Stuttgart · New York

PAPER
Michael Addition of Cyclohexanone to Nitroolefins
3797
Table 2 Michael Reactions of Cyclohexanone (6) to Nitroolefins 7 Catalyzed by 2ea
O
O
Ar
2e/PhCOOH
(10 mol%)
NO2
Ar
+
NO2
n-hexane, r.t.
6
Entry
1
7a–k
Ar
8a–l
Product
Time (h)
11
Yield (%)b
dr (syn/anti)c
96:4
ee (%)d
92
Ph
8a
8a
8b
8b
8c
8d
8e
8f
93
87
84
80
90
80
93
92
78
85
78
69
88
87
97
92
2e
Ph
48
99:1
96
3
4-ClC6H4
4-ClC6H4
2-ClC6H4
4-MeC6H4
2,4-Cl2C6H3
4-BrC6H4
3-BrC6H4
4-FC6H4
4-FC6H4
4-HOC6H4
2-thienyl
2-thienyl
1-naphthyl
Ph
12
95:5
91
4e
48
98:2
95
5
12
98:2
93
6
24
95:5
91
7
10
98:2
98
8
10.5
31
97:3
98
9
8g
8h
8h
8i
96:4
93
10
11e
12
13
14e
15
16f
11
97:3
90
53
99:1
94
7.5 d
18
90:10
90:10
93:7
89
8j
83
8j
41
89
8k
8l
47
97:3
94
12
98:2
90
a The reaction was conducted with catalyst 2e (10 mol%), benzoic acid (10 mol%), 7 (0.5 mmol) and 6 (10 equiv) in n-hexane (1 mL).
b Isolated yields.
c Determined by chiral HPLC analysis of the mixture of syn/anti products.
d Determined by chiral HPLC.
e The reaction was conducted at 0 °C.
f Tetrahydro-4H-pyran-4-one was used as the Michael donor.
The absolute configuration of the major Michael adduct
8a was determined to be (2S,1¢R) by NMR analysis and
N
S
N
H
the comparison of HPLC retention times with those in the
literature.6 This can be explained according to the sug-
gested transition state A (Figure 2). During the course of
the Michael addition, the secondary amine part of the cat-
alyst reacted with cyclohexanone to form the enamine in-
termediate while the thiourea part of the catalyst activated
the nitroolefins by the double hydrogen-bonding. Accord-
ingly, we propose that the re-face of the enamine would
attack at the re-face of the nitrostyrene.
H
O
A
O
O
2S
1'R
N
NO2
N
re face
Ph
8a
Figure 2 Proposed transition state for asymmetric Michael addition
The model reaction could also be conducted in aqueous
media. We have run the reaction in brine,9 and to our great
delight, the results are comparable with those in organic
solvents (Equation 1).
O
O
Ph
2e/PhCOOH
(10 mol%)
NO2
Ph
+
NO2
brine (1 mL), r.t.
yield: 82%
ee: 93%
dr: 97:3
6
7a
8a
In conclusion, we have developed a series of readily tun-
able and bifunctional secondary amine-thiourea catalysts
for the direct Michael additions of cyclohexanone to ni-
troolefins.10 Excellent enantio- and diastereoselectivities
Equation 1
Synthesis 2006, No. 22, 3795–3800 © Thieme Stuttgart · New York

3798
Y.-J. Cao et al.
PAPER
Catalyst 2d
have been obtained at an ambient temperature. Further in-
vestigation of the scope of these catalysts as well as the
mechanistic aspects is underway in our laboratory.
The title compound was prepared according to the general proce-
dure as described above in 62% yield.
1H NMR (400 MHz, CDCl3/TMS): d = 5.03 (s, 2 H), 3.71–3.53 (m,
3 H), 3.00 (s, 2 H), 1.97–1.81 (m, 4 H), 1.63–1.45 (m, 11 H).
1H NMR spectra were recorded on Varian Mercury 400 (400 MHz)
spectrophotometers. Chemical shifts are reported in ppm from the
solvent resonance as the internal standard (CDCl3: 7.26 ppm). 13C
NMR spectra were recorded on Varian Mercury 400 (100 MHz)
spectrophotometers with complete proton decoupling (CDCl3: 77.0
ppm). Chiral HPLC was performed on an Agilent 1100 series in-
strument with chiral columns [Chirapak AS, AD, OD and OJ col-
umns, (Daicel Chemical Ind., Ltd.)]. Elementary analyses were
taken on a Vario EL III elementary analysis instrument.
13C NMR (100 MHz, CDCl3/TMS): d = 181.6, 58.7, 52.9, 456, 29.0,
28.5, 25.5.
Catalyst 2e
The title compound was prepared according to the general proce-
dure as described above in 75% yield.
1H NMR (400 MHz, CDCl3/TMS): d = 7.17–6.97 (s, 4 H), 3.73 (s,
1 H), 3.45 (m, 2 H), 2.86–2.34 (m, 3 H), 2.17 (s, 3 H), 1.93–1.24 (m,
4 H).
13C NMR (100 MHz, CDCl3/TMS): d = 180.6, 136.4, 134.2, 129.8,
124.8, 57.6, 48.9, 46.2, 28.8, 25.7, 20.9.
Unless otherwise noted, materials were purchased from commercial
suppliers and used without further purification. Dichloromethane
and trichloromethane were freshly distilled from calcium hydride.
Petroleum ether and ethyl acetate for flash column chromatography
were distilled before use. Flash column chromatography was per-
formed using 200–300 mesh silica gel.
Catalyst 3
The title compound was prepared according to the general proce-
dure as described above by using isocyanate instead of isothiocyan-
ate in 75% yield.
Catalysts 2; General Procedure
1H NMR (400 MHz, CDCl3/TMS): d = 7.39–7.37 (s, 2 H), 7.14–
7.13 (s, 2 H), 5.28 (s, 1 H), 3.44–3.31 (m, 3 H), 2.85 (m, 2 H), 2.62–
2.56 (s, 1 H), 1.84–1.63 (m, 3 H), 1.47–1.41 (m, 1 H).
13C NMR (100 MHz, CDCl3/TMS): d = 157.5, 139.5, 128.7, 122.2,
118.8, 60.3, 45.8, 41.2, 31.0, 24.0.
N-Boc-(S)-2-aminomethylpyrrolidine (1 g, 5 mmol) was dissolved
in CH2Cl2 (10 mL). The mixture was cooled to 0 °C and the appro-
priate isothiocyanate (5 mmol) was added dropwise to this solution.
After the addition was complete, the mixture was allowed to warm
to r.t. and stirred for 30 min. The solvent was then removed under
reduced pressure. The residue was dissolved in a mixture of TFA–
CH2Cl2 (1:4, 20 mL) and stirred for 2 h at r.t. The mixture was bas-
ified with concd aq ammonia and extracted with CH2Cl2 (3 × 30
mL). After the removal of the solvent under vacuum, the residue
was purified by flash column chromatography on silica gel (eluent,
EtOAc–MeOH, 1:1) to afford catalyst 2 as a white solid in 62–75%
isolated yields.
Michael Addition of Cyclohexanone (6) to Nitroolefins 7; Gen-
eral Procedure
Catalyst 2e (13 mg, 0.05 mmol), benzoic acid (6 mg, 0.05 mmol)
and cyclohexanone (6; 490 mg, 5 mmol, 10 equiv) were dissolved
in n-hexane (1 mL). After stirring the mixture for 15 min at r.t., the
corresponding nitroolefin 7 (0.5 mmol, 1 equiv) was added and the
mixture was stirred for the time given in Table 2 (monitored by
TLC, petroleum ether–EtOAc, 4:1). The mixture was then concen-
trated under reduced pressure, and the resulting residue was purified
by flash column chromatography on silica gel (petroleum ether–
EtOAc, 20:1 to 5:1) to obtain the desired product as a white solid.
Relative and absolute configurations of the products were deter-
mined by comparison with the known 1H NMR, 13C NMR spectra,
and chiral HPLC analysis.
Catalyst 2a
This catalyst was prepared according to the general procedure as de-
scribed above in 70% isolated yield.
1H NMR (400 MHz, CDCl3/TMS): d = 8.0 (s, 2 H), 7.99–7.78 (m,
2 H), 7.53–7.28 (m, 5 H), 6.85 (br, 1 H), 3.74–3.71 (m, 1 H), 3.36–
3.27 (m, 2 H), 2.62–2.47 (m, 2 H), 1.87–1.71 (m, 1 H), 1.51–1.43
(m, 2 H), 1.25–1.21 (m, 1 H).
13C NMR (100 MHz, CDCl3/TMS): d = 181.3, 134.4, 132.3, 129.8,
128.3, 126.9, 126.7, 125.6, 125.1, 122.5, 57.0, 49.1, 46.0, 28.7,
25.5.
2-[2¢-Nitro-1¢-phenylethyl]cyclohexanone (8a)
The title compound was prepared according to the general proce-
dure as described above in 93% yield.
Catalyst 2b
HPLC: Chiralpak AS-H, i-PrOH–hexane (25:75), flow rate 1.0 mL/
min, l = 254 nm; tR (minor isomer) = 10.1 min, tR (major isomer) =
14.6 min; ee = 93%.
The title compound was prepared according to the general proce-
dure as described above in 62% yield.
1H NMR (400 MHz, CDCl3/TMS): d = 4.05 (s, 1 H), 3.49–3.31 (m,
1H NMR (400 MHz, CDCl3/TMS): d = 7.34–7.16 (m, 5 H), 4.94
(dd, J = 4.8, 12.8 Hz, 1 H), 4.63 (dd, J = 10.0, 11.2 Hz, 1 H), 3.79–
3.74 (m, 1 H), 2.69–2.68 (m, 1 H), 2.49–2.37 (m, 2 H), 2.09–2.05
(m, 1 H), 1.79–1.54 (m, 3 H), 1.26–1.21 (m, 2 H).
13C NMR (100 MHz, CDCl3/TMS): d = 211.9, 137.7, 128.9, 128.1,
127.7, 78.8, 52.5, 43.9, 42.7, 33.2, 28.5, 25.0.
3 H), 2.97 (s, 2 H), 2.86 (s, 1 H), 1.98–1.65 (m, 14 H).
13C NMR (100 MHz, CDCl3/TMS): d = 181.9, 53.2, 47.6, 45.7,
32.7, 28.6, 25.5, 24.7 (2 ×).
Catalyst 2c
The title compound was prepared according to the typical proce-
dure, as described above in 72% yield.
1H NMR (400 MHz, CDCl3/TMS): d = 8.04 (s, 2 H,), 7.78 (br, 1 H),
7.63–7.57 (s, 1 H), 6.85 (br, 1 H), 3.55 (s, 1 H), 3.49–3.31 (m, 2 H),
3.12 (s, 1 H), 2.86 (s, 1 H), 1.97–1.93 (m, 2 H), 1.76–1.72 (m, 1 H),
1.58–1.51 (m, 1 H).
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C,
67.2; H, 6.62; N, 5.63.
2-[1-(4-Chlorophenyl)-2-nitroethyl]cyclohexanone (8b)
The title compound was prepared according to the general proce-
dure as described above in 84% yield.
13C NMR (100 MHz, CDCl3/TMS): d = 183.3, 134.4, 142.1, 131.7,
131.3, 124.5, 122.5, 121.8, 117.2, 59.4, 50.7, 46.1, 28.3, 27.1.
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
min, l = 254 nm; tR (minor isomer) = 13.4 min, tR (major isomer) =
20.0 min; ee = 91%.
Synthesis 2006, No. 22, 3795–3800 © Thieme Stuttgart · New York

PAPER
Michael Addition of Cyclohexanone to Nitroolefins
3799
1H NMR (400 MHz, CDCl3/TMS): d = 7.30 (d, J = 8.4 Hz, 1 H),
7.28 (d, J = 8.4 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 8.0
Hz, 1 H), 4.94 (dd, J = 4.4, 12.4 Hz, 1 H), 4.60 (dd, J = 10.2, 11.2
Hz, 1 H), 3.79–3.73 (m, 1 H), 2.67–2.61 (m, 1 H), 2.48–2.36 (m, 2
H), 2.09–2.07 (m, 1 H), 1.80–1.54 (m, 3 H), 1.26–1.18 (m, 2 H).
1H NMR (400 MHz, CDCl3/TMS): d = 7.47 (d, J = 8.0 Hz, 1 H),
7.45 (d, J = 8.0 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 2 H), 4.94 (dd,
J = 4.4, 12.8 Hz, 1 H), 4.60 (dd, J = 10.4, 12.8 Hz, 1 H), 3.78–3.63
(m, 1 H), 2.66–2.64 (m, 1 H), 2.48–2.36 (m, 2 H), 2.10–2.06 (m, 1
H), 1.81–1.55 (m, 3 H), 1.24–1.20 (m, 2 H).
13C NMR (100 MHz, CDCl3/TMS): d = 211.5, 136.2, 133.5, 129.5,
129.1, 78.5, 52.3, 43.3, 42.7, 33.1, 29.6, 28.4, 25.0.
13C NMR (100 MHz, CDCl3/TMS): d = 211.4, 136.8, 132.0, 129.9,
121.6, 78.4, 52.2, 43.4, 42.7, 33.1, 28.4, 25.0.
Anal. Calcd for C14H16ClNO3: C, 59.68; H, 5.72; N, 4.97. Found: C,
60.21; H, 5.94; N, 4.79.
Anal. Calcd for C14H16BrNO3: C, 51.55; H, 4.94; N, 4.29. Found: C,
51.35; H, 4.98; N, 4.20.
2-[1-(2-Chlorophenyl)-2-nitroethyl]cyclohexanone (8c)
The title compound was prepared according to the general proce-
dure as described above in 90% yield.
2-[1-(3-Bromophenyl)-2-nitroethyl]cyclohexanone (8g)
The title compound was prepared according to the general proce-
dure as described above in 93% yield.
HPLC: Chiralpak AD-H, i-PrOH–hexane (5:95), flow rate 1.0 mL/
min, l = 254 nm; tR (minor isomer) = 27.6 min, tR (major isomer) =
49.3 min; ee = 93%.
HPLC: Chiralpak AS-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
min, l = 254 nm; tR (minor) = 13.6 min, tR (major) = 27.1 min;
ee = 93%.
1H NMR (400 MHz, CDCl3/TMS): d = 7.38–7.18 (m, 4 H), 4.90
(dd, J = 5.6, 10.8 Hz, 2 H), 4.30 (dd, J = 8.4, 14.0 Hz, 1 H), 2.93–
2.87 (m, 1 H), 2.48–2.34 (m, 2 H), 2.12–2.06 (m, 1 H), 1.82–1.54
(m, 3 H), 1.38–1.26 (m, 2 H).
1H NMR (400 MHz, CDCl3/TMS): d = 7.41–7.11 (m, 4 H), 4.94
(dd, J = 4.4, 12.8 Hz, 1 H), 4.61 (dd, J = 10, 12.8 Hz, 1 H), 3.78–
3.65 (m, 1 H), 2.66–2.65 (m, 1 H), 2.48–2.36 (m, 2 H), 2.10–2.06
(m, 1 H), 1.81–1.55 (m, 3 H), 1.29–1.21 (m, 2 H).
13C NMR (100 MHz, CDCl3/TMS): d = 211.6, 135.4, 134.5, 130.2,
128.8, 127.3, 77.3, 51.6, 42.7, 40.8, 32.9, 28.4, 25.2.
13C NMR (100 MHz, CDCl3/TMS): d = 211.4, 140.2, 131.1, 130.9,
130.4, 126.9, 122.9, 78.3, 52.2, 43.5, 42.7, 33.1, 28.4, 25.0.
Anal. Calcd for C14H16ClNO3: C, 59.68; H, 5.72; N, 4.97. Found: C,
59.65; H, 5.78; N, 4.81.
Anal. Calcd for C14H16BrNO3: C, 51.55; H, 4.94; N, 4.29. Found: C,
51.44; H, 4.95; N, 4.20.
2-[1-(4-Methylphenyl)-2-nitroethyl]cyclohexanone (8d)
The title compound was prepared according to the general proce-
dure as described above in 80% yield.
2-[1-(4-Fluorophenyl)-2-nitroethyl]cyclohexanone (8h)
The title compound was prepared according to the general proce-
dure as described above in 85% yield.
HPLC: Chiralpak AD-H, i-PrOH–hexane (2:98), flow rate 0.5 mL/
min, l = 254 nm; tR (minor isomer) = 18.0 min, tR (major isomer) =
23.0 min; ee = 91%.
HPLC: Chiralpak OD-H, i-PrOH–hexane (5:95), flow rate 1.0 mL/
min, l = 254 nm; tR (minor) = 20.2 min, tR (major) = 23.0 min;
ee = 94%.
1H NMR (400 MHz, CDCl3/TMS): d = 7.13 (d, J = 8.0 Hz 1 H),
7.11 (d, J = 8.0 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 7.04 (d, J = 8.0
Hz, 1 H), 4.92 (dd, J = 4.0, 12.4 Hz, 1 H), 4.59 (dd, J = 10.0, 12.4
Hz, 1 H), 3.75–3.69 (m, 1 H), 2.69–2.63 (m, 1 H), 2.48–2.30 (m, 2
H), 2.09–2.04 (m, 1 H), 1.78–1.53 (m, 3 H), 1.26–1.19 (m, 2 H).
13C NMR (100 MHz, CDCl3/TMS): d = 212.0, 137.3, 134.5, 129.5,
127.9, 78.9, 52.4, 43.5, 42.6, 33.1, 28.4, 24.9, 20.9.
1H NMR (400 MHz, CDCl3/TMS): d = 7.27–7.02 (m, 4 H), 4.95
(dd, J = 4.0, 12.8 Hz, 1 H), 4.74 (dd, J = 10.4, 12.8 Hz, 1 H), 3.75–
3.69 (m, 1 H), 2.69–2.63 (m, 1 H), 2.46–2.38 (m, 2 H), 2.10–2.08
(m, 1 H), 1.82–1.59 (m, 3 H), 1.27–1.23 (m, 2 H).
13C NMR (100 MHz, CDCl3/TMS): d = 211.6, 162.4, 159.9, 131.0,
130.9, 129.6, 129.5, 124.6, 124.4, 116.0, 115.8, 77.4, 50.9, 42.7,
39.9, 33.2, 28.4, 25.1.
Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C,
68.14; H, 7.32; N, 5.30.
Anal. Calcd for C14H16FNO3: C, 63.39; H, 6.08; N, 5.28. Found: C,
63.62; H, 6.34; N, 5.07.
2-[1-(2,4-Dichlorophenyl)-2-nitroethyl]cyclohexanone (8e)
The title compound was prepared according to the general proce-
dure as described above in 93% yield.
2-[1-(4-Hydroxyphenyl)-2-nitroethyl]cyclohexanone (8i)
The title compound was prepared according to the general proce-
dure as described above in 69% yield.
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
min, l = 254 nm; tR (minor) = 14.2 min, tR (major) = 22.7 min;
ee = 98%.
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
min, l = 254 nm; tR (minor) = 12.2 min, tR (major) = 11.0 min;
ee = 89%.
1H NMR (400 MHz, CDCl3/TMS): d = 7.41 (s, 1 H), 7.40–7.17 (m,
2 H), 4.89 (dd, J = 7.6, 12.8 Hz, 2 H), 4.28–4.22 (m, 1 H), 2.90–2.83
(m, 1 H), 2.49–2.34 (m, 2 H), 2.12–2.09 (m, 1 H), 1.84–1.55 (m, 3
H), 1.38–1.26 (m, 2 H).
13C NMR (100 MHz, CDCl3/TMS): d = 211.3, 135.2, 134.1, 134.0,
130.1, 127.7, 77.3, 51.6, 42.7, 40.6, 33.0, 28.4, 25.2.
1H NMR (400 MHz, CDCl3/TMS): d = 7.02 (d, J = 8.6 Hz, 1 H),
6.99 (d, J = 8.6 Hz, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 6.75 (d, J = 8.8
Hz, 1 H), 4.90 (dd, J = 7.2 Hz, 1 H), 4.56 (t, J = 10.4 Hz, 1 H), 3.70
(s, 1 H), 3.56–3.50 (m, 1 H), 2.64–2.61 (m, 1 H), 2.47–2.37 (m, 2
H), 2.09–2.07 (m, 1 H), 1.76–1.56 (m, 3 H), 1.31–1.22 (m, 2 H).
13C NMR (100 MHz, CDCl3/TMS): d = 213.3, 155.4, 129.4, 115.9,
79.2, 52.7, 43.2, 42.7, 33.2, 29.7, 28.6, 24.9.
Anal. Calcd for C14H15Cl2NO3: C, 53.18; H, 4.78; N, 4.43. Found:
C, 52.49; H, 4.81; N, 4.24.
Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.24; H, 6.45; N, 5.30.
2-[1-(4-Bromophenyl)-2-nitroethyl]cyclohexanone (8f)
The title compound was prepared according to the general proce-
dure as described above in 92% yield.
2-(2-Nitro-1-thiophen-2-ylethyl)cyclohexanone (8j)
The title compound was prepared according to the general proce-
dure as described above in 88% yield.
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
min, l = 254 nm; tR (minor) = 14.15 min, tR (major) = 22.7 min;
ee = 98%.
Synthesis 2006, No. 22, 3795–3800 © Thieme Stuttgart · New York

3800
Y.-J. Cao et al.
PAPER
HPLC: Chiralpak AS-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
min, l = 254 nm; tR (minor) = 16.7 min, tR (major) = 22.7 min;
ee = 83%.
1H NMR (400 MHz, CDCl3/TMS): d = 7.22 (d, 1 H, J = 4.8 Hz),
6.94–6.87 (m, 2 H), 4.89 (dd, J = 4.4, 12.4 Hz, 1 H), 4.64 (dd,
J = 9.6, 12.8 Hz, 1 H), 4.16–4.11 (m, 1 H), 2.71–2.65 (m, 1 H),
2.48–2.33 (m, 2 H), 2.12–2.7 (m, 1 H), 1.94–1.59 (m, 3 H), 1.37–
1.27 (m, 2 H).
(2) For metal-catalyzed Michael addition of nitrostyrene, see:
(a) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2003, 125, 3700. (b) Watanabe, M.; Ikagawa,
A.; Wang, H.; Murata, K.; Ikariya, T. J. Am. Chem. Soc.
2004, 126, 11148. (c) Evans, D. A.; Seidel, D. J. Am. Chem.
Soc. 2005, 127, 9958; and references cited therein.
(3) (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3,
2423. (b) Enders, D.; Seki, A. Synlett 2002, 26.
(4) (a) Betancort, J. M.; Barbas, C. F. III Org. Lett. 2001, 3,
3737. (b) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611.
(c) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett.
2003, 5, 2559. (d) Hayashi, Y.; Gotoh, H.; Tamura, T.;
Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc.
2005, 127, 16028. (e) Mase, N.; Thayumanavan, R.;
Tanaka, F.; Barbas, C. F. III Org. Lett. 2004, 6, 2527.
(f) Chi, Y.-G.; Gellman, S. H. Org. Lett. 2005, 7, 4253.
(g) Wang, W.; Wang, J.; Li, H. Angew. Chem. Int. Ed. 2005,
44, 1369.
13C NMR (100 MHz, CDCl3/TMS): d = 211.1, 140.4, 126.8, 126.5,
124.9, 79.1, 53.2, 42.5, 39.3, 32.6, 28.2, 25.0.
Anal. Calcd for C12H15NO3S: C, 56.90; H, 5.97; N, 5.53. Found: C,
57.0; H, 6.06; N, 5.40.
2-[1-Naphthalen-1-yl-2-nitroethyl]cyclohexanone (8k)
The title compound was prepared according to the general proce-
dure as described above in 97% yield.
HPLC: Chiralpak AS-H, i-PrOH–hexane (50:50), flow rate 0.7 mL/
min, l = 254 nm; tR (minor) = 12.5 min, tR (major) = 17.8 min;
ee = 94%.
1H NMR (400 MHz, CDCl3/TMS): d = 8.16 (m, 1 H), 7.85 (d,
J = 7.6 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.55–7.24 (m, 4 H), 5.06
(dd, J = 4.0, 12.4 Hz, 1 H), 4.88 (dd, J = 9.2, 22.0 Hz, 1 H), 4.76 (s,
1 H), 2.50 (m, 1 H), 2.42–2.38 (m, 2 H), 2.06–2.03 (m, 1 H), 1.69–
1.46 (m, 3 H), 1.27–1.21 (m, 2 H).
(5) For selected reports on thiourea catalysts, see:
(a) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289.
(b) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2003, 125, 12672. (c) Okino, T.; Hoashi, Y.; Furukawa, T.;
Xu, X.-N.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
(d) Dessole, G.; Herrera, R. H.; Ricci, A. Synlett 2004,
2374. (e) Tsogoeva, S. B.; Yalalov, D. A.; Hateley, M. J.;
Weckbecker, C.; Huthmacher, K. Eur. J. Org. Chem. 2005,
4995. (f) Takemoto, Y. J. Org. Biomol. Chem. 2005, 3,
4299. (g) Taylor, M.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2006, 45, 1520. (h) Li, H.; Wang, J.; Zu, L.-S.; Wang, W.
Tetrahedron Lett. 2006, 47, 2585. (i) Connon, S. J. Chem.
Eur. J. 2006, 12, 5418; and references cited therein.
(6) Reports about Michael addition of cyclohexanone to
nitroolefins: (a) Cobb, A. J. A.; Longbottom, D. A.; Shaw,
D. M.; Ley, S. V. Chem. Commun. 2004, 1808. (b) Ishii, T.;
Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc.
2004, 126, 9558. (c) Córdova, A.; Xu, Y.-M. Chem.
Commun. 2006, 460. (d) Xu, Y.-M.; Zou, W.-B.; Sundén,
H.; Ibrahem, I.; Córdova, A. Adv. Synth. Catal. 2006, 348,
418. (e) Luo, S.-Z.; Mi, X.-L.; Zhang, L.; Liu, S.; Xu, H.;
Cheng, J.-P. Angew. Chem. Int. Ed. 2006, 45, 3093.
(f) Tsogoeva, S. B.; Wei, S.-W. Chem. Commun. 2006,
1451. (g) Zhu, M.-K.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.;
Gong, L.-Z. Tetrahedron: Asymmetry 2006, 17, 491.
(h) Huang, H.-B.; Jacobsen, E. N. J. Am. Chem. Soc. 2006,
128, 7170; and references cited therein.
13C NMR (100 MHz, CDCl3/TMS): d = 212.3, 134.6, 133.9, 129.0,
128.1, 126.5, 125.8, 125.3, 123.6, 122.7, 78.7, 53.8, 42.8, 36.7,
33.2, 28.6, 25.2.
Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.52; H, 6.78; N, 4.43.
2-[1-Phenyl-2-nitroethyl]tetrahydro-4H-pyran-4-one (8l)
The title compound was prepared according to the general proce-
dure as described above in 93% yield.
HPLC: Chiralpak AD-H, i-PrOH–hexane (10:90), flow rate 1.0 mL/
min, l = 254 nm; tR (minor) = 14.2 min, tR (major) = 22.7 min;
ee = 98%.
1H NMR (400 MHz, CDCl3/TMS): d = 7.37–7.29 (m, 3 H), 7.25–
7.19 (m, 2 H), 4.76–4.60 (m, 2 H), 4.01–3.95 (m, 1 H), 3.08–2.93
(m, 3 H), 2.88–2.75 (m, 3 H), 2.63–2.59 (m, 1 H), 2.48–2.42 (m, 1
H).
13C NMR (100 MHz, CDCl3/TMS): d = 209.4, 136.4, 129.2, 128.2,
128.1, 78.5, 54.9, 44.5, 43.4, 35.0, 31.5.
(7) (a) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.;
Xiao, W.-J. Org. Lett. 2005, 7, 4543. (b) Li, X.-Y.; Chen, J.-
R.; Meng, X.; Xiao, W.-J. Acta Cryst. 2005, E61, o2730.
(c) Li, D.-P.; Guo, Y.-C.; Ding, Y.; Xiao, W.-J. Chem.
Commun. 2006, 799.
Anal. Calcd for C13H15NO4: C, 58.55; H, 5.70; N, 5.28. Found: C,
58.73; H, 5.81; N, 5.24.
(8) The reaction proceeded slowly, and there were only trace
amounts of products formed even after seven days.
(9) For selected examples of organocatalytic reactions in water,
see: (a) Hayashi, Y.; Sumlya, T.; Takahashi, J.; Gotoh, H.;
Urushlma, T.; Shoji, M. Angew. Chem. Int. Ed. 2006, 45,
958. (b) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe,
K.; Tanaka, F.; Barbas, C. F. III J. Am. Chem. Soc. 2006,
128, 734. (c) Mase, N.; Watanable, K.; Yoda, H.; Takabe,
K.; Tanaka, F.; Barbas, C. F. III J. Am. Chem. Soc. 2006,
128, 4966. (d) Dziedzic, P.; Zou, W.-B.; Háfren, J.;
Córdova, A. Org. Biomol. Chem. 2006, 4, 38; and references
cited therein. (e) Zu, L.-S.; Wang, J.; Li, H.; Wang, W. Org.
Lett. 2006, 8, 3077.
Acknowledgment
We are grateful to the National Science Foundation of China
(200472021), the National Basic Research Program of China
(2004CCA00100), the Program for New Century Excellent Talents
in University (NCET-05-0672), and the Hubei Province Science
Fund for Distinguished Young Scholar (2004ABBC011), for sup-
port of this research.
References
(1) Review of asymmetric Michael addition of nitroolefins:
Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem.
2002, 1877.
(10) During our preparation of this manuscript, Tang and co-
workers reported a similar result, see: Cao, C.-L.; Ye, M.-C.;
Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901.
Synthesis 2006, No. 22, 3795–3800 © Thieme Stuttgart · New York