A highly chemo- and enantioselective nitroaldol reaction of haloenals: Preparation of chiral functionalized allylic alcohols

Article abstract of DOI:10.1016/j.tetasy.2012.01.011

An efficient L1/Cu(II)-catalyzed highly chemoselective and enantioselective nitroaldol reaction of α- or β-haloenals with nitromethane has been described. The reaction delivered chiral functionalized allylic alcohols bearing halo and nitro groups with excellent results (up to 94% yield and 99% ee) under mild reaction conditions.

Full text of DOI:10.1016/j.tetasy.2012.01.011

Tetrahedron: Asymmetry 23 (2012) 124–129
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A highly chemo- and enantioselective nitroaldol reaction of haloenals:
preparation of chiral functionalized allylic alcohols
⇑
Lianghu Gu, Yirong Zhou, Jingli Zhang, Yuefa Gong
School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient L1/Cu(II)-catalyzed highly chemoselective and enantioselective nitroaldol reaction of a- or b-
Received 6 December 2011
Accepted 5 January 2012
Available online 18 February 2012
haloenals with nitromethane has been described. The reaction delivered chiral functionalized allylic alco-
hols bearing halo and nitro groups with excellent results (up to 94% yield and 99% ee) under mild reaction
conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
O
OH
X
O
X
b)
a)
H
Nu
Henry (nitroaldol) reactions between nitroalkanes and alde-
hydes provide valuable intermediates b-hydroxy nitroalkanes,
Nu-
H
Nu-
Nu
which can be transformed into b-amino alcohols, aziridines, a-hy-
e)
droxy carboxylic acids, and other complex target compounds.1 In
recent years, much progress has been made in the enantioselective
version of the Henry reaction by developing various new chiral li-
gands. In this work, much attention has mainly been focused on
the reaction of simple aromatic and aliphatic aldehydes.2,3
d)
O
O
X
c)
H
H
X
NR3
Nu
As useful building blocks, haloenals are usually employed for
constructing versatile heterocyclic compounds,4 carbocycles,5 and
quaternary carbon centers.6 The halo atom on the C@C bond in
the enal is activated by the electron-withdrawing carbonyl group,
and can be readily replaced by other functional groups. As shown
in Scheme 1, the presence of two reactive sites (C@O and @C–X)
in the haloenal molecule makes it possible to follow different
pathways under basic conditions, such as paths (a),4b,c,7 (b)5,8
X = Cl, Br
Scheme 1. Possible reaction modes of b-haloenals under base conditions.
nitromethane has not been reported. Thus, we attempted the reac-
tion between haloenals and nitromethane in the presence of the
Cu(II)-diamine system. This reaction proceeded smoothly and gave
the nitroaldol products b-nitro allylic alcohols, which are impor-
tant intermediates for a wide range of pharmaceutical substances
and biologically active compounds because of their numerous syn-
thetic applications.11 Herein, we report the details of the highly
chemo- and enantioselective reaction between haloenals and
nitromethane.
and (c).4d,e,9 Recently, Ma et al. reported
a DBU-promoted
Morita-Baylis–Hillman reaction10 and Michael addition reaction6a
of haloenals (path d). We have developed a novel TBAF-promoted
intermolecular crossed reaction between haloenals and electron-
deficient olefins, in which the vinylogous enolates generated by
the deprotonation at the
the Michael acceptors at their
c
-position preferred to combine with
a
-position (path e).6b
2. Results and discussion
Very recently, we developed an efficient chiral secondary dia-
mine ligand for the copper-catalyzed asymmetric nitroaldol reac-
tion.3d As a continuation of this work, we wondered what would
happen between a haloenal and a nitroalkane in the presence of
a catalyst, especially with regard to the chemoselectivity and
enantioselectivity during the reaction. To the best of our
knowledge, the asymmetric nitroaldol reaction of haloenals with
Initially, we chose the reaction of 2-chlorocyclohex-1-enecarb-
aldehyde 1a with nitromethane 2 as the model reaction (Table 1).
Based on our previous work,3d several ligands and copper(II) chlo-
ride were utilized in the reaction with diisopropylethylamine
(DIPEA) as the additive base in THF at 4 °C. Among the ligands
L1–L6, L1 was found to be a potentially useful one for the reaction
and gave product 3a in a 48% yield with 87% enantiomeric excess
⇑
Corresponding author. Tel./fax: +86 027 87543632.
E-mail address: gongyf@mail.hust.edu.cn (Y. Gong).
after 10 h (entry 1). When ligand L2, derived from D-proline, was
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.01.011

L. Gu et al. / Tetrahedron: Asymmetry 23 (2012) 124–129
125
Table 1
Table 2
Ligand screeninga
Optimization of reaction parametersa
Entry
Copper salt
Solvent
THF
THF
THF
THF
THF
THF
THF
Base
Yieldb (%)
eec (%)
O
H
OH
Cl
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
CuCl2ꢀ2H2O
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
48
68
43
20
52
60
50
39
51
74
45
35
58
58
10
22
34
58
48
80
87
88
83
27
79
90
78
48
30
29
62
20
76
90
28
42
93
94
96
95
5 mmol% ligand +
NO2
Cu(OAc)2ꢀH2O
5 mmol% CuCl2·2H2O
CH3NO2
CuBr2
+
CuSO4ꢀ5H2O
CuCN
CuCl
CuBr
CuI
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
DIPEA (1.0 equiv),
Cl
º
THF, 4 C, 10h
2
1a
3a
THF
CH3OH
MeNO2
MeCN
CH2Cl2
Et2O
THF
THF
THF
THF
THF
N
H
N
H
N
N
H
N
N
H
H
L1
H
L3
L2
Ph
DMAP
N
H
Imd
N
N
H
N
H2N
H2N
pyridine
NMM
NMM
NMM
H
H
L4
L5
L6
CuCl2ꢀ2H2O
THF
THF
Entry
Ligand
Yieldb
48
eec (%)
Cu(OAc)2ꢀH2O
a
Reactions were carried out on
a 0.5 mmol scale of 1a with 10 equiv of
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
87
ꢁ31
73
nitromethane in a mixture of 2.0 mL of solvent, 5 mol % of ligand L1 and 5 mol % of
copper salts in the presence of 1.0 equiv of base at 4 °C for 12 h.
45
36
43
43
50
b
Isolated yield (%).
Determined by chiral HPLC analysis.
Im = Imidazole.
ꢁ36
c
74
d
80
a
Reactions were carried out on a 0.5 mmol scale of 1a with 10 equiv of nitro-
methane in a mixture of 2.0 mL of THF, 5 mol % of ligand and 5 mol % of CuCl2ꢀ2H2O
were added, while the ee value remained the same. A further in-
crease in the amount of nitromethane caused a decrease in both
the ee value and the yield.
in the presence of 1.0 equiv of DIPEA at 4 °C for 10 h.
b
Isolated yield, approx. 50% of 1a was recovered.
c
Ee was determined by HPLC analysis using Chiracel AD-H as a column.
Table 3
Reagent loading screeninga
used instead, the opposite (R)-configuration product was obtained
with much lower enantioselectivity (entry 2). A similar change in
stereoselectivity was also observed in the cases of L3 and L4 de-
rived from (+)-(1S,2S,5R)-menthylamine, but their enantioselectiv-
ities were relatively poor. Ligands L5 and L6 also gave inferior
results (entries 5 and 6).
Further optimization was carried out by assessing copper salts,
bases, and solvents. Among the copper salts listed in Table 2,
CuCl2ꢀ2H2O, Cu(OAc)2ꢀH2O, and CuCl gave high ee values with little
differences in the yields (entries 1, 2, and 6). For the best enanti-
oselectivity, CuCl was chosen to estimate further the reaction sol-
vents. In nitromethane, an improved yield but much lower ee value
was observed in comparison to that in THF (entry 10). In view of
the enantioselectivity, THF proved to be the most suitable solvent
for this reaction (entries 1 and 9–13).
Next, various bases were tested by utilizing a CuCl/L1 catalytic
system in THF at 4 °C (entries 14–18). A satisfactory enantioselec-
tivity was achieved when N-methylmorpholine (NMM) was used
as the base additive, with an ee value of up to 94% being achieved
(entry 18). Thus, NMM was finally chosen as the additive to further
optimize the reaction conditions. Since nearly the same ee values
were observed previously in the cases of CuCl2ꢀ2H2O, Cu(OAc)2ꢀ
H2O, and CuCl (entries 1, 2, and 6), we examined the copper salts
again by changing DIPEA into NMM (entries 19 and 20). As a con-
sequence, CuCl2ꢀ2H2O gave the highest ee (96%), while Cu(OAc)2ꢀ
H2O provided the highest yield up to 80% with 95% ee. In addition
to the nitroaldol product, a certain amount of dehydrated side-
product nitroolefin was obtained during the reaction. In order to
avoid the dehydration, we tried to perform the reactions at a lower
temperature (Table 3, entries 1–3). At ꢁ20 °C, 3a was afforded in a
88% yield with 99% ee using Cu(OAc)2ꢀH2O (entry 3). The effect of
the amount of nitromethane was also evaluated (entries 4 and
5). The highest yield was achieved when 20 equiv of nitromethane
Entry
Copper salt
MeNO2 (equiv)
Yieldb (%)
eec (%)
1
2
3
4
5
CuCl
10
10
10
20
40
58
62
88
94
85
97
98
99
99
94
CuCl2ꢀ2H2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
a
Reactions were carried out on a 0.5 mmol scale of 1a in a mixture of 2.0 mL of
THF, 5 mol % of ligand L1 and 5 mol % of copper salt in the presence of 1.0 equiv of
NMM at ꢁ20 °C for 48 h.
b
Isolated yield (%).
c
Determined by chiral HPLC analysis.
On the basis of the optimized reaction parameters, the scope of
haloenals was explored by treatment with 20 equiv of nitrometh-
ane in the presence of 5 mol % of L1/Cu(OAc)2ꢀH2O and 1.0 equiv
of NMM in THF at ꢁ20 °C (Table 4). With the cyclic haloenals
1a–f, the reaction provided the expected products 3a–f in high to
excellent yields and with excellent enantioselectivities. In most
cases, the ee values were above 95%, regardless of the size of the
cyclic haloenals and the type of halo atoms at the b-position. With
regards to the acyclic haloenals, the ee values varied remarkably
with different substituent groups. Haloenals 1g and 1h gave much
lower ee values. In addition, heteroaromatic haloenals 1k was also
tolerated, giving the desired product with good results.
a-Haloe-
nals 1i and 1j were also studied under the same conditions and dif-
ferent results were observed. It seems that the substituent group
on the carbon near to the aldehyde group significantly influences
the enantioselectivity of this reaction. Haloenals 1l–n with bulky
groups at the
a-position provided the nitroaldol products 3l–n
with more than 95% ee values, albeit with a decrease in yield.
To account for the stereochemical outcome of this reaction, the
absolute configuration of 4e (solid) derived from 3e (liquid) was
confirmed by X-ray crystal analysis as shown in Figure 1. These

126
L. Gu et al. / Tetrahedron: Asymmetry 23 (2012) 124–129
Table 4
Enantioselective Henry reaction of aldehydes with nitromethanea,b,c,d
OH
5 mmol% ligand L1 +
5 mmol% Cu(OAc)2*H2O
NO2
CH3NO2
RCHO
+
R
4-methylmorpholine
(1.0 equiv),
2
3
1
THF, -20 °C
OH
OH
OH
Cl
NO2
NO2
NO2
Cl
Cl
3a, 94% yield, 99% ee
3b, 92% yield, 99% ee
3c, 86% yield, 96% ee
OH
OH
OH
NO2
NO2
NO2
Br
Br
Br
3f, 84% yield, 99% ee
3d, 80% yield, 97% ee
3e, 93% yield, 97% ee
Cl
OH
Cl
OH
Br
NO2
NO2
NO2
HO
3g, 82% yield, 86% ee
3i, 78% yield, 93% ee
3h, 72% yield, 82% ee
F
Cl
Cl
S
NO2
F
HO
NO2
HO
NO2
HO
3j, 84% yield, 76% ee
3k, 90% yield, 88% ee
3l, 73% yield, 98% ee
Cl
Cl
Cl
NO2
Cl
NO2
HO
3m, 68% yield, 97% ee
HO
3n, 65% yield, 97% ee
a
Reactions were carried out on a 0.5 mmol scale of haloenals with 20 equiv of nitromethane in a mixture of 2.0 mL of THF, 5 mol % of
ligand L1 and 5 mol % of Cu(OAc)2ꢀH2O in the presence of 1.0 equiv of 4-methylmorpholine at ꢁ20 °C.
b
Isolated yield.
Determined by chiral HPLC analysis.
The reaction time for 1a–f was 48 h, for 1h–n was 96 h.
c
d
OH
OH
1) Zn/HCl
NH2
NO2
2) recrystallization in CH2Cl2
Br
Br
(S)-4e
(S)-3e, 97% ee
Scheme 2. The derivative of (S)-3e.
3. Conclusion
In conclusion, we have developed a highly chemoselective and
enantioselective nitroaldol reaction between - or b-haloenals
a
and nitromethane by treatment of 5 mol % of L1–Cu(OAc)2ꢀH2O un-
der mild reaction conditions. The reaction not only provides a wide
variety of new b-nitroalcohol compounds in high to excellent
yields (up to 94%) with excellent enantioselectivities (up to 99%
ee), but also provides a new method to construct functionalized
allylic alcohols. Further applications of this methodology are cur-
rently underway in our laboratory.
Figure 1. X-ray structure analysis of (S)-4e.12
results are in agreement with our previous observations,3d which
revealed that the nitronate would attack the aldehyde from the
re face when L1 was used. Therefore, the absolute configuration
of 4e was assigned as (S) (Scheme 2).

L. Gu et al. / Tetrahedron: Asymmetry 23 (2012) 124–129
127
33.81, 68.47, 77.62, 130.09, 130.38. IR (film): 3461, 2938, 2886,
2863, 1718, 1658, 1556, 1509, 1434, 1378, 1058, 825, 668. HRMS
(EI, m/z): calcd for C8H12NO3Cl (M+), 205.0506, found 205.0503;
HPLC (Chiralpak AD-H, Hexane–i-PrOH = 90: 10, flow rate:
0.5 mL/min, k = 210 nm), tminor = 16.3, tmajor = 18.4, 99% ee.
4. Experimental
4.1. General
Solvents were purified according to standard procedures and
distilled before use. Reagents and starting materials purchased
from commercial suppliers were used without further purification
unless otherwise stated. For thin-layer chromatography (TLC),
silica gel plates GF254 were used and compounds were visualized
by irradiation with UV light, I2, or by treatment with basic KMnO4.
NMR spectra were measured on a 400 MHz spectrometer. 1H NMR
chemical shifts were reported in ppm with tetramethylsilane (TMS,
d 0 ppm) as the internal standard. Data for 1H NMR are reported as
follows: chemical shift (ppm), and multiplicity (s = singlet, d = dou-
blet, t = triplet, q = quartet, m = multiplet, br = broad). Data for 13C
NMR are reported as ppm. High resolution mass spectral analyses
(HRMS) were measured using EI, ESI ionization. High performance
liquid chromatography (HPLC) analysis was performed on chiral
columns. Optical rotations were measured in the solvent indicated.
Flash chromatography was carried out on silica gel 200–300 mesh.
The molecular ion peak of acyclic b-hydroxy nitroalkanes 3g–n
could not be detected through the HRMS analyses, so two of them,
3g, 3k, were reduced by Zn/HCl to provide the b-hydroxy amin-
oalkanes 4g, 4k, which were detected by HRMS.
4.6. (S)-1-(2-Chlorocyclopent-1-enyl)-2-nitroethanol 3b
½
a 2D5
ꢃ
¼ ꢁ12:9 (c 0.9, CHCl3); Colorless oil. 1H NMR (CDCl3
400 MHz): d 1.92–2.09 (m, 2H), 2.29–2.42 (m, 1H), 2.61 (dd,
J = 10.8, 4.6 Hz, 3H), 2.93 (s, 1H), 4.41 (dd, J = 13.1, 3.4 Hz, 1H),
4.54 (dd, J = 13.1, 9.5 Hz, 1H), 5.33 (dd, J = 9.4, 3.3 Hz, 1H). 13C
NMR (CDCl3 100 MHz): d 20.58, 29.71, 37.97, 65.50, 77.77, 130.44,
133.44. IR (film): 3443, 2958, 2925, 2855, 1657, 1621, 1556, 1441,
1379, 1071, 888, 682. HRMS (EI, m/z): calcd for C7H10NO3Cl (M+),
191.0349, found 191.0345; HPLC (Chiralpak AD-H, Hexane–i-
PrOH = 90:10, flow rate: 0.5 mL/min, k = 210 nm), tminor = 17.6,
tmajor = 19.6, 99% ee.
4.7. (S)-1-(2-Chlorocyclohept-1-enyl)-2-nitroethanol 3c
½
a 2D5
ꢃ
¼ ꢁ15:1 (c 1.1, CHCl3); Colorless oil. 1H NMR (CDCl3
400 MHz): d 1.68–1.45 (m, 4H), 1.81–1.69 (m, 2H), 2.41–2.24 (m,
2H), 2.62 (dd, J = 10.9, 3.5 Hz, 2H), 2.76 (s, 1H), 4.38 (qd, J = 12.9,
6.6 Hz, 2H), 5.52 (dd, J = 9.3, 3.8 Hz, 1H). 13C NMR (CDCl3
100 MHz): d 24.89, 26.24, 31.34, 38.97, 69.39, 77.48, 134.49,
134.82. IR (film): 3440, 2926, 2853, 1649, 1613, 1556, 1510,
1446, 1378, 1074, 892, 740. HRMS (EI, m/z): calcd for C9H14NO3Cl
(M+), 219.0662, found 219.0658; HPLC (Chiralpak AD-H, Hexane–
i-PrOH = 90:10, flow rate: 0.5 mL/min, k = 210 nm), tminor = 16.7,
tmajor = 21.3, 96% ee.
4.2. Preparation of substrates 1a–n
A variety of haloenals were synthesized according to the litera-
ture; 1a–c,13 1d–f,14 1g–h,15 1i,16 1j,17 1k–n.15 The 1H and 13C NMR
of the products were in agreement with the literature data.
4.3. Procedure for the catalytic enantioselective Henry reaction
of haloenals with nitromethane 3
4.8. (S)-1-(2-Bromocyclopent-1-enyl)-2-nitroethanol 3d
½
a 2D5
ꢃ
¼ ꢁ11:2 (c 1.0, CHCl3); Pale yellow oil. 1H NMR (CDCl3
Ligand L1 (6.0 mg, 0.0250 mmol, 5.0 mol %) and Cu(OAc)2ꢀH2O
(5.0 mg, 0.0250 mmol, 5.0 mol %) were added to a test tube con-
taining absolute THF (2 mL). The solution was stirred for 1 h to give
a blue solution at room temperature. To the resulting solution,
aldehyde 1 (0.5 mmol), nitromethane (5 mmol, 20 equiv), and N-
methylmorpholine (54 lL, 0.5 mmol, 1.0 equiv) were added suc-
cessively and the tube was introduced in a bath at the reaction
temperature without special precautions to exclude moisture or
air. After the indicated time, 180 lL of 3 M HCl aqueous were
400 MHz): d 1.89–2.06 (m, 2H), 2.22–2.36 (m, 1H), 2.56 (dtd,
J = 7.9, 6.0, 2.6 Hz, 1H), 2.94 (br, 1H), 2.62–2.74 (m, 2H), 4.41
(ddd, J = 13.1, 3.3, 1.4 Hz, 1H), 4.53 (ddd, J = 13.0, 9.5, 1.0 Hz, 1H),
5.30 (d, J = 9.4 Hz, 1H). 13C NMR (CDCl3 100 MHz): d 21.47, 30.18,
40.16, 67.01, 77.69, 120.29, 137.02. IR (film): 3442, 2958, 2926,
2855, 1657, 1621, 1557, 1441, 1380, 1071, 889. HRMS (EI, m/z):
calcd for C7H10NO3Br (M+), 234.9884, found 234.9879; HPLC (Chir-
alpak AD-H, Hexane–i-PrOH = 90:10, flow rate: 0.5 mL/min,
k = 210 nm), tminor = 17.8, tmajor = 19.1, 97% ee.
added, and the mixture was concentrated and purified directly
by column chromatography on silica gel, eluting with petroleum
ether and ethyl acetate to afford the corresponding product.
4.9. (S)-1-(2-Bromocyclohex-1-enyl)-2-nitroethanol 3e
½
a 2D5
ꢃ
¼ ꢁ7:15 (c 1.0, CHCl3); Colorless oil. 1H NMR (CDCl3
4.4. Procedure for the reduction of b-hydroxy nitroalkanes with
Zn/HCl 4
400 MHz): d 1.80–1.58 (m, 4H), 2.10–1.93 (m, 1H), 2.43–2.29 (m,
1H), 2.61–2.45 (m, 2H), 2.81 (br, 1H), 4.46 (d, J = 6.1 Hz, 2H), 5.47
(t, J = 6.3 Hz, 1H). 13C NMR (CDCl3 100 MHz): d 24.32, 25.61,
21.77 36.62, 71.33, 77.56, 122.60, 132.72. IR (film): 3446, 2938,
2884, 2862, 1653, 1616, 1556, 1514, 1377, 1074, 753, 664. HRMS
(EI, m/z): calcd for C8H12NO3Br (M+), 249.0001, found 248.9997;
HPLC (Chiralpak AD-H, Hexane–i-PrOH = 90:10, flow rate: 0.5 mL/
min, k = 210 nm), tminor = 33.8, tmajor = 37.0, 97% ee.
Zinc powder (314 mg, 4.78 mmol) was added to a solution of 3
(0.100 mmol) in ethanol/H2O (3.4:0.8 mL) followed by concen-
trated HCl (0.66 mL). The mixture was stirred at room temperature
for 4 h. Aqueous saturated NaHCO3 (10 mL) and water (10 mL)
were added, and the mixture was extracted with EtOAc
(3 ꢂ 25 mL). The organic phase was dried (MgSO4), concentrated
under reduced pressure, and the residue was concentrated and
purified directly by column chromatography on silica gel, eluting
with CH2Cl2 and CH3OH to afford the corresponding product.
4.10. (S)-1-(2-Bromocyclohept-1-enyl)-2-nitroethanol 3f
½
a 2D5
ꢃ
¼ ꢁ12:4 (c 1.2, CHCl3); Pale yellow oil. 1H NMR (CDCl3
400 MHz): d 1.39–1.63 (m, 4H), 1.65–1.85 (m, 2H), 2.21–2.45 (m,
2H), 2.72 (dd, J = 10.9, 3.5 Hz, 2H), 2.76 (s, 1H), 4.48 (qd, J = 12.9,
6.6 Hz, 2H), 5.55 (dd, J = 9.3, 3.8 Hz, 1H). 13C NMR (CDCl3 100 MHz):
d 24.96, 26.04, 31.37, 41.45, 72.49, 77.37, 126.17, 137.92. IR (film):
3443, 2957, 2923, 2852, 1556, 1438, 1379, 1067, 886, 675. HRMS
(EI, m/z): calcd for C9H14NO3Br (M+), 263.0157, found 263.0156; HPLC
4.5. (S)-1-(2-Chlorocyclohex-1-enyl)-2-nitroethanol 3a
½
a 2D5
ꢃ
¼ ꢁ8:7 (c 1.1, CHCl3); Colorless oil. 1H NMR (CDCl3
400 MHz): d 1.68 (m, 4H), 2.00 (dd, J = 15.6, 2.4 Hz, 1H), 2.29–
2.48 (m, 3H), 2.71 (s, 1H), 4.33–4.64 (m, 2H), 5.53 (dd, J = 9.0,
3.7 Hz, 1H). 13C NMR (CDCl3 100 MHz): d 21.72 23.37, 24.65,

128
L. Gu et al. / Tetrahedron: Asymmetry 23 (2012) 124–129
(Chiralpak AD-H, Hexane–i-PrOH = 90:10, flow rate: 0.5 mL/min,
k = 210 nm), tminor = 17.0, tmajor = 20.8, 99% ee.
1H), 4.54 (dd, J = 13.0, 9.5 Hz, 1H), 5.02 (dd, J = 9.5, 3.3 Hz, 1H),
7.21–7.32 (m, 2H), 7.35–7.46 (m, 3H). 13C NMR (CDCl3 100 MHz): d
14.02, 68.58, 78.33, 128.34, 128.46, 128.76, 128.90, 129.11, 130.67,
133.27, 137.30. IR (film): 3402, 3045, 2996, 2934, 1615, 1567,
1536, 1489, 1379, 1108, 745. HPLC (Chiralpak AS-H, Hexane–i-
PrOH = 90:10, flow rate: 0.5 mL/min, k = 210 nm), tmajor = 23.6,
tminor = 41.7, 98% ee.
4.11. (S,Z)-4-Bhloro-1-nitro-4-phenylbut-3-en-2-ol Z-3g
½
a 2D5
ꢃ
¼ ꢁ22:8 (c 0.9, CHCl3); Yellow oil. 1H NMR (CDCl3
400 MHz): d 2.87 (br, 1H) 4.58 (qd, J = 13.4, 5.9 Hz, 2H), 5.46
(ddd, J = 8.4, 7.3, 3.3 Hz, 1H), 6.15 (d, J = 7.3 Hz, 1H), 7.35–7.45
(m, 3H), 7.54–7.66 (m, 2H). 13C NMR (CDCl3 100 MHz): d 67.38,
78.15, 123.51, 126.54, 128.52, 129.70, 136.14, 136.51. IR (film):
3395, 3060, 1636, 1554, 1513, 1493, 1446, 1337, 1076, 762, 692.
HPLC (Chiralpak AD-H, Hexane–i-PrOH = 90:10, flow rate: 0.5 mL/
min, k = 210 nm), tmajor = 27.0, tminor = 29.7, 86% ee.
4.17. (S,Z)-4-Chloro-3-(chloromethyl)-1-nitro-4-phenylbut-3-
en-2-ol Z-3m
½
a 2D5
ꢃ
¼ ꢁ141:15 (c 1.0, CHCl3); Yellow oil. 1H NMR (CDCl3
400 MHz): d 2.95 (d, J = 3.4 Hz, 1H), 4.43–4.46 (m, 1H), 4.47 (d,
J = 2.5 Hz, 1H), 4.58 (d, J = 11.3 Hz, 1H), 4.80 (dd, J = 13.7, 10.2 Hz,
1H), 5.12 (d, J = 10.2 Hz, 1H), 7.30–7.35 (m, 2H), 7.42–7.46 (m,
4H). 13C NMR (CDCl3 100 MHz): d 39.00, 67.87, 78.57, 128.06,
128.92, 129.89, 131.23, 136.14, 139.51. IR (film): 3395, 3061,
2924, 1595, 1556, 1516, 1489, 1378, 1077, 767, 700. HPLC (Chir-
alpak AS-H, Hexane–i-PrOH = 90:10, flow rate: 0.5 mL/min,
k = 210 nm), tmajor = 27.0, tminor = 30.4, 97% ee.
4.12. (S,Z)-4-Chloro-1-nitro-4-p-tolylbut-3-en-2-ol Z-3h
½
a 2D5
ꢃ
¼ ꢁ25:6 (c 0.9, CHCl3); Yellow oil. 1H NMR (CDCl3
400 MHz): d 2.35 (s, 3H), 3.13 (br, 1H), 4.54 (dd, J = 11.3, 5.9 Hz,
2H), 5.33–5.55 (m, 1H), 6.10 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 8.0 Hz,
2H), 7.46 (d, J = 8.2 Hz, 2H). 13C NMR (CDCl3 100 MHz): d 21.09,
67.38, 78.23, 122.51, 126.38, 129.13, 133.31, 136.47, 139.86. IR
(film): 3391, 3094, 2923, 1610, 1554, 1509, 1417, 1335, 1077,
816. HPLC (Chiralpak AS-H, Hexane–i-PrOH = 90:10, flow rate:
0.5 mL/min, k = 210 nm), tmajor = 29.7, tminor = 35.6, 82% ee.
4.18. (S,Z)-4-Chloro-3-(chloromethyl)-1-nitro-4-p-tolylbut-3-
en-2-ol Z-3n
½
a 2D5
ꢃ
¼ ꢁ206:3 (c 1.2, CHCl3); Yellow oil; 1H NMR (CDCl3
4.13. (R,E)-3-Bromo-1-nitro-4-phenylbut-3-en-2-ol E-3i
400 MHz): d 2.95 (d, J = 3.4 Hz, 3H), 4.44 (dd, J = 6.8, 4.3 Hz, 1H),
4.46–4.51 (m, 2H), 4.58 (dd, J = 11.3, 0.4 Hz, 1H), 4.80 (dd,
J = 13.7, 10.2 Hz, 1H), 5.12 (d, J = 10.2 Hz, 1H), 7.21–7.26 (m, 4H).
13C NMR (CD3COCD3 100 MHz): d 14.92, 39.13, 40.38, 67.83,
78.50, 125.74, 128.46, 131.03, 132.16, 139.26, 141.49. IR (film):
3438, 3033, 2956, 2922, 2852, 1630, 1591, 1552, 1489, 1422,
1380, 1088, 820. HPLC (Chiralpak AS-H, Hexane–i-PrOH = 90:10,
flow rate: 0.5 mL/min, k = 210 nm), tmajor = 46.0, tminor = 71.9, 97%
ee.
½
a 2D5
ꢃ
¼ þ19:8 (c 1.0, CHCl3); Pale yellow oil. 1H NMR (CDCl3
400 MHz): d 3.23 (s, 1H), 4.61 (dd, J = 13.1, 8.8 Hz, 1H), 4.72 (dd,
J = 13.1, 3.4 Hz, 1H), 5.08 (d, J = 7.5 Hz, 1H), 7.31–7.42 (m, 3H),
7.56–7.65 (m, 2H). 13C NMR (CDCl3 100 MHz): d 74.08, 78.91,
121.54, 128.24, 128.76, 129.04, 130.83, 133.98. IR (film): 3049,
3057, 2966, 1636, 1598, 1555, 1493, 1446, 1378, 1076, 756, 692,
522. HPLC (Chiralpak OD-H, Hexane–i-PrOH = 90:10, flow rate:
0.5 mL/min, k = 210 nm), tmajor = 38.9, tminor = 33.6, 93% ee.
4.19. (S)-2-Amino-1-(2-bromocyclohex-1-enyl)ethanol 4e
4.14. (R,E)-3-Fluoro-4-(4-fluorophenyl)-1-nitrobut-3-en-2-ol E-3j
½
a 2D5
ꢃ
¼ þ14:05 (c 0.23, CHCl3); White solid, mp: 114–116 °C; 1H
½
a 2D5
ꢃ
¼ þ33:6 (c 1.0, CHCl3); Yellow oil. 1H NMR (CDCl3
NMR (CD3COCD3 400 MHz): d 1.59–1.78 (m, 4H), 2.01–2.13 (m,
4H), 2.20–2.34 (m, 1H), 2.47 (dt, J = 6.5, 2.7 Hz, 2H), 2.76 (dd,
J = 11.9, 7.3 Hz, 1H), 3.32 (dd, J = 11.9, 6.8 Hz, 1H), 4.78 (t,
J = 7.0 Hz, 1H). 13C NMR (CD3COCD3 100 MHz): d22.82, 25.43,
26.74, 37.56, 50.81, 79.83, 119.51, 137.41. HRMS (ESI, m/z): calcd
for C8H15NOBr ([M+H]+), 220.0332, found 220.0332.
400 MHz): d 3.26 (s, 1H), 4.66 (qd, J = 13.5, 6.0 Hz, 2H), 4.95–5.13
(m, 1H), 5.97 (d, J = 39.4 Hz, 1H), 6.99–7.10 (m, 2H), 7.43–7.53
(m, 2H). 13C NMR (CDCl3 100 MHz): d 67.65, 67.98, 77.57, 107.55,
107.60, 115.49, 115.71, 127.78, 127.81, 127.84, 130.57, 130.65,
130.73, 153.24, 153.26, 155.89, 155.91, 160.95, 160.99, 163.42,
163.46. 19F NMR (376 MHz, CDCl3):
d
ꢁ119.72, ꢁ119.70,
ꢁ119.62, ꢁ119.59, ꢁ112.59, ꢁ112.57. IR (film): 3080, 3063,
2975, 1646, 1500, 1555, 1473, 1461, 1378, 1243, 1150, 1110,
756, 682. HPLC (Chiralpak AD-H, Hexane–i-PrOH = 90:10, flow
rate: 0.5 mL/min, k = 210 nm), tmajor = 41.0, tminor = 44.9, 76% ee.
4.20. (Z)-1-Amino-4-chloro-4-phenylbut-3-en-2-ol Z-4g
Thick oil; 1H NMR (CDCl3 400 MHz): d 2.62 (br, 3H), 2.80 (dd,
J = 12.8, 8.1 Hz, 1H), 2.98 (d, J = 12.8 Hz, 1H), 4.71 (td, J = 7.8,
3.8 Hz, 1H), 6.20 (d, J = 7.5 Hz, 1H), 7.33–7.38 (m, 3H), 7.60 (m,
2H). 13C NMR (CDCl3 100 MHz): d 46.15, 70.55, 126.51, 128.09,
128.37, 128.99, 134.21, 137.23. HRMS (ESI, m/z): calcd for
4.15. (S,E)-4-Chloro-1-nitro-4-(thiophen-2-yl)but-3-en-2-ol E-3k
½
a 2D5
ꢃ
¼ ꢁ30:35 (c 1.1, CHCl3); Red oil. 1H NMR (CDCl3 400 MHz):
d 2.98 (s, 1H), 4.38–4.78 (m, 2H), 5.42 (td, J = 7.7, 4.0 Hz, 1H), 6.11
C
10H13NOCl ([M+H]+), 198.0680, found 198.0678.
(d, J = 7.5 Hz, 1H), 7.00 (dd, J = 5.0, 3.8 Hz, 1H), 7.20–7.42 (m, 2H).
13C NMR (CDCl3 100 MHz):
d 67.02, 78.20, 121.28, 127.20,
4.21. (E)-1-Amino-4-chloro-4-(thiophen-2-yl)but-3-en-2-ol E-4k
127.33, 127.56, 129.76, 139.78. IR (film): 3405, 3070, 2956, 1611,
1555, 1498, 1417, 1331, 1081, 814, 712. HPLC (Chiralpak AS-H,
Hexane–i-PrOH = 90:10, flow rate: 0.5 mL/min, k = 210 nm),
tmajor = 37.9, tminor = 47.3, 88% ee.
Thick red oil; 1H NMR (CDCl3 400 MHz): d 2.79 (dd, J = 12.9,
8.2 Hz, 1H), 2.90 (dd, J = 12.9, 3.6 Hz, 1H), 3.66 (br, 3H), 4.67 (td,
J = 7.9, 3.9 Hz, 1H), 6.15 (d, J = 7.7 Hz, 1H), 6.93 (ddd, J = 5.2, 2.7,
1.1 Hz, 1H), 7.17–7.21 (m, 1H), 7.23 (dd, J = 2.4, 1.2 Hz, 1H). 13C
NMR (CDCl3 100 MHz): d 45.95 69.68, 126.14, 126.23, 126.44,
127.38, 127.46, 140.97. HRMS (ESI, m/z): calcd for C8H11NOSCl
([M+H]+), 204.0244, found 204.0239;
4.16. (S,E)-4-Chloro-3-methyl-1-nitro-4-phenylbut-3-en-2-ol E-3l
½
a 2D5
ꢃ
¼ ꢁ50:05 (c 1.0, CHCl3); Yellow oil. 1H NMR (CDCl3
400 MHz): d 2.56 (br, 1H), 2.01 (s, 3H), 4.34 (dd, J = 13.0, 3.4 Hz,

L. Gu et al. / Tetrahedron: Asymmetry 23 (2012) 124–129
129
Chem. 2010, 75, 1313–1316; (l) Yang, W.; Liu, H.; Du, D.-M. Org. Biomol. Chem.
2010, 8, 2956–2960; (m) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw,
J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692–12693; (n) Trost, B. M.;
Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861–863; (o) Sasai, H.; Suzuki, T.;
Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418–4420.
4. (a) Takahashi, H.; Yoshida, K.; Yanagisawa, A. J. Org. Chem. 2009, 74, 3632–
3640; (b) Samanta, K.; Kar, G. K.; Sarkar, A. K. Tetrahedron Lett. 2008, 49, 1461–
1464; (c) Some, S.; Dutta, B.; Ray, J. K. Tetrahedron Lett. 2006, 47, 1221–1224;
(d) Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes, M. O. Org. Lett.
2004, 6, 2471–2474; (e) Cho, C. S.; Lim, D. K.; Heo, N. H.; Kim, T.; Shim, S. C.
Chem. Commun. 2004, 104–105.
Acknowledgments
This work was financially supported by grants from National
Science Foundation of China (Nos. 21172082 and 20872041). The
Center of Analysis and Testing of Huazhong University of Science
and Technology is gratefully acknowledged for characterization
of the new compounds.
References
5. (a) Mal, S. K.; Ray, D.; Ray, J. K. Synlett 2005, 2135–2140; (b) Mal, S. K.; Ray, D.;
Ray, J. K. Tetrahedron Lett. 2004, 45, 277–279.
1. (a) Bandini, M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici, C. Chem.
Commun. 2007, 616–618; (b) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org.
Lett. 2002, 4, 2621–2623; (c) Ono, N. The Nitro Group in Organic Synthesis;
Wiley-VCH: New York, 2001; (d) Shibasaki, M.; Gröer, H. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, 1999; Vol. III, pp 1075–1090; (e) Rosini, G. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 2, pp
321–340.
2. For recent reviews on the catalytic asymmetric Henry reaction, see: (a) Palomo,
C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561–2574; (b) Boruwa, J.;
Gogoi, N.; Saikia, P. P.; Barua, N. Tetrahedron: Asymmetry 2006, 17, 3315–3326;
(c) Palomo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442–
5444.
3. For recent examples of asymmetric Henry reactions: (a) Zhou, Y.; Gong, Y. Eur. J.
Org. Chem. 2011, 76, 6092–6099; (b) Maggi, R.; Lanari, D.; Oro, C.; Sartori, G.;
Vaccaro, L. Eur. J. Org. Chem. 2011, 5551–5554; (c) Gualandi, A.; Cerisoli, L.;
Stoeckli-Evans, H.; Savoia, D. J. Org. Chem. 2011, 76, 3399–3408; (d) Zhou, Y.;
Dong, J.; Zhang, F.; Gong, Y. J. Org. Chem. 2011, 76, 588–600; (e) Dhahagani, K.;
Rajesh, J.; Kannan, R.; Rajagopal, G. Tetrahedron: Asymmetry 2011, 22, 857–865;
(f) Reddy, B. V. S.; Reddy, S. M.; Manisha, S.; Madan, C. Tetrahedron: Asymmetry
2011, 22, 530–535; (g) Guo, Z.-L.; Zhong, S.; Li, Y.-B.; Lu, G. Tetrahedron:
Asymmetry 2011, 22, 238–245; (h) Wei, Y.; Yao, L.; Zhang, B.; He, W.; Zhang, S.
Tetrahedron 2011, 67, 8552–8558; (i) Xin, D.; Ma, Y.; He, F. Tetrahedron:
Asymmetry 2010, 21, 333–338; (j) Steurer, M.; Bolm, C. J. Org. Chem. 2010, 75,
3301–3310; (k) Noole, A.; Lippur, K.; Metsala, A.; Lopp, M.; Kanger, T. J. Org.
6. (a) Yao, W.; Wu, Y.; Wang, G.; Zhang, Y.; Ma, C. Angew. Chem., Int. Ed. 2009, 48,
9713–9716; (b) Zhang, J.; Gong, Y. Org. Lett. 2011, 13, 176–179.
7. Yasmin, N.; Ray, J. K. Synlett 2010, 0924–0930.
8. (a) Shimizu, M.; Goto, H.; Hayakawa, R. Org. Lett. 2002, 2, 4097–4099; (b) Cho,
C. S.; Kim, J. U.; Choi, H. J. J. Organomet. Chem. 2008, 693, 3677–3680.
9. Cho, C. S.; Kima, H. B.; Ren, W. X.; Yoon, N. S. Appl. Organomet. Chem. 2010, 24,
817–820.
10. For seminal studies on the DBU-prompted Morita-Baylis–Hillman reaction,
see: (a) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311–2312; For a
review on ammonium enolates, see: (b) Gaunt, M. J.; Johansson, C. C. C. Chem.
Rev. 2007, 107, 5596–5605.
11. (a) Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449–455; (b) Sousa, S. E.;
O’Brien, P.; Pilgram, C. D. Tetrahedron Lett. 2001, 42, 8081–8083; (c) Lu, X.; Zhu,
G.; Wang, Z. Synlett 1998, 115–121; (d) Corey, E. J.; Guzman-Perez, A.;
Lazerwith, S. E. J. Am. Chem. Soc. 1997, 119, 11769–11776; (e) Kazmaier, U.;
Schneider, C. Synlett 1996, 975–977.
12. The data for X-ray crystal analysis of (S)-4e has been deposited at the CCDC
(No. 853950).
13. Gelalcha, F. G.; Schulze, B. J. Org. Chem. 2002, 67, 8400–8406.
14. Jana, R.; Paul, S.; Biswas, A.; Ray, J. K. Tetrahedron Lett. 2010, 51, 273–276.
15. Shaffer, A. R.; Schmidt, J. A. R. Chem. Eur. J. 2009, 15, 2662–2673.
16. Bovonsombat, P.; Rujiwarangkul, R.; Bowornkiengkai, T.; Leykajarakul, J.
Tetrahedron Lett. 2007, 48, 8607–8610.
17. Luo, F.; Wang, P.; Gong, Y. Tetrahedron Lett. 2010, 51, 1693–1695.