Catalytic asymmetric nitroaldol (Henry) reactions with copper(II)/ cyclopropane-based bisoxazoline complexes

Article abstract of DOI:10.1016/j.tetasy.2012.06.014

A series of cyclopropane-based bisoxazolines were synthesized from (R)- and (S)-amino alcohols, and applied to copper-catalyzed enantioselective nitroaldol reactions between nitromethane and various aldehydes. The reactions generated β-hydroxy nitroalkanes in high yields (97%) and with good enantioselectivities (up to 87% ee). The effects of the oxazoline stereocenters constructed in the Henry reactions were also studied. 2012 Elsevier Ltd.

Full text of DOI:10.1016/j.tetasy.2012.06.014

Tetrahedron: Asymmetry 23 (2012) 965–971
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Tetrahedron: Asymmetry
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Catalytic asymmetric nitroaldol (Henry) reactions with
copper(II)/cyclopropane-based bisoxazoline complexes
⇑
⇑
Jianyou Mao, Xin Nie, Min Wang, Qian Wang, Bing Zheng, Qinghua Bian , Jiangchun Zhong
Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2012
Accepted 15 June 2012
A series of cyclopropane-based bisoxazolines were synthesized from (R)- and (S)-amino alcohols, and
applied to copper-catalyzed enantioselective nitroaldol reactions between nitromethane and various
aldehydes. The reactions generated b-hydroxy nitroalkanes in high yields (97%) and with good enantiose-
lectivities (up to 87% ee). The effects of the oxazoline stereocenters constructed in the Henry reactions
were also studied.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Chiral bisoxazolines have emerged as one of the most attractive
ligands for asymmetric catalysis,1 because they offer an advanta-
geous combination of structural diversity, convenient synthesis,
and excellent enantioselectivity for a wide range of reactions.
Although a large variety of chiral bisoxazolines have been prepared
from malonate,2 tartrate,3 ferrocene or cyclohexane,4 biphenyl or
binaphthyl,5 pyridine6, and other derivatives, formidable chal-
lenges remain in terms of the design and evaluation of novel bisox-
azoline ligands. Such challenges increase the requirements for
chiral catalysis. Cyclopropane-based ligands can exhibit high
enantioselectivity for many catalytic reactions because of their
highly variable platform and unusual bond angles; these ligands
also offer a well-ordered chiral environment.7 Apart from our
own efforts,8 however, very few efficient chiral cyclopropane-
based ligands 1–5 have been reported,7,8 motivating us to incorpo-
rate cyclopropanes into bisoxazoline ligands to explore their
potential utility in asymmetric catalytic reactions.
Ph
Ph
c-hexyl
c-hexyl
N
OH
N
O
OH
RO
5a: R= TBS
5b: R= TBDPS
4
The asymmetric nitroaldol (Henry) reaction has become a pow-
erful synthetic tool for the enantioselective construction of car-
bon–carbon bonds. The resulting b-hydroxy nitroalkanes provide
efficient access to valuable bifunctional compounds, such as b-ami-
no alcohols and a
-hydroxy carboxylic acids.9 Given its significance,
researchers have developed numerous asymmetric protocols,
which involve the use of BINOL,10 bisoxazolidines,11 cinchona alka-
loids,12 dinuclear zinc complexes,13 amino alcohols,8e,14 diamine,15
chiral Schiff bases, and tetrahydro-bisisoquinoline ligands.16 To the
best of our knowledge, only a few reports on bisoxazoline catalysts
for Henry reactions have been published.17 We previously reported
the application of novel cyclopropane-based bisoxazolines 8a–8d
in catalytic enantioselective Diels–Alder additions.18 To screen
the effects of the configuration of the 4-substituent on the oxazo-
line and to develop novel chiral catalysts without privileged struc-
tures in asymmetric Henry reactions, we herein synthesized two
new compounds 8e and 8f, which were the enantiomers of 8a
and 8d, respectively, and describe in full detail the synthesis of
chiral cyclopropane-based bisoxazolines and their applications as
chiral ligands in copper-catalyzed asymmetric Henry reactions.
SPh
SR
Ph
P
Ph
PPh2
N
O
OH
2a: R= Et
2b: R= Me
1
3
⇑
Corresponding authors. Tel.: +86 010 62731356; fax: +86 010 62820325 (Q.B.);
tel.: +86 010 62731356; fax: +86 010 62820325 (J.Z.).
E-mail addresses: bianqinghua@cau.edu.cn (Q. Bian), dr_zhongjiangchun@
yahoo.com.cn (J. Zhong).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.014

966
J. Mao et al. / Tetrahedron: Asymmetry 23 (2012) 965–971
was first converted into new dihydroxy cyclopropane diamides
2. Results and discussion
7a–7f with (R)- and (S)-amino alcohols; subsequent reaction with
p-toluenesulfonyl chloride and triethylamine in the presence of a
catalytic amount of 4-(dimethylamino) pyridine produced 8a–8f.
Ligands 8a–8f were evaluated in copper-catalyzed Henry reac-
tions between nitromethane and benzaldehyde 9a (Table 1).17a
The results indicated that varying the substitution on the oxazoline
ring had considerable effects on the enantioselectivity of the reac-
tions. The bisoxazoline ligands with an i-Pr group 8a presented
higher ee values than did 8c with a Bn group (entry 1 vs entry
3); the more hindered ligands 8b and 8d decreased the enantiose-
lectivity greatly (entries 2 and 4). Furthermore, the absolute con-
figuration of the Henry adducts could be controlled by the
configuration of the 4-substituent on the oxazoline, 8a with an
(S)-i-Pr group furnished (R)-enantiomers, while 8e with an (R)-i-
Pr group generated (S)-enantiomers. Thus, bisoxazoline ligand 8e
was the ligand of choice, yielding a nitro alcohol product with
64% ee (entry 5).
Bisoxazoline ligands 8a–8f were prepared by following the
method reported by Evans (Scheme 1).19 Dicarbonyl chloride 6
R
*
H2N
OH
H
N
H
N
R
R
Cl
Cl
*
*
CHCl3, Et3N, 0-5oC
O
O
O
O
OH
HO
6
7
TsCl, DMAP, Et3N
CH2Cl2, 25oC
O
O
N
*
R
N
*
8
R
The Henry reaction of benzaldehyde with nitromethane was
tested to determine the optimal conditions for asymmetric cata-
lytic reactions (Table 2). The ee values of product 10a remained al-
most unchanged in the three solvents examined (entries 1–3).
Although replacing Cu(OAc)2ꢀH2O with Cu(OAc)2 slightly improved
the enantioselectivity (entry 4 vs entry 2), the use of Cu(OTf)2
yielded no product (entry 5). The addition of 4 Å molecular sieves
or base promoters, such as pyridine and triethyl-amine, was not
beneficial to the enantioselectivity; instead a loss of enantioselec-
tivity was observed (entries 6–8). Further optimization of this pro-
cess showed that the reaction may be performed with lower
catalyst loading (3 mol %; entry 10). The temperature had a signif-
icant effect on the ee values; lowering the temperature of the reac-
tion from 25 °C to 0 °C considerably increased the ee values (entry
4 vs entry 11). These experiments demonstrated that the best re-
sults can be obtained with 6 mol % of ligand 8e and 5 mol % of
Cu(OAc)2 in isopropanol at 0 °C (entry 11).
With the optimal ligand and conditions identified, we explored
the scope of the reactions (Table 3). In general, good to high enan-
tiomeric excesses (69–87% ee) were observed at 0 °C with various
aldehydes. Strong electron withdrawing groups, such as NO2 or F,
significantly reduced enantioselectivity (entries 6 and 7). Except
for 9f and 9g, other ortho-, meta-, and para-substituted benzalde-
hydes presented consistently good enantiomeric excesses (81–
87% ee, entries 2–5 and 8–14). In particular, a noteworthy result
a: R=i-Pr (S), b: R=t-Bu (S), c: R=Bn (S), d: R=Ph (S),
e: R=i-Pr (R), f: R=Ph (R)
Scheme 1. Synthesis of chiral cyclopropane-based bisoxazoline ligands 8a–8f.
Table 1
Ligand survey of the Henry reactionsa
CH3NO2
OH
*
O
Cu(OAc)2·H2O (5mol%)
NO2
H
bisoxazoline ligand (6 mol%)
EtOH, rt
9a
10a
Entry
Ligand
Time (h)
Yieldb (%)
eec (%)
Configd
1
2
3
4
5
6
(S,S)-8a
(S,S)-8b
(S,S)-8c
(S,S)-8d
(R,R)-8e
(R,R)-8f
72
98
72
72
48
48
91
66
90
58
74
72
62
6
46
4
64
4
(R)
—
(R)
—
(S)
—
a
All reactions were performed at room temperature on a 0.5 mmol scale with
6 mol % of ligand and 5 mol % of Cu(OAc)2ꢀH2O.
b
Values are isolated yields after chromatographic purification.
Enantiomeric excess was determined by HPLC using a Chiracel OD-H column.
The absolute configuration was assigned by comparing their specific rotations
c
d
with data from the literature.17a
Table 2
Optimization of the reaction conditions between nitromethane and benzaldehydea
OH
O
NO2
Lewis acid
Ligand 8e, solvent
H
+
CH3NO2
10a
9a
Entry
Lewis acid
Catalyst (mol %)
Temp (°C)
Solvent
Additive
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
5
5
5
5
5
5
5
5
10
3
25
25
25
25
25
25
25
25
25
25
0
EtOH
—
—
—
—
74
74
70
75
0
72
82
80
72
70
70
50
64
66
62
72
—
69
55
57
68
71
85
82
i-PrOH
MeOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
EtOH
—
MS
Et3N
Pyridine
—
—
—
—
9
10
11
12
Cu(OAc)2
Cu(OAc)2ꢀH2O
5
5
0
a
All reactions were performed on a 0.5 mmol scale in aldehyde.

J. Mao et al. / Tetrahedron: Asymmetry 23 (2012) 965–971
967
1H and 13C NMR spectra were recorded at 300 and 75 MHz, respec-
tively. Low- and high-resolution mass spectra were obtained with
an ESI mass spectrometer or an Agilent instrument using the TOF
MS technique. Optical rotations were measured on a Perkin–Elmer
PE-341 polarimeter. Enantiomeric excesses (ee) were determined
by chiral HPLC analyses using chiral columns (Chiralcel OD-H, Chir-
alpak AS-H or AD-H), and elution with isopropanol–hexanes.
Table 3
Henry reactions of nitromethane with various aldehydesa
OH
O
CH3NO2
Cu(OAc)2 (5 mol%)
NO2
R
R
H
*
10
ligand 8e (6 mol%)
i-PrOH, 0oC
9
Entry
R
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ph
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
2-FC6H4
4-NO2C6H4
2-CH3OC6H4
3-CH3OC6H4
4-CH3OC6H4
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-EtOC6H4
2,4-(MeO)2C6H3
3,5-(MeO)2C6H3
2,6-(MeO)2C6H3
2-Naphthyl
n-C7H15
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
10s
10t
10u
70
95
96
80
88
84
91
96
95
63
93
65
97
70
90
96
97
96
60
75
65
85
81
82
81
81
73
68
82
81
86
83
86
83
87
79
83
84
73
69
77
74
4.2. General procedure for the preparation of dihydroxy
cyclopropane diamides 719
To a cold (0 °C) solution of amino alcohol (22.5 mmol) and Et3N
(10 mL, 72 mmol) in CHCl3 (60 mL), a solution of dimethyl cyclo-
propane dicarbonyl chloride (1.8 g, 9 mmol) was slowly added in
CHCl3 (30 mL). The reaction mixture was allowed to warm to room
temperature and was stirred for 24 h. The mixture was then
washed with saturated brine, dried over Na2SO4, filtered, and con-
centrated. The residue was purified by silica gel chromatography
(MeOH/EtOAc) to produce solid white powder 7.
9
10
11
12
13
14
15
16
17
18
19
20
21
4.2.1. (1R,2S)-N,N0-Bis[(1S)-1-hydroxymethyl-2-methyl-propyl]-
3,3-dimethyl-1,2-cyclopropanediamide 7a
White solid powder. Yield: 62%. Mp: 121–122 °C. ½a D20
¼ ꢂ30:0
ꢁ
(c 1.0, CHCl3). 1H NMR (300 MHz, DMSO) d: 8.62 (d, J = 8.7 Hz, 1H),
8.33 (d, J = 9.0 Hz, 1H), 4.56 (t, J = 5.4 Hz, 1H), 4.51 (t, J = 5.7 Hz,
1H), 3.67–3.58 (m, 2H), 3.38–3.29 (m, 4H), 1.88–1.77 (m, 2H),
1.74 (s, 2H), 1.21 (s, 3H), 1.17 (s, 3H), 0.85–0.80 (m, 12H); 13C
NMR (75 MHz, DMSO) d: 169.8, 169.7, 61.5, 56.0, 55.91, 55.90,
34.83, 34.78, 28.7, 28.0, 27.9, 24.2, 19.85, 19.79, 17.8, 17.7, 15.7.
EI MS (70 eV) m/z: 328 [M]+, 298, 226, 140, 69, 41. HRMS: Calcd
for C17H32N2O4 [M]+ 328.2362. Found: 328.2366.
PhCH@CH
Cyclohexyl
a
All reactions were performed at 0 °C on a 0.5 mmol scale with 6 mol % of ligand
and 5 mol % of Cu(OAc)2 in isopropanol.
Values are isolated yields after chromatographic purification.
Enantiomeric excess was determined by HPLC using Chiracel OD-H, Chiralpak
AS-H or AD-H columns. The absolute configuration was assigned by comparing
their specific rotations or the HPLC elution order with data from the literature.
b
c
(87% ee) was obtained with 4-ethoxybenzaldehyde. Even for the
two substituted benzaldehydes, 9o–9q, good enantioselectivities
were achieved (entries 15–17). The other aromatic aldehydes, such
as 2-naphthaldehyde and cinnamaldehyde, also showed good ee
values (entries 18 and 20). The substrate scope was not limited
to aromatic aldehydes; aliphatic aldehydes 9s and 9u were effec-
tive substrates, generating nitroaldol products with 69% ee and
74% ee, respectively (entries 19 and 21).
4.2.2. (1R,2S)-N,N0-Bis[(1S)-1-hydroxymethyl-2,2-di-
methylpropyl]-3,3-dimethyl-1,2-cyclopropane-diamide 7b
White solid powder. Yield: 66%. Mp: 190–192 °C. ½a D20
¼ ꢂ29:6
ꢁ
(c 2.0, CHCl3). 1H NMR (300 MHz, DMSO) d: 8.65 (d, J = 9.0 Hz, 1H),
8.27 (d, J = 9.6 Hz, 1H), 4.40 (t, J = 5.7 Hz, 1H), 4.34 (t, J = 5.1 Hz,
1H), 3.68–3.52 (m, 4H), 3.34–3.23 (m, 2H), 1.78 (s, 2H), 1.23 (s,
3H), 1.20 (s, 3H), 0.86 (s, 9H), 0.84 (s, 9H). 13C NMR (75 MHz,
DMSO) d: 169.97, 169.95, 61.04, 61.02, 59.11, 59.07, 34.9, 33.7,
33.4, 28.8, 27.1, 27.0, 24.4, 16.1. EI MS (70 eV) m/z: 356 [M]+,
326, 299, 240, 140, 57, 43. Anal. Calcd C19H36N2O4: C, 64.01; H,
10.18; N, 7.86. Found: C, 63.80; H, 10.03; N, 7.67.
3. Conclusion
A series of cyclopropane-based chiral bisoxazolines 8a–8f have
been conveniently prepared from (R)- and (S)-amino alcohols.
Using the ligands without any additives, the Henry reactions gave
the corresponding b-nitro alcohols in good to high enantioselectiv-
ities (up to 87% ee) from various aldehydes; even with low catalyst
loading (3 mol %), good enantioselectivities were obtained. In par-
ticular, the two enantiomers of b-nitro alcohols could be obtained;
bisoxazoline 8a with an (S)-i-Pr group furnished the (R)-enantio-
mers; while 8e with an (R)-i-Pr group generated the (S)-enantio-
mers. The application of these bisoxazolines in other asymmetric
catalytic reactions is currently under investigation.
4.2.3. (1R,2S)-N,N0-Bis[(1S)-2-hydroxy-1-phenyl-methylethyl]-
3,3-dimethyl-1,2-cyclopropanediamide 7c
White solid powder. Yield: 67%. Mp 142–143 °C. ½a D20
¼ ꢂ39:2
ꢁ
(c 2.0, CHCl3). 1H NMR (300 MHz, DMSO) d: 8.75 (d, J = 8.1 Hz,
1H), 8.44 (d, J = 8.4 Hz, 1H), 7.26–7.13 (m, 10H), 4.76 (t,
J = 5.7 Hz, 1H), 4.73 (t, J = 4.2 Hz, 1H), 3.97–3.89 (m, 2H), 3.40–
3.24 (m, 4H), 2.89–2.80(m, 2H), 2.65–2.50 (m, 2H), 1.60 (d,
J = 3.0 Hz, 2H), 1.12 (s, 3H), 0.84 (s, 3H). 13C NMR (75 MHz, DMSO)
d: 169.4, 169.3, 139.31, 139.27, 129.2, 128.2, 128.1, 126.00, 125.97,
63.0, 62.6, 53.1, 52.7, 36.8, 36.7, 34.6, 34.3, 28.5, 24.3, 15.1. EI MS
(70 eV) m/z: 424 [M]+, 394, 274, 140, 91, 60, 41. Anal. Calcd
4. Experimental
4.1. General
C25H32N2O4: C, 70.73; H, 7.60; N, 6.60. Found: C, 70.66; H, 7.52;
N, 6.53.
4.2.4. (1R,2S)-N,N0-Bis[(1S)-2-hydroxy-1-phenylethyl]-3,3-
All reactions were performed under an argon atmosphere. Sol-
vents were dried according to standard procedures and distilled
before use. All reagents were purchased commercially and used
without further purification, unless stated otherwise. cis-3,3-Dim-
ethylcyclopropane dicarbonyl chloride 6 was prepared following
the methods in the literature.20a,b Melting points were recorded
using a Cole-Parmer Melt-Temp apparatus and are uncorrected.
dimethyl-1,2-cyclopropanediamide 7d
White solid powder. Yield: 46%. Mp 135–137 °C. ½a D20
¼ þ64:8
ꢁ
(c 2.0, CHCl3). 1H NMR (300 MHz, DMSO) d: 9.11 (d, J = 8.1 Hz,
1H), 9.01 (d, J = 8.4 Hz, 1H), 7.32–7.18 (m, 10H), 4.92–4.78 (m,
4H), 3.57–3.47 (m, 4H), 1.82 (s, 2H), 1.23 (s, 3H), 1.16 (s, 3H). 13C
NMR (75 MHz, DMSO) d: 169.5, 169.3, 141.21, 141.17, 128.14,
128.12, 127.1, 127.0, 126.8, 65.0, 64.9, 55.4, 55.2, 34.7, 34.3, 28.7,

968
J. Mao et al. / Tetrahedron: Asymmetry 23 (2012) 965–971
24.7, 15.6. EI MS (70 eV) m/z: 366 [M-2CH3]+, 347, 260, 243, 229,
140, 106, 96, 41. Anal. Calcd C23H28N2O4: C, 69.67; H, 7.12; N,
7.07. Found: C, 69.62; H, 7.07; N, 7.04.
4.05 (m, 2H), 3.88–3.81 (m, 2H), 3.15–2.99 (m, 2H), 2.61–2.53
(m, 2H), 1.81 (d, J = 0.9 Hz, 2H), 1.44 (s, 3H), 1.25 (s, 3H). 13C
NMR (75 MHz, CDCl3) d: 164.1, 163.8, 138.4, 138.2, 129.1, 129.0,
128.43, 128.37, 126.32, 126.27, 71.0, 67.6, 67.5, 41.8, 41.6, 28.3,
26.5, 26.4, 24.6, 16.6. EI MS (70 eV), m/z: 388 [M]+, 297, 163, 91,
67, 41. HRMS: Calcd for C25H28N2O2 [M]+ 388.2151. Found:
388.2150.
4.2.5. (1R,2S)-N,N0-Bis[(1R)-1-hydroxymethyl-2-methylpropyl]-
3,3-dimethyl-1,2-cyclopropanediamide 7e
White solid powder. Yield: 64%. Mp 121–122 °C. ½a D25
¼ þ35:0
ꢁ
(c 1.0, CHCl3). 1H NMR (300 MHz, DMSO) d: 8.64 (d, J = 8.7 Hz,
1H), 8.32 (d, J = 9.0 Hz, 1H), 4.56 (t, J = 5.4 Hz, 1H), 4.50 (t,
J = 5.7 Hz, 1H), 3.67–3.58 (m, 2H), 3.39–3.27 (m, 4H), 1.99–1.77
(m, 2H), 1.74 (s, 2H), 1.21 (s, 3H), 1.17 (s, 3H), 0.85–0.73 (m,
12H). 13C NMR (75 MHz, DMSO) d: 170.62, 170.56, 61.9, 56.4,
35.21, 35.16, 28.9, 28.44, 28.40, 24.9, 20.18, 20.15, 18.18, 18.14,
16.1. MS m/z: 329 [M+H]+, 311, 226, 208, 152, 140, 132. HRMS:
Calcd for C17H33N2O4 [M+H]+ 329.2440. Found: 329.2435.
4.3.4. (1R,2S)-1,2-Bis[4(S)-phenyloxazolin-2-yl]-3,3-
dimethylcyclopropane 8d
Colorless oil. Yield: 45%. ½a D20
ꢁ
¼ ꢂ152:3 (c 2.0, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.34–7.11 (m, 10H), 5.19–5.12 (m, 2H),
4.58–4.48 (m, 2H), 3.99–3.90 (m, 2H), 1.96 (d, J = 10.2 Hz, 2H),
1.58 (s, 3H), 1.32 (s, 3H). 13C NMR (75 MHz, CDCl3) d: 165.0,
164.5, 142.7, 142.6, 128.6, 128.4, 127.3, 127.2, 127.0, 126.7, 74.1,
70.2, 70.0, 28.4, 26.8, 26.3, 25.1, 16.8. EI MS (70 eV), m/z: 360
[M]+, 345, 276, 242, 120, 104, 91, 43, 29. HRMS: Calcd for
4.2.6. (1R,2S)-N,N0-Bis[(1R)-2-hydroxy-1-phenylethyl]-3,3-
dimethyl-1,2-cyclopropanediamide 7f
C
23H24N2O2 [M]+ 360.1838. Found: 360.1853.
White solid powder. Yield: 45%. Mp 137–138 °C. ½a D25
¼ ꢂ77:5 (c
ꢁ
2.0, CHCl3). 1H NMR (300 MHz, DMSO) d: 9.13 (d, J = 8.1 Hz, 1H), 9.03
(d, J = 8.1 Hz, 1H), 7.27–7.21 (m, 10H), 4.89–4.82 (m, 2H), 3.63–3.47
(m, 6H), 1.81 (s, 2H), 1.18 (s, 3H), 1.15 (s, 3H). 13C NMR (75 MHz,
DMSO) d: 169.6, 169.4, 141.2, 141.1, 128.2, 128.1, 127.1, 127.0,
126.8, 65.0, 64.8, 55.4, 55.3, 34.7, 34.3, 28.6, 24.8, 15.6. HRMS: Calcd
for C23H29N2O4 [M+H]+ 397.2127. Found: 397.2124.
4.3.5. (1R,2S)-1,2-Bis[4(R)-isopropyloxazolin-2-yl]-3,3-
dimethylcyclopropane 8e
Colorless oil. Yield: 70%. ½a D25
ꢁ
¼ þ126:5 (c 2.4, CHCl3) 1H NMR
(300 MHz, CDCl3) d: 4.20–4.09 (m, 2H), 3.88–3.79 (m, 4H), 1.84–
1.65 (m, 4H), 1.42 (s, 3H), 1.23 (s, 3H), 0.96 (t, J = 6.96 Hz, 6H),
0.87 (t, J = 6.87 Hz, 6H). 13C NMR (75 MHz, CDCl3) d: 163.7, 163.2,
72.6, 72.3, 69.6, 69.4, 32.8, 32.6, 28.4, 26.6, 26.4, 24.5, 19.1, 19.0,
18.5, 18.1, 16.7; EI MS m/z: 293 [M+H]+, 226, 208, 185, 168, 152,
4.3. General procedure for the preparation of cyclopropane-
based bisoxazoline ligands 819
140. HRMS: Calcd for
293.2197.
C
17H29N2O2 [M+H]+ 293.2229. Found:
To a solution of dihydroxy diamide 7 (9.0 mmol), Et3N (5.52 mL,
39.6 mmol) and a catalytic amount of 4-(dimethylamino)pyridine
(0.121 g, 0.99 mmol) in CH2Cl2 (72 mL), a solution of p-toluenesul-
fonyl chloride (3.433 g, 18 mmol) in CH2Cl2 (42 mL) was added
slowly. The reaction mixture was then stirred at room temperature
for 27 h. The mixture was then diluted with CH2Cl2 (200 mL), and
washed with saturated aqueous NH4Cl, Na2CO3 and brine succes-
sively. The organic layer was dried over Na2SO4, filtered, and con-
centrated under reduced pressure to give a pale yellow viscous oil.
The residue was purified by neutral Al2O3 column chromatography
(pet ether/EtOAc) to afford 8 as colorless oil or white solid.
4.3.6. (1R,2S)-1,2-Bis[4(R)-phenyloxazolin-2-yl]-3,3-
dimethylcyclopropane 8f
Colorless oil. Yield: 53%. ½a D25
ꢁ
¼ þ160:2 (c 1.5, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.35–7.12 (m, 10H), 5.19–5.12 (m, 2H),
4.58–4.48 (m, 2H), 3.99–3.90 (m, 2H), 1.96 (d, J = 2.1 Hz, 2H),
1.58 (s, 3H), 1.32 (s, 3H). 13C NMR (75 MHz, CDCl3) d: 164.9,
164.5, 142.6, 142.5, 128.5, 128.3, 127.3, 127.1, 126.9, 126.7, 74.0,
70.1, 69.8, 28.3, 26.7, 26.2, 25.1, 16.8. EI MS m/z: 360 [M]+, 345,
276, 199, 184, 155, 104, 91, 83, 56. HRMS: Calcd for C23H24N2O2
[M]+ 360.1838. Found: 360.1842.
4.3.1. (1R,2S)-1,2-Bis[4(S)-isopropyloxazolin-2-yl]-3,3-
4.4. General procedure for the asymmetric Henry reaction17a
dimethylcyclopropane 8a
Colorless oil. Yield: 82%. ½a D20
ꢁ
¼ ꢂ131:3 (c 1.6, CHCl3). 1H NMR
Ligand 8 (0.03 mmol) was mixed with Cu(OAc)2 (4.54 mg,
0.025 mmol) under an argon atmosphere. Isopropanol (1.0 mL)
was then added, and the mixture was stirred for 1 h. To the result-
ing clear solution, nitromethane (0.3 mL, 5 mmol) and the alde-
hyde (0.5 mmol) were added via syringe. Stirring was continued
at 0 °C until TLC-control indicated the complete consumption of
the aldehyde. The reaction mixture was diluted with saturated
aqueous NH4Cl (10 mL) and extracted with EtOAc (3 ꢃ 20 mL).
The volatile components were removed under reduced pressure
and the crude products were purified by column chromatography
to give the desired products. Enantiomeric excess was determined
by HPLC with a Chiralcel OD-H, Chiralpak AD-H, or AS-H column,
and the absolute configurations of the nitroaldol products were as-
signed by comparing their specific rotations or the HPLC elution or-
der with data from the literature.
(300 MHz, CDCl3) d: 4.23–4.10 (m, 2H), 3.88–3.79 (m, 4H), 1.80
(d, J = 3.6 Hz, 2H), 1.76–1.65 (m, 2H), 1.42 (s, 3H), 1.23 (s, 3H),
0.97 (t, J = 7.2 Hz, 6H), 0.87 (t, J = 6.9 Hz, 6H). 13C NMR (75 MHz,
CDCl3) d: 163.7, 163.2, 72.5, 72.2, 69.5, 69.4, 32.7, 32.5, 28.3,
26.6, 26.4, 24.4, 19.1, 19.0, 18.5, 18.1, 16.7. EI MS (70 eV) m/z:
292[M]+, 277, 249, 163, 136, 69, 41. HRMS: Calcd for C17H28N2O2
[M]+ 292.2151. Found: 292.2149.
4.3.2. (1R,2S)-1,2-Bis[4(S)-tert-butyloxazolin-2-yl]-3,3-
dimethylcyclopropane 8b
White solid. Yield: 52%. Mp 42–43 °C, ½a D20
¼ ꢂ135:8 (c 2.1,
ꢁ
CHCl3). 1H NMR (300 MHz, CDCl3) d: 4.15–4.04 (m, 2H), 3.92–3.75
(m, 4H), 1.82 (d, J = 4.8 Hz, 2H), 1.43 (s, 3H), 1.23 (s, 3H), 0.90 (s,
9H), 0.87 (s, 9H). 13C NMR (75 MHz, CDCl3) d: 163.9, 163.2, 76.2,
75.7, 68.0, 67.9, 33.5, 28.5, 27.1, 26.4, 26.1, 25.9, 24.6, 16.8. EI MS
(70 eV), m/z: 320 [M]+, 305, 279, 263, 205, 163, 136, 123, 57, 41.
HRMS: Calcd for C19H32N2O2 [M]+ 320.2464. Found: 320.2462.
4.4.1. (S)-2-Nitro-1-phenylethanol 10a17a
Colorless oil. Yield 70%. ½a D20
ꢁ
¼ þ47:9 (c 1.5, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.41–7.33 (m, 5H), 5.46–5.41 (m, 1H), 4.63–
4.46 (m, 2H), 2.93 (d, J = 3.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) d:
138.1, 128.8, 128.7, 125.8, 81.0, 70.8. HRMS (TOF): Calcd for
C8H9NNaO3 [M+Na]+: 190.0480, Found: 190.0476. Enantiomeric
excess was determined by HPLC with a Chiralcel OD-H column
4.3.3. (1R,2S)-1,2-Bis[4(S)-benzyloxazolin-2-yl]-3,3-
dimethylcyclopropane 8c
Colorless oil. Yield: 39%. ½a D20
ꢁ
¼ ꢂ56:5 (c 0.78, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.30–7.16 (m, 10H), 4.37–4.30 (m, 2H), 4.11–

J. Mao et al. / Tetrahedron: Asymmetry 23 (2012) 965–971
969
(80:20 n-hexanes/isopropanol, 1.0 mL/min, 230 nm); minor (R)-
enantiomer tR = 8.3 min, major (S)-enantiomer tR = 10.3 min; 85%
ee.
column (95:5 n-hexanes/isopropanol, 0.8 mL/min, 230 nm); minor
(R)-enantiomer tR = 23.3 min, major (S)-enantiomer tR = 24.6 min;
73% ee.
4.4.2. (R)-2-Nitro-1-phenylethanol 10a17a
4.4.8. (S)-1-(4-Nitrophenyl)-2-nitroethanol 10g15a
Colorless oil. Yield 91%. ½a D20
ꢁ
¼ ꢂ29:6 (c 1.8, CHCl3). 1H NMR
White solid. Yield 91%. ½a D20
ꢁ
¼ þ20:0 (c 1.6, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.41–7.33 (m, 5H), 5.46–5.41 (m, 1H), 4.63–
4.46 (m, 2H), 2.93 (d, J = 3.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) d:
138.1, 128.8, 128.7, 125.8, 81.0, 70.8. HRMS (TOF): Calcd for
C8H9NNaO3 [M+Na]+: 190.0480, Found: 190.0474. Enantiomeric
excess was determined by HPLC with a Chiralcel OD-H column
(80:20 n-hexanes/isopropanol, 1.0 mL/min, 230 nm); major (R)-
enantiomer tR = 8.7 min, minor (S)-enantiomer tR = 10.5 min; 62%
ee.
(300 MHz, CDCl3) d: 8.29–8.24 (m, 2H), 7.63 (d, J = 8.6 Hz, 2H),
5.62 (dd, J = 7.7, 4.6 Hz, 1H), 4.66–4.55 (m, 2H), 3.20 (br s, 1H).
13C NMR (75 MHz, CDCl3) d: 148.1, 144.9, 126.9, 124.2, 80.6, 69.9.
HRMS (TOF): Calcd for C8H8N2NaO5 [M+Na]+: 235.0331, Found:
235.0322. Enantiomeric excess was determined by HPLC with a
Chiralcel OD-H column (80:20 n-hexanes/isopropanol, 1.0 mL/
min, 230 nm); minor (R)-enantiomer tR = 12.8 min, major (S)-enan-
tiomer tR = 15.3 min; 68% ee.
4.4.3. (S)-1-(3-Chlorophenyl)-2-nitroethanol 10b21a
4.4.9. (S)-1-(2-Methoxyphenyl)-2-nitroethanol 10h17a
Colorless oil. Yield 95%. ½a D20
ꢁ
¼ þ27:3 (c 1.6, CHCl3). 1H NMR
Yellow oil. Yield 96%. ½a D20
ꢁ
¼ þ40:9 (c 1.8, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.42–7.25 (m, 4H), 5.46–5.41 (m, 1H), 4.61–
4.47 (m, 2H), 3.09 (d, J = 3.94 Hz, 1H). 13C NMR (75 MHz, CDCl3)
d: 140.0, 134.7, 130.2, 128.9, 126.1, 124.0, 80.8, 70.1. HRMS
(TOF): Calcd for C8H8ClNNaO3 [M+Na]+: 224.0090, Found:
224.0089. Enantiomeric excess was determined by HPLC with a
Chiralcel OD-H column (80:20 n-hexanes/isopropanol, 1.0 mL/
min, 230 nm); minor (R)-enantiomer tR = 8.4 min, major (S)-enan-
tiomer tR = 10.3 min; 81% ee.
(300 MHz, CDCl3) d: 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 7.36–7.30 (m,
1H), 7.04–7.00 (m, 1H), 6.91 (d, J = 8.3 Hz, 1H), 5.63 (d, J = 6.8 Hz,
1H), 4.68–4.53 (m, 2H), 3.88 (s, 3H), 3.14 (br s, 1H). 13C NMR
(75 MHz, CDCl3) d: 156.0, 129.8, 127.2, 125.9, 121.1, 110.5, 79.8,
67.8, 55.4. HRMS (TOF): Calcd for C9H11NNaO4 [M+Na]+:
220.0586, Found: 220.0572. Enantiomeric excess was determined
by HPLC with a Chiralcel OD-H column (80:20 n-hexanes/isopropa-
nol, 1.0 mL/min, 230 nm); minor (R)-enantiomer tR = 8.0 min, ma-
jor (S)-enantiomer tR = 9.0 min; 82% ee.
4.4.4. (S)-1-(4-Chlorophenyl)-2-nitroethanol 10c17a
Colorless oil. Yield 96%. ½a D20
ꢁ
¼ þ30:4 (c 0.6, CHCl3). 1H NMR
4.4.10. (S)-1-(3-Methoxyphenyl)-2-nitroethanol 10i21a
(300 MHz, CDCl3) d: 7.39–7.26 (m, 4H), 5.45–5.40 (m, 1H), 4.60–
4.45 (m, 2H), 3.08 (d, J = 3.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) d:
136.5, 134.6, 129.0, 127.3, 80.8, 70.2. HRMS (TOF): Calcd for
C8H8ClNKO3 [M+K]+: 239.9830, Found: 239.9824. Enantiomeric ex-
cess was determined by HPLC with a Chiralcel OD-H column (80:20
n-hexanes/isopropanol, 1.0 mL/min, 230 nm); minor (R)-enantio-
mer tR = 8.1 min, major (S)-enantiomer tR = 9.8 min; 82% ee.
Colorless oil. Yield 95%. ½a D20
ꢁ
¼ þ29:5 (c 1.4, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.33–7.26 (m, 1H), 6.96–6.86 (m, 3H), 5.42
(d, J = 9.3 Hz, 1H), 4.62–4.46 (m, 2H), 3.81 (s, 3H), 2.97 (br s, 1H).
13C NMR (75 MHz, CDCl3) d: 159.8, 139.8, 129.9, 118.0, 114.2,
111.4, 81.0, 70.7, 55.2. HRMS (TOF): Calcd for C9H11NNaO4
[M+Na]+: 220.0586, Found: 220.0584. Enantiomeric excess was
determined by HPLC with a Chiralcel OD-H column (80:20 n-hex-
anes/isopropanol, 1.0 mL/min, 230 nm); minor (R)-enantiomer
tR = 13.9 min, major (S)-enantiomer tR = 18.2 min; 81% ee.
4.4.5. (S)-1-(3-Bromophenyl)-2-nitroethanol 10d21b
Colorless oil. Yield 80%. ½a D20
ꢁ
¼ þ23:4 (c 1.6, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.58–7.25 (m, 4H), 5.46–5.41 (m, 1H), 4.61–
4.47 (m, 2H), 3.03 (d, J = 3.9 Hz, 1H), 13C NMR (75 MHz, CDCl3) d:
140.3, 131.8, 130.5, 129.0, 124.5, 122.8, 80.8, 70.1. HRMS (TOF):
Calcd for C8H8BrNNaO3 [M+Na]+: 267.9585, Found: 267.9572.
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (80:20 n-hexanes/isopropanol, 1.0 mL/min,
230 nm); minor (R)-enantiomer tR = 9.0 min, major (S)-enantiomer
tR = 11.6 min; 81% ee.
4.4.11. (S)-1-(4-Methoxyphenyl)-2-nitroethanol 10j21a
Colorless oil. Yield 63%. ½a D20
ꢁ
¼ þ29:4 (c 1.5, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.34–7.29 (m, 2H), 6.94–6.90 (m, 2H), 5.40
(dd, J = 9.5, 3.2 Hz, 1H), 4.64–4.45 (m, 2H), 3.81 (s, 3H), 2.75 (br
s, 1H). 13C NMR (75 MHz, CDCl3) d: 160.0, 130.2, 127.3, 114.4,
81.2, 70.6, 55.3. HRMS (TOF): Calcd for C9H11NNaO4 [M+Na]+:
220.0586. Found: 220.0577. Enantiomeric excess was determined
by HPLC with a Chiralcel OD-H column (80:20 n-hexanes/isopropa-
nol, 1.0 mL/min, 230 nm); minor (R)-enantiomer tR = 11.2 min, ma-
jor (S)-enantiomer tR = 13.6 min; 86% ee.
4.4.6. (S)-1-(4-Bromophenyl)-2-nitroethanol 10e15a
White solid. Yield 88%. ½a D20
ꢁ
¼ þ25:8 (c 1.4, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.56–7.52 (m, 2H), 7.31–7.26 (m, 2H), 5.46–
5.41 (m, 1H), 4.61–4.46 (m, 2H), 2.90 (d, J = 3.9 Hz, 1H). 13C NMR
(75 MHz, CDCl3) d: 137.0, 132.2, 127.6, 123.0, 80.9, 70.3. HRMS
(TOF): Calcd for C8H8BrNKO3 [M+K]+: 283.9325, Found: 283.9319.
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (80:20 n-hexanes/isopropanol, 1.0 mL/min,
230 nm); minor (R)-enantiomer tR = 8.9 min, major (S)-enantiomer
tR = 11.3 min; 81% ee.
4.4.12. (S)-1-(2-Methylphenyl)-2-nitroethanol 10k17a
Colorless oil. Yield 93%. ½a D20
ꢁ
¼ þ41:4 (c 1.3, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.52–7.49 (m, 1H), 7.27–7.17 (m, 3H), 5.69–
5.64 (m, 1H), 4.57–4.39 (m, 2H), 2.78–2.77 (m, 1H), 2.38 (s, 3H).
13C NMR (75 MHz, CDCl3) d: 136.2, 134.4, 130.7, 128.5, 126.6,
125.5, 80.1, 67.8, 18.7. HRMS (TOF): Calcd for C9H11NNaO3
[M+Na]+: 204.0637. Found: 204.0632. Enantiomeric excess was
determined by HPLC with a Chiralcel OD-H column (85:15 n-hex-
anes/isopropanol, 0.8 mL/min, 215 nm); minor (R)-enantiomer
tR = 7.7 min, major (S)-enantiomer tR = 11.8 min; 83% ee.
4.4.7. (S)-1-(2-Fluorophenyl)-2-nitroethanol 10f21c
Colorless oil. Yield 84%. ½a D20
ꢁ
¼ þ37:6 (c 1.8, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.56–7.53 (m, 1H), 7.37–7.32 (m, 1H), 7.26–
7.19 (m, 1H), 7.11–7.05 (m, 1H), 5.74 (dd, J = 8.0, 4.15 Hz, 1H),
4.65–4.54 (m, 2H), 3.07 (br s, 1H). 13C NMR (75 MHz, CDCl3) d:
160.9, 157.7, 130.4, 127.5, 125.0, 115.5, 79.6, 65.4. HRMS (TOF):
Calcd for C8H8FNNaO3 [M+Na]+: 208.0386, Found: 208.0387. Enan-
tiomeric excess was determined by HPLC with a Chiralcel OD-H
4.4.13. (S)-1-(3-Methylphenyl)-2-nitroethanol 10l15a
Colorless oil. Yield 65%. ½a D20
ꢁ
¼ þ36:4 (c 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.31–7.15 (m, 4H), 5.42–5.37 (m, 1H), 4.62–
4.45 (m, 2H), 2.89 (d, J = 3.8 Hz, 1H), 2.36 (s, 3H). 13C NMR
(75 MHz, CDCl3) d: 138.7, 138.1, 129.5, 128.8, 126.5, 122.9, 81.1,
70.9, 21.2. HRMS (TOF): Calcd for C9H11NNaO3 [M+Na]+:

970
J. Mao et al. / Tetrahedron: Asymmetry 23 (2012) 965–971
204.0637. Found: 204.0634. Enantiomeric excess was determined
by HPLC with a Chiralcel OD-H column (80:20 n-hexanes/isopropa-
nol, 1.0 mL/min, 230 nm); minor (R)-enantiomer tR = 7.4 min, ma-
jor (S)-enantiomer tR = 8.4 min; 86% ee.
5.57 (d, J = 6.9 Hz, 1H), 4.68–4.51 (m, 2H), 3.04 (br s, 1H). 13C
NMR (75 MHz, CDCl3) d: 135.4, 133.3, 133.1, 128.8, 128.0, 127.7,
126.59, 126.56, 125.2, 123.1, 81.0, 71.0. HRMS (TOF): Calcd for
C
12H11NNaO3 [M+Na]+: 240.0637, Found: 240.0639. Enantiomeric
excess was determined by HPLC with a Chiralcel OD-H column
(80:20 n-hexanes/isopropanol, 1.0 mL/min, 230 nm); minor (R)-
enantiomer tR = 23.4 min, major (S)-enantiomer tR = 33.4 min;
73% ee.
4.4.14. (S)-1-(4-Methylphenyl)-2-nitroethanol 10m15a
White solid. Yield 97%. ½a D20
ꢁ
¼ þ37:4 (c 1.8, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.29–7.19 (m, 4H), 5.42 (dd, J = 9.44, 3.10 Hz,
1H), 4.64–4.45 (m, 2H), 2.77 (s, 1H), 2.36 (s, 3H). 13C NMR
(75 MHz, CDCl3) d: 138.9, 135.1, 129.6, 125.8, 81.2, 70.9, 21.1.
HRMS (TOF): Calcd for C9H11NNaO3 [M+Na]+: 204.0637, Found:
204.0635. Enantiomeric excess was determined by HPLC with a
Chiralcel OD-H column (80:20 n-hexanes/isopropanol, 1.0 mL/
min, 230 nm); minor (R)-enantiomer tR = 8.8 min, major (S)-enan-
tiomer tR = 10.7 min; 83% ee.
4.4.20. (S)-1-Nitrononan-2-ol 10s1d
Colorless oil. Yield 60%. ½a D20
ꢁ
¼ þ6:2 (c 1.2, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 4.47–4.29 (m, 3H), 2.66 (d, J = 4.7 Hz, 1H),
1.57–1.29 (m, 12H), 0.89 (m, J = 6.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3) d: 80.6, 68.7, 33.7, 31.6, 29.2, 29.0, 25.1, 22.5, 13.9. HRMS
(TOF): Calcd for C9H19NNaO3 [M+Na]+: 212.1263. Found:
212.1266. Enantiomeric excess was determined by HPLC with a
Chiralpak AS-H column (98:2 n-hexanes/isopropanol, 1.0 mL/min,
210 nm); major (S)-enantiomer tR = 7.0 min, minor (R)-enantiomer
tR = 7. 8 min; 69% ee.
4.4.15. (+)-1-(4-Ethoxyphenyl)-2-nitroethanol 10n
White solid. Yield 70%. ½a D20
ꢁ
¼ þ32:5 (c 1.1, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.31–7.26 (m, 2H), 6.93–6.88 (m, 2H), 5.42–
5.36 (m, 1H), 4.63–4.44 (m, 2H), 4.03 (q, J = 7.0 Hz, 2H), 2.76 (dd,
J = 3.6, 1.1 Hz, 1H). 1.41 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d: 159.2, 130.1, 127.2, 114.8, 81.1, 70.5, 63.5, 14.6. HRMS (TOF):
Calcd for C10H13NNaO4 [M+Na]+: 234.0742. Found: 234.0736.
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (80:20 n-hexanes/isopropanol, 1.0 mL/min,
230 nm); minor enantiomer tR = 8.9 min, major enantiomer,
tR = 10.1 min; 87% ee.
4.4.21. (S,E)-1-Nitro-4-phenyl-3-buten-2-ol 10t21a
Pale yellow solid. Yield 75%. ½a D20
ꢁ
¼ þ3:7 (c 1.2, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 7.41–7.26 (m, 5H), 6.79 (dd, J = 16.0, 1.2 Hz,
1H), 6.15 (dd, J = 15.9, 6.3 Hz, 1H), 5.09–5.03 (m, 1H), 4.56–4.47
(m, 2H), 2.62 (s, 1H). 13C NMR (75 MHz, CDCl3) d: 135.5, 133.7,
128.7, 128.5, 126.7, 124.9, 79.8, 69.6. HRMS (TOF): Calcd for
C
10H11NNaO3 [M+Na]+: 216.0637, Found: 216.0635. Enantiomeric
excess was determined by HPLC with a Chiralcel OD-H column
(80:20 n-hexanes/isopropanol, 1.0 mL/min, 230 nm); major (S)-
enantiomer tR = 18.6 min, minor (R)-enantiomer tR = 21.3 min;
77% ee.
4.4.16. (+)-1-(2,4-Dimethoxyphenyl)-2-nitroethanol 10o
Pale yellow solid. Yield 90%. ½a D20
ꢁ
¼ þ34:7 (c 1.2, CHCl3). 1H
NMR (300 MHz, CDCl3) d: 7.33–7.26 (m, 1H), 6.53–6.47 (m, 2H),
5.55 (dd, J = 7.2, 5.3 Hz, 1H), 4.63–4.53 (m, 2H), 3.85 (s, 3H), 3.81
(s, 3H), 3.07 (br s, 1H). 13C NMR (75 MHz, CDCl3) d: 161.1, 157.1,
128.0, 118.5, 104.6, 98.7, 80.0, 67.6, 55.38, 55.36. HRMS (TOF):
Calcd for C10H13NNaO5 [M+Na]+: 250.0691. Found: 250.0694.
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (80:20 n-hexanes/isopropanol, 1.0 mL/min,
230 nm); minor enantiomer tR = 9.7 min, major enantiomer
tR = 13.3 min; 79% ee.
4.4.22. (S)-1-Cyclohexyl-2-nitroethanol 10u17a
Colorless oil. Yield 65%. ½a D20
ꢁ
¼ þ13:7 (c 1.2, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 4.52–4.38 (m, 2H), 4.13–4.06 (m, 1H), 2.60
(d, J = 5.2 Hz, 1H), 1.81–1.77 (m, 3H), 1.71–1.65 (m, 2H), 1.24–
1.20 (m, 1H) 1.17–1.07 (m, 5H). 13C NMR (75 MHz, CDCl3) d:
79.3, 72.8, 41.3, 28.5, 27.8, 26.0, 25.8, 25.6. HRMS (TOF): Calcd
for C8H15NNaO3 [M+Na]+: 196.0950, Found: 196.0943. Enantio-
meric excess was determined by HPLC with a Chiralpak AD-H col-
umn (90:10 n-hexanes/isopropanol, 1.0 mL/min, 210 nm); minor
(R)-enantiomer tR = 8.1 min, major (S)-enantiomer tR = 8.9 min;
74% ee.
4.4.17. (S)-1-(3,5-Dimethoxyphenyl)-2-nitroethanol 10p15e
White solid. Yield 96%. ½a D20
ꢁ
¼ þ24:4 (c 1.1, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 6.54 (d, J = 2.2 Hz, 2H), 6.43 (t, J = 2.2 Hz,
1H), 5.42–5.36 (m, 1H), 4.63–4.47 (m, 2H), 3.80 (s, 6H), 2.84 (d,
J = 3.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) d: 161.1, 140.5, 103.8,
100.5, 81.1, 70.9, 55.3. HRMS (TOF): Calcd for C10H13NNaO5
[M+Na]+: 250.0691. Found: 250.0695. Enantiomeric excess was
determined by HPLC with a Chiralcel OD-H column (80:20 n-hex-
anes/isopropanol, 1.0 mL/min, 230 nm); major (S)-enantiomer
tR = 8.0 min, minor (R)-enantiomer tR = 9.6 min; 83% ee.
Acknowledgments
We thank the Twelfth Five-year Science and Technology Sup-
port Program (2012BAK25B03), China Postdoctoral Science Foun-
dation Funded Project (2012M510621) and the National Basic
Research Program of China (81102340) for their financial support.
4.4.18. (ꢂ)-1-(2,6-Dimethoxyphenyl)-2-nitroethanol 10q
References
White solid. Yield 97%. ½a D20
ꢁ
¼ ꢂ9:2 (c 1.8, CHCl3). 1H NMR
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