The synthesis of chiral tridentate ligands from L-proline and their application in the copper(II)-catalyzed enantioselective Henry reaction

Article abstract of DOI:10.1016/j.tetasy.2017.05.013

A series of chiral tridentate ligands derived from readily available enantiopure L-proline were designed and synthesized. The ligands together with Cu(OAc)₂ were successfully used in asymmetric Henry reactions. Various structurally divergent aldehydes and nitromethane were converted into versatile β-nitro alcohols in MeOH at room temperature with very good yields (up to 85%) and enantioselectivities (up to 86%).

Full text of DOI:10.1016/j.tetasy.2017.05.013

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The synthesis of chiral tridentate ligands from L-proline
and their application in the copper(II)-catalyzed enantioselective
Henry reaction
a,
Daqian Xu a,b, Qiangsheng Sun b, Zhengjun Quan a, Wei Sun b, , Xicun Wang
⇑
⇑
a College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, Gansu, China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, and Suzhou Research Center of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, Gansu, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral tridentate ligands derived from readily available enantiopure L-proline were designed
Received 7 April 2017
Revised 15 May 2017
Accepted 23 May 2017
Available online xxxx
and synthesized. The ligands together with Cu(OAc)2 were successfully used in asymmetric Henry reac-
tions. Various structurally divergent aldehydes and nitromethane were converted into versatile b-nitro
alcohols in MeOH at room temperature with very good yields (up to 85%) and enantioselectivities (up
to 86%).
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
previous works.23 Herein we have design and prepared a series
of chiral tridentate ligands derived from readily available L-proline
The Henry reaction is one of the most important CAC bond
forming reactions producing b-nitro alcohols.1 Since it is highly
atom economic and the resultant products can be conveniently
transformed into aminoalcohol, diamines by reduction or carbonyl
compounds by Nef reaction,2,3 the Henry reaction has received
much attention due to its diverse applications in synthetic chem-
istry.4 It is not surprising that considerable effort has been devoted
to the development of the catalytic asymmetric Henry reaction
over the past few decades. Shibasaki et al. developed a series of
bimetallic catalyst for the enantioselective Henry reaction.5–8 Since
then, a great number of metal9,10 based catalysts as well as
organocatalysts11,12 have been successfully established in the
development of asymmetric Henry reactions. Various chiral
ligands, such as Salen,13 iminopyridine,14 oxazoline,15 amino alco-
hol,16 Schiff,17 sulfonylamide,18 pyrrole,19 imidazole,20 and nitric
oxide21 are involved. In spite of these successful achievements,
the development of highly effective catalysts for catalytic asym-
metric Henry reactions is still of great interest.
and evaluated these ligands in copper-catalyzed asymmetric Henry
reactions.
Our group has focused on the development of chiral metal com-
plexes derived from an inexpensive rigid skeleton over the past
decade and these catalysts have been successfully used in many
reactions, such as epoxidation.24 Encouraged by these results, we
envisioned that these in situ generated chiral complexes bearing
Lewis acid and Brønsted base would promote the Henry reaction
efficiently under mild conditions. The chiral ligands were synthe-
sized by introduction of benzimidazole into L-proline followed by
alkylation or reductive amination as shown in Scheme 1. Different
large groups were modified through reductive amination using sal-
icylaldehydes for the stereoselectivity of the asymmetric Henry
reaction.
2. Results and discussion
Initially, we studied the reactivities and selectivities of the tri-
dentate chiral ligands in Henry reactions using p-nitrobenzalde-
hyde and nitromethane as model substrates in the presence of
anhydrous Cu(OAc)2 (5 mol %) at room temperature in ethanol. It
was found that the complex generated in situ from 5 mol % L2
and Cu(OAc)2 catalyzed the Henry reaction efficiently, giving 84%
yield and 76% ee (Table 1, entry 2). Although L7 proved to be effec-
tive in furnishing the desired b-nitro alcohol with 85% yield, the
enantioselectivity of the reaction was extremely low (Table 1,
entry 7, racemic). Other analogues of the tridentate ligand L1,
Cocurrent activation is usually employed combining Lewis acid
and Brønsted base in Henry reactions,22 in which the metal center
of the complex activates the aldehyde and the chiral ligand facili-
tates the deprotonation of nitroalkane. Copper has exhibited effec-
tive activities in Henry reaction as a Lewis acid on the basis of
⇑
Corresponding authors.
E-mail address: wsun@licp.cas.cn (W. Sun).
http://dx.doi.org/10.1016/j.tetasy.2017.05.013
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.013

2
D. Xu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
R3
R1
N
OH
1. NMM,
R1
N
isopropyl chloroformate,
O
THF, 0 oC, 12h
R2
O
N
N
R4
2. HOAc, 60 oC, 2h
3.CH3COCl, methanol,
60 oC, 2h
NaBH(OAc)3, 12h,
methanol
N
R2
N
H
N
OH
OH
R3
Boc
R1
R4
+
NH
TEA, 12h
methanol
Cl
N
R2
NH2
R1
: R1 = Me, R2 = H, R3 = t-Bu, R4 = t-Bu
L1
L2: R1 = Me, R2 = H, R3 = Ph, R4 = H
N
L3: R1 = Me, R2 = t-Bu, R3 = Ph, R4 = H
: R1 = Me, R2 = Ph, R3 = Ph, R4 = H
: R1 = Me, R2 = t-Bu, R3 = H, R4 = H
: R1 = Bn, R2 = H, R3 = Ph, R4 = H
L4
L5
L6
R2
N
N
1
2
N
L7
: R =Me, R =H
Scheme 1. Preparation of chiral tridentate ligands derived from
L
-proline.
Table 1
Optimization of the ligands and copper salts for the asymmetric Henry reactiona
O
OH
II
I
NO2
Ln
, Cu /Cu
(S)
H
CH3NO2
+
EtOH, rt, 24h
O2N
O2N
1m
2
3m
Entry
Lewis acid (ꢁ%)
Ligand (ꢁ%)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Cu(OAc)2 (5 mol %)
Cu(OAc)2 (5 mol %)
Cu(OAc)2 (5 mol %)
Cu(OAc)2 (5 mol %)
Cu(OAc)2 (5 mol %)
Cu(OAc)2 (5 mol %)
Cu(OAc)2 (5 mol %)
CuCl2 (5 mol %)
CuBr2 (5 mol %)
Cu(OTf)2 (5 mol %)
CuOTf (5 mol %)
CuI (5 mol %)
Cu(OAc)2 (2 mol %)
Cu(OAc)2 (1 mol %)
L1 (5 mol %)
L2 (5 mol %)
L3 (5 mol %)
L4 (5 mol %)
L5 (5 mol %)
L6 (5 mol %)
L7 (5 mol %)
L2 (5 mol %)
L2 (5 mol %)
L2 (5 mol %)
L2 (5 mol %)
L2 (5 mol %)
L2 (2 mol %)
L2 (1 mol %)
L2 (10 mol %)
75
84
65
66
76
68
85
—
—
—
—
69
82
56
88
54
76
63
69
56
71
rac
—
—
—
—
70
81
79
79
9
10
11
12
13
14
15
Cu(OAc)2 (10 mol %)
a
b
c
Reactions were performed with p-nitrobenzaldehyde 1 (0.5 mmol), Ln (5 mol %), copper salt (5 mol %), and nitromethane 2 (5 mmol) in EtOH (1 mL) at room temperature.
Isolated yields after column chromatography.
Determined by HPLC on a chiral stationary phase with a Daicel OD-H column.
L3–L6 were also examined, however, the yields and enantioselec-
tivities of the reactions were not improved (Table 1, entries 1, 3–
6). Different copper salts were tested using 5 mol % L2 as the chiral
ligand but the results did not improve (Table 1, entries 8–12).
Additionally, the amount of Lewis acid Cu(OAc)2 and Brønsted base
L2 were screened (Table 1, entries 13–15). It was shown that 2 mol
% of the catalyst proved to be the best loading for the asymmetric
Henry reaction giving 82% yield with 81% ee at room temperature
(Table 1, entry 13).
Furthermore, the effect of solvents and temperature on Henry
reaction was evaluated carefully. The results revealed that the
polar protic solvents (Table 2, entries 1–2) were better than aprotic
solvents (Table 2, entries 3–7). When the Henry reaction was car-
ried out in MeOH at room temperature, 85% yield and 86% ee were
obtained (Table 2, entry 2). Since the Henry reaction was reversi-
ble, we also studied the Henry reaction using substrate 2 as the sol-
vent to improve the yield. The yield and enantioselectivity of the
reaction in nitromethane were better than those reactions in other
aprotic solvents (Table 2, entry 8, 80% yield and 76% ee). However,
the results obtained in MeNO2 were not as good as in MeOH
(Table 2, entry 2 vs 8). We then studied the temperature effect
on the Henry reaction in MeOH. Unfortunately, lowering the reac-
tion temperature to 0 °C and ꢀ10 °C did not improve the enantios-
electivities of the Henry reaction while the yield decreased
(Table 2, entries 9–10). Therefore, the best result was achieved in
the presence of 2 mol % anhydrous Cu(OAc)2 and L2 in MeOH at
room temperature, which gave b-nitro alcohol in 85% yield and
with 86% ee after 24 h.
With the optimized conditions in hand, we next explored the
scope of the Henry reaction with respect to aldehydes. In general,
both aliphatic and aromatic aldehydes were well tolerated and
very good yields (up to 85%) and enantioselectivities (up to 86%)
were obtained under mild conditions as shown in Table 3. First,
benzaldehyde 1a gave the desired product in 76% yield and with
77% ee under the standard reaction condition (Table 3, entry 1).
Benzaldehydes 1b–1g bearing electron-donating groups on the
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.013

D. Xu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 2
The effect of solvents and temperature on the asymmetric Henry reactiona
Me
N
O
OH
L2 (2 mol%),
N
Cu(OAc)2 (2 mol%)
NO2
N
H
CH3NO2
(S)
+
solvent, T, 24h
OH
Ph
O2N
O2N
L2
1m
2
3m
Entry
Solvent
T (°C)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
EtOH
25
25
25
25
25
25
25
25
0
82
85
72
70
66
68
78
80
60
17
81
86
60
45
61
60
65
76
86
85
MeOH
PhCH3
MeCN
THF
Et2O
CH2Cl2
CH3NO2
MeOH
MeOH
ꢀ10
a
b
c
Reactions were performed with p-nitrobenzaldehyde 1 (0.5 mmol), L2 (2 mol %), anhydrous Cu(OAc)2 (2 mol %), and nitromethane (5 mmol) in 1 mL solvent.
Isolated yields after column chromatography.
Determined by HPLC on a chiral stationary phase with a Daicel OD-H column.
Table 3
Substrate scope of the asymmetric Henry reaction with respect to the aldehydesa
Me
N
L2 (2 mol%),
Cu(OAc)2 (2 mol%)
O
N
OH
N
CH3NO2
+
NO2
(S)
R
H
MeOH, rt
R
OH
Ph
1
2
3
L2
Entry
R
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
C6H5 1a
48
48
48
48
48
24
48
24
48
48
48
48
24
24
24
48
48
48
48
48
76
78
73
65
79
76
81
76
74
67
80
78
85
84
83
72
70
62
71
69
77
85
86
63
83
75
84
70
82
48
80
81
86
84
76
75
64
77
82
67
4-Me-C6H4 1b
3-Me-C6H4 1c
2-Me-C6H4 1d
4-MeO-C6H4 1e
3-MeO-C6H4 1f
4-t-Bu-C6H4 1g
4-Cl-C6H4 1h
9
3-Cl-C6H4 1i
10
11
12
13
14
15
16
17
18
19
20
2,4-DiCl-C6H3 1j
4-Br-C6H4 1k
3-Br-C6H4 1l
4-NO2-C6H4 1m
3-NO2-C6H4 1n
4-CF3-C6H4 1o
Heliotropin 1p
1-Naphthaldehyde 1q
Furfural 1r
CH3(CH2)6 1s
C6H5(CH2)2 1t
a
b
c
Reactions were performed with aldehyde (0.5 mmol) and nitromethane (5 mmol) in MeOH (1 mL) at room temperature.
Isolated yields after column chromatography.
Determined by HPLC on chiral stationary phase.
benzene ring were investigated (Table 3, entries 2–7). It was found
that Me-, MeO- or t-Bu substituted substrates underwent the
Henry reaction smoothly with good yields (up to 81%) and enan-
tioselectivities (up to 86%). 2-Me-benzaldehyde 1d was also trans-
formed successfully although the yield and enantioselectivity were
moderate (Table 3, entry 4). We evaluated the electron-withdraw-
ing groups on benzene ring of benzaldehydes (Table 3, entries
8–15). Halogenated benzaldehydes 1h–1l and benzaldehydes bear-
ing strongly electron-withdrawing groups 1m–1o, such as ANO2,
ACF3, generated the products with good yields (up to 85%) and
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.013

4
D. Xu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
enantioselectivities (up to 86%). Similarly, it was observed that
benzaldehyde 1j bearing substituent at the ortho-position
4. Experimental
4.1. General
a
(Table 3, entry 10) only afforded moderate yield (67%) and low
enantioselectivity (48%). Furthermore, piperonal 1p, 1-naphthalde-
hyde 1q and furfural 1r were also suitable for the Henry reaction
and formed the corresponding b-nitro alcohols with moderate
yields and enantioselectivities (Table 3, entries 16–18). It is note-
worthy that aliphatic aldehydes 1s and 1t were converted success-
fully with moderate yields and good enantioselectivities (Table 3,
entries 19–20). The absolute configuration of the products was
assigned as (S) by comparison of HPLC chromatogram and the
specific rotation with those reported in the literature.22
In order to rationalize the stereoselective outcome of the
asymmetric Henry reaction, we propose that the steric hindrance
of the benzene ring at the ortho-position of salicylaldehyde
repulses the benzene ring of the substrates as shown in Figure 1.
Nitromethane coordinates with copper complex at the weak coor-
dination site to release the acetate ion, which facilitates the fol-
lowing deprotonation, while the aldehydes coordinate with the
copper center at the rest of strong coordination site.22b Thus,
nitromethane attacks the aldehydes through the Re face to afford
(S)-enriched products.
All solvents and commercial reagents were used as supplied
without further purification. Room temperature (rt) refers to 20–
25 °C. NMR spectra were recorded on
a Bruker Avance III
400 MHz spectrometer operating at 400 MHz for 1H NMR and
100 MHz for 13C NMR in deuterated solvent. The chemical shifts
(d) are quoted in ppm and coupling constants (J) in Hz. All coupling
constants were determined by analysis using MestReNova v6.1.0
software. High resolution mass spectra (HRMS) were acquired by
Bruker microTOF-QII spectrometer (ESI) at 296(2)K. GC-MS was
acquired by an Agilent 7890A/5975C. TLC inspections were on sil-
ica gel GF254 plates and TLC visualization was carried out with
ultraviolet light (254 nm). Flash column chromatography was gen-
erally performed on silica gel (200–300 mesh).
4.2. Synthesis of ligands
4.2.1. Synthesis of (S)-2-(pyrrolidin-2-yl)-1H-benzimidazole
R1
R1
N
NH
1. NMM, isopropyl chloroformate,
THF, 0 oC, 12h
O
NH2
+
N
2. HOAc, 60 oC, 2h
OH
R2
N
H
N
Boc
3. CH3COCl, methanol, 60 oC, 2h
R2
R1 = Me, Bn
2 = t-Bu, Ph, H
R
A solution of L-Boc-proline (2.15 g, 10 mmol) and N-methyl
3. Conclusion
morpholine (NMM, 1 mL, 10 mmol) in THF (20 mL) was treated
at 0 °C with isobutyl chloroformate (1.2 mL, 10 mmol). After
10 min at 0 °C, 1,2-phenylenediamine (10 mmol) was added.
The reaction mixture was allowed to stir while slowly warm-
ing to room temperature (1 h) and then stirred for 24 h. The
solvent was evaporated, and the residue was extracted with
EtOAc from H2O. The EtOAc layer was washed with 5%
NaHCO3, brine and dried over Na2SO4. The solution was fil-
tered, the solvent was evaporated, and the residual solid was
dissolved in glacial AcOH (10 mL). The solution was heated
at 65 °C for 1 h. After the solvent was evaporated, the residue
was purified using column chromatography (petroleum ether/
In conclusion, a series of chiral tridentate ligands were prepared
successfully from readily available -proline. The resulting in situ
L
chiral copper complexes in the presence of anhydrous Cu(OAc)2
delivered the asymmetric Henry reaction smoothly to provide
(S)-enriched b-nitro alcohols with very good yields (up to 85%)
and enantioselectivities (up to 86%) under mild conditions in
MeOH. A range of aldehydes were well tolerated in the asymmetric
Henry reaction without any additives or bases. In particular, ali-
phatic aldehydes gave the desired products in good yield (71%)
and enantioselectivity (82%). Further investigations into the modi-
fication of chiral tridentate ligands and the mechanism of the
stereoselective outcome are underway in our laboratory.
H
O
H
O
N
N
O
O
H
N
H
N
Me
Me
N
N
N
N
I
I
I
C
C
I
u
u
O
O
O
O
Si-attack
Re-attack
OAc
R
OAc
H
R
H
disfavored
favored
Figure 1. The proposed mechanism of the asymmetric Henry reaction.
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.013

D. Xu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
ethyl acetate = 3:1) to give the corresponding benzimidazole as
a white solid.
N
N
A solution of the derived benzimidazole was re-dissolved in
methanol (20 mL) and cooled to 0 °C, after which 1 mL acetyl chlo-
ride was added slowly. After 10 min at 0 °C, the system was heated
to 60 °C for 2 h, after which the solvent was evaporated, and the
residue was dissolved in CHCl3 (10 mL). Next 3 M NaOH was added
and the pH was adjusted to 9, extracted with another two portions
of CHCl3 (2 ꢁ 10 mL). The combined the organic layers were
washed with NaHCO3, brine and dried over Na2SO4. After the sol-
vent was evaporated, the residue was purified using column chro-
matography (methanol/ ethyl acetate 1:2) to give the (S)-2-
N
OH
L1, White solid, 60% yield, ½a D20
= ꢀ32.0 (c 0.1, CHCl3), mp 151–
ꢂ
153 °C, 1H NMR (400 MHz, CDCl3) d 10.58 (s, 1H), 7.85–7.71 (m,
1H), 7.24–7.25 (m, 3H), 7.16 (s, 1H), 6.56 (s, 1H), 4.10 (d,
J = 13.1 Hz, 2H), 3.49 (s, 2H), 3.41 (d, J = 13.2 Hz, 1H), 3.34–3.21
(pyrrolidin-2-yl)-1H-benzimidazole as
yield).
a
white solid (90–95%
R3
R1
OH
N
R1
O
R4
N
N
R2
N
NaBH(OAc)3, 12h,
methanol
R2
N
H
N
OH
R3
R4
4.2.2. Synthesis of L1–L7
solution of (S)-2-(pyrrolidin-2-yl)-1H-benzimidazole was
(m, 1H), 2.71 (d, J = 7.8 Hz, 1H), 2.51–2.35 (m, 1H), 2.28–2.13 (m,
2H), 2.01–2.17 (m, 1H), 1.40 (s, 9H), 1.18 (s, 9H). 13C NMR
(101 MHz, CDCl3) d 154.2, 154.0, 142.2, 140.2, 135.7, 135.4,
123.2, 122.9, 122.5, 122.1, 121.7, 119.7, 109.1, 57.1, 53.4, 34.9,
34.0, 31.6, 31.1, 29.6, 23.5. HRMS (ESI) calcd for C27H37N3ONa [M
+Na]+: 442.2829, found: 442.2824.
A
dissolved in methanol (20 mL) under an argon atmosphere at
room temperature, after which salicylaldehyde (1.1 equiv) was
added and stirred for 2 h until the solvent changed to yellow.
Next NaBH(OAc)3 (1.5 equiv) was added in two portions, stirred
for another 10 h when the raw materials were consumed com-
pletely detected by TLC. The solvent was evaporated and
quenched with NH4Cl aq., then extracted with CHCl3
(3 ꢁ 10 mL). The organic layers were combined and washed with
NaHCO3, brine and dried over Na2SO4. After the solvent was evap-
orated, the residue was purified using column chromatography
(methanol/ethyl acetate 1:10) to give the target product L1–L6
as a white solid, 45–65% yield.
N
N
N
OH
Ph
L2, White solid, 65% yield, ½a D20
ꢂ
= +70.0 (c 0.1, CHCl3), mp 173–
175 °C, 1H NMR (400 MHz, CDCl3) d 11.01 (s, 1H), 7.76 (ddd,
J = 3.8, 2.3, 0.6 Hz, 1H), 7.69–7.56 (m, 2H), 7.41 (dd, J = 10.4,
4.7 Hz, 2H), 7.35–7.17 (m, 5H), 6.89 (dd, J = 7.4, 1.4 Hz, 1H), 6.78
(t, J = 7.5 Hz, 1H), 4.26 (d, J = 13.1 Hz, 1H), 4.09–3.91 (m, 1H),
3.67 (s, 3H), 3.37 (d, J = 13.2 Hz, 1H), 3.31–3.20 (m, 1H), 2.56 (dd,
J = 16.9, 7.9 Hz, 1H), 2.46–2.31 (m, 1H), 2.16–1.99 (m, 2H), 1.99–
1.84 (m, 1H). 13C NMR (101 MHz, CDCl3) d 154.6, 154.5, 138.9,
136.0, 130.1, 129.6, 128.9, 128.3, 127.9, 126.6, 123.4, 122.6,
122.2, 119.8, 118.7, 109.0, 60.5, 56.8, 53.2, 30.7, 30.0, 23.1. HRMS
(ESI) calcd for C25H25N3O2Na [M+Na]+: 406.1889, found:406.1894.
A
solution of (S)-2-(pyrrolidin-2-yl)-1H-benzimidazole
(1 mmol) was dissolved in methanol (20 mL) under an argon
atmosphere at room temperature. Next 2-chloromethyl-pyri-
dine (1.1 equiv) was added with TEA (1.5 equiv) and stirred
for 10 h. The solvent was evaporated and then water added,
and extracted with CHCl3 (3 ꢁ 10 mL). The organic layers were
combined and washed with NaHCO3, brine and dried over
Na2SO4. After the solvent was evaporated, the residue was
purified using column chromatography (methanol/ethyl acet-
N
N
N
OH
Ph
ate 1:10) to give the target product L7 as
a brown oil
(248 mg), 85% yield.
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.013

6
D. Xu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
L3, White solid, 55% yield, ½a D20
ꢂ
= +46.0 (c 0.1, CHCl3), mp 210–
L6, White solid, 45% yield, ½a D20
ꢂ
= +42.0 (c 0.1, CHCl3), mp 112–
212 °C, 1H NMR (400 MHz, CDCl3) d 7.79 (d, J = 1.4 Hz, 1H), 7.69–
7.56 (m, 2H), 7.49–7.33 (m, 3H), 7.31 (dt, J = 9.2, 4.3 Hz, 1H), 7.24
(dd, J = 9.3, 3.3 Hz, 2H), 6.88 (dd, J = 7.3, 1.3 Hz, 1H), 6.78 (t,
J = 7.5 Hz, 1H), 4.24 (d, J = 13.2 Hz, 1H), 4.15–4.03 (m, 1H), 3.65
(s, 3H), 3.44 (s, 1H), 3.28 (dd, J = 6.3, 2.6 Hz, 1H), 2.60 (dd,
J = 16.5, 7.7 Hz, 1H), 2.48–2.34 (m, 1H), 2.23–2.06 (m, 2H), 1.96
(ddd, J = 11.8, 9.5, 3.0 Hz, 1H), 1.39 (d, J = 4.1 Hz, 9H). 13C NMR
(101 MHz, CDCl3) d 154.6, 145.7, 142.0, 138.7, 133.9, 130.0,
129.5, 128.8, 128.1, 127.9, 126.6, 123.2, 120.7, 118.7, 116.0,
108.4, 100.0, 77.3, 77.2, 77.0, 76.7, 60.3, 56.7, 53.2, 34.8, 31.8,
30.7, 30.0, 23.1. HRMS (ESI) calcd for C29H33N3ONa [M+Na]+:
462.2516, found: 462.2512.
114 °C, 1H NMR (400 MHz, CDCl3) d 8.45 (dd, J = 4.8, 0.8 Hz, 1H),
7.76 (d, J = 8.0 Hz, 1H), 7.40 (td, J = 7.7, 1.8 Hz, 1H), 7.26 (ddd,
J = 7.2, 6.0, 3.2 Hz, 4H), 7.19–7.06 (m, 3H), 7.03–6.92 (m, 3H),
5.95 (d, J = 16.9 Hz, 1H), 5.48 (d, J = 16.9 Hz, 1H), 4.11 (t,
J = 8.2 Hz, 1H), 3.80 (dd, J = 115.1, 13.6 Hz, 2H), 3.22 (dd, J = 11.8,
4.9 Hz, 1H), 2.43 (dd, J = 17.2, 8.6 Hz, 1H), 2.19 (ddd, J = 15.8, 7.8,
5.0 Hz, 1H), 2.03–1.72 (m, 3H). 13C NMR (101 MHz, CDCl3) d
158.0, 154.4, 148.7, 142.2, 136.5, 136.1, 136.1, 128.8, 127.5,
125.9, 123.3, 122.7, 122.1, 121.8, 119.5, 109.9, 63.2, 60.2, 53.9,
47.1, 30.6, 22.9. HRMS (ESI) calcd for C31H29N3ONa [M+Na]+:
482.2203, found: 482.2207.
N
N
N
N
N
N
Ph
N
OH
Ph
L7, Brown oil, 85% yield, ½a D20
ꢂ
= +36.0 (c 0.1, CHCl3), 1H NMR
L4, White solid, 61% yield, ½a D20
ꢂ
= +40.0 (c 0.1, CHCl3), mp 81–
83 °C, 1H NMR (400 MHz, CDCl3) d 7.98 (d, J = 1.2 Hz, 1H), 7.63
(dd, J = 12.4, 4.8 Hz, 4H), 7.53 (d, J = 1.6 Hz, 1H), 7.42 (dt, J = 17.0,
7.6 Hz, 4H), 7.37–7.27 (m, 3H), 7.22 (dt, J = 12.3, 6.4 Hz, 1H), 6.90
(dd, J = 13.0, 6.8 Hz, 1H), 6.78 (dd, J = 9.4, 5.6 Hz, 1H), 4.24 (d,
J = 13.3 Hz, 1H), 4.14–4.02 (m, 1H), 3.68 (s, 3H), 3.44 (d,
J = 13.3 Hz, 1H), 3.36–3.23 (m, 1H), 2.58 (m, 1H), 2.42 (m, 1H),
2.25–2.10 (m, 3H), 1.96 (m, 1H). 13C NMR (101 MHz, CDCl3) d
154.9, 154.5, 142.3, 141.8, 138.7, 136.1, 135.5, 130.1, 129.5,
128.8, 128.7, 128.1, 127.9, 127.5, 126.7, 126.6, 123.2, 122.5,
118.8, 118.1, 109.3, 60.5, 56.9, 53.4, 30.7, 30.1, 23.2. HRMS (ESI)
calcd for C31H29N3ONa [M+Na]+: 482.2203, found: 482.2200.
(400 MHz, CDCl3) d 8.45 (dd, J = 4.8, 0.8 Hz, 1H), 7.78–7.64 (m,
1H), 7.47 (td, J = 7.7, 1.8 Hz, 1H), 7.37–7.13 (m, 4H), 7.06–6.91
(m, 1H), 4.11 (t, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.95–3.58 (m, 2H),
3.35–3.18 (m, 1H), 2.47 (dd, J = 17.1, 8.9 Hz, 1H), 2.40–2.31 (m,
1H), 2.20–2.05 (m, 2H), 1.96 (ddd, J = 7.5, 6.0, 2.2 Hz, 1H). 13C
NMR (101 MHz, CDCl3)
d 158.5, 154.1, 148.8, 136.7, 136.1,
123.1, 122.3, 121.8, 119.4, 108.9, 63.6, 60.3, 54.0, 30.4, 30.3,
23.0. HRMS (ESI) calcd for C18H20N4Na [M+Na]+: 315.1580, found:
315.1577.
4.3. General procedure for asymmetric Henry reaction
Ligand L2 (2 mol %) and anhydrous Cu(OAc)2 were added to
MeOH (1 mL) in a 10 mL flask at room temperature under air con-
dition, after which the substrate (0.5 mmol) and CH3NO2 were
added after stirring for 1 h and the mixture was stirred for a certain
time. After the reaction was completed, the mixture was concen-
trated under vacuum. The crude residue was purified directly by
flash column chromatography with silica gel to give pure products.
The absolute configuration of the products was assigned as (S) by
comparison of HPLC chromatogram and optical rotation to the
literature.
N
N
N
OH
L5, White solid, 60% yield, ½a D20
ꢂ
= +17.0 (c 0.1, CHCl3), mp 178–
180 °C, 1H NMR (400 MHz, CDCl3) d 7.84 (d, J = 1.4 Hz, 1H), 7.38
(dd, J = 8.5, 1.8 Hz, 1H), 7.29–7.22 (m, 1H), 7.17 (dd, J = 11.0,
4.3 Hz, 1H), 6.95 (dd, J = 12.6, 7.0 Hz, 2H), 6.73 (td, J = 7.3, 0.9 Hz,
1H), 4.30 (d, J = 12.9 Hz, 1H), 4.02–3.92 (m, 1H), 3.71 (s, 3H), 3.21
(dd, J = 15.6, 8.1 Hz, 2H), 2.51–2.36 (m, 2H), 2.08–1.87 (m, 3H),
1.39 (s, 9H). 13C NMR (101 MHz, CDCl3) d 157.6, 155.3, 133.9,
129.1, 128.8, 123.6, 120.6, 118.5, 116.6, 116.0, 108.2, 56.4, 53.0,
34.8, 31.9, 30.8, 29.9, 23.0. HRMS (ESI) calcd for C23H29N3ONa [M
+Na]+: 386.2203, found: 386.2198.
4.3.1. (S)-2-Nitro-1-phenylethanol 3a16e
OH
NO2
Ph
N
Colorless oil (76% yield, 77% ee). Chiral HPLC analysis with Chi-
ralcel OD-H column (90/10 hexanes:isopropanol, 1.0 mL/min,
215 nm, 25 °C); tR(minor) = 18.4 min, tR(major) = 22.8 min; ½a D20
ꢂ
=
N
N
+17.0 (c 0.2, CHCl3). 1H NMR (400 MHz, CDCl3) d 7.55–7.27 (m,
5H), 5.40 (dd, J = 9.6, 3.1 Hz, 1H), 4.56 (dd, J = 13.3, 9.6 Hz, 1H),
4.46 (dd, J = 13.3, 3.1 Hz, 1H), 3.10 (s, 1H).13C NMR (101 MHz,
CDCl3) d 138.1, 129.0, 128.9, 126.0, 81.2, 71.0.
OH
Ph
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.013

D. Xu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
4.3.2. (S)-1-(4-Methyphenyl)-2-nitroethanol 3b25
Colorless oil (76% yield, 83% ee). Chiral HPLC analysis with Chi-
ralcel OD-H column (90/10 hexanes:isopropanol, 1.0 mL/min,
215 nm, 25 °C);); tR(minor) = 14.7 min, tR(major) = 18.9 min;
½
a 2D0 = +15.5 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3) d 7.28 (d,
ꢂ
OH
J = 8.6 Hz, 2H), 6.95–6.85 (m, 2H), 5.35 (dd, J = 9.6, 3.1 Hz, 1H),
4.56 (dd, J = 13.1, 9.6 Hz, 1H), 4.44 (dd, J = 13.1, 3.2 Hz, 1H), 3.79
(s, 3H), 3.09 (s, 1H). 13C NMR (101 MHz, CDCl3) d 159.9, 130.3,
127.3, 114.3, 81.2, 70.6, 55.3.
NO2
4.3.6. (S)-1-(3-Methoxyphenyl)-2-nitroethanol 3f25
Colorless oil (78% yield, 85% ee). Chiral HPLC analysis with Chi-
ralcel AD-H column (90/10 hexanes:isopropanol, 1.0 mL/min,
215 nm, 25 °C); tR(minor) = 15.3 min, tR(major) = 14.3 min; ½a D20
ꢂ
=
+26.0 (c 1.6, CHCl3). 1H NMR (400 MHz, CDCl3) d 7.19 (m, 4H),
5.32 (dt, J = 9.4, 3.3 Hz, 1H), 4.52 (dd, J = 13.1, 9.6 Hz, 1H), 4.41
(dd, J = 13.1, 3.3 Hz, 1H), 3.16 (d, J = 3.8 Hz, 1H), 2.33 (s, 3H). 13C
NMR (101 MHz, CDCl3) d 138.8, 135.3, 129.6, 125.9, 81.2, 70.8, 21.1.
OH
NO2
OMe
4.3.3. (S)-1-(3-Methyphenyl)-2-nitroethanol 3c25
Colorless oil (76% yield, 75% ee). Chiral HPLC analysis with Chi-
ralcel OD-H column (90/10 hexanes:isopropanol, 1.0 mL/min,
OH
NO2
215 nm, 25 °C); tR(minor) = 24.5 min, tR(major) = 32.6 min; ½a D20
ꢂ
=
+14.5 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3) d 7.44 (dd, J = 7.5,
1.4 Hz, 1H), 7.33 (ddt, J = 8.0, 5.1, 2.6 Hz, 1H), 7.01 (td, J = 7.5,
0.8 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.63 (ddd, J = 9.3, 6.2, 3.3 Hz,
1H), 4.65 (dd, J = 13.1, 3.3 Hz, 1H), 4.57 (dd, J = 13.1, 9.2 Hz, 1H),
3.88 (s, 3H), 3.16 (d, J = 6.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) d
136.3, 134.5, 130.8, 128.7, 126.7, 125.6, 80.2, 67.9, 18.8.
Colorless oil (73% yield, 86% ee). Chiral HPLC analysis with Chi-
ralcel AD-H column (95/5 hexanes:isopropanol, 1.0 mL/min,
215 nm, 25 °C); tR(minor) = 12.8 min, tR(major) = 12.1 min; ½a D20
ꢂ
=
4.3.7. (S)-1-(4-tBu-phenyl)-2-nitroethanol 3g
+27.0 (c 0.8, CHCl3). 1H NMR (400 MHz, CDCl3)
d 7.26 (t,
J = 7.5 Hz, 1H), 7.21–7.10 (m, 3H), 5.34 (dd, J = 9.6, 3.1 Hz, 1H),
4.53 (dd, J = 13.2, 9.6 Hz, 1H), 4.43 (dd, J = 13.2, 3.1 Hz, 1H),3.13
(s, 1H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) d 138.8, 138.2,
129.6, 128.9, 126.6, 123.0, 81.2, 71.0, 21.4.
OH
NO2
4.3.4. (S)-1-(2-Methyphenyl)-2-nitroethanol 3d25
OH
White solid (81% yield, 84% ee), mp 66–68 °C. Chiral HPLC anal-
ysis with Chiralcel OD-H column (90/10 hexanes:isopropanol,
0.8 mL/min, 215 nm, 25 °C); tR(minor) = 16.9 min, tR(major)
NO2
= 24.7 min; ½a 2D0
ꢂ
= +11.6 (c 1.2, EtOH). 1H NMR (400 MHz, CDCl3)
d 7.46–7.37 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 5.41 (dd,
J = 9.7, 3.0 Hz, 1H), 4.59 (dd, J = 13.3, 9.7 Hz, 1H), 4.48 (dd,
J = 13.3, 3.0 Hz, 1H), 2.81 (s, 1H), 1.31 (s, 9H). 13C NMR (101 MHz,
CDCl3) d 152.1, 135.1, 125.9, 125.7, 81.2, 70.8, 34.6, 31.2.
Colorless oil (65% yield, 63% ee). Chiral HPLC analysis with Chi-
ralcel OD-H column (90/10 hexanes:isopropanol, 1.0 mL/min,
215 nm, 25 °C); tR(minor) = 21.6 min, tR(major) = 19.8 min; ½a D20
ꢂ
=
+9.0 (c 0.2, CHCl3) 1H NMR (400 MHz, CDCl3) d 7.52 – 7.40 (m,
1H), 7.28 – 7.19 (m, 2H), 7.18 – 7.08 (m, 1H), 5.60 (dt, J = 9.6,
3.1 Hz, 1H), 4.47 (dd, J = 13.3, 9.7 Hz, 1H), 4.36 (dd, J = 13.3,
3.1 Hz, 1H). 3.09 (d, J = 3.6 Hz, 1H), 2.34 (s, 3H). 13C NMR
(101 MHz, CDCl3) d 136.3, 134.5, 130.8, 128.7, 126.7, 125.6, 80.2,
67.9, 18.8.
4.3.8. (S)-1-(4-Chlorophenyl)-2-nitroethanol 3h16e
OH
NO2
4.3.5. (S)-1-(4-Methoxyphenyl)-2-nitroethanol 3e16e
Cl
OH
Colorless oil (76% yield, 70% ee). Chiral HPLC analysis with AD-H
NO2
column (90/10 hexanes:isopropanol, 1.0 mL/min, 215 nm, 25 °C);
tR(minor) = 18.3 min, tR(major) = 23.7 min;
½
a 2D0
= +24.0 (c 0.2,
ꢂ
MeO
EtOH). 1H NMR (400 MHz, CDCl3) d 7.53–7.26 (m, 4H), 5.41 (dt,
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.013

8
D. Xu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Colorless oil (78% yield, 81% ee). Chiral HPLC analysis with AD-H
J = 9.3, 3.4 Hz, 1H), 4.55 (dd, J = 13.3, 9.4 Hz, 1H), 4.47 (dd, J = 13.3,
3.2 Hz, 1H), 3.25 (d, J = 3.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) d
136.6, 134.7, 129.2, 127.3, 81.0, 70.3.
column (90/10 hexanes:isopropanol, 1.0 mL/min, 215 nm, 25 °C);
tR(minor) = 10.5 min, tR(major) = 13.6 min;
½
a 2D0
= +19.8 (c 0.4,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3) d 7.53 (d, J = 1.7 Hz, 1H), 7.46
(m, 1H), 7.31–7.19 (m, 2H), 5.38 (dt, J = 8.8, 3.2 Hz, 1H), 4.64–
4.29 (m, 2H), 3.45 (d, J = 3.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) d
140.4, 132.0, 130.6, 129.1, 124.6, 123.0, 80.9, 70.2.
4.3.9. (S)-1-(3-Chlorophenyl)-2-nitroethanol 3i26
OH
NO2
4.3.13. (S)-2-Nitro-1-(4-nitrophenyl)ethanol 3m16e
OH
Cl
NO2
Colorless oil (74% yield, 82% ee). Chiral HPLC analysis with AD-H
column (90/10 hexanes:isopropanol, 1.0 mL/min, 215 nm, 25 °C);
O2N
tR(minor) = 11.1 min, tR(major) = 13.8 min;
½
a 2D0
= +28.3 (c 2.6,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3) d 7.41 (s, 1H), 7.36–7.31 (m,
2H), 7.31–7.21 (m, 1H), 5.42 (dd, J = 9.2, 3.3 Hz, 1H), 4.64–4.35
(m, 2H), 3.15 (s, 1H). 13C NMR (101 MHz, CDCl3) d 140.1, 134.9,
130.3, 129.1, 126.2, 124.1, 80.9, 70.3
Yellow oil (85% yield, 86% ee). Chiral HPLC analysis with OD-H
column (90/10 hexanes:isopropanol, 1.0 mL/min, 215 nm, 25 °C);
tR(minor) = 15.8 min, tR(major) = 19.4 min;
½
a 2D0
= +16.5 (c 0.2,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3) d 8.23 (d, J = 8.7 Hz, 2H), 7.63
(d, J = 8.7 Hz, 2H), 5.63 (dd, J = 7.4, 4.8 Hz, 1H), 4.67–4.55 (m, 2H),
3.49 (s, 1H). 13C NMR (101 MHz, CDCl3) d 148.0, 145.2, 127.0,
124.1, 80.6, 70.0.
4.3.10. (S)-1-(2,4-Dichlorophenyl)-2-nitroethanol 3j25
OH
NO2
4.3.14. (S)-2-Nitro-1-(3-nitrophenyl)ethanol 3n25
Cl
Cl
White solid (67% yield, 48% ee), mp 68–70 °C. Chiral HPLC analy-
OH
sis with OD-H column (90/10 hexanes:isopropanol, 1.0 mL/min,
NO2
215 nm, 25 °C); tR(minor) = 6.6 min, tR(major) = 6.8 min; ½a D20
ꢂ
=
+8.0 (c 0.4, CHCl3). 1H NMR (400 MHz, CDCl3) d 7.61 (d, J = 8.4 Hz,
1H), 7.41 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 5.79 (ddd,
J = 9.4, 3.8, 2.4 Hz, 1H), 4.65 (dd, J = 13.7, 2.3 Hz, 1H), 4.42 (dd,
J = 13.7, 9.5 Hz, 1H), 3.15 (d, J = 4.2 Hz, 1H). 13C NMR (101 MHz,
CDCl3) d 135.2, 134.1, 132.0, 129.5, 128.5, 128.00, 79.0, 67.4.
NO2
White solid (84% yield, 84% ee), mp 74–75 °C. Chiral HPLC anal-
ysis with AD-H column (90/10 hexanes:isopropanol, 1.0 mL/min,
4.3.11. (S)-1-(4-Bromophenyl)-2-nitroethanol 3k16e
215 nm, 25 °C); tR(minor) = 15.8 min, tR(major) = 17.9 min; ½a D20
ꢂ
=
+12.9 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d 8.32 (dd, J = 2.6,
1.2 Hz, 1H), 8.21 (ddd, J = 8.2, 2.2, 0.9 Hz, 1H), 7.79 (d, J = 7.7 Hz,
1H), 7.62 (t, J = 8.0 Hz, 1H), 5.63 (dd, J = 8.2, 4.2 Hz, 1H), 4.77 –
4.51 (m, 2H), 3.31 (s, 1H).13C NMR (101 MHz, CDCl3) d 148.5,
140.2, 132.0, 130.1, 123.8, 121.1, 80.6, 69.8.
OH
NO2
Br
4.3.15. (S)-2-Nitro-1-(4-trifluoromethylphenyl)ethanol 3o27
Colorless oil (80% yield, 80% ee). Chiral HPLC analysis with OD-H
column (90/10 hexanes:isopropanol, 1.0 mL/min, 215 nm, 25 °C);
tR(minor) = 10.9 min, tR(major) = 14.0 min;
½
a 2D0
= +13.5 (c 1,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3) d 7.51 (d, J = 8.4 Hz, 2H), 7.26
(d, J = 8.4 Hz, 2H), 5.40 (dd, J = 9.3, 3.1 Hz, 1H), 4.51 (qd, J = 16.6,
13.3, 6.3 Hz, 2H), 3.25 (s, 1H). 13C NMR (101 MHz, CDCl3) d 137.1,
132.1, 127.6, 122.9, 80.9, 70.3.
OH
NO2
F3C
4.3.12. (S)-1-(3-Bromophenyl)-2-nitroethanol 3l25
Colorless oil (83% yield, 76% ee). Chiral HPLC analysis with OD-H
column (90/10 hexanes:isopropanol, 0.8 mL/min, 215 nm, 25 °C);
OH
tR(minor) = 16.9 min, tR(major) = 24.7 min;
½
a 2D0
= +11.6 (c 1.2,
ꢂ
EtOH). 1H NMR (400 MHz, CDCl3) d 7.66 (d, J = 8.2 Hz, 2H), 7.54
(d, J = 8.2 Hz, 2H), 5.53 (dd, J = 9.1, 3.3 Hz, 1H), 4.56 (qd, J = 13.5,
6.3 Hz, 2H), 3.23 (s, 1H). 13C NMR (101 MHz, CDCl3) d 141.9,
130.6, 127.8, 126.3, 119.7, 80.8, 70.3.
NO2
Br
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.013

D. Xu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
9
4.3.16. (S)-1-(Benzo[d][1,3]dioxol-5-yl)-2-nitroethan-1-ol 3p
(s, 1H), 1.63–1.42 (m, 3H), 1.29 (m, 9H), 0.88 (m, 3H). 13C NMR
(101 MHz, CDCl3) d 80.71, 6.7, 33.7, 31.7, 29.2, 29.0, 25.17, 22.6,
14.0.
OH
4.3.20. (S)-1-Nitro-4-phenylbutan-2-ol 3t16e
NO2
O
O
NO2
OH
White solid (72% yield, 75% ee), mp 87–89 °C. Chiral HPLC analysis
with IC column (90/10 hexanes:isopropanol, 1.0 mL/min, 215 nm,
25 °C); tR(minor) = 15.3 min, tR(major) = 12.7 min; ½a D20
ꢂ
= +28.0 (c
0.5, EtOH). 1H NMR (400 MHz, CDCl3) d 7.00–6.72 (m, 3H), 5.37
(dd, J = 9.5, 3.1 Hz, 1H), 4.57 (dd, J = 13.3, 9.5 Hz, 2H), 4.47 (dd, J
= 13.3, 3.1 Hz, 2H), 2.73 (s, 1H).13C NMR (101 MHz, CDCl3) d
148.2, 148.1, 131.9, 119.6, 108.6, 106.3, 101.4, 81.2, 70.8.
Colorless oil (69% yield, 67% ee). Chiral HPLC analysis with OD-H
column (90/10 hexanes:isopropanol, 1.0 mL/min, 215 nm, 25 °C);
tR(minor) = 17.1 min, tR(major) = 18.5 min;
½
a 2D0
= +6.0 (c 0.2,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3) d 7.30 (m, 2H), 7.25–7.14 (m,
3H), 4.42–4.35 (m, 2H), 4.35–4.24 (m, 1H), 2.85 (m, J = 14.4, 9.0,
5.7 Hz, 1H), 2.79 – 2.66 (m, 2H), 2.09 – 1.55 (m, 2H). 13C NMR
(101 MHz, CDCl3) d 140.6, 128.6, 128.4, 126.3, 80.6, 67.8, 35.1, 31.3.
4.3.17. (S)-2-Nitro-1-(naphthyl)ethanol 3q16e
OH
Acknowledgments
NO2
We thank the National Natural Science Foundation of China
(21473226, 21362031) for financial support.
A. Supplementary data
White solid (70% yield, 64% ee), mp 51–53 °C. Chiral HPLC anal-
ysis with OD-H column (90/10 hexanes:isopropanol, 1.0 mL/min,
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.05.
013.
215 nm, 25 °C); tR(minor) = 12.5 min, tR(major) = 19.1 min; ½a D20
ꢂ
=
+5.0 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d 7.99 (d, J = 8.2 Hz,
1H), 7.90–7.86 (m, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 7.2 Hz,
1H), 7.60–7.41 (m, 3H), 6.25–6.13 (m, 1H), 4.69–4.54 (m, 2H),
3.03 (s, 1H). 13C NMR (101 MHz, CDCl3) d 133.7, 133.6, 129.5,
129.4, 129.3, 127.1, 126.1, 125.5, 123.8, 121.8, 80.8, 68.3.
References
1. Sasai, H. In 2.13 The Henry (Nitroaldol) Reaction A2; Knochel, Paul, Ed.; Elsevier:
Amsterdam, 2014; p 543.
2. Pinnick, H. W. In The Nef Reaction; John Wiley & Sons, 2004.
3. Ballini, R.; Petrini, M. Adv. Synth. Catal. 2015, 357, 2371–2402.
4. Sukhorukov, A. Y.; Sukhanova, A. A.; Zlotin, S. G. Tetrahedron 2016, 72, 6191–
6281.
4.3.18. (S)-2-Nitro-1-(furanyl)ethanol 3r28
5. Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114,
4418–4420.
OH
6. Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org.
Chem. 1995, 60, 7388–7389.
O
NO2
7. Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. 1997, 36, 1236–1256.
8. Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187–2209.
9. Pavel, D.; Lydie, H.; Milos, S. Curr. Org. Syn. 2014, 11, 879–888.
10. Karimi, B.; Enders, D.; Jafari, E. Synthesis 2013, 45, 2769–2812.
11. Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal. 2015,
357, 253–281.
Colorless oil (62% yield, 77% ee). Chiral HPLC analysis with OD-H
column (90/10 hexanes:isopropanol, 1.0 mL/min, 215 nm, 25 °C);
tR(minor) = 14.4 min, tR(major) = 15.5 min;
½
a 2D0
= +11.0 (c 0.2,
ꢂ
12. Alegre-Requena, J. V.; Marques-Lopez, E.; Herrera, R. P. Adv. Synth. Catal. 2016,
358, 1801–1809.
CHCl3). 1H NMR (400 MHz, CDCl3) d 7.42 (d, J = 12.2 Hz, 1H), 6.37
(t, J = 2.1 Hz, 2H), 5.43 (dd, J = 9.1, 3.6 Hz, 1H), 4.75 (dd, J = 13.4,
9.1 Hz, 1H), 4.64 (dd, J = 13.4, 3.6 Hz, 1H), 3.37 (s, 1H). 13C NMR
(101 MHz, CDCl3) d 150.7, 143.1, 110.6, 108.2, 78.3, 64.7.
13. For salen ligands, please see: (a) Kogami, Y.; Nakajima, T.; Ikeno, T.; Yamada, T.
Synthesis 2004, 1947–1950; (b) Xiong, Y.; Wang, F.; Huang, X.; Wen, Y. H.; Feng,
X. M. Chem. Eur. J. 2007, 13, 829–833; (c) Park, J.; Lang, K.; Abboud, K. A.; Hong,
S. J. Am. Chem. Soc. 2008, 130, 16484–16485; (d) Guo, J.; Mao, J. C. Chirality
2009, 21, 619–627; (e) Kowalczyk, R.; Kwiatkowski, P.; Skarzewski, J.; Jurczak,
J. J. Org. Chem. 2009, 74, 753–756; (f) White, J. D.; Shaw, S. Org. Lett. 2012, 14,
6270–6273; (g) Ouyang, G. H.; He, Y. M.; Fan, Q. H. Chem. Eur. J. 2014, 20,
16454–16457.
4.3.19. (S)-1-Nitrononan-2-ol 3s23l
14. For iminopyridine ligands, please see: (a) Blay, G.; Climent, E.; Fernandez, I.;
Hernandez-Olmos, V.; Pedro, J. Tetrahedron: Asymmetry 2006, 17, 2046–2049;
(b) Blay, G.; Climent, E.; Fernandez, I.; Hernandez-Olmos, V.; Pedro, J.
Tetrahedron: Asymmetry 2007, 18, 1603–1612; (c) Solinas, M.; Sechi, B.;
Baldino, S.; Chelucci, G. J. Mol. Catal. Chem 2013, 378, 206–212.
15. For oxazoline ligands, please see: (a) Ginotra, S. K.; Singh, V. K. Org. Biomol.
Chem. 2007, 5, 3932–3937; (b) Lang, K.; Park, J.; Hong, S. J. Org. Chem. 2010, 75,
6424–6435; (c) Yang, W.; Du, D. M. Eur. J. Org. Chem. 2011, 1552–1556; (d)
Balaraman, K.; Vasanthan, R.; Kesavan, V. Synthesis 2012, 44, 2455–2462; (d)
Wolinska, E. Tetrahedron 2013, 69, 7269–7278; (e) Tang, L. W.; Dong, X.; Zhou,
Z. M.; Liu, Y. Q.; Dai, L.; Zhang, M. RSC Adv. 2015, 5, 4758–4765; (f) Cruz, H.;
Aguirre, G.; Madrigal, D.; Chavez, D. Tetrahedron: Asymmetry 2016, 27, 1217–
1221.
OH
NO2
Colorless oil (71% yield, 82% ee). Chiral HPLC analysis with OD-H
column (90/10 hexanes:isopropanol, 1.0 mL/min, 215 nm, 25 °C);
tR(minor) = 28.5 min, tR(major) = 42.5 min;
½
a 2D0
ꢂ
= +14.0 (c 0.2,
CHCl3). 1H NMR (400 MHz, CDCl3) d 4.52 – 4.34 (m, 3H), 2.91
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.013

10
D. Xu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
16. For amino alcohol ligands, please see: (a) Colak, M.; Aral, T.; Hosgoren, H.
Tetrahedron: Asymmetry 2007, 18, 1129–1133; (b) Ma, K. Y.; You, J. S. Chem. Eur.
J. 2007, 13, 1863–1871; (c) Kim, H. Y.; Oh, K. Org. Lett. 2009, 11, 5682–5685; (d)
Xin, D. Y.; Ma, Y. D.; He, F. Tetrahedron: Asymmetry 2010, 21, 333–338; (e) Guo,
Z. L.; Zhong, S.; Li, Y. B.; Lu, G. Tetrahedron: Asymmetry 2011, 22, 238–245; (f)
Jin, W.; Li, X. C.; Wan, B. S. J. Org. Chem. 2011, 76, 484–491; (g) Zheng, B.; Wang,
M.; Li, Z. Y.; Bian, Q. H.; Mao, J. Y.; Li, S. N.; Liu, S. Z.; Wang, M. A.; Zhong, J. C.;
Guo, H. Tetrahedron: Asymmetry 2011, 22, 1156–1160; (h) Xu, F.; Lei, C.; Yan, L.;
Tu, J. X.; Li, G. Q. Chirality 2015, 27, 761–765; (i) Xu, F.; Yan, L.; Lei, C.; Zhao, H.;
Li, G. Tetrahedron: Asymmetry 2015, 26, 338–343; (j) Lu, G. H.; Zheng, F.; Wang,
L.; Guo, Y. X.; Li, X.; Cao, X. J.; Wang, C. P.; Chi, H. J.; Dong, Y.; Zhang, Z.
Tetrahedron: Asymmetry 2016, 27, 732–739.
17. For Schiff ligands, please see: (a) Lai, G. Y.; Wang, S. J.; Wang, Z. Tetrahedron:
Asymmetry 2008, 19, 1813–1819; (b) Ingalsbe, M. L.; St Denis, J. D.; Gleason, J.
L.; Savage, G. P.; Priefer, R. Synthesis 2010, 98–102; (c) Boobalan, R.; Lee, G. H.;
Chen, C. P. Adv. Synth. Catal. 2012, 354, 2511–2520; (d) Cheng, H. G.; Lu, L. Q.;
Wang, T.; Chen, J. R.; Xiao, W. J. Chem. Commun. 2012, 5596–5598; (e) He, F. Y.;
Ma, Y. D.; Zhao, L.; Duan, W. Z.; Chen, J. Q.; Zhao, Z. Tetrahedron: Asymmetry
2012, 23, 809–817; (f) Yao, L.; Wei, Y.; Wang, P. A.; He, W.; Zhang, S. Y.
Tetrahedron 2012, 68, 9119–9124; (g) Jiao, T. Q.; Tu, J. X.; Li, G. Q.; Xu, F. J. Mol.
Catal. Chem 2016, 416, 56–62.
18. For sulfonylamide ligands, please see: (a) Arai, T.; Takashita, R.; Endo, Y.;
Watanabe, M.; Yanagisawa, A. J. Org. Chem. 2008, 73, 4903–4906; (b)
Rachwalski, M.; Lesniak, S.; Sznajder, E.; Kielbasinski, P. Tetrahedron:
Asymmetry 2009, 20, 1547–1549; (c) Steurer, M.; Bolm, C. J. Org. Chem. 2010,
75, 3301–3310; (d) Li, Y.; Deng, P.; Zeng, Y. M.; Xiong, Y.; Zhou, H. Org. Lett.
2016, 18, 1578–1581; (e) Novakova, G.; Drabina, P.; Frumarova, B.; Sedlak, M.
Adv. Synth. Catal. 2016, 358, 2541–2552.
19. Gualandi, A.; Cerisoli, L.; Stoeckli-Evans, H.; Savoia, D. J. Org. Chem. 2011, 76,
3399–3408.
20. For imidazole ligands, please see: (a) Bures, F.; Szotkowski, T.; Kulhanek, J.;
Pytela, O.; Ludwig, M. Tetrahedron: Asymmetry 2006, 17, 900–907; (b) Zhou, Y.
R.; Gong, Y. F. Eur. J. Org. Chem. 2011, 6092–6099; (c) Filippova, L.; Stenstrom,
Y.; Hansen, T. V. Molecules 2015, 20, 6224–6236.
A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2003, 125, 12692–12693.
23. For copper complexes, please see: (a) Maheswaran, H.; Prasanth, K. L.; Krishna,
G. G.; Ravikumar, K.; Sridhar, B.; Kantam, M. L. Chem. Commun. 2006, 4066–
4068; (b) Breuning, M.; Hein, D.; Steiner, M.; Gessner, V. H.; Strohmann, C.
Chem. Eur. J. 2009, 15, 12764–12769; (c) Sanjeevakumar, N. Tetrahedron:
Asymmetry 2009, 20, 1842–1847; (d) Selvakumar, S.; Sivasankaran, D.; Singh,
V. K. Org. Biomol. Chem. 2009, 7, 3156–3162; (e) Noole, A.; Lippur, K.; Metsala,
A.; Lopp, M.; Kanger, T. J. Org. Chem. 2010, 75, 1313–1316; (f) Chougnet, A.;
Zhang, G. Q.; Liu, K. G.; Haussinger, D.; Kagi, A.; Allmendinger, T.; Woggon, W.
D. Adv. Synth. Catal. 2011, 353, 1797–1806; (g) Ji, Y. Q.; Qi, G.; Judeh, Z. M. A.
Eur. J. Org. Chem. 2011, 4892–4898; (h) Lu, D. F.; Zhou, Y. R.; Li, Y. J.; Yan, S. B.;
Gong, Y. F. J. Org. Chem. 2011, 76, 8869–8878; (i) Reddy, B. V. S.; Reddy, S. M.;
Manisha, S. Tetrahedron: Asymmetry 2011, 22, 530–535; (j) Zhou, Y. R.; Dong, J.
F.; Zhang, F. L.; Gong, Y. F. J. Org. Chem. 2011, 76, 588–600; (k) Zielinska-Blajet,
M. Tetrahedron: Asymmetry 2011, 22, 351–355; (l) Zhao, C. H.; Liu, F.; Gou, S.
Tetrahedron: Asymmetry 2014, 25, 278–283; (m) Das, A.; Choudhary, M. K.;
Kureshy, R. I.; Jana, K.; Verma, S.; Khan, N. U. H.; Abdi, S. H. R.; Bajaj, H. C.;
Ganguly, B. Tetrahedron 2015, 71, 5229–5237; (n) Niedziejko, P.; Szewczyk, M.;
Kalicki, P. Tetrahedron: Asymmetry 2015, 26, 1083–1094; (o) Scharnagel, D.;
Muller, A.; Prause, F.; Eck, M.; Goller, J.; Milius, W.; Breuning, M. Chem. Eur. J.
2015, 21, 12488–12500; (p) Rexiti, R.; Lu, J.; Wang, G.; Sha, F.; Wu, X.
Tetrahedron: Asymmetry 2016, 27, 923–929; (q) Lai, G. Y.; Guo, F. F.; Zheng, Y.
Q.; Fang, Y.; Song, H. G.; Xu, K.; Wang, S. J.; Zha, Z. G.; Wang, Z. Y. Chem. Eur. J.
2011, 17, 1114–1117; (r) Xu, K.; Lai, G. Y.; Zha, Z. G.; Pan, S. S.; Chen, H. W.;
Wang, Z. Y. Chem. Eur. J. 2012, 18, 12357–12362.
24. For the development of ligands derived from L-proline by our group, please see:
(a) Wang, B.; Miao, C. X.; Wang, S. F.; Kuhn, F. E.; Xia, C. G.; Sun, W. J.
Organomet. Chem. 2012, 715, 9–12; (b) Wang, B.; Miao, C. X.; Wang, S. F.; Xia, C.
G.; Sun, W. Chem. Eur. J. 2012, 18, 6750–6753; (c) Wang, B.; Wang, S. F.; Xia, C.
G.; Sun, W. Chem. Eur. J. 2012, 18, 7332–7335; (d) Wang, X.; Miao, C. X.; Wang,
S. F.; Xia, C. G.; Sun, W. ChemCatChem 2013, 5, 2489–2494; (e) Shen, D. Y.;
Miao, C. X.; Wang, S. F.; Xia, C. G.; Sun, W. Eur. J. Inorg. Chem. 2014, 5777–5782;
(f) Du, J. Y.; Xu, D. Q.; Zhang, C. X.; Xia, C. G.; Wang, Y.; Sun, W. Dalton Trans.
2016, 45, 10131–10135.
21. For nitric oxide ligands, please see: (a) Qin, B.; Xiao, X.; Liu, X. H.; Huang, J. L.;
Wen, Y. H.; Feng, X. M. J. Org. Chem. 2007, 72, 9323–9328; (b) Mei, H. J.; Xiao,
X.; Zhao, X. H.; Fang, B.; Liu, X. H.; Lin, L. L.; Feng, X. M. J. Org. Chem. 2015, 80,
2272–2280.
22. For cocurrent activation of the asymmetric Henry reaction, please see: (a)
Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861–863; (b) Evans, D.
25. Jiang, J. J.; Shi, M. Tetrahedron: Asymmetry 2007, 18, 1376–1382.
26. Yao, J. Q.; Qi, G.; Judeh, Z. M. Tetrahedron: Asymmetry 2011, 22, 929–935.
27. Ibrahim, F.; Jaber, N.; Guérineau, V.; Hachem, A.; Ibrahim, G.; Mellah, M.
Tetrahedron: Asymmetry 2013, 24, 1395–1401.
28. Gu, L. H.; Zhou, Y. R.; Zhang, J. L.; Gong, Y. Tetrahedron: Asymmetry 2012, 23,
124–129.
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.013