Synthesis and computation of diastereomeric phenanthroline-quinine ligands and their application in asymmetric Henry reaction

Article abstract of DOI:10.1016/j.tet.2013.10.010

A class of chiral ligands has been developed by combining phenanthroline with quinine in a one-step method that does not require resolution. The synthesized three ligands were then coordinated with Cu^(II) and the performance of the resultant ch

Full text of DOI:10.1016/j.tet.2013.10.010

Tetrahedron 69 (2013) 10644e10652
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and computation of diastereomeric
phenanthrolineequinine ligands and their application in
asymmetric Henry reaction
,
Lili Zhang a, Hao Wu b, Zhongyue Yang b, Xiufang Xu b, Haitao Zhao c, Yaodong Huang a
*
,
,
Yongmei Wang b
*
a Key Laboratory of Systems Bioengineering, Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072,
China
b State Key Laboratory of Elemento-Organic Chemistry, Department of Chemistry, Nankai University, Tianjin 300071, China
c Department of Chemistry, Tianjin University, Tianjin 300072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 May 2013
Received in revised form 3 October 2013
Accepted 5 October 2013
Available online 21 October 2013
A class of chiral ligands has been developed by combining phenanthroline with quinine in a one-step
method that does not require resolution. The synthesized three ligands were then coordinated with
Cu(II) and the performance of the resultant chiral catalysts in the asymmetric Henry reaction was eval-
uated. Moderate to good yields (up to 86%) with high enantioselectivities (up to 99% ee) were observed in
the reactions catalyzed by one of the three catalysts. Theoretical calculations were performed to analyze
the catalytic activities of the different Cu(II)-ligand catalysts. Three different ligands were investigated
and one ligand was found to adopt an unexpected five-coordinated mode; the second coordinated with
two nitrogen atoms of phenanthroline to give a complex, which activated both substrates of Henry re-
Keywords:
Chiral phenanthroline
Quinine
Henry reaction
Copper
action; the third was unable to form a complex with Cu(II)
.
Ó 2013 Elsevier Ltd. All rights reserved.
Mechanistic study
1. Introduction
attention has been paid to CeH bond activation catalyzed by phe-
nanthrolines with metals.10 However, only a few examples of this
basic scaffold with chiral groups have been reported for asym-
metric catalysis. These include cyclopropanation,11 allylic alkyl-
ation,12 hydrosilylation,11b,13 transfer hydrogenation,14 and allylic
oxidation.15 To our surprise, there has not been a single example of
the asymmetric Henry reaction catalyzed by this class of ligands.
Moreover, most of the chiral phenanthroline ligands reported in the
literature were synthesized via long routes that required multiple
steps and the chiral elements generally required a final resolution
step by preparative chiral HPLC. With this in mind, the design of
simple and easily accessible chiral phenanthroline ligands for
asymmetric catalysis is very important.
Cinchona alkaloids are regarded as one of the most important
chirality inducers and they have found applications in chiral ligands
and asymmetric organocatalysis.16 These alkaloids have some po-
tential for asymmetric catalysis owning to their chiral recognition
capabilities, their structural diversity and their conformational
characteristics.
The asymmetric Henry reaction is an atom economical and
powerful method for stereoselective carbonecarbon bond forma-
tion. The resulting chiral adducts,
niently converted into -amino alcohols,
b
-nitro alcohols, can be conve-
b
a
-hydroxy carboxylic
acids, aziridines, and other complex target molecules, which are
then used as highly versatile building blocks for the synthesis of
biological natural products and pharmaceutical agents.1,2 Since the
pioneering work of Shibasaki et al. in 1992,3a remarkable efforts
have been devoted toward the design of novel chiral ligands for
asymmetric metal catalyzed Henry reactions.3e8 Most of the chiral
ligands have focused on 1-(2-hydroxynaphthalen-1-yl) naph-
thalen-2-ols (BINOLs),3 bisoxazolines (BOXs),4 amino alcohols,5 bis-
amines,6 N,N0-dioxides,7 amino/imino-pyridines,8 and Schiff bases
(Salen-types).9
Ligands based on 1,10-phenanthrolines can chelate a wide va-
riety of different metals. Over the last two decades, considerable
Considering the features of quinine and phenanthroline, it is
interesting to see what will happen after the combination of the
two compounds. Thus some phenanthrolineecinchona hybrid
* Corresponding authors. E-mail addresses: huangyaodong@tju.edu.cn
(Y. Huang), ymw@nankai.edu.cn (Y. Wang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.010

L. Zhang et al. / Tetrahedron 69 (2013) 10644e10652
10645
chiral catalysts for the asymmetric Henry reaction were designed,
synthesized, and tested. Herein, a one-step method for a novel class
of chiral phenanthrolineequinine ligands was developed and ap-
plied to asymmetric copper(II)-catalyzed Henry reaction, the cat-
alytic activities of the catalysts in the reaction were also
investigated through theoretical calculations in order to explain the
unusually high enantioselectivity and great difference of the
organocatalysts.
2. Results and discussion
The chiral phenanthrolineecinchona ligands were constructed
by combining 2-bromo-1,10-phenanthroline with cinchona alka-
loids with a chiral element being provided by the cinchona alka-
loids. Several advantages are associated with this strategy: 1) an
easily accessed catalytic system with only one-step; 2) both of the
starting materials are commercially available; 3) a readily modified
structure, which is useful for diverse catalytic applications; and 4)
selective production of either enantiomeric product without the
need for a resolution process. Initially, chiral phenanthroline li-
gands were synthesized by nucleophilic substitution between 2-
bromo-1,10-phenanthroline 1 and quinine in DMSO. The mixture
was treated with NaH at 80e90 ꢀC for 5 h to give the diastereomeric
products L1 and L2, which were easily separated by flash chro-
matography in moderate yields (Scheme 1). Treatment of 2,9-
dibromo-1,10-phenanthroline 2 with quinine in the same pro-
cedure led to the only one product L3, which is probably due to the
effect of the bromine atom (Scheme 1). The absolute configurations
of L1 and L3 were unambiguously determined by X-ray crystal-
lography to be 9-(R) (Figs. 1 and 2). The configuration of L2 was
deduced to be 9-(S) according to the reported literature.17
Fig. 1. X-ray crystal structure of the complex (R)-L1eCuCl2.
loading was tested and this resulted in lower yields although
comparable enantioselectivities were achieved (Table 1, entries 7
and 8). Further investigations showed that the reaction is highly
sensitive to the nature of the solvent (Table 1, entries 9e15). A
mixed solvent of THF and i-PrOH (1:1) was found to be the best
solvent, affording a moderate yield and high enantioselectivity
(Table 1, entry 17, 57% yield, 85% ee).
Because the Henry reaction is thought to generate a nitronate
intermediate, a base is usually added to the reaction system to in-
crease the reactivity of the catalyst.6d,p Therefore a series of bases
were tested in the reaction and the results are summarized in
Table 2. As expected, the activity of the catalyst and the yield of the
Scheme 1. Synthetic route to chiral phenanthroline ligands derived from quinine.
The enantiopure phenanthroline ligands L1eL3 were then
screened to evaluate their abilities to promote the copper(II)-
catalyzed enantioselective Henry reaction between benzaldehyde
(3a) and nitromethane (4a) in the presence of CuCl2$2H2O (5 mol %)
in EtOH at room temperature. Gratifyingly, (S)-L2 promoted the
reaction smoothly, giving the desired product (5a) with moderate
yield and good enantioselectivity (Table 1, entry 2, 68% yield, 75%
ee). In sharp contrast, only traces of the product could be detected
when (R)-L1 and (R)-L3 were used, even when a higher tempera-
ture or a longer reaction time was used (Table 1, entries 1 and 3).
Different copper salts were then tested to evaluate the effect of
the counterions on the reaction. No improvements in enantiose-
lectivity were obtained (Table 1, entries 4e6). Then smaller catalyst
product (5a) were significantly improved (Table 2, entries 1e5). N-
Meemorpholine was the optimal additive in terms of yield and
enantioselectivity (Table 2, entry 5, 83% yield, 80% ee). Lowering the
temperature of the reaction led to an impressive improvement in
the enantioselectivity, albeit in a lower yield (entry 6, 70% yield,
90% ee). No significant improvements in yields and ee values were
achieved by changing the amount of the base, although comparable
enantioselectivities were obtained (entries 7e9).
Having optimized the reaction conditions, the generality of the
catalytic system for aldehydes bearing different substituents was
then investigated (Table 3). A wide range of aldehydes bearing
electron-withdrawing and electron-donating groups all reacted
under the optimized reaction conditions with moderate to good

10646
L. Zhang et al. / Tetrahedron 69 (2013) 10644e10652
Table 2
Effect of bases on the Henry reactiona
Entry
Bases
Et3N
DIPEA
DABCO
Morpholine
N-Meemorpholine
N-Meemorpholine
N-Meemorpholine
N-Meemorpholine
N-Meemorpholine
Loading (%)b
Time (h)
Yieldc (%)
eed (%)
1
2
3
4
5
5
5
5
5
5
1
3
10
20
20
20
20
20
38
34
34
34
78
75
70
62
83
70
44
52
75
71
76
77
79
80
90
89
86
87
5
6e
7e
8e
9e
a
Unless otherwise stated, all reactions were carried out with 3a (0.25 mmol) and
4a (2.5 mmol) in THF/iPrOH (1:1, 1 mL) in the presence of CuCl2$2H2O (5 mol %) and
L2 (6 mol %) at room temperature.
b
Equivalent based on benzaldehyde 3a.
Isolated yield.
Determined by HPLC analysis (Chiralcel OD-H column).
Reaction was carried out at 0 ꢀC.
c
d
e
Table 3
Enantioselective Henry reaction of aldehydes with nitroalkanesa
Fig. 2. X-ray crystal structure of (R)-L3.
∗
∗
Table 1
Optimization of reaction conditionsa
Entry
R1
R2
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ph (5a)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
Et
Et
38
36
36
38
14
15
38
36
17
36
36
41
38
38
41
17
41
41
21
24
21
21
68
50
68
47
83
79
73
60
62
65
58
67
69
65
50
86
52
49
55
62
68
52
90
81
77
76
71
66
88
92
90
84
84
89
90
81
86
86
3-ClC6H4 (5b)
2,4-ClC6H4 (5c)
4-FC6H4 (5d)
4-NO2C6H4 (5e)
2-MeOC6H4 (5f)
3-MeOC6H4 (5g)
4-MeOC6H4 (5h)
2,4-MeOC6H4 (5i)
2-MeC6H4 (5j)
4-MeC6H4 (5k)
4-HOC6H4 (5l)
2-Thiophenyl (5m)
2-Furyl (5n)
3-Furyl (5o)
PhCH]CH (5p)
n-Pr (5q)
i-Pr (5r)
Cyclohexyl (5s)
Ph (5t)
Entry
L
Metal salts
Solvents
Time (h) Yieldb (%) eec (%)
1
2
3
4
5
6
L1 CuCl2$2H2O
L2 CuCl2$2H2O
L3 CuCl2$2H2O
L2 Cu(OTf)2
L2 Cu(OAc)2$H2O
L2 Cu(NO3)2$3H2O EtOH
L2 CuCl2$2H2O
L2 CuCl2$2H2O
L2 CuCl2$2H2O
L2 CuCl2$2H2O
L2 CuCl2$2H2O
L2 CuCl2$2H2O
L2 CuCl2$2H2O
L2 CuCl2$2H2O
L2 CuCl2$2H2O
L2 CuCl2$2H2O
L2 CuCl2$2H2O
EtOH
EtOH
EtOH
EtOH
EtOH
120
72
120
72
72
72
72
72
72
68
92
68
120
44
40
21
21
Trace
68
Trace
43
77
46
58
36
42
33
38
30
52
60
73
56
57
ndd
75
ndd
65
57
66
76
73
85
81
79
76
78
77
75
81
85
9
10
11
12
13
14
15
16
17
18
19
20d
21d
22d
7e
8f
9
10
11
12
13
14
15
16
17
EtOH
EtOH
THF
CH2Cl2
CH3CN
CHCl3
Toluene
MeOH
i-PrOH
85
82
86
79/89
99/88
59/89
4-MeO (5u)
2-Thiophenyl (5y)
THF/EtOH¼1:1
THF/iPrOH¼1:1
a
Reactions were performed on a 0.25 mmol scale: CuCl2$2H2O (5 mol %), L2
(6 mol %) were stirred in THF/i-PrOH (1:1, 1 mL) at room temperature for 1 h, then
a
Unless otherwise stated, all reactions were carried out with 3a (0.25 mmol) and
4a (2.5 mmol) in the solvent (1 mL) in the presence of Cu(II) salts (5 mol %) and Li-
gands (6 mol %) at room temperature.
the aldehyde
3 (1 equiv), nitropropane 4 (10 equiv) and N-Meemorpholine
(5 mol %) were added and the reaction mixture was stirred for intend time at 0 ꢀC.
b
b
Isolated yield.
Determined by HPLC analysis.
Isolated yield.
Determined by HPLC analysis (Chiralcel OD-H column).
Not determined.
3 mol % CuCl2$2H2O and 3.3 mol % ligand were used.
c
c
d
d
5t, dr¼35/65; 5u, dr¼52:48; 5y, dr¼46:51.
e
f
1 mol % CuCl2$2H2O and 1.1 mol % ligand were used.
affording the desired products in 50e86% yields and 86e90% ee.
Notably, there appears to be a significant tolerance for aliphatic
aldehydes, including those with alicyclic and cyclic substitutions
(Table 3, entries 17e19). Finally, nitropropane was investigated and
the corresponding adducts were obtained in high to excellent
enantioselectivities, albeit with moderate diastereoselectivities
(Table 3, entries 20e22).
yields and moderate to high enantioselectivities (Table 3, entries
1e12, 47e83% yields, 66e92% ee). Generally, the benzaldehydes
with electron-donating groups gave higher enantioselectivities
than those with electron-withdrawing groups (Table 3, entries 2e5
vs 7e12). A substitution at the ortho-position of R1 had a detri-
mental effect on the ee value (Table 3, entries 6e8, 14, 15). Heter-
oaromatic aldehydes (Table 3, entries 13e15) and cinnamaldehyde
(Table 3, entry 16) were also suitable for this catalytic system,
To explain the significantly different catalytic activities of the
three ligands in Henry reaction, theoretical calculation is an

L. Zhang et al. / Tetrahedron 69 (2013) 10644e10652
10647
essential and efficient method. For this purpose, great endeavor
was devoted to cultivate single crystals from the ligands and their
complexes. However, apart from L3 and L1eCuCl2, all attempts to
obtain single crystals suitable for X-ray analysis failed. From the X-
ray crystal structure, (R)-L1 was found to coordinate with Cu(II) to
give a Cu(II)eL1 complex, which is an inactive catalyst for the Henry
reaction. The X-ray crystallography structure suggested that three
nitrogen atoms including the bridge-head nitrogen atom of the
quinine coordinate to the copper, giving an unexpected five-
coordinate complex (Fig. 1). To the best of our knowledge, there
has been no report about this novel complexation of phenanthro-
line ligands with Cu(II). The absolute configuration of the complex
was determined to be 9-(R), and thus L1 was also deduced to be 9-
(R), which is the same as quinine.
h
3-L1 complex (7.1872 Debye, Table 4, entries 1 and 2). In this case,
the polarity of the Cu(II)eL2 complex ( 3-L2) would be lower than
that of the Cu(II)eL1 complex ( 3-L1) and it is inconsistent with the
TLC results. However, if the Cu(II)eL2 complex is four-dentate (h2
L2), the dipole moment of
2-L2 is higher than that of 3-L1 (Table
h
h
-
h
h
4, entries 1 and 3), which is in agreement with the TLC results.
Therefore, Cu(II) is more likely to coordinate to the two nitrogen
atoms of the phenanthroline. Second, the changes of the dihedral
angles in two ligands before and after they coordinate to copper
(Fig. 3) also support a four-dent0ate s0tructure. The dihedral angles
0
0
C1eN2eN3eN4 and C1 eN2 eN3 eN4 , as shown in Fig. 3a, were
149.0ꢀ and 129.9ꢀ, respectively. The change of the dihedral angle
(C1eN2eN3eN4) between L2 and
than the change of the dihedral angle (C1 eN2 eN3 eN4 ) between
L1 and
that the
complex. A more deformed structure will lead to higher energy and
less stability of it. Accordingly, it should be difficult to form the 3-
nitrogen-coordinate
ergy of
2-L2 is higher than that of
indicating that the transformation from
vorable. Therefore, CuCl2 binds to the two nitrogen atoms of the
phenanthroline to form a four-dentate
2-L2 complex, which is
able to activate the reaction between substrates 3a and 4a.
To obtain insight into the mechanism of the reaction of L3 with
CuCl2, its product was checked by mass spectrometry using elec-
trospray ionization (ESI) model. The spectrum only gave m/z 583.1
([Mþ3H]þ, 100%) and 584.1 ([Mþ4H]þ, 28%) while no peaks re-
lating to complex product were observed, implying L3 did not co-
ordinate with cupric salt. However, under the same reaction and
examination conditions, the one of L2 gave m/z 503.2 ([MþH]þ,
100%), 504.2 ([Mþ2H]þ, 33%), 600.2 ([MþCuCl]þ, 50%), 602.2
([MþCuClþ2H]þ, 39%), 603.3 ([MþCuClþ3H]þ, 15%), 604.2
([MþCuClþ4H]þ, 9%), 605.2 ([MþCuClþ5H]þ, 4%). The observation
of m/z 503.2 and 504.2 is expected since some complexes may
decompose during the ionization. The peak cluster of 600.2e605.2
indicates unambiguously L2 forms complex product with CuCl2. L3
can not form a complex with Cu(II) and thus is inactive for the Henry
reaction. The geometries of L1 and L3 with their van der Waals radii
are shown in Fig. 4 and a comparison shows that the Br atom
probably sterically blocks the attack of the copper ion, which could
be the reason that the complex did not form.
h
3-L2 was almost0six times larger
0
0
0
Notably, L2 also formed a Cu(II)eL2 complex. However, this
complex is an efficient enantioselective catalyst in the Henry re-
action. Even though a single crystal of the Cu(II)eL2 complex could
not be obtained, the different catalytic activity indicates that there
must be crucial differences between the two structures of the
complexes that significantly affect their catalytic activities.
h
3-L1 (Table 4, entries 1 and 2, Fig. 3b and c). This suggests
h
3-L2 complex is much more distorted than the 3-L1
h
h
3-L2 complex. Finally, the binding free en-
h
h
3-L2 (Table 4, entries 2 and 3),
2-L2 to 3-L2 is not fa-
Computational study has been performed to help understanding
the different catalytic activities of these copper complexes. All
possible isomers of the species under computation have been
considered, and the most stable ones are screened out by confor-
mation search and further geometry optimization. Geometry op-
timization and frequency analysis on the most stable species have
been performed using the B3LYP functional and a basis set of 6-
31G* for all the atoms. All calculations were carried out with
Gaussian 09.18 Table 4 listed the binding energies, dipole moments
and dihedral angle changes after the two ligands L1 and L2 co-
ordinated to Cu(II) salts. The optimized geometry of the Cu(II)eL1
complex is consistent with the X-ray crystallography structure, in
which two chlorine atoms bind to copper while three nitrogen
atoms coordinate with copper to form a five-dentate pattern (Table
h
h
h
4, h
3-L1). As well known, Cu(II) could have up to six coordinate sites.
Thus, in the Cu(II)eL1 complex not enough coordinate sites are
remained to coordinate simultaneously to the substrates 3a and 4a.
This is the reason why the reaction between 3a and 4a cannot occur
with Cu(II)eL1 complex.
Table 4
Binding energies, dipole moments and dihedral angle changes after the two ligands
L1 and L2 coordinated to Cu(II) salts
Based on the above theoretical calculations, a possible transition
state, which explains the stereochemical outcome of the reaction is
proposed in Scheme 2. According to the model proposed by Evans
et al.,4d the aldehyde and nitromethane coordinate to the copper
center in such a way that there is a maximum activation for the
reactive partners. Thus, the oxygen atom of the nitromethane ap-
proaches the metal center from the axial side and the carbonyl
oxygen atom comes in from the equatorial side. The nucleophilic
carbon of the nitronate ion forms in situ by the deprotonation of the
nitromethane and then attack the aldehyde from the Re-face to give
the R isomer.
Entry
Complex
Binding energy
(kcal/mol)d
Dihedral angle
change (ꢀ)e
Dipole moment
(Debye)
1a
2b
3c
h
h
h
3-L1
3-L2
2-L2
ꢁ69.9
ꢁ64.5
ꢁ67.1
11.2
61.4
d
7.1872
6.7957
10.6340
a
The five-dentate Cu(II)eL1 complex was indicated as
h
3-L1.
The hyposized five-dentate Cu(II)eL2 complex, which was similar as Cu(II)eL1
complex was indicated as
3-L2 for computational study.
The four-dentate Cu(II)eL2 complex was indicated as
b
h
c
h
2-L2.
d
e
Binding energy ¼ GM ꢁ G
ꢁ GMꢁnoCu where G is Gibbs free energy.
CuCl2
Dihedral angle change is the difference between the dihedral angles
C1eN2eN3eN4 and C10eN20eN30eN4 in ligands and that in Cu(II)eL complexes,
0
respectively.
3. Conclusion
In comparison, it is proposed that L2 coordinates to Cu(II)
through the two nitrogen atoms of phenanthroline to form a four-
A novel class of chiral phenanthroline ligands has been de-
veloped by combining 1,10-phenanthroline with quinine. These
chiral ligands can be easily prepared through a one-step procedure
with commercially available starting materials and do not require
any resolution. The ligand L2 was coordinated to Cu(II) and then was
employed in the asymmetric Henry reaction with good substrate
generality, moderate to good yields and high enantioselectivities.
Theoretical calculations showed that L2 coordinated with two ni-
trogen atoms of phenanthroline to give a Cu(II)eL2 complex, which
was able to activate both aldehyde and nitroalkane in the reaction.
dentate copper complex (Table 4,
simultaneously to the substrates 3a and 4a and thus catalyzes the
h
2-L2), which can coordinate
reaction. The evidence for this structural proposal of h
2-L2 is sup-
ported by three facts. First, the Cu(II)eL2 complex was located much
lower on the same thin layer chromatography (TLC) plate than the
Cu(II)eL1 complex, indicating the two complexes have different
structures. The computational study showed that if the Cu(II)eL2
was five dentate (
complex would be 6.7957 Debye, which is lower than that of the
h h
3-L2) then the dipole moment of the 3-L2

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L. Zhang et al. / Tetrahedron 69 (2013) 10644e10652
Fig. 3. (a) The dihedral angle 4(C1eN2eN3eN4) in (R)-L1 and 4(C10eN20eN30eN40) in (S)-L2; (b) Dihedral angle of the ligand (R)-L1 and the complex (R)-
the ligand (S)-L2 and the complex (S)-
3-L2.
h
3-L1; (c) Dihedral angle of
h
Scheme 2. Proposed transition state for the catalytic asymmetric Henry reaction.
Fig. 4. Geometry of (R)-L1 and (R)-L3 shown in van der Waals radius.
4. Experimental section
4.1. General
L1 with the opposite configuration to L2 reacted with Cu(II) to form
an unexpected five-coordinate complex, which had no vacant 4d
orbital to catalyze the reaction. This novel complexation is signifi-
cantly different from all previously reported chiral phenanthroline
ligands. L3 did not coordinate with Cu(II) because of the hindrance
of Br atom. The development of more chiral phenanthroline ligands
for asymmetric syntheses is currently underway.
Chemicals and solvents were purchased from commercial sup-
pliers and used as received, unless otherwise stated. 1H and 13C
NMR spectra were recorded on a Bruker DPX 400 spectrometers.
Chemical shifts are reported in parts per million from tetrame-
thylsilane with the solvent resonance as the internal standard.

L. Zhang et al. / Tetrahedron 69 (2013) 10644e10652
10649
Multiplicity was indicated as follows: s (singlet), d (doublet), t
4.3. General experimental procedure for Henry reaction
(triplet), q (quartet), m (multiplet), dd (doublet of doublet), br s
(broad singlet). Coupling constants were reported in Hertz (Hz).
Accurate mass data and routine mass data were obtained with an
Agilent Technologies 6520 Accurate-Mass Q-TOF LC/MS instrument
and a LCQ Advantage MAX instrument, respectively, under ESI
model. Optical rotations were measured with a PerkineElmer 341
polarimeter at 25 ꢀC. HPLC analysis was performed with a Shi-
madzu CTO-10 AS instrument and a Chiralpak AD-H column pur-
chased from Daicel Chemical Industries, LTD.
The mixture of L2 (7.5 mg, 0.015 mmol) and CuCl2$2H2O (2.1 mg,
0.0125 mmol) was stirred in THF/i-PrOH (1:1, 1 mL) at room tem-
perature under N2 protection for 1 h to form the complex. The
resulting mixture was cooled to 0 ꢀC, then nitroalkanes (2.5 mmol),
N-Meemorpholine (1.4 mL) and aldehydes (0.25 mmol) were added
and stirring continued for intend time at 0 ꢀC. The solvent was
removed under reduced pressure and the resulting mixture was
directly purified by column chromatography to afford the Henry
reaction product.
4.2. Synthesis of ligands L1eL3
(R)-2-Nitro-1-phenylethanol (5a, Table 4, entry 1).4d The title
compound was prepared according to the general procedure and
purified by column chromatography (petroleum ether/ethyl
acetate¼6:1). Enantiomeric excess (90% ee, Table 4, entry 1) was
determined by HPLC (Chiralcel OD-H), hexane/i-PrOH¼90:10,
1.0 mL/min, 254 nm, major enantiomer (R) tr¼12.847 min, minor
enantiomer (S) tr¼16.136 min; 1H NMR (400 MHz, CDCl3):
To a solution of NaH (5 equiv, 20 mmol) in 10 mL DMSO was
added quinine (4 mmol) and the mixture was stirred for 1 h at room
temperature. Then 2-bromo-1,10-phenanthroline 1 (6 mmol) or
2,9-dibromo-1,10-phenanthroline 2 (6 mmol) was added and the
reaction was kept for 5 h at 80e90 ꢀC under stirring. The mixture
was cooled to room temperature and 20 mL H2O was added care-
fully, following extracted with CH2Cl2 (3ꢂ20 mL). The organic
phases were combined, washed with brine, dried over anhydrous
Na2SO4, and evaporated in vacuo. The residue was purified by flash
d
7.43e7.29 (m, 5H), 5.39 (m, 1H), 4.56 (dd, J¼13.2, 9.6 Hz, 1H), 4.46
(dd, J¼13.2, 3.1 Hz, 1H), 3.27 (d, J¼3.6 Hz, 1H). 13C NMR (101 MHz,
CDCl3):
d 138.28, 129.04, 128.96, 126.01, 81.28, 71.01.
(R)-1-(3-Chlorophenyl)-2-nitroethanol (5b, Table 4, entry 2).19
The title compound was prepared according to the general pro-
cedure and purified by column chromatography (petroleum ether/
ethyl acetate¼6:1). Enantiomeric excess (73% ee, Table 4, entry 2)
was determined by HPLC (Chiralcel OD-H), hexane/i-PrOH¼90:10,
1.0 mL/min, 215 nm, major enantiomer (R) tr¼12.731 min, minor
enantiomer (S) tr¼16.514 min; 1H NMR (400 MHz, CDCl3):
chromatography to afford L1eL3.
24
L1: White powder, mp 101e103 ꢀC; [
a
]
þ3.0 (c 1.4, CH2Cl2);
D
IR (KBr) nmax: 2927, 1618, 1504, 1454, 1349, 1260, 1076, 1027, 993,
850 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
9.06 (d, J¼3.1 Hz, 1H), 8.73
(d, J¼4.5 Hz, 1H), 8.36 (s, 1H), 8.13 (m, J¼7.1 Hz, 2H), 8.04e7.92 (m,
2H), 7.73 (d, J¼4.4 Hz, 1H), 7.65 (d, J¼8.7 Hz, 1H), 7.61e7.51 (m,
2H), 7.36 (dd, J¼9.1, 2.0 Hz, 1H), 7.28 (d, J¼8.5 Hz, 1H), 5.81e5.68
(m, 1H), 5.06e4.88 (m, 2H), 4.21 (s, 3H), 3.50 (t, J¼8.3 Hz, 1H),
3.40e3.22 (m, 2H), 2.87 (d, J¼13.3 Hz, 1H), 2.77e2.66 (m, 1H),
2.37 (s, 1H), 2.17e2.07 (m, 1H), 1.91 (s, 1H), 1.85e1.66 (m, 2H), 1.55
d
7.50e7.12 (m, 4H), 5.34 (dd, J¼9.1, 3.5 Hz, 1H), 4.46 (m, J¼13.3,
6.3 Hz, 2H), 3.65 (s, 1H). 13C NMR (101 MHz, CDCl3):
130.37, 129.01, 126.23, 124.23, 80.95, 70.28.
d 140.31, 134.77,
(R)-1-(2, 4-Dichlorophenyl)-2-nitroethanol (5c, Table 4, entry
3).6n The title compound was prepared according to the general
procedure and purified by column chromatography (petroleum
ether/ethyl acetate¼6:1). Enantiomeric excess (77% ee, Table 4,
entry 3) was determined by HPLC (Chiralcel AD-H), hexane/i-
PrOH¼90:10, 0.5 mL/min, 254 nm, major enantiomer (R)
tr¼14.592 min, minor enantiomer (S) tr¼17.432 min; 1H NMR
(s, 1H). 13C NMR (101 MHz, CDCl3):
d 161.35, 158.54, 149.48, 147.16,
144.48, 143.89, 140.96, 139.86, 136.27, 131.33, 129.12, 126.86,
125.97, 125.18, 124.23, 123.00, 122.60, 118.52, 115.00, 113.69,
101.67, 73.20, 59.68, 56.72, 42.85, 39.26, 29.70, 27.60, 26.99, 21.34.
HRMS: calculated for [MþH]þ C32H30N4O2 503.2442, found
503.2443.
24
L2: White yellow powder, mp 205e206 ꢀC; [
a
]
þ178.2 (c
(400 MHz, CDCl3):
d
7.61 (d, J¼8.4 Hz, 1H), 7.40 (d, J¼2.0 Hz, 1H),
D
0.7, CH2Cl2); IR (KBr) nmax: 3389, 2926, 1618, 1504, 1454, 1354,
7.34 (dd, J¼8.4, 2.0 Hz, 1H), 5.79 (m, J¼9.4, 3.9, 2.4 Hz, 1H), 4.64 (dd,
J¼13.7, 2.3 Hz, 1H), 4.42 (dd, J¼13.7, 9.5 Hz, 1H), 3.20 (d, J¼4.2 Hz,
1251, 1134, 1026, 918, 848 cmꢁ1 1H NMR (400 MHz, CDCl3):
.
d
9.05 (s, 1H), 8.77 (d, J¼4.2 Hz, 1H), 8.13 (dd, J¼28.8, 8.3 Hz, 3H),
1H). 13C NMR (101 MHz, CDCl3):
128.60, 127.99, 79.09, 67.44.
d 135.24, 134.16, 132.09, 129.51,
7.95 (m, J¼10.2 Hz, 2H), 7.76e7.48 (m, 5H), 7.37 (d, J¼8.8 Hz, 1H),
5.74 (dd, J¼17.1, 6.7 Hz, 1H), 5.24e5.03 (m, 2H), 4.13 (d,
J¼26.2 Hz, 3H), 3.88e3.75 (m, 1H), 3.27 (s, 2H), 2.72 (s, 1H), 2.02
(d, J¼17.1 Hz, 2H), 1.71 (d, J¼11.0 Hz, 1H), 1.53 (s, 1H), 1.35e1.17
(R)-1-(4-Fluorophenyl)-2-nitroethanol (5d, Table 4, entry 4).4d
The title compound was prepared according to the general pro-
cedure and purified by column chromatography (petroleum ether/
ethyl acetate¼6:1). Enantiomeric excess (76% ee, Table 4, entry 4)
was determined by HPLC (Chiralcel OD-H), hexane/i-PrOH¼90:10,
0.8 mL/min, 215 nm, major enantiomer (R) tr¼13.513 min, minor
enantiomer (S) tr¼115.837 min; 1H NMR (400 MHz, CDCl3):
(m, 3H). 13C NMR (101 MHz, CDCl3):
d 160.57, 158.40, 149.23,
147.36, 144.93, 143.13, 139.60, 137.70, 136.31, 131.63, 128.98,
127.71, 126.32, 125.52, 124.07, 122.65, 122.31, 116.90, 115.15,
102.63, 58.02, 56.35, 54.12, 41.70, 37.03, 30.92, 29.68, 26.76,
24.79. HRMS: calculated for [MþH]þ C32H30N4O2 503.2442,
d
7.43e7.29 (m, 2H), 7.14e7.00 (m, 2H), 5.41 (dd, J¼9.5, 3.2 Hz, 1H),
found 503.2443.
4.56 (dd, J¼13.2, 9.5 Hz, 1H), 4.47 (dd, J¼13.2, 3.2 Hz, 1H), 3.27 (d,
24
L3: White yellow powder, mp 195e197 ꢀC; [
a
]
ꢁ103.7 (c 0.5,
J¼66.4 Hz, 1H). 13C NMR (101 MHz, CDCl3):
d 164.09, 134.03, 127.84,
D
CH2Cl2); IR (KBr) nmax: 2927, 1619, 1579, 1490, 1449, 1364, 1267,
116.07, 81.15, 70.34.
1232, 1109, 1026, 970, 852 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
8.75
(R)-2-Nitro-1-(4-nitrophenyl)ethanol (5e, Table 4, entry 5).4d
The title compound was prepared according to the general pro-
cedure and purified by column chromatography (petroleum ether/
ethyl acetate¼5:1). Enantiomeric excess (71% ee, Table 4, entry 5)
was determined by HPLC (Chiralcel OD-H), hexane/i-PrOH¼85:15,
1.0 mL/min, 215 nm, major enantiomer (R) tr¼15.571 min, minor
(d, J¼4.4 Hz, 1H), 8.08 (d, J¼8.7 Hz, 1H), 8.00e7.84 (m, 4H), 7.73 (d,
J¼4.3 Hz, 1H), 7.64 (dd, J¼18.4, 8.5 Hz, 2H), 7.53 (d, J¼8.6 Hz, 1H),
7.34 (dd, J¼9.1, 2.1 Hz, 1H), 7.20 (d, J¼8.6 Hz, 1H), 5.90e5.78 (m, 1H),
5.00 (m, J¼12.7 Hz, 2H), 4.04 (s, 3H), 3.66e3.55 (m, 1H), 3.44 (d,
J¼11.6 Hz, 1H), 3.23e3.10 (m, 1H), 2.74 (d, J¼12.6 Hz, 2H), 2.34 (s,
1H), 1.91 (d, J¼31.7 Hz, 4H), 1.60 (s, 1H). 13C NMR (101 MHz, CDCl3):
enantiomer (S) tr¼19.195 min; 1H NMR (400 MHz, CDCl3):
d 8.26 (d,
d
161.61,158.14,147.36,145.39,144.71,143.02,141.80,139.50,138.04,
J¼8.7 Hz, 2H), 7.63 (d, J¼8.7 Hz, 2H), 5.61 (d, J¼4.3 Hz, 1H),
131.45, 127.85, 127.39, 126.45, 125.37, 123.38, 122.22, 119.83, 114.57,
114.01, 101.76, 74.49, 59.41, 58.31, 56.77, 56.34, 42.77, 39.69, 30.94,
27.78. HRMS: calculated for [MþH]þ C32H29BrN4O2 581.1547, found
581.1548.
4.69e4.50 (m, 2H), 3.45 (s, 1H). 13C NMR (101 MHz, CDCl3):
d 148.10,
145.14, 126.98, 124.19, 80.68, 69.98.
(R)-1-(2-Methoxyphenyl)-2-nitroethanol (5f, Table 4, entry 6).4d
The title compound was prepared according to the general

10650
L. Zhang et al. / Tetrahedron 69 (2013) 10644e10652
procedure and purified by column chromatography (petroleum
ether/ethyl acetate¼6:1). Enantiomeric excess (66% ee, Table 4,
entry 6) was determined by HPLC (Chiralcel OD-H), hexane/i-
PrOH¼90:10, 0.8 mL/min, 215 nm, major enantiomer (R)
tr¼13.740 min, minor enantiomer (S) tr¼16.487 min; 1H NMR
J¼11.0 Hz, 3H). 13C NMR (101 MHz, CDCl3):
d 138.83, 135.41, 129.67,
125.97, 81.29, 70.89, 21.17.
(R)-1-(4-Hydroxyphenyl)-2-nitroethanol (5l, Table 4, entry
12).6o The title compound was prepared according to the general
procedure and purified by column chromatography (petroleum
ether/ethyl acetate¼3:1). Enantiomeric excess (89% ee, Table 4,
entry 12) was determined by HPLC (Chiralcel OJ-H), hexane/i-
PrOH¼70:30, 0.8 mL/min, 215 nm, major enantiomer (R)
tr¼14.101 min, minor enantiomer (S) tr¼16.844 min; 1H NMR
(400 MHz, CDCl3):
d
7.44e7.28 (m, 2H), 6.96 (m, J¼24.4, 15.7, 4.4 Hz,
2H), 5.60 (dd, J¼9.3, 3.1 Hz, 1H), 4.59 (dd, J¼12.8, 3.2 Hz, 1H), 4.49
(dd, J¼12.8, 9.3 Hz,1H), 3.84 (d, J¼6.6 Hz, 3H), 3.66 (d, J¼6.4 Hz,1H).
13C NMR (101 MHz, CDCl3):
110.66, 79.90, 67.56, 55.42.
d 156.07, 129.76, 127.06, 126.35, 121.00,
(400 MHz, DMSO):
d
9.49 (d, J¼23.4 Hz, 1H), 7.49e7.10 (m, 2H), 6.80
(R)-1-(3-Methoxyphenyl)-2-nitroethanol (5g, Table 4, entry
7).20 The title compound was prepared according to the general
procedure and purified by column chromatography (petroleum
ether/ethyl acetate¼6:1). Enantiomeric excess (88% ee, Table 4,
entry 7) was determined by HPLC (Chiralcel OD-H), hexane/i-
PrOH¼90:10, 1.0 mL/min, 215 nm, major enantiomer (R)
tr¼21.053 min, minor enantiomer (S) tr¼27.262 min; 1H NMR
(m, J¼20.0, 17.5 Hz, 2H), 5.91 (s, 1H), 5.28e4.43 (m, 3H). 13C NMR
(101 MHz, DMSO):
d 157.10, 128.96, 127.45, 114.93, 82.04, 69.81.
(S)-2-Nitro-1-(thiophen-2-yl)ethanol (5m, Table 4, entry 13).6n
The title compound was prepared according to the general pro-
cedure and purified by column chromatography (petroleum ether/
ethyl acetate¼6:1). Enantiomeric excess (90% ee, Table 4, entry 13)
was determined by HPLC (Chiralcel OD-H), hexane/i-PrOH¼90:10,
0.5 mL/min, 215 nm, major enantiomer (R) tr¼27.999 min, minor
enantiomer (S) tr¼30.711 min; 1H NMR (400 MHz, CDCl3):
(400 MHz, CDCl3):
d
7.30 (m, J¼8.1 Hz, 1H), 6.90 (m, J¼14.2, 8.4,
4.5 Hz, 3H), 5.44e5.35 (m, 1H), 4.58 (dd, J¼13.1, 9.6 Hz, 1H), 4.48
(dd, J¼13.1, 3.1 Hz, 1H), 3.81 (s, 3H), 3.42 (d, J¼3.7 Hz, 1H). 13C NMR
d
7.43e7.26 (m, 1H), 7.18e6.94 (m, 2H), 5.69 (dd, J¼9.3, 3.3 Hz, 1H),
(101 MHz, CDCl3):
81.27, 70.90, 55.35.
d
159.98, 139.98, 130.11, 118.16, 114.35, 111.55,
4.65 (m, J¼16.7, 13.3, 6.4 Hz, 2H), 3.60 (s, 1H). 13C NMR (101 MHz,
CDCl3):
d 141.43, 127.28, 126.15, 125.13, 80.84, 67.05.
(R)-1-(4-Methoxyphenyl)-2-nitroethanol (5h, Table 4, entry
8).6n The title compound was prepared according to the general
procedure and purified by column chromatography (petroleum
ether/ethyl acetate¼6:1). Enantiomeric excess (92% ee, Table 4,
entry 8) was determined by HPLC (Chiralcel OD-H), hexane/i-
PrOH¼85:15, 0.8 mL/min, 215 nm, major enantiomer (R)
tr¼14.708 min, minor enantiomer (S) tr¼17.596 min; 1H NMR
(S)-1-(Furan-2-yl)-2-nitroethanol (5n, Table 4, entry 14).6n The
title compound was prepared according to the general procedure
and purified by column chromatography (petroleum ether/ethyl
acetate¼6:1). Enantiomeric excess (81% ee, Table 4, entry 14) was
determined by HPLC (Chiralcel AD-H), hexane/i-PrOH¼97:3, 0.5 mL/
min, 254 nm, major enantiomer (R) tr¼51.923 min, minor enantio-
mer (S) tr¼56.810 min; 1H NMR (400 MHz, CDCl3):
d 7.42 (d,
(400 MHz, CDCl3):
d
7.30 (d, J¼8.6 Hz, 2H), 6.91 (d, J¼8.7 Hz, 2H),
J¼0.8 Hz, 1H), 6.53e6.33 (m, 2H), 5.47 (dd, J¼9.0, 3.2 Hz, 1H), 4.78
5.38 (d, J¼7.9 Hz, 1H), 4.59 (dd, J¼13.1, 9.6 Hz, 1H), 4.46 (dd, J¼13.1,
(dd, J¼13.4, 9.0 Hz, 1H), 4.67 (dd, J¼13.4, 3.5 Hz, 1H), 3.16 (s, 1H). 13
C
3.1 Hz, 1H), 3.79 (d, J¼9.2 Hz, 3H), 3.02 (s, 1H). 13C NMR (101 MHz,
NMR (101 MHz, CDCl3): d 150.79,143.19,110.68,108.19, 78.44, 64.85.
CDCl3):
d
160.01, 130.32, 127.32, 114.40, 81.30, 70.68, 55.38.
(S)-1-(Furan-3-yl)-2-nitroethanol (5o, Table 4, entry 15).21 The
title compound was prepared according tothegeneralprocedure and
purified by column chromatography (petroleum ether/ethyl
acetate¼6:1). Enantiomeric excess (86% ee, Table 4, entry 15) was
determined by HPLC(Chiralcel AD-H), hexane/i-PrOH¼90:10,1.0mL/
min, 215 nm, major enantiomer (R) tr¼12.052 min, minor enantio-
(R)-1-(2,4-Dimethoxyphenyl)-2-nitroethanol (5i, Table 4, entry
9). The title compound was prepared according to the general
procedure and purified by column chromatography (petroleum
ether/ethyl acetate¼6:1). It was a colorless oily compound. Enan-
tiomeric excess (90% ee, Table 4, entry 9) was determined by HPLC
(Chiralcel OD-H), hexane/i-PrOH¼90:10,1.0 mL/min, 215 nm, major
enantiomer (R) tr¼14.768 min, minor enantiomer (S)
mer (S) tr¼16.430 min; 1H NMR (400 MHz, CDCl3):
d 7.63e7.18 (m,
2H), 6.37 (d, J¼0.9 Hz, 1H), 5.35 (dd, J¼9.2, 3.4 Hz, 1H), 4.58 (dd,
tr¼22.478 min; 1H NMR (400 MHz, CDCl3):
d
7.29 (d, J¼8.4 Hz, 1H),
J¼13.1, 9.2 Hz, 1H), 4.50 (dd, J¼13.1, 3.5 Hz,1H), 3.39 (s,1H). 13C NMR
6.47 (m, J¼12.1, 9.0, 4.9 Hz, 2H), 4.80 (d, J¼6.9 Hz, 1H), 4.56 (m,
J¼6.6 Hz, 2H), 3.79 (dd, J¼19.9, 8.0 Hz, 6H), 3.50 (d, J¼5.9 Hz, 1H).
(101 MHz, CDCl3): d 144.04, 139.99, 123.55, 108.10, 80.29, 64.13.
(R,E)-1-Nitro-4-phenylbut-3-en-2-ol (5p, Table 4, entry 16).22
The title compound was prepared according to the general pro-
cedure and purified by column chromatography (petroleum ether/
ethyl acetate¼6:1). Enantiomeric excess (86% ee, Table 4, entry 16)
was determined by HPLC (Chiralcel OD-H), hexane/i-PrOH¼85:15,
0.8 mL/min, 215 nm, major enantiomer (R) tr¼31.843 min, minor
enantiomer (S) tr¼28.015 min; 1H NMR (400 MHz, CDCl3):
13C NMR (101 MHz, CDCl3):
d 161.10, 157.20, 130.61, 127.95, 118.72,
104.63, 80.12, 75.60, 67.54, 55.42. HRMS: calculated for [MþH]þ
C10H13NO5 228.0867, found 228.0865.
(R)-1-(2-Methyphenyl)-2-nitroethanol (5j, Table 4, entry 10).4d
The title compound was prepared according to the general pro-
cedure and purified by column chromatography (petroleum ether/
ethyl acetate¼6:1). Enantiomeric excess (84% ee, Table 4, entry 10)
was determined by HPLC (Chiralcel OD-H), hexane/i-PrOH¼85:15,
0.8 mL/min, 215 nm, major enantiomer (R) tr¼9.507 min, minor
enantiomer (R) tr¼13.965 min; 1H NMR (400 MHz, CDCl3):
d
7.34e7.24 (m, 5H), 6.67 (dd, J¼15.7, 9.5 Hz, 1H), 6.12e5.97 (m, 1H),
4.59e4.45 (m, 1H), 4.39 (dd, J¼6.7, 3.6 Hz, 2H), 3.32 (s, 1H). 13C NMR
(101 MHz, CDCl3):
80.06, 69.70.
d 133.41, 128.83, 128.54, 126.85, 125.37, 121.32,
d
7.51e7.12 (m, 4H), 5.60 (m, J¼9.6, 3.1 Hz, 1H), 4.47 (dd, J¼13.2,
(R)-1-Nitropentyl-2-ol (5q, Table 4, entry 17).23 The title com-
pound was prepared according to the general procedure and pu-
rified by column chromatography (petroleum ether/ethyl
acetate¼6:1). Enantiomeric excess (85% ee, Table 4, entry 17) was
determined by HPLC (Chiralcel AD-H), hexane/i-PrOH¼95:5,
1.0 mL/min, 215 nm, major enantiomer (R) tr¼14.555 min, minor
enantiomer (S) tr¼23.733 min; 1H NMR (400 MHz, CDCl3):
9.7 Hz, 1H), 4.37 (dd, J¼13.2, 2.7 Hz, 1H), 3.28 (d, J¼3.6 Hz, 1H), 2.35
(s, 3H). 13C NMR (101 MHz, CDCl3):
126.76, 125.67, 80.30, 67.94, 18.85.
d 136.44, 134.61, 130.87, 128.67,
(R)-1-(4-Methyphenyl)-2-nitroethanol (5k, Table 4, entry 11).6n
The title compound was prepared according to the general pro-
cedure and purified by column chromatography (petroleum ether/
ethyl acetate¼6:1). Enantiomeric excess (84% ee, Table 4, entry 11)
was determined by HPLC (Chiralcel OD-H), hexane/i-PrOH¼95:5,
0.5 mL/min, 215 nm, major enantiomer (R) tr¼17.917 min, minor
d
4.43e4.29 (m, 2H), 4.30e4.20 (m, 1H), 3.65 (d, J¼5.4 Hz, 1H),
1.51e1.42 (m, 2H),1.41e1.30 (m, 2H), 0.90 (dd, J¼9.9, 4.2 Hz, 3H). 13
C
NMR (101 MHz, CDCl3):
d 80.84, 68.53, 35.79, 18.34, 13.61.
enantiomer (S) tr¼21.810 min; 1H NMR (400 MHz, CDCl3):
d
7.21 (m,
(R)-3-Methyl-1-nitro-butyl-2-ol (5r, Table 4, entry 18).4d The
title compound was prepared according to the general procedure
and purified by column chromatography (petroleum ether/ethyl
J¼22.3, 8.1 Hz, 4H), 5.33 (d, J¼9.6 Hz, 1H), 4.53 (dd, J¼13.1, 9.6 Hz,
1H), 4.42 (dd, J¼13.1, 3.2 Hz, 1H), 3.36 (d, J¼3.6 Hz, 1H), 2.33 (d,

L. Zhang et al. / Tetrahedron 69 (2013) 10644e10652
10651
acetate¼6:1). Enantiomeric excess (82% ee, Table 4, entry 18) was
determined by HPLC (Chiralcel OD-H), hexane/i-PrOH¼98:2,
0.5 mL/min, 215 nm, major enantiomer (R) tr¼30.822 min, minor
Key Laboratory of Elemento-Organic Chemistry is gratefully
acknowledged.
enantiomer (S) tr¼33.880 min; 1H NMR (400 MHz, CDCl3):
d 4.40
References and notes
(m, J¼22.0, 12.7, 6.1 Hz, 2H), 4.12e3.98 (m, 1H), 3.43 (d, J¼5.6 Hz,
1H), 1.73 (d, J¼6.3 Hz, 1H), 0.92 (m, J¼6.5 Hz, 6H). 13C NMR
1. (a) Luzzio, F. A. Tetrahedron 2001, 57, 915e945; (b) Ono, N. The Nitro Group in
Organic Synthesis; Wiley-VCH: New York, NY, 2001.
(101 MHz, CDCl3):
d 79.43, 73.51, 31.78, 18.29, 17.40.
2. For recent examples, see: (a) Uraguchi, D.; Nakamura, S.; Ooi, T. Angew. Chem.
2010, 49, 7562e7565; (b) Metro, T. X.; Cochi, A.; Gomez Pardo, D.; Cossy, J. J.
Org. Chem. 2011, 76, 2594e2602; (c) Liu, L.; Zhang, S.; Xue, F.; Lou, G.; Zhang, H.;
Ma, S.; Duan, W.; Wang, W. Chem.dEur. J. 2011, 17, 7791e7795; (d) Lai, G.; Guo,
F.; Zheng, Y.; Fang, Y.; Song, H.; Xu, K.; Wang, S.; Zha, Z.; Wang, Z. Chem.dEur. J.
2011, 17, 1114e1117; (e) Kureshy, R. I.; Das, A.; Khan, N.-u. H.; Abdi, S. H. R.; Bajaj,
H. C. ACS Catal. 2011, 1, 1529e1535; (f) Guo, Z.-L.; Deng, Y.-Q.; Zhong, S.; Lu, G.
Tetrahedron: Asymmetry 2011, 22, 1395e1399; (g) Nitabaru, T.; Kumagai, N.;
Shibasaki, M. Angew. Chem., Int. Ed. 2012, 51, 1644e1647.
3. For recent examples on asymmetric Henry reaction based on BINOLs-derived
ligands, see: (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418e4420; (b) Sasai, H.; Suzuki, T.; Itoh, N.; Shibasaki, M.
Tetrahedron Lett. 1993, 34, 851e854; (c) Sasai, H.; Suzuki, T.; Itoh, N.; Tanaka, K.;
Date, T.; Okamura, K.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 10372e10373;
(d) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org.
Chem. 1995, 60, 7388e7389; (e) Iseki, K.; Oishi, S.; Sasai, H.; Shibasaki, M.
Tetrahedron Lett. 1996, 37, 9081e9084; (f) Shibasaki, M.; Yoshikawa, N. Chem.
Rev. 2002, 102, 2187e2209; (g) Palomo, C.; Oiarbide, M.; Mielgo, A. Angew.
Chem., Int. Ed. 2004, 43, 5442e5444; (h) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J.
Org. Chem. 2007, 2561e2574; (i) Blay, G.; Hernandez-Olmos, V.; Pedro, J. R.
Synlett 2011, 1195e1211.
4. For recent examples on asymmetric Henry reaction based on BOX ligands, see:
(a) Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem. Commun. 2001, 2222e2223;
(b) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J.
Am. Chem. Soc. 2001, 123, 5843e5844; (c) Christensen, C.; Juhl, K.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2002, 67, 4875e4881; (d) Evans, D. A.; Seidel, D.;
Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125,
12692e12693; (e) Risgaard, T.; Gothelf, K. V.; Jorgensen, K. A. Org. Biomol. Chem.
2003, 1, 153e156; (f) Lu, S.-F.; Du, D.-M.; Zhang, S.-W.; Xu, J. Tetrahedron:
Asymmetry 2004, 15, 3433e3441; (g) Du, D.-M.; Lu, S.-F.; Fang, T.; Xu, J. J. Org.
Chem. 2005, 70, 3712e3715; (h) Ginotra, S. K.; Singh, V. K. Org. Biomol. Chem.
2007, 5, 3932e3937; (i) Toussaint, A.; Pfaltz, A. Eur. J. Org. Chem. 2008,
4591e4597; (j) Gaab, M.; Bellemin-Laponnaz, S.; Gade, L. H. Chem.dEur. J. 2009,
15, 5450e5462; (k) Spangler, K. Y.; Wolf, C. Org. Lett. 2009, 11, 4724e4727; (l)
Xu, H.; Wolf, C. Chem. Commun. 2010, 8026e8028; (m) Didier, D.; Magnier-
Bouvier, C.; Schulz, E. Adv. Synth. Catal. 2011, 353, 1087e1095; (n) Maggi, R.;
Lanari, D.; Oro, C.; Sartori, G.; Vaccaro, L. Eur. J. Org. Chem. 2011, 2011,
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1169e1175.
(R)-1-Cyclohexyl-2-nitroethanol (5s, Table 4, entry 19).4d The
title compound was prepared according to the general procedure
and purified by column chromatography (petroleum ether/ethyl
acetate¼6:1). Enantiomeric excess (86% ee, Table 4, entry 19) was
determined by HPLC (Chiralcel AD-H), hexane/i-PrOH¼95:5,
0.7 mL/min, 215 nm, major enantiomer (R) tr¼18.313 min, minor
enantiomer (S) tr¼19.588 min; 1H NMR (400 MHz, CDCl3):
d 4.46
(m, J¼21.9, 12.7, 6.1 Hz, 2H), 4.07 (s, 1H), 3.48 (s, 1H), 1.89e1.72 (m,
3H), 1.67 (dd, J¼14.9, 7.3 Hz, 2H), 1.45 (m, J¼12.4, 6.2, 3.1 Hz, 1H),
1.32e1.15 (m, 3H), 1.15e1.03 (m, 2H). 13C NMR (101 MHz, CDCl3):
d
79.45, 72.95, 41.45, 28.69, 27.92, 25.85.
(1R,2R)-2-nitro-1-phenylbutan-1-ol (5t, Table 4, entry 20).6n
The title compound was prepared according to the general pro-
cedure and purified by column chromatography (petroleum ether/
ethyl acetate¼6:1). Enantiomeric excess (86% ee, Table 1, entry 8)
was determined by HPLC (Chiralcel AS-H), hexane/i-PrOH¼95:5,
0.8 mL/min, 215 nm, anti: major enantiomer tr¼16.295 min, minor
enantiomer tr¼14.373 min, syn: major enantiomer tr¼22.682 min,
minor enantiomer tr¼18.061 min; 1H NMR (400 MHz, CDCl3):
d
7.58e7.15 (m, 5H), 4.98 (dd, J¼32.8, 7.5 Hz,1H), 4.64e4.48 (m,1H),
3.52 (s, 1H), 1.77 (m, J¼14.5, 10.9, 7.3 Hz, 1H), 1.32 (m, J¼14.8, 7.5,
3.4 Hz, 1H), 0.83 (m, J¼29.8, 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3):
d
138.78, 129.07, 127.06, 126.44, 95.31, 23.84, 9.85.
(1S,2R)-1-(4-Methoxyphenyl)-2-nitrobutan-1-ol (5u, Table 4,
entry 21).8d The title compound was prepared according to the
general procedure and purified by column chromatography (pe-
troleum ether/ethyl acetate¼6:1) to give colorless oil. Enantiomeric
excess (86% ee, Table 1, entry 8) was determined by HPLC (Chiralcel
AD-H), hexane/i-PrOH¼95:5, 1.0 mL/min, 215 nm, anti: major en-
antiomer tr¼17.237 min, minor enantiomer tr¼18.603 min, syn:
5. For recent examples on asymmetric Henry reaction based on amino alcohols
ligands, see: (a) Kim, H. Y.; Oh, K. Org. Lett. 2009, 11, 5682e5685; (b) Reddy, B.
V. S.; Reddy, S. M.; Manisha, S.; Madan, C. Tetrahedron: Asymmetry 2011, 22,
530e535; (c) Guo, Z.-L.; Zhong, S.; Li, Y.-B.; Lu, G. Tetrahedron: Asymmetry 2011,
22, 238e245; (d) Qin, D.-D.; Lai, W.-H.; Hu, D.; Chen, Z.; Wu, A.-A.; Ruan, Y.-P.;
Zhou, Z.-H.; Chen, H.-B. Chem.dEur. J. 2012, 18, 10515e10518; (e) Xu, K.; Lai, G.;
Zha, Z.; Pan, S.; Chen, H.; Wang, Z. Chem.dEur. J. 2012, 18, 12357e12362.
6. For recent examples on asymmetric Henry reaction based on bisamines ligands,
see: (a) Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.; Yanagisawa, A.
Angew. Chem. 2006, 45, 5978e5981; (b) Maheswaran, H.; Prasanth, K. L.;
Krishna, G. G.; Ravikumar, K.; Sridhar, B.; Kantam, M. L. Chem. Commun. 2006,
4066e4068; (c) Arai, T.; Watanabe, M.; Yanagisawa, A. Org. Lett. 2007, 9,
3595e3597; (d) Arai, T.; Takashita, R.; Endo, Y.; Watanabe, M.; Yanagisawa, A. J.
major
enantiomer
tr¼23.030
min,
minor
7.26 (m, J¼5.7 Hz, 2H),
enantiomer
tr¼24.785 min; 1H NMR (400 MHz, CDCl3):
d
6.90 (m, J¼7.5 Hz, 2H), 4.98 (dd, J¼30.5, 7.6 Hz, 1H), 4.66e4.47 (m,
1H), 3.79 (d, J¼9.2 Hz, 3H), 2.92 (s, 1H), 1.80 (m, J¼14.5, 10.9, 7.3 Hz,
1H), 1.38 (m, J¼14.6, 7.4, 3.4 Hz, 1H), 0.87 (dd, J¼24.3, 16.9 Hz, 3H).
13C NMR (101 MHz, CDCl3):
75.14, 55.35, 23.95, 10.07.
d 160.03, 130.87, 128.22, 114.35, 95.47,
(1S,2R)-2-Nitro-1-(thiophen-2-yl)butan-1-ol (5y, Table 4, entry
22).24 The title compound was prepared according to the general
procedure and purified by column chromatography (petroleum
ether/ethyl acetate¼6:1). Enantiomeric excess (86% ee, Table 1,
entry 8) was determined by HPLC (Chiralcel AD-H), hexane/i-
PrOH¼95:5, 0.8 mL/min, 215 nm, anti: major enantiomer
tr¼15.912 min, minor enantiomer tr¼15.248 min, syn: major en-
antiomer tr¼22.375 min, minor enantiomer tr¼21.640 min; 1H
_
Org. Chem. 2008, 73, 4903e4906; (e) Kowalczyk, R.; Sidorowicz, q.; Skarzewski,
J. Tetrahedron: Asymmetry 2008, 19, 2310e2315; (f) Zhang, G.; Yashima, E.;
Woggon, W.-D. Adv. Synth. Catal. 2009, 351, 1255e1262; (g) Breuning, M.; Hein,
D.; Steiner, M.; Gessner, V. H.; Strohmann, C. Chem.dEur. J. 2009, 15,
12764e12769; (h) Selvakumar, S.; Sivasankaran, D.; Singh, V. K. Org. Biomol.
Chem. 2009, 7, 3156e3162; (i) Jin, W.; Li, X.; Huang, Y.; Wu, F.; Wan, B. Chem.
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3301e3310; (k) Noole, A.; Lippur, K.; Metsala, A.; Lopp, M.; Kanger, T. J. Org.
€
NMR (400 MHz, CDCl3):
d
7.35 (d, J¼5.0 Hz, 1H), 7.10e6.97 (m, 2H),
Chem. 2010, 75, 1313e1316; (l) Chougnet, A.; Zhang, G.; Liu, K.; Haussinger, D.;
€
Kagi, A.; Allmendinger, T.; Woggon, W.-D. Adv. Synth. Catal. 2011, 353,
5.30 (d, J¼8.9 Hz, 1H), 4.69e4.59 (m, 1H), 2.97 (s, 1H), 1.85 (m,
J¼14.6, 10.6, 7.3 Hz, 1H), 1.56 (m, J¼14.8, 7.5, 3.9 Hz, 1H), 0.91 (m,
1797e1806; (m) Lu, D.; Zhou, Y.; Li, Y.; Yan, S.; Gong, Y. J. Org. Chem. 2011, 76,
8869e8878; (n) Zhou, Y.; Dong, J.; Zhang, F.; Gong, Y. J. Org. Chem. 2011, 76,
588e600; (o) Gualandi, A.; Cerisoli, L.; Stoeckli-Evans, H.; Savoia, D. J. Org.
Chem. 2011, 76, 3399e3408; (p) Jin, W.; Li, X.; Wan, B. J. Org. Chem. 2011, 76,
484e491; (q) Yao, Q. J.; Judeh, Z. M. A. Tetrahedron 2011, 67, 4086e4092.
7. For recent examples on asymmetric Henry reaction based on N,N-dioxide li-
gands, see: (a) Zhou, H.; Peng, D.; Qin, B.; Hou, Z. R.; Liu, X. H.; Feng, X. M. J. Org.
Chem. 2007, 72, 10302e10304; (b) Qin, B.; Xiao, X.; Liu, X. H.; Huang, J. L.; Wen,
Y. H.; Feng, X. M. J. Org. Chem. 2007, 72, 9323e9328; (c) Tan, C.; Liu, X. H.; Wang,
L. W.; Wang, J.; Feng, X. M. Org. Lett. 2008, 10, 5305e5308.
J¼7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3):
d 141.74, 127.18, 126.60,
126.25, 95.30, 71.15, 23.84, 9.89.
Conflict of interest
None.
8. For recent examples on asymmetric Henry reaction based on imino(amino)-
ꢀ
ꢀ
pyridine ligands, see: (a) Blay, G.; Climent, E.; Fernandez, I.; Hernandez-Ol-
Acknowledgements
mos, V.; Pedro, J. R. Tetrahedron: Asymmetry 2006, 17, 2046e2049; (b) Blay, G.;
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Climent, E.; Fernandez, I.; Hernandez-Olmos, V.; Pedro, J. R. Tetrahedron:
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Generous financial support by the National Basic Research
Program of China (973 Program: 2010CB833300) and the State

10652
L. Zhang et al. / Tetrahedron 69 (2013) 10644e10652
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€
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~
€
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€
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