Enantioselective organocatalytic michael addition of aliphatic ketones to nitrodienes

Article abstract of DOI:10.1080/00397911.2010.529227

A highly enantioselective Michael addition of aliphatic ketones to nitrodienes has been achieved that is catalyzed by readily available chiral thioureas derived from (1R,2R)-diphenylethane-1,2-diamine. Treatment of ketones with nitrodienes in the presence

Full text of DOI:10.1080/00397911.2010.529227

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Enantioselective Organocatalytic
Michael Addition of Aliphatic Ketones to
Nitrodienes
Tianxiong He a & Xin-Yan Wu a
a Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
Shanghai, P. R. China
Accepted author version posted online: 10 Aug 2011. Version of
record first published: 01 Nov 2011
To cite this article: Tianxiong He & Xin-Yan Wu (2012): Enantioselective Organocatalytic Michael
Addition of Aliphatic Ketones to Nitrodienes, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 42:5, 667-677
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Synthetic Communications1, 42: 667–677, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.529227
ENANTIOSELECTIVE ORGANOCATALYTIC MICHAEL
ADDITION OF ALIPHATIC KETONES TO NITRODIENES
Tianxiong He and Xin-Yan Wu
Key Laboratory for Advanced Materials and Institute of Fine Chemicals,
East China University of Science and Technology, Shanghai, P. R. China
GRAPHICAL ABSTRACT
Abstract A highly enantioselective Michael addition of aliphatic ketones to nitrodienes has
been achieved that is catalyzed by readily available chiral thioureas derived from
(1R,2R)-diphenylethane-1,2-diamine. Treatment of ketones with nitrodienes in the pres-
ence of 10 mol% thiourea 1a and 10 mol% benzoic acid in toluene provided the desired
Michael adducts with excellent enantioselectivities (up to 99% ee) and modest to excellent
yields (up to 97%).
Keywords Enantioselective organocatalysis; ketone; nitrodiene; nitro-Michael reaction;
primary amine-thiourea
INTRODUCTION
The asymmetric Michael reaction of nucleophiles to nitroalkenes is a useful
tool for the construction of highly functionalized chiral building blocks.[1] In the past
decade, there has been significant progress in developing various efficient chiral orga-
nocatalysts for the enantioselective Michael addition of ketones to nitroalkenes.[2]
However, the excellent enantioselective Michael addition of acetone to nitroolefins
has been seldom reported.[3] Therefore, the development of a highly effective orga-
nocatalyst for the asymmetric Michael reaction with acetone as the donor would
be desirable.
To the best of our knowledge, only a few studies have related the organocata-
lytic asymmetric Michael addition of nucleophiles to nitrodienes. Tan et al.[4] and
Hayashi’s group[5] reported independently a highly diastereo- and enantioselective
tandem Michael=Henry reaction using nitrodiene as Michael acceptor. Alexakis
Received December 29, 2009.
Address correspondence to Xin-Yan Wu, Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology, Shanghai 200237, P. R. China. E-mail:
xinyanwu@ecust.edu.cn
667

668
T. HE AND X.-Y. WU
and coworkers[6] presented a successful application of (S)-diphenylprolinol silyl ether
in the asymmetric Michael addition of aldehydes to nitrodienes. Cheng[7] and Chua[8]
with coworkers reported independently the highly enantioselective Michael addition
of cyclohexanone to ((1E,3E)-4-nitrobuta-1,3-dienyl)benzene with L-proline deriva-
tives as organocatalysts. We[9] recently succeeded in the asymmetric organocatalyzed
Michael addition of aromatic ketones and nitrodienes with chiral primary
amine-thiourea.[3a-d,10] Herein, we report the highly enantioselective Michael addi-
tions of aliphatic ketones to nitrodienes catalyzed by chiral primary amine-thiourea.
RESULTS AND DISCUSSION
In the initial studies, the chiral bifunctional organocatalysts 1a–h (Figure 1)
were screened in the Michael addition reaction between acetone and nitrodiene 2a.
As illustrated in Table 1, catalyst 1a provided the desired product 3a in good yield
(75%) with excellent enantioselectivity (94% ee, entry 1). The addition of acid such
as PhCOOH or AcOH could improve the chemical yield without enantioselectivity
variety (entries 2 and 3). The addition of base such as dimethylaminopyridine
(DMAP) resulted in a decrease of enantioselectivity (entry 4). The Michael reactions
involving other thioureas were investigated in the presence of PhCOOH. The results
indicated that the acidity of the N-H of the thiourea group has a strong effect on the
catalytic activity and enantioselectivity in the process. Compared to 1a, catalyst 1b
with a strong electron-withdrawing group gave product 3a in poor yield and lower
enantioselectivity (78% ee, entry 5). Thioureas 1c and 1d bearing other aryl groups
provided similar results as 1b (entries 6 and 7). The additional chirality in molecule
1e and 1f had no positive effect on the enantioselectivity, while the chemical yields
declined obviously (entries 8 and 9). Catalyst 1g with a substituent at the benzyl
group afforded the product in lower yield with same enantioselectivity as 1a
(entry 10). Catalyst 1h bearing n-butyl group gave 3a in good yield (80%), but the
enantioselectivity was worse than the others (entry 11).
Next we investigated the effects of solvents for this Michael addition using
catalyst 1a. As shown in Table 2, the chemical yields varied significantly in different
solvents. In Et2O, the desired adduct was observed in a moderate yield because of the
poor solubility of the nitrodiene 2a (43%, entry 2). However, in the case of tetrahy-
furan (THF), the product was obtained in trace amounts (entry 7). Moderate yields
were obtained using CH2Cl2, CHCl3, i-PrOH, and t-BuOH as solvents (50–70%,
Figure 1. Various chiral primary amine-thiourea organocatalysts.

ENANTIOSELECTIVE ORGANOCATALYTIC MICHAEL ADDITION
669
Table 1. Catalytic asymmetric Michael addition of acetone to nitrodiene 2a
Entry
Catalyst
Additive
Yield (%)a
Ee (%)b
1
2
1a
1a
1a
1a
1b
1c
1d
1e
1f
None
75
85
80
78
43
35
32
54
55
65
80
94
94
94
92
78
86
91
88
93
94
73
PhCOOH
AcOH
DMAP
3
4
5
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
6
7
8
9
10
11
1g
1h
aIsolated yield after silica-gel column chromatography.
bDetermined by chiral HPLC analysis (Chiralpak AS-H column, hexane=i-PrOH 95:5).
entries 3–6). Surprisely, using EtOH as solvent provided lower chemical yield and
enantioselectivity than using other alcohols such as i-PrOH and t-BuOH (entry 9
vs 5 and 6). Also the product was formed in poor yield in acetone (25%, entry 8).
The use of toluene led to the best yield (85%, entry 1). In general, all the screened
solvents gave good to excellent enantioselectivities (70–96% ee). The greatest
enantioselectivity was 96% ee with i-PrOH as the solvent. Considering both yield
and enantioselectivity, toluene was chosen as solvent for further investigation.
Table 2. Effect of solvents on the asymmetric Michael addition of acetone to nitrodiene 2a
Entry
Solvent
Yield (%)a
Ee (%)b
1
2
3
4
5
6
7
8
9
Toluene
Et2O
85
43
70
50
68
70
5
94
90
90
91
96
82
85
82
70
CH2Cl2
CHCl3
i-PrOH
t-BuOH
THF
Acetone
EtOH
25
30
aIsolated yield after silica-gel column chromatography.
bDetermined by chiral HPLC analysis (Chiralpak AS-H column, hexane=i-PrOH 95:5).

670
T. HE AND X.-Y. WU
Under the optimized reaction conditions, various nitrodienes were examined
with acetone as the Michael donor. The results in Table 3 indicated that other nitro-
dienes with electro-donating or electro-withdrawing substituents on aromatic group
were less reactive than nitrodiene 2a (entries 2–6 vs entry 1), while the enantioselec-
tivity had no obvious change (92–95% ee). Because 1-((1E,3E)-4-nitrobuta-1,3-
dienyl)benzene (2a) was more reactive, it was then selected to react with other ali-
phatic ketones. In all the cases except entry 10, the enantioselectivity was excellent
(94–99% ee). However, all these reactions provided the Michael adducts in low dia-
stereoselectivities (ranging from 83=17 to 69=31). Among the Michael reactions
involving cyclic ketones such as cyclohexanone, cyclopentanone, and cyclohepta-
none as Michael donor, we found that the smaller the ring size, the faster the reac-
tion rate (entries 7–9). The Michael reaction between cyclopentanone and nitrodiene
2a completed in 24 h with 97% yield and 99% ee of the major diastereomer (entry 7),
while only a trace amount of desired product was observed with cycloheptanone as
Michael donor even after 4 days (entry 9). In contrast to the carbon analogs, lower
enantioselectivity (83% ee) was obtained for tetrahydropyran-4-one (entry 10).
3-Pentanone was less reactive and afforded the product in poor yield (25%,
entry 12). When using 2-butanone as donor, the reaction took place at the more
substituted site, presumably because the enamine intermediate formed under ther-
modynamic control.[11] The adduct was obtained in good yield (75%) and modest
diastereoselectivity (83:17) (entry 11). Surprisingly, when the 4-methylpentan-2-one
Table 3. Catalytic asymmetric Michael addition of ketones to nitrodienes
Entry
R1
R2
Ar
Product
Time (d)
dra
Yield (%)b
Ee (%)c
1
2
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
C6H5
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
2,4-Cl2C6H3
4-MeC6H4
C6H5
3a
3b
3c
3d
3e
3f
3
3
3
3
3
3
1
3
4
3
3
4
4
—
—
85
62
94
94
3
—
—
60
50
95
95
4
5
—
—
42
40
92
94
6
7
(CH2)3
(CH2)4
(CH2)5
3g
3h
3i
70:30
78:22
n.d.d
69:31
83:17
76:24
—
97
84
99
8
C6H5
C6H5
97
9
trace
90
n.d.d
83
10
11
12
13
(CH2)2O(CH2)
C6H5
C6H5
3j
Me
Et
Me
Me
H
3k
3l
75
25
99
99
C6H5
C6H5
i-Bu
3m
35
94
aThe diastereomer ratio was determined by 1H NMR spectroscopy.
bIsolated yield after silica-gel column chromatography.
cEe values of the major diastereomer, which were determined by chiral HPLC analysis using Chiralpak
AD-H, Chiralpak AS-H, or Chiralcel OD-H columns.
dNot determined.

ENANTIOSELECTIVE ORGANOCATALYTIC MICHAEL ADDITION
671
was reacted with nitrodiene 2a under the same conditions, the less hindered methyl
group reacted preferentially, giving the product in 35% yield because of poor conver-
sion (entry 13). We assume that the thermodynamic enamine was too hindered to
react, so the enamine formed under kinetic condition afforded the methyl adduct.
Nevertheless, the reaction rate was very slow because of the low concentration of
kinetic enamine in solution.
CONCLUSION
In conclusion, we have developed a highly enantioselective Michael reaction of
aliphatic ketones with nitrodienes catalyzed by chiral primary amine thioureas. With
10 mol% of the simple thiourea 1a in the presence of PhCOOH, the nitro-Michael
adducts were obtained in excellent enantioselectivities (92–99% ee) and modest to
high yield (40–97%) for most of the tested substrates.
EXPERIMENTAL
Optical rotations were measured on a WZZ-2A digital polarimeter at the wave-
length of the sodium D-line (589 nm). 1H NMR and 13C NMR spectra were recorded
on Bruker 500 or 400 spectrometer using CDCl3 as a solvent. The chemical shifts of
1H NMR spectra were recorded in parts per million (ppm, d) relative to tetramethyl-
silane (d, 0.00) and coupling constants (Hz). The chemical shifts of 13C NMR spectra
were recorded in parts per million (ppm) from tetramethylsilane with the solvent as
the internal standard (CDCl3: 77.0 ppm). Infrared (IR) spectra were recorded on
Nicolet Magna-IR 550 spectrometer. High-resolution mass spectra (HRMS) were
recorded on Micromass GCT spectrometer with electron impact (EI) or electrospray
ionization (ESI) resource. High-performance liquid chrometography (HPLC) analy-
sis was performed on a Waters 510 with 2487 detector using Daicel Chiralpak AS-H,
Chiralpak AD-H, and Chiralcel OD-H column.
Toluene, THF, and ether were distilled from sodium-benzophenone. Dichloro-
methane and chloroform were distilled from CaH2. Ethanol was distilled from magnes-
ium. Various aliphatic ketones were commercially available and used after distillation.
Thin-layer chromatography (TLC) was performed on silica gel plates. Column chro-
matography was performed using silica-gel (300–400 mesh) eluting with ethyl acetate
and petroleum ether. Compounds were visualized by ultraviolet (UV) and KMnO4.
General Procedure for the Michael Reaction of Ketone and
Nitrodiene
1-((1R,2R)-2-Amino-1,2-diphenylethyl)-3-benzylthiourea
(1a)
(7.22 mg,
0.02 mmol) and PhCOOH (2.44 mg, 0.02 mmol) were added to a vial containing
ketone (1 mmol) and toluene (2 mL) at 25 ꢀC. The mixtures were stirred vigorously
for 10 min, and then nitrodiene (0.2 mmol) was added. After the reaction mixture
was stirred for the appropriate time (monitored by TLC), the solvent was removed
and the residue was purified by column chromatography on silica gel to afford the
desired pure product. The diastereomer ratios were determined by 1H NMR
spectroscopy. Ee values were determined by chiral HPLC analysis.

672
T. HE AND X.-Y. WU
(S,E)-4-(Nitromethyl)-6-phenylhex-5-en-2-one (3a)[12]
20
Yield: 85%; ½aꢁD ¼ þ 14.0 (c 0.25, CHCl3); 94% ee. Chiral HPLC analysis:
Chiralpak AS-H, hexane=i-PrOH ¼ 95=5, UV 254 nm, flow rate 1.0 mL=min,
1
tR ¼ 27.2 min (major), 31.4 min (minor); H NMR (CDCl3, 400 MHz) d: 7.30–7.22
(m, 4H), 7.20–7.15 (m, 1H), 6.46 (d, J ¼ 15.8 Hz, 1H), 6.00 (dd, J ¼ 15.8, 8.4 Hz,
1H), 4.54–4.43 (m, 2H), 3.45 (m, 1H), 2.68 (d, J ¼ 6.4 Hz, 2H), 2.11 (s, 3H); IR (film,
cmꢂ1): n 2968, 1713, 1548, 1448, 1409, 1369, 1202, 965, 749, 693; HRMS (EI) calcd.
for C13H15NO3(M): 233.1052, found: 233.1059.
(S,E)-4-(Nitromethyl)-6-(4-nitrophenyl)hex-5-en-2-one (3b)
20
Yield: 62%; ½aꢁD ¼ þ10.8 (c 0.25, CHCl3); 94% ee. Chiral HPLC analysis:
Chiralpak AD-H, hexane=i-PrOH ¼ 90=10, UV 254 nm, flow rate 1.0 mL=min,
1
tR ¼ 82.7 min (major), 87.6 min (minor); H NMR (CDCl3, 500 MHz) d: 8.09 (d,
J ¼ 8.7 Hz, 2H), 7.39 (d, J ¼ 8.7 Hz, 2H), 6.54 (d, J ¼ 15.9 Hz, 1H), 6.22 (dd,
J ¼ 15.9, 8.6 Hz, 1H), 4.58–4.54 (m, 1H), 4.52–4.48 (m, 1H), 3.51 (m, 1H), 2.73 (d,
J ¼ 6.4 Hz, 2H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) d: 204.2, 146.2, 141.5,
130.4, 128.2, 126.0, 123.0, 77.2, 43.6, 35.9, 29.4; IR (film, cmꢂ1): n 2963, 2923,
2852, 1716, 1552, 1516, 1344, 1261, 1095, 1021, 801, 550; HRMS (EI) calcd. for
C13H14NO3(M-NO2): 232.0974, found: 232.0965.
(S,E)-4-(Nitromethyl)-6-(3-nitrophenyl)hex-5-en-2-one (3c)
20
Yield: 60%; ½aꢁD ¼ þ 16.0 (c 0.3, CHCl3); 95% ee. Chiral HPLC analysis:
Chiralpak AD-H, hexane=i-PrOH ¼ 90=10, UV 254 nm, flow rate 1.0 mL=min,
1
tR ¼ 55.0 min (major), 60.4 min (minor); H NMR (CDCl3, 500 MHz) d: 8.12 (s,
1H), 8.03 (d, J ¼ 8.2 Hz, 1H), 7.56 (d, J ¼ 7.7 Hz, 1H), 7.42 (t, J ¼ 8.0, 8.0 Hz, 1H),
6.53 (d, J ¼ 15.9 Hz, 1H), 6.18 (dd, J ¼ 15.9, 8.6 Hz, 1H), 4.58–4.54 (m, 1H),
4.51–4.47 (m, 1H), 3.52 (m, 1H), 2.72 (d, J ¼ 6.5 Hz, 2H), 2.14 (s, 3H); 13C NMR
(100 MHz, CDCl3) d: 204.2, 147.5, 136.9, 131.4, 130.3, 128.8, 128.6, 121.6, 119.9,
77.3, 43.6, 35.8, 29.4; IR (film, cmꢂ1): n 2922, 1716, 1552, 1528, 1352, 1164, 1076,
971, 734, 676, 552, 472; HRMS (EI) calcd. for C13H14NO3(M-NO2): 232.0974,
found: 232.0951.
(S,E)-4-(Nitromethyl)-6-(2-nitrophenyl)hex-5-en-2-one (3d)
20
Yield: 50%; ½aꢁD ¼ þ17.5 (c 0.2, CHCl3); 95% ee. Chiral HPLC analysis:
Chiralpak AD-H, hexane=i-PrOH ¼ 93=7, UV 254 nm, flow rate 1.0 mL=min,
1
tR ¼ 39.2 min (major), 41.7 min (minor); H NMR (CDCl3, 500 MHz) d: 7.89 (d,
J ¼ 8.0 Hz, 1H), 7.50 (m, 1H), 7.43 (d, J ¼ 7.4 Hz, 1H), 7.35 (m, 1H), 6.94 (d,
J ¼ 15.8 Hz, 1H), 6.04 (dd, J ¼ 15.8, 8.1 Hz, 1H), 4.59–4.50 (m, 2H), 3.51 (m, 1H),
2.75 (d, J ¼ 6.5 Hz, 2H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) d: 204.5,
146.5, 132.4, 131.3, 130.8, 128.1, 128.0, 127.6, 123.6, 77.3, 43.5, 35.6, 29.4; IR (film,
cmꢂ1): n 2921, 1716, 1552, 1471, 1379, 1164, 1101, 1049, 972, 563, 471; HRMS (EI)
calcd. for C13H14NO3(M-NO2): 232.0974, found: 232.0981.

ENANTIOSELECTIVE ORGANOCATALYTIC MICHAEL ADDITION
673
(S,E)-6-(2,4-Dichlorophenyl)-4-(nitromethyl)hex-5-en-2-one (3e)
20
Yield: 42%; ½aꢁD ¼ þ15.6 (c 0.4, CHCl3); 93% ee. Chiral HPLC analysis:
Chiralpak AD-H, hexane=i-PrOH ¼ 93=7, UV 254 nm, flow rate 1.0 mL=min,
1
tR ¼ 17.1 min (major), 18.4 min (minor); H NMR (CDCl3, 500 MHz) d: 7.32–7.29
(m, 2H), 7.12 (d, J ¼ 6.6 Hz, 1H), 6.76 (d, J ¼ 15.9 Hz, 1H), 6.02 (dd, J ¼ 15.9,
8.4 Hz, 1H), 4.57–4.47 (m, 2H), 3.53–3.46 (m, 1H), 2.73 (m, 2H), 2.14 (s, 3H); 13C
NMR (100 MHz, CDCl3) d: 204.4, 133.1, 132.6, 132.0, 128.9, 128.4, 127.6, 126.7,
126.3, 77.3, 43.6, 35.9, 29.4; IR (film, cmꢂ1): n 2921, 1716, 1552, 1522, 1434, 1346,
1165, 1075, 968, 862, 787, 741; HRMS (EI) calcd. for C13H12 Cl2O (M-NO2-H):
256.0236, found: 256.0248.
(S,E)-4-(Nitromethyl)-6-p-tolylhex-5-en-2-one (3f)
20
Yield: 40%; ½aꢁD ¼ þ7.0 (c 0.23, CHCl3); 94% ee. Chiral HPLC analysis:
Chiralpak AS-H, hexane=i-PrOH ¼ 90=10, UV 254 nm, flow rate 1.0 mL=min,
1
tR ¼ 15.3 min (major), 18.7 min (minor); H NMR (CDCl3, 500 MHz) d: 7.22 (d,
J ¼ 8.0 Hz, 2H), 7.11 (d, J ¼ 8.0 Hz, 2H), 6.49 (d, J ¼ 15.8 Hz, 1H), 6.02 (dd,
J ¼ 15.8, 8.6 Hz, 1H), 4.60–4.57 (m, 1H), 4.53–4.50 (m, 1H), 3.51 (m, 1H), 2.74 (d,
J ¼ 6.5 Hz, 2H), 2.33 (s, 3H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) d: 204.7,
136.9, 132.3, 132.2, 128.3, 125.3, 124.1, 77.6, 44.0, 36.0, 29.5, 20.2; IR (film,
cmꢂ1): n 2919, 1715, 1550, 1373, 1163, 1027, 967, 567, 482; HRMS (EI) calcd. for
C14H17NO3(M): 247.1208, found: 247.1209.
(E)-2-(1-Nitro-4-phenylbut-3-en-2-yl)cyclopentanone (3g)
Yield: 97%; dr: 70:30; 99% ee for major diastereomer and 99% ee for minor dia-
stereomer. Chiral HPLC analysis: Chiralpak AS-H, hexane=i-PrOH ¼ 85=15, UV
254 nm, flow rate 1.0 mL=min, tR ¼ 10.8 min (minor diastereomer, minor), 11.6 min
(major diastereomer, major), 13.4 min (minor diastereomer, major), 20.8 min (major
diastereomer, minor); diastereomer mixtures [dr 70:30 (major diastereomer=minor
1
diastereomerꢃ)]; H NMR (CDCl3, 400 MHz) d: 7.34–7.23 (m, 5H þ 2.15Hꢃ), 6.54
(d, J ¼ 15.6 Hz, 0.43Hꢃ), 6.49 (d, J ¼ 16.0 Hz, 1H), 5.94 (dd, J ¼ 15.6, 9.2 Hz,
1H þ 0.43Hꢃ), 4.94–4.89 (m, 1H), 4.84–4.74 (m, 0.86Hꢃ), 4.58–4.53 (m, 1H),
3.44–3.36 (m, 1H), 3.35–3.30 (m, 0.43Hꢃ), 2.44–2.23 (m, 2H þ 0.86Hꢃ), 2.21–1.97
(m, 3H þ 1.29Hꢃ), 1.86–1.70 (m, 2H þ 0.86Hꢃ); 13C NMR (100 MHz, CDCl3) d:
219.2, 218.3, 136.1, 136.0, 135.7, 134.7, 128.6(2C), 128.2, 128.1, 126.5(2C), 124.5,
123.8, 77.9, 77.8, 50.2, 49.7, 42.8, 42.0, 39.3, 38.5, 27.4, 26.9, 20.8, 20.5; IR (film,
cmꢂ1): n 2972, 2918, 2881, 1731, 1552, 1383, 964, 741, 691; HRMS (ESI) calcd.
for C15H17NO3Na (M þ Na): 282.1106, found: 282.1111.
(E)-2-(1-Nitro-4-phenylbut-3-en-2-yl)cyclohexanone (3h)[7,8]
Yield: 84%; dr: 78:22; 97% ee for syn diastereomer and 90% ee for anti diaster-
eomer. Chiral HPLC analysis: Chiralpak AS-H, hexane=i-PrOH ¼ 80=20, UV
254 nm, flow rate 0.5 mL=min, tR ¼ 18.0 min (syn, major), 19.3 min (anti, minor),
20.2 min (anti, major), 25.7 min (syn, minor); diastereomer mixtures [dr 78:22 (syn=
1
antiꢃ)]; H NMR (CDCl3, 400 MHz) d: 7.36–7.21 (m, 5H þ 1.4Hꢃ), 6.49 (d,

674
T. HE AND X.-Y. WU
J ¼ 16.0 Hz, 1H), 6.48 (d, J ¼ 16.0 Hz, 0.28Hꢃ), 6.28 (dd, J ¼ 14.8, 9.6 Hz, 0.28Hꢃ),
6.02 (dd, J ¼ 16.0, 9.6 Hz, 1H), 4.71–4.66 (m, 1H þ 0.56Hꢃ), 4.60–4.55 (m, 1H),
3.39–3.31 (m, 1H), 3.22–3.16 (m, 0.28Hꢃ), 2.64–2.51 (m, 1H þ 0.28Hꢃ), 2.48–2.29
(m, 2H þ 0.56Hꢃ), 2.21–2.04 (m, 2H þ 0.56Hꢃ), 1.96–1.86 (m, 1H þ 0.28Hꢃ),
1.78–1.61 (m, 2H þ 0.84Hꢃ), 1.51–1.40 (m, 1H).
(E)-3-(1-Nitro-4-phenylbut-3-en-2-yl)-tetrahydropyran-4-one (3j)
Yield: 90%; dr: 69:31; 83% ee for major diastereomer and 91% ee for minor dia-
stereomer. Chiral HPLC analysis: Chiralpak AD-H, hexane=i-PrOH ¼ 90=10, UV
254 nm, flow rate 1.0 mL=min, tR ¼ 23.5 min (minor diastereomer, minor), 25.1 min
(minor diastereomer, major), 41.0 min (major diastereomer, major), 56.2 min (major
diastereomer, minor); diastereomer mixtures [dr 69:31 (major diastereomer=minor
1
diastereomerꢃ)]; H NMR (CDCl3, 400 MHz) d: 7.35–7.24 (m, 5H þ 2.25Hꢃ), 6.54
(d, J ¼ 16.0 Hz, 1H), 6.48 (d, J ¼ 16.0 Hz, 0.45Hꢃ), 6.23 (dd, J ¼ 16.0, 9.6 Hz,
0.45Hꢃ), 5.94 (dd, J ¼ 15.8, 9.6 Hz, 1H), 4.77–4.68 (m, 1H þ 0.90Hꢃ), 4.55–4.50 (m,
1H), 4.23–4.16 (m, 2H þ 0.90Hꢃ), 3.83–3.53 (m, 2H þ 0.90Hꢃ), 3.47–3.36 (m, 1H),
3.26–3.13 (m, 0.45Hꢃ), 2.89–2.79 (m, 0.45Hꢃ), 2.78–2.61 (m, 2H þ 0.45Hꢃ),
2.53–2.47 (m, 1H), 2.43–2.37 (m, 0.45Hꢃ); 13C NMR (100 MHz, CDCl3) d: 205.8,
205.3, 134.9, 134.8, 134.4, 134.3, 127.6 (2C), 127.2 (2C), 125.6, 125.5, 123.0, 122.8,
77.0, 76.9, 70.3, 70.0, 67.8, 67.1, 51.1, 51.0, 42.0, 41.9, 40.0, 38.5; IR (film, cmꢂ1):
n 2991, 2971, 2858, 1702, 1556, 1385, 1232, 1152, 971, 748, 691; HRMS (ESI) calcd.
for C15H17NO4Na (M þ Na): 298.1055, found: 298.1056.
(E)-3-Methyl-4-(nitromethyl)-6-phenylhex-5-en-2-one (3k)
Yield: 75%; dr: 83:17; 99% ee for major diastereomer; the minor diastereomer
was not separated by chiral HPLC. Chiral HPLC analysis: Chiralpak AD-H,
hexane=i-PrOH ¼ 90=10, UV 254 nm, flow rate 0.5 mL=min, tR ¼ 19.2 min (minor
diastereomer), 20.4 min (major diastereomer, major), 21.9 min (major diastereomer,
minor); diastereomer mixtures [dr 83:17 (major diastereomer=minor diastereomerꢃ)];
1H NMR (CDCl3, 400 MHz) d: 7.35–7.23 (m, 5H þ 1.00Hꢃ), 6.53 (d, J ¼ 15.6 Hz,
0.20Hꢃ), 6.50 (d, J ¼ 15.6 Hz, 1H), 6.15 (dd, J ¼ 15.6, 9.2 Hz, 1H), 5.97 (dd,
J ¼ 15.8, 9.6 Hz, 0.20Hꢃ), 4.65–4.60 (m, 1H), 4.57–4.49 (m, 1H þ 0.40Hꢃ),
3.34–3.17 (m, 1H þ 0.20Hꢃ), 2.87–2.70 (m, 1H þ 0.20Hꢃ), 2.25 (s, 0.60Hꢃ), 2.18 (s,
3H), 1.23 (d, J ¼ 7.2 Hz, 3H), 1.19 (d, J ¼ 7.2 Hz, 0.60Hꢃ); 13C NMR (100 MHz,
CDCl3) d: 209.3, 209.0, 135.1(2C), 133.9, 133.8, 127.6(2C), 127.1, 127.0, 125.5(2C),
123.8, 123.7, 77.0, 76.6, 47.1, 46.9, 43.4, 42.6, 28.3, 28.1, 13.9, 13.4; IR (film,
cmꢂ1): n 2985, 2930, 1709, 1544, 1448, 1385, 1168, 1080, 974, 750, 693; HRMS
(ESI) calcd. for C14H17NO3Na (M þ Na): 270.1106, found: 270.1108.
(E)-4-Methyl-5-(nitromethyl)-7-phenylhept-6-en-3-one (3l)
Yield: 25%; dr: 76:24; 99% ee for major diastereomer and 92% ee for minor
diastereomer. Chiral HPLC analysis: Chiralcel OD-H, hexane=i-PrOH ¼ 95=5, UV
254 nm, flow rate 0.5 mL=min, tR ¼ 36.4 min (minor diastereomer, minor), 39.4 min
(major diastereomer, minor), 49.7 min (major diastereomer, major), 60.9 min (minor

ENANTIOSELECTIVE ORGANOCATALYTIC MICHAEL ADDITION
675
diastereomer, major); diastereomer mixtures [dr 76:24 (major diastereomer=minor
1
diastereomerꢃ)]; H NMR (CDCl3, 400 MHz) d: 7.38–7.24 (m, 5H þ 1.55Hꢃ), 6.55
(d, J ¼ 16.0 Hz, 0.31Hꢃ), 6.51 (d, J ¼ 16.0 Hz, 1H), 6.17 (dd, J ¼ 16.0, 9.2 Hz, 1H),
5.99 (dd, J ¼ 15.6, 9.6 Hz, 0.31Hꢃ), 4.67–4.63 (m, 1H), 4.60–4.51 (m, 1H þ 0.62Hꢃ),
3.37–3.17 (m, 1H þ 0.31Hꢃ), 2.87–2.76 (m, 1H þ 0.31Hꢃ), 2.65–2.39 (m,
2H þ 0.62Hꢃ), 1.23 (d, J ¼ 7.2 Hz, 3H), 1.19 (d, J ¼ 7.2 Hz, 0.93Hꢃ), 1.11 (t,
J ¼ 7.2 Hz, 0.93Hꢃ), 1.05 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d:
213.1, 212.7, 136.2(2C), 134.8(2C), 128.6(2C), 128.1, 128.0, 126.5(2C), 125.1(2C),
78.0, 77.6, 47.2, 47.1, 44.5, 43.9, 35.5, 35.2, 15.4, 14.5, 7.7, 7.6; IR (film, cmꢂ1): n
2978, 2938, 1714, 1548, 1380, 1080, 966, 750, 693; HRMS (ESI) calcd. for
C15H19NO3Na (M þ Na): 284.1263, found: 284.1269.
(E)-2-Methyl-6-(nitromethyl)-8-phenyloct-7-en-4-one (3m)
20
Yield: 35%; ½aꢁD ¼ þ 12.9 (c 0.35, CHCl3); 94% ee. Chiral HPLC analysis:
Chiralpak AD-H, hexane=i-PrOH ¼ 90=10, UV 254 nm, flow rate 0.5 mL=min,
1
tR ¼ 17.6 min (major), 18.4 min (minor); H NMR (CDCl3, 500 MHz) d: 7.26–7.16
(m, 5H), 6.46 (d, J ¼ 16.0 Hz, 1H), 6.00 (dd, J ¼ 15.8, 8.8 Hz, 1H), 4.55–4.43 (m,
2H), 3.52–3.43 (m, 1H), 2.63 (d, J ¼ 6.8 Hz, 2H), 2.24 (d, J ¼ 7.2 Hz, 2H),
2.11–2.04 (m, 1H), 0.84 (d, J ¼ 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) d:
206.8, 135.2, 132.3, 127.6, 127.0, 125.4(2C), 77.6, 51.3, 43.5, 36.0, 23.5, 21.5; IR (film,
cmꢂ1): n 2961, 1713, 1548, 1380, 1262, 1021, 966, 750, 693; HRMS (ESI) calcd. for
C16H21NO3 Na (M þ Na): 298.1419, found: 298.1412.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (20772029)
and the New Century Excellent Talents in University (NCET-07-0286) for financial
support.
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