Highly stereoselective epoxidation of O-protected 3-hydroxy-1-nitroalkenes

Full text of DOI:10.1016/j.tet.2009.08.010

Tetrahedron 65 (2009) 8362–8366
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly stereoselective epoxidation of O-protected 3-hydroxy-1-nitroalkenes
*
*
´
´
´
Amit Jain, Santiago Rodrıguez , Irakusne Lopez, Florenci V. Gonzalez
`
`
´
Departament de Qu´ımica Inorganica i Organica, Universitat Jaume I, 12080 Castello, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2009
Received in revised form 5 August 2009
Accepted 6 August 2009
Available online 11 August 2009
The diastereoselectivity of the nucleophilic epoxidation of O-protected 3-hydroxy-1-nitroalkenes was
investigated. Epoxidation of the O-protected 3-hydroxy-1-nitroalkenes was highly stereoselective, giving
rise to the anti isomer. The resulting nitroepoxides have been transformed into nitroaldols through
hydrogenation. The nucleophilic epoxidation of nitroalkenes was found to be irreversible. Models to
explain the observed stereoselectivities are proposed.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Nitrocompounds
Epoxidation
Nitroaldols
1. Introduction
Nitroalkenes 1, 2, and 4 gave rise to the anti isomer in a high ster-
eoselective fashion (entries 2, 3, and 6, Table 1). The epoxidation of
Nitroalkenes are extremely versatile reagents, which have found
extensive applications in organic synthesis.1 Asymmetric epoxida-
tion of chiral nitroalkenes provides chiral nitroepoxides that can be
converted into useful chiral building blocks.2 We previously com-
nitroalkene 3 having a methyl group in the double bond resulted to
be less selective (entries 4 and 5, Table 1).
Table 1
municated the epoxidation of g
-hydroxy enoates3 and now wish to
Epoxidation of O-protected 3-hydroxy-1-nitroalkenes
report that the epoxidation of O-protected 3-hydroxy-1-nitro-
alkenes is highly stereoselective (dr up to 19/1). We believe this
finding will find synthetic applications.
OR2 R3
OR2 R3
TBPLi, THF
-70 °C, 6h
R1
NO2
R1
NO2
O
EtLi solna
anti/synb
Product
Yield (%)
2. Results
Entry
Substrate
1
2
3
4
5
6
1
1
2
3
3
4
Benzene/cyclohexane
Dibutylether
Dibutylether
Dibutylether
Benzene/cyclohexane
Dibutylether
3/1
19/1
9/1
3.5/1
2/1
10/1
5
5
6
7
7
8
72
75
70
75
70
88c
3-Hydroxy-1-nitroalkenes 1–4 were prepared from O-protected
(S)-lactaldehyde or (S)-mandelaldehyde by a nitroaldol reaction
followed by activation of the resulting alcohols to the mesylate and
then elimination4 (Scheme 1).
a
Two commercial ethyl lithium solutions were used: 0.5 M in benzene/cyclo-
hexane (9/1) solution from Aldrich and 1.7 M in dibutylether solution from Acros.
OR2 R3
OR2
CHO
1. R3CH2NO2, Et3N
b
Ratio measured by 13C NMR of the crude reaction mixtures.
R1
NO2
R1
2. MsCl, DIPEA
-70 °C to rt
c
16 mol % of peroxide intermediate 14 was also obtained.
1 R1=Me, R2=TBS, R3=H
2 R1=Me, R2=Bn, R3=H
3 R1=Me, R2=TBS, R3=Me
4 R1=Ph, R2=TBS, R3=H
The diastereoselectivity of the epoxidation of nitroalkenes
proved to be dependent on the commercial organolithium solution.
If the organolithium solution is in dibutylether then the selectivity
is better than in benzene/cyclohexane (9/1). This solvent effect can
be rationalized in terms of the solvation or aggregation7 of the
lithium species by the solvent: the better the solvent coordinates to
lithium, the better selectivity is observed.
Scheme 1. Preparation of 1-nitroalkenes.
Nitroalkenes 1–45 were epoxidized using lithium tert-butyl-
peroxide6 as the oxidizing reagent in THF as solvent at ꢀ70 ꢁC.
From the epoxidation reaction of nitroalkene 4 some peroxide
intermediate 14 was isolated.
* Corresponding authors. Tel.: þ34 964729156; fax: þ34 964728214.
´
E-mail address: fgonzale@qio.uji.es (S. Rodrıguez).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.010

A. Jain et al. / Tetrahedron 65 (2009) 8362–8366
8363
If the epoxidation reaction of compound 2 was carried out using
potassium tert-butylperoxide, then a better selectivity was ob-
served (Scheme 2).
A nucleophilic epoxidation reaction is thought to proceed by the
addition of a tert-butyl-peroxy anion to the activated double bond,
giving rise to an enolate (Scheme 5). Upon elimination of tert-
butoxide from the enolate, the epoxide is furnished.
BnO
Me
BnO
Me
O
N
CH3
TBPK, THF
-70 °C, 6h
O
1)
CH3
NO2
NO2
O
Li
+
R
O
O
O
2
6
CH3
(dr 19/1)
65%
CH3
CH3
O
R
O
R
CH3
CH3
CH3
CH3
O
O
N
O
N
Scheme 2. Epoxidation using potassium tert-butylperoxide.
Li
O
O
The resulting nitroepoxides were submitted to hydrogenation
giving rise to the corresponding anti nitroaldols (Scheme 3). Ox-
imes 10 and 12 were also obtained as secondary products in the
hydrogenation reaction of compounds 5 and 6, respectively.8
Compound 8 was hydrogenated using ammonium formate9 instead
of hydrogen furnishing anti aldol 13. Hydrogenation of peroxyether
14 furnished also compound 13.
CH3
O
R
2)
CH3
CH3
O
CH3
O
N
O
O
Li
CH3
+
NO2
R
O
CH3
Scheme 5. Mechanism of nucleophilic epoxidation of nitroalkenes.
OH
TBSO
N
TBSO
TBSO
To conduct a meaningful analysis of transition states, it was
necessary to determine whether the epoxidation reaction is kinetic
(irreversible) or reversible, it is whether the initial Michael addition
of the peroxy anion to the nitroalkene is irreversible or reversible.
Then tert-butyl-peroxyether 14 was treated with LHMDS in the
presence of chalcone, nitroepoxide 8 was obtained,14 and chalcone
was recovered.3b The epoxidation of the chalcone was never ob-
served, demonstrating the irreversibility of the reaction.
H2
Pd/C
80%
+
+
Me
H
Me
NO2
Me
NO2
NO2
O
10
9
OH
5
OH
OH
E/Z=2/1
OH
BnO
N
BnO
BnO
H2
Pd/C
84%
Me
H
Me
NO2
Me
O
12
11
OH
6
E/Z=2/1
TBSO
Ph
TBSO
TBSO
Ph
The stereoselectivity in the epoxidation of compounds 1–4 can
H2
NH4HCOO
Pd/C
45%
be accounted for by the models depicted in Scheme 6.15
NO2
14
Ph
NO2 Pd/C
NO2
O
O
13
OH
66%
8
O
R3
NO2
NO2
R3
R2O
Scheme 3. Hydrogenation of nitroepoxides.
H
anti
R1
OR2
H
R1
The stereochemistry of the resulting nitroaldols 9 and 13 and
therefore of the preceding nitroepoxides 5 and 8 was assigned by
comparison with reported data in the literature.10 The spectro-
scopic data for 9 and 13 were identical to those previously
described, denoting relative anti stereochemistry for nitroepoxides
5 and 8, respectively.11
The stereochemistry of nitroaldol 11 and therefore of the pre-
ceding nitroepoxide 6 was assigned through chemical correlation
with nitroaldol 9 as follows: compound 9 was deprotected and the
resulting diol was cyclized using benzylidene diethyl acetal and
p-toluene sulfonic acid12 furnishing a 2/1 mixture of acetals 16 and
17, which were separated by column chromatography. Both acetals
7 and 8 exhibited NOE effects between H-2 and H-3, and between
H-1 and methyl. Then compound 16 was submitted to reductive
opening using sodium cyanoborohydride in the presence of tri-
fluoroacetic acid13 giving rise to nitroaldol 11 (Scheme 4).
t-BuOOLi
H
B
H
A
t-BuOOLi
Scheme 6. Kinetic models to explain anti stereoselectivity.
To explain the anti-selectivity observed for compounds 1, 2, and
4, transition state geometry A (Scheme 6) would be electronically
favored because the alkoxy group is anti. However, there is steric
repulsion between the incoming reagent and the R1 group.
Transition state geometry B also furnishes anti isomer and would
explain the poor selectivity observed for compound 3 due to
1,3-allylic strain between the alkoxy group and vinylic methyl
group.
3. Conclusions
In summary, the nucleophilic epoxidation of O-protected 3-hy-
droxy-1-nitroalkenes is a highly diastereoselective reaction that
favors the anti isomer. The nucleophilic epoxidation of nitroalkenes
is an irreversible process because the enolization of a 2-peroxy
nitrocompound gives only the nitroepoxide. The observed selec-
tivities for epoxides 5–8 can be explained by modified Felkin–Anh
models.
TBSO
HO
Me
HF-py
93%
Me
NO2
NO2
15
9
OH
OH
Benzylidene
p-TsOH
dimethyl acetal
55%
NOE
NOE
BnO
Me
Me
Me
NO2
NO2
+
2
1
4. Experimental section
3
NaCNBH3
CF3COOH
55%
NO2
H
H
2
H
H
O
O
O
17
O
16
OH
11
4.1. General experimental methods
NOE
NOE
Ph
Ph
:
1
All solvents used in reactions were freshly distilled from
appropriate drying agents before use. 1H NMR spectra and 13C NMR
Scheme 4. Chemical correlation of nitroepoxides.

8364
A. Jain et al. / Tetrahedron 65 (2009) 8362–8366
spectra were measured in CDCl3 (1H, 7.24 ppm; 13C 77.0 ppm) so-
lution at 30 ꢁC on a 300 MHz Mercury Varian or a 500 MHz Innova
1005, 973, 903, 832, 778, 724 cmꢀ1. HRMS (FAB) m/z calcd for
C11H23NO3Si [M]: 245.1447, found: 245.1458.
´
Varian NMR spectrometer at the Serveis Centrals d’Instrumentacio
´
Cientıfica de la Universitat Jaume I. Mass spectra were measured in
4.2.3. ((R,E)-3-Nitro-1-phenylallyloxy)(tert-butyl)dimethylsilane
a QTOF I (quadrupole–hexapole-TOF) mass spectrometer with an
orthogonal Z-spray-electrospray interface (Micromass, Manchester,
UK). IR spectra were recorded as oily films on NaCl plates on
a Perkin–Elmer 2000 FT-IR spectrometer. EM Science Silica Gel 60
was used for column chromatography while TLC was performed
with E. Merck precoated plates (Kieselgel 60, F254, 0.25 mm). Unless
otherwise specified, all reactions were carried out under argon
atmosphere with magnetic stirring. About the X-ray crystallo-
graphic study, the crystals are air stable and were mounted on the
tip of a glass fiber with the use of epoxi cement. X-ray diffraction
experiment was carried out on a Bruker SMART CCD diffractometer
4. Yield¼15%. [a2D5]¼þ39.4 (c¼0.4, CHCl3). 1H NMR (300 MHz,
CDCl3)
d
7.41–7.23 (7H, m), 5.45 (1H, d, J¼2.7 Hz), 0.92 (9H, s), 0.09
(3H, s), ꢀ0.06 (3H, s). 13C NMR (CDCl3)
d
144.6, 140.1, 138.6, 129.2,
2928, 1526,
. HRMS (EI) m/z calcd for
128.8, 126.6, 72.4, 26.0, 18.5, ꢀ4.6, ꢀ4.8 ppm. IR (NaCl)
n
1351, 1255, 1125, 838, 779 cmꢀ1
C15H23NO3Si [M]: 225.1287, found: 225.1295.
4.3. Experimental procedure for the preparation
of 11 from 16/17
To a solution of compounds 16 and 17 (3/1) (30 mg, 0.13 mmol)
in dimethylformamide (1 mL) and 3 Å molecular sieves was added
sodium cyanoborohydride (45 mg, 0.67 mmol) and then a solution
using Mo K
a
radiation (
l¼0.71073 Å) at room temperature. The
data were collected with a frame width of 0.3ꢁ in
u
and a counting
time of 30 and 60 s per frame for compounds 2 and 3 at a crystal to
detector distance of 4 cm. The diffraction frames were integrated
using the SAINT package and corrected for absorption with
SADABS.10 The structures were solved by direct methods and re-
fined by the full-matrix method based on F2 using the SHELXTL
software package.11 All non hydrogen atoms were refined aniso-
tropically. Hydrogen atoms were generated geometrically, assigned
isotropic thermal parameters, and allowed to ride on their
respective parent carbon atoms.
of trifluoroacetic acid (105 mL, 1.35 mmol) in dimethylformamide
(0.8 mL). The resulting mixture was stirred at room temperature for
24 h. Then was diluted with dichloromethane and neutralized
using a saturated sodium hydrogen carbonate aqueous solution,
then extracted with dichloromethane, washed with brine, dried
(Na2SO4), filtered, and concentrated. Then the solvent was removed
under reduced pressure. The resulting mixture was purified
through chromatography (silica gel, CH2Cl2/MeOH (9/1)) to afford
3 mg of compound 11 (yield over recovered starting material¼55%).
4.4. General experimental procedure for the epoxidation
4.2. General experimental procedure for the preparation
of nitroalkenes 1–4
To a ꢀ70 ꢁC cold THF (3.5 mL) was added TBHP (3.3 M in tolu-
ene)16 (2.2 mmol) and then ethyl lithium (1.61 mmol). The result-
ing mixture was stirred at ꢀ70 ꢁC for 15 min and then a solution of
the nitroalkene (1.46 mmol) in THF (2 mL) was added dropwise and
then the mixture was stirred at ꢀ70 ꢁC for 6 h. Then solid Na2SO3
(120 mg) was added in one portion and stirring for 15 min, then
diluted with satd aq NH4Cl soln and extracted with Et2O (3ꢂ30 mL),
the organic layers were washed (brine), dried (Na2SO4), and con-
centrated. The crude oil was purified through chromatography
(silica gel, hexanes/EtOAc (9/1) and (8/2)).
To a solution of O-protected (S)-lactaldehyde (or (S)-man-
delaldehyde) (23.92 mmol) in nitromethane (or nitroethane)
(119.60 mmol) was added triethyl amine (0.50 mL, 3.56 mmol). The
resulting mixture was stirred at room temperature for 3 h. Then the
excess of nitromethane (or nitroethane) was removed under re-
duced pressure. The resulting mixture of diastereomeric nitroaldols
(anti/syn¼ca. 6/4) in the form of yellow oil was submitted to the
next step without any further purification.
To a ꢀ70 ꢁC cold solution of nitroaldols (anti/syn¼ca. 6/4) in
dichloromethane (50 mL) was added dropwise methanesulfonyl-
chloride (2.24 mL, 28.89 mmol) and then a solution of N,N-diiso-
propylethylamine (10.48 mL, 60.19 mmol) in dichloromethane
(10 mL). The mixture was stirred at ꢀ70 ꢁC for 2 h and then was
allowed to warm to room temperature. Then was quenched with
water (10 mL) and extracted with CH2Cl2 (4ꢂ30 mL), the organic
layers were washed with HCl 1 N and brine, dried (Na2SO4), and
concentrated. The crude oil was purified through chromatography
(silica gel, hexanes/EtOAc (9/1) and (8/2)) to afford the corre-
sponding nitroalkene as a yellow oil.
4.4.1. ((S)-1-((2S,3R)-3-Nitrooxiran-2-yl)ethoxy)(tert-butyl)di-
25
methylsilane 5. Yield¼75%. [
a
]
¼ꢀ27.6 (c¼2.5, CHCl3). 1H NMR
D
(CDCl3)
d
5.33 (1H, s), 4.06 (1H, qd, J¼6.5 and 2.5 Hz), 3.42 (1H, dd,
J¼2.5 and 1.0 Hz), 1.27 (3H, d, J¼6.5 Hz), 0.86 (9H, s), 0.05 (s, 3H),
0.04 (s, 3H). 13C NMR (CDCl3)
77.8, 63.8, 61.9, 25.7, 20.3, 18.0, ꢀ5.0,
ꢀ5.1 ppm. IR (NaCl) 2957, 2932, 2837, 2856, 1736, 1571, 1473, 1377,
d
n
1362, 1255, 1166, 1130, 1104, 1053, 1005, 983, 936, 836, 779, 720,
667 cmꢀ1. HRMS (EI) m/z calcd for C10H21NO4Si [M]: 247.1238,
found: 247.1238.
4.4.2. (2S,3R)-2-((S)-1-(Benzyloxy)ethyl)-3-nitrooxirane
25
4.2.1. ((S,E)-4-Nitrobut-3-en-2-yloxy)(tert-butyl)dimethylsilane
6. Yield¼70%. [
a]
¼ꢀ92.8 (c¼0.5, CHCl3). 1H NMR (CDCl3)
d 7.39–
D
1. Yield¼70%. [a2D5]¼þ3.3 (c¼0.5, CHCl3). 1H NMR (CDCl3)
d
7.16
7.31 (5H, m), 5.40 (1H, s), 4.57 (2H, d), 3.75 (1H, qd, J¼6.5 and
(1H, dd, J¼13.0, 4.0 Hz), 7.02 (1H, dd, J¼13.0, 2.0 Hz), 4.52 (1H, ddq,
3.0 Hz), 3.50 (1H, d, J¼3.5 Hz), 1.32 (3H, d, J¼6.5 Hz). 13C NMR
J¼6.5, 3.0, 1.5 Hz), 1.25 (3H, d, J¼7.0 Hz), 0.83 (9H, s), 0.01 (3H, s),
(CDCl3)
d 137.7, 128.8, 128.2, 127.9, 78.5, 72.4, 70.4, 61.2, 17.4 ppm. IR
0.00 (3H, s). 13C NMR (CDCl3)
d
146.1, 139.3, 65.9, 26.1, 23.7, 18.5,
(NaCl) n 3065, 3032, 2981, 2934, 2872, 1741, 1567, 1497, 1454, 1365,
ꢀ4.5, ꢀ4.7 ppm. IR (NaCl)
n
3122, 2959, 2923, 2856, 1653, 1529,
1101, 1058, 956, 924, 806, 737, 699 cmꢀ1. HRMS (EI) m/z calcd for
1351, 1255, 1156, 1093, 1053, 835, 776, 665 cmꢀ1. HRMS (EI) m/z
C11H13NO4 [M]: 223.0845, found: 223.0860.
calcd for C10H21NO3Si [M]: 231.1291, found: 231.1298.
4.4.3. ((S)-1-((2S,3R)-3-Methyl-3-nitrooxiran-2-yl)ethoxy)(tert-
25
4.2.2. ((S,E)-4-Nitropent-3-en-2-yloxy)(tert-butyl)dimethylsilane
butyl)dimethylsilane 7. Yield¼75%. [
a
]
¼ꢀ20.2 (c¼0.5, CHCl3). 1H
D
3. Yield¼68%. [a2D5]¼þ11.9 (c¼0.5, CHCl3). 1H NMR (CDCl3)
d
6.99
NMR (CDCl3)
d
3.74 (1H, qd, J¼6.5 Hz) (major isomer), 3.51 (1H, qd,
(1H, d, J¼8.0 Hz), 4.55 (1H, dq, J¼7.5 and 6.5 Hz), 2.16 (3H, s), 1.28
J¼6.5 Hz) (minor isomer), 3.35 (1H, d, J¼8.0 Hz) (minor isomer), 3.26
(1H, d, J¼6.5 Hz) (major isomer), 1.95 (1H, s) (major isomer), 1.86
(1H, s) (minor isomer),1.25 (3H, d, J¼6.5 Hz) (major isomer),1.18 (3H,
d, J¼6.5 Hz) (minor isomer), 0.83 (9H, s) (minor isomer), 0.81 (9H, s)
(3H, d, J¼6.5 Hz), 0.86 (9H, s), 0.05 (s, 3H), 0.02 (s, 3H). 13C NMR
(CDCl3)
(NaCl)
d
145.8, 138.9, 65.4, 26.0, 23.6, 18.0, 12.8, ꢀ4.8, ꢀ4.9 ppm. IR
n
2957, 2930, 2858, 1529, 1473, 1389, 1336, 1254, 1133, 1090,

A. Jain et al. / Tetrahedron 65 (2009) 8362–8366
8365
(major isomer), 0.04 (3H, s) (minor isomer), 0.01 (3H, s) (major
isomer), 0.00 (3H, s) (minor isomer), 0.00 (3H, s) (major isomer). 13C
isomer), 3.30 (1H, br s),1.15 (1H, d, J¼6.0 Hz) (major isomer),1.11 (1H,
d, J¼6.5 Hz) (minor isomer), 0.88 (9H, s) (minor isomer), 0.87 (9H, s)
(major isomer), 0.08 (3H, s) (minor isomer), 0.06 (3H, s) (major
NMR (CDCl3)
d 194.0 (major isomer), 185.3 (minor isomer), 72.6
(minor isomer), 68.0 (major isomer), 61.5 (major isomer), 59.0 (mi-
nor isomer), 25.6 (major isomer), 25.6 (minor isomer), 21.6 (major
and minor isomer), 20.4 (major and minor isomer), 18.0 (major
isomer), 17.9 (minor isomer), ꢀ4.0 (minor isomer), ꢀ4.3 (major
isomer). 13C NMR (CDCl3)
d 151.7 (minor isomer), 150.8 (major iso-
mer), 73.5 (major isomer), 70.8 (major isomer), 69.8 (minor isomer),
68.8 (minor isomer), 25.8 (major and minor isomer), 19.3 (major
isomer), 18.2 (minor isomer), 18.0 (minor isomer), 17.9 (major iso-
mer), ꢀ4.4 (major isomer), ꢀ4.6 (minor isomer), ꢀ4.8 (major and
isomer), ꢀ4.9 (minor isomer), ꢀ5.0 (major isomer) ppm. IR (NaCl)
n
2957, 2932, 2897, 2859, 1563,1473,1388,1362,1258,1198,1152,1107,
1061, 986, 959, 920, 885, 836, 778, 666 cmꢀ1. HRMS (EI) m/z calcd for
C11H23NO4Si [M]: 261.1396, found: 261.1392.
minor isomer) ppm. IR (NaCl) n 3346, 2956, 2931, 2887, 2859, 1660,
1473,1377,1257,1100,1006, 972, 938, 886, 837, 777, 676 cmꢀ1. HRMS
(EI) m/z calcd for C10H24NO3Si [MþHþ]: 234.1517, found: 234.1525.
25
4.4.4. ((S)-((2S,3R)-3-Nitrooxiran-2-yl)(phenyl)methoxy)(tert-bu-
4.5.3. (2R,3S)-3-(Benzyloxy)-1-nitrobutan-2-ol 11. Yield¼84%. [
a
]
¼
D
25
tyl)dimethylsilane 8. Yield¼75%. [
a
]
¼þ20.6 (c¼0.52, CHCl3). 1H
þ71.9 (c¼0.6, CHCl3). 1H NMR (CDCl3)
d 7.30–7.38 (m, 5H), 4.65 (1H, d,
D
NMR (CDCl3)
d
7.49–7.40 (5H, m), 5.60 (1H, s) (major isomer), 5.39
J¼11.5 Hz), 4.60 (1H, dd, J¼13.5 and 3.0 Hz), 4.48–4.43 (2H, m), 4.25
(1H, ddd, J¼8.0, 5.5 and 3.0 Hz), 3.63 (1H, dq, J¼6.0 and 5.5 Hz), 2.81
(1H, s) (minor isomer), 5.05 (1H, s) (major isomer), 4.85 (1H, d,
J¼4.0 Hz) (minor isomer), 3.73 (1H, d, J¼4.0 Hz) (minor isomer),
3.65 (1H, s) (major isomer), 0.98 (9H, s) (minor isomer), 0.95 (9H, s)
(major isomer), 0.17 (3H, s) (minor isomer), 0.15 (3H, s) (major
isomer), 0.03 (3H, s) (minor isomer), 0.00 (3H, s) (major isomer). 13C
(1H, br s), 1.28 (3H, d, J¼6.0 Hz). 13C NMR (CDCl3)
d 137.6, 128.6, 128.0.
127.8, 77.7, 75.3, 71.9, 15.6 ppm. IR (NaCl)
n 3433, 3032, 2919, 1727,
1554, 1496, 1454, 1379, 1260, 1089, 800, 738, 698 cmꢀ1. HRMS (FAB)
m/z calcd for C11H16NO4 [MþHþ]: 226.1079, found: 226.1080.
NMR (CDCl3)
d 138.5 (major isomer), 138.5 (minor isomer), 128.9,
128.8, 128.7, 128.6, 126.4, 126.2 (major and minor isomer), 79.1
(minor isomer), 77.6 (major isomer), 71.9 (minor isomer), 70.2
(major isomer), 62.4 (major isomer), 61.8 (minor isomer), 25.8
(major and minor isomer), 18.2 (major and minor isomer), ꢀ4.8
(minor isomer), ꢀ4.9 (major isomer), ꢀ5.0 (minor isomer), ꢀ5.1
4.5.4. (2R,3S)-3-(Benzyloxy)-2-hydroxybutanal oxime 12. 1H NMR
(CDCl3, 300 MHz)
d
7.51 (1H, d, J¼5.4 Hz) (major isomer), 7.26–7.37
(5H, m), 6.83 (1H, d, J¼5.1 Hz) (minor isomer), 4.99 (1H, dd, J¼5.1 and
3.9 Hz) (minor isomer), 4.64 (1H, d, J¼12.0 Hz) (minor isomer), 4.65
(1H, d, J¼11.7 Hz) (major isomer), 4.56 (1H, d, J¼12.0 Hz) (minor
isomer), 4.51 (1H, d, J¼11.7 Hz) (major isomer), 4.27 (1H, t, J¼4.8 Hz)
(major isomer), 3.93 (1H, dq, J¼6.6 and 3.9 Hz) (minor isomer), 3.70
(1H, dq, J¼6.3 and 4.5 Hz) (major isomer), 1.22 (1H, d, J¼6.3 Hz)
(major isomer), 1.20 (1H, d, J¼6.9 Hz) (minor isomer). 13C NMR
(major isomer) ppm. IR (NaCl) n 2929, 2857, 1707, 1569, 1471, 1362,
1255, 1153, 975, 837, 780, 755, 689 cmꢀ1. HRMS (EI) m/z calcd for
C15H23NO4Si [M]: 309.1396, found: 309.1382.
4.4.5. ((1S,2R)-2-(tert-Butyl-peroxy)-3-nitro-1-phenylpropoxy)(tert-
(CDCl3, 75 MHz) d 151.9 (minor isomer), 150.6 (major isomer),138.0,
20
butyl)dimethylsilane 14. [
(CDCl3)
a
]
¼þ57.7 (c¼0.84, CHCl3). 1H NMR
128.7, 128.0, 127.9, 127.7, 76.8 (major isomer), 75.1 (minor isomer),
72.0 (major isomer), 71.1 (major isomer), 71.0 (minor isomer), 67.6
(minor isomer),15.1 (major isomer),14.9 (minor isomer) ppm. HRMS
(FAB) m/z calcd for C11H16NO3 [MþHþ]: 210.1130, found: 210.1123.
D
d
7.45–7.40 (5H, m), 5.21 (2H, m), 4.80 (1H, m), 4.65 (1H, m),
4.47 (1H, m), 1.24 (9H, s), 0.98 (9H, s), 0.18 (3H, s), 0.01 (3H, s). 13C
NMR (CDCl3) 140.5, 128.8, 128.3, 126.3, 86.0, 81.7, 73.8, 73.2, 26.7,
d
26.1, 18.6, ꢀ4.6, ꢀ4.7 ppm. IR (NaCl)
n 2930, 1560, 1364, 1101, 837,
779 cmꢀ1
.
HRMS (FAB) m/z calcd for C19H34NO5Si [MþHþ]:
4.5.5. (1S,2R)-1-(tert-Butyldimethylsilyloxy)-3-nitro-1-phenyl-
20
384.2206, found: 384.2195.
propan-2-ol 13. Yield¼45% from 8; 66% from 14. [
a]
¼þ48.2
D
(c¼0.5, CHCl3) (lit.8
[
a2D0]¼þ51.8 (c¼1.3, CHCl3)). 1H NMR (CDCl3,
4.5. General experimental procedure for the hydrogenation
of nitroepoxides
300 MHz)
d
7.25–7.40 (5H, m), 4.77 (1H, d, J¼5.1 Hz), 4.46 (2H, m),
4.38 (1H, m), 2.48 (1H, br s), 0.91 (9H, s), 0.07 (3H, s), ꢀ0.14 (3H, s).
13C NMR (CDCl3, 75 MHz)
d
139.8, 128.8, 128.7, 126.5, 77.1, 76.3, 73.6,
A solution of nitroepoxide (1 mmol) in anhydrous methanol
(2 mL) was added to a pre-hydrogenated suspension of Pd/C (10% in
Pd) (40 mg) in anhydrous methanol (20 mL). The resulting mixture
was stirred under hydrogen atmosphere at room temperature for
15 h. Then was filtered through Celite and concentrated under
vacuum. The resulting light yellow oil was purified through chro-
matography (silica gel, hexanes/EtOAc (7/3) and (6/4)) to afford the
corresponding nitroaldol and an (E/Z) mixture of oximes.
25.7, 18.1, ꢀ4.6, ꢀ5.1 ppm. IR (NaCl)
n 3630, 2939, 2860, 1553, 1258,
1082, 847, 450 cmꢀ1. HRMS (FAB) m/z calcd for C15H26NO4Si
[MþHþ]: 312.1639, found: 312.1631.
4.5.6. (2R,3S)-1-Nitrobutane-2,3-diol 15. To a solution of com-
pound 9 (100 mg, 0.40 mmol) in THF (5 mL) and pyridine (480 mL)
was added a previously prepared solution of hydrogen fluoride–
pyridine complex (65–70% in hydrogen fluoride) (1.05 mL) in THF
(9.7 mL) and pyridine (817 mL). The resulting mixture was stirred at
4.5.1. (2R,3S)-3-(tert-Butyldimethylsilyloxy)-1-nitrobutan-2-ol
room temperature for 26 h. Then sodium hydrogen carbonate was
added. Then the resulting suspension was filtered and washed with
dichloromethane and the solvent was removed under reduced
pressure. The resulting mixture was purified through chromato-
graphy (silica gel, CH2Cl2, CH2Cl22/5MeOH (9/1) and (8/2)) to afford
25
9. Yield¼80%. [
a
]
¼þ22.3 (c¼2.5, CHCl3). 1H NMR (CDCl3)
d 4.55
D
(1H, dd, J¼13.0 and 2.5 Hz), 4.38 (1H, dd, J¼13.0 and 9.0 Hz), 4.08
(1H, m), 3.83 (1H, q, J¼6.5 Hz), 1.18 (3H, d, J¼6.5 Hz), 0.86 (9H, s),
0.06 (3H, s), 0.05 (3H, s). 13C NMR (CDCl3)
d 77.8, 73.2, 69.8, 25.7,
19.8, 17.8, ꢀ4.4, ꢀ5.0 ppm. IR (NaCl)
n
3447, 2956, 2931, 2888, 2859,
50 mg (93%) of compound 15. [
(CD3OD)
a
]
¼þ39.5 (c¼2.4, CHCl3). 1H NMR
D
1737, 1558, 1473, 1378, 1257, 1147, 1091, 1006, 978, 837, 778,
668 cmꢀ1. HRMS (EI) m/z calcd for C10H21NO3Si [MꢀH2O]: 231.1291,
found: 231.1297.
d
4.76 (1H, dd, J¼13.0 and 3.0 Hz), 4.39 (1H, dd, J¼13.0 and
10.0 Hz), 4.01 (1H, m), 3.63 (1H, dq, J¼6.5 Hz), 3.35 (1H, s), 1.23 (1H,
d, J¼6.5 Hz). 13C NMR (CD3OD)
d 80.8, 75.5, 70.6, 20.7 ppm. IR (NaCl)
n
3300, 2922, 1652, 1544, 1378, 1098 cmꢀ1
.
4.5.2. (2R,3S)-3-(tert-Butyldimethylsilyloxy)-2-hydroxybutanal oxime
10. 1H NMR (CDCl3)
d
9.26 (1H, br s), 7.44 (1H, d, J¼6.5 Hz) (major
4.5.7. (2S,4S,5R)-4-Methyl-5-(nitromethyl)-2-phenyl-1,3-dioxolane
16. To a solution of diol 15 (50 mg, 0.37 mmol) in benzene (0.5 mL)
isomer), 6.76 (1H, d, J¼6.5 Hz) (minor isomer), 4.75 (1H, t, J¼4.5 Hz)
(minor isomer), 4.17 (1H, dq, J¼6.5 and 4.5 Hz) (minor isomer), 4.05
(1H, t, J¼5.5 Hz) (major isomer), 3.90 (1H, dq, J¼6.5 Hz) (major
were added benzylidene dimethyl acetal (60
mL, 0.4 mmol) and
p-toluene sulfonic acid (8.5 mg, 0.45 mmol). The resulting mixture

8366
A. Jain et al. / Tetrahedron 65 (2009) 8362–8366
Wiley-VCH: New York, NY, 2001; (d) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J.
Org. Chem. 2002, 12, 1877; (e) Aizpea, Z.; Mendoza, L.; Vivanco, S.; Aldaba, E.;
Carrascal, T.; Lecea, B.; Arrieta, A.; Zimmerman, T.; Vidal-Vanaclocha, F.; Cossı´o,
F. P. Angew. Chem., Int. Ed. 2005, 44, 2903.
2. (a) Enders, D.; Kramps, L.; Zhu, J. Tetrahedron: Asymmetry 1998, 9, 3959;
(b) Vankar, Y. D.; Shah, K.; Bawa, A.; Singh, S. P. Tetrahedron 1991, 47, 8883;
(c) Jackson, R. F. W.; Kirk, J. M.; Palmer, N. J.; Waterson, D.; Wythes, M. J.
J. Chem. Soc., Chem. Commun. 1993, 889; (d) Adams, Z. M.; Jackson, R. F. W.;
Palmer, N. J.; Rami, H. K.; Wythes, M. J. J. Chem. Soc., Perkin Trans. 1 1999,
937; (e) Jackson, R. F. W.; Palmer, N. J.; Wythes, M. J.; Clegg, W.; Elsegood,
M. R. J. Org. Chem. 1995, 60, 6431; (f) Ambroise, L.; Jackson, R. F. W. Tet-
rahedron Lett. 1996, 37, 2311; (g) Jackson, R. F. W.; Kirk, J. M.; Palmer, N. J.;
Waterson, D.; Wythes, M. J. Org. Biomol. Chem. 2007, 5, 3157.
was heated connected to a distillation system until benzene–
methanol azeotropic mixture distilled (bp 57 ꢁC) and then refluxed
for 6 h. Then the reaction mixture was cooled down to room tem-
perature. Then was diluted with dichloromethane and neutralized
using a saturated sodium hydrogen carbonate aqueous solution,
then extracted with dichloromethane, washed with brine, dried
(Na2SO4), filtered, and concentrated. Then the solvent was removed
under reduced pressure. The resulting mixture was purified
through chromatography (silica gel, hexanes/EtOAc (9/1)) to afford
34 mg of compound 16 and 11 mg of compound 17 (yield¼55%).
1H NMR (CDCl3)
d 7.54–7.50 (2H, m), 7.46–7.42 (3H, m), 5.99 (1H, s),
´
´
´
3. (a) Rodrıguez, S.; Izquierdo, J.; Lopez, I.; Gonzalez, F. V. Tetrahedron 2006, 62,
11112; (b) Lo´ pez, I.; Rodrı´guez, S.; Izquierdo, J.; Gonza´lez, F. V. J. Org. Chem. 2007,
72, 6614; For other papers related to enoate epoxidations, see: (c) Enders, D.;
Zhu, J.; Kramps, L. Liebigs Ann. 1997, 1101.
4.88 (1H, ddd, J¼10.0, 6.5, and 3.0 Hz), 4.69 (1H, dd, J¼13.0 and
3.0 Hz), 4.58 (1H, dd, J¼13.0 and 10.0 Hz), 4.52 (1H, dq, J¼6.5 and
3.5 Hz), 1.32 (3H, d, J¼6.5 Hz). 13C NMR (CDCl3)
d
136.30, 129.65,
2935,
4. (a) Melton, J.; McMurry, J. E. J. Org. Chem. 1975, 40, 2138; (b) Ayerbe, M.; Cossı´o,
F. P. Tetrahedron Lett. 1995, 36, 4447.
5. The epoxidation over the non-protected 3-hydroxy-1-nitroalkenes readily
prepared through deprotection of compounds 1 and 4 did not furnish the
128.47, 126.47, 103.84, 75.75, 74.60, 14.03 ppm. IR (NaCl)
n
2854, 1557,1376, 1093, 710 cmꢀ1. HRMS (EI) m/z calcd for C11H13NO4
expected nitroepoxides but
compounds.
a
complex mixture of non-epoxidic
[M]: 223.0845, found: 223.0848.
6. Meth-Cohn, O.; Moore, C.; Taljaard, H. C. J. Chem. Soc., Perkin Trans. 1 1988, 2663.
7. Boche, G.; Mo¨bus, K.; Harms, K.; Lohrenz, J. C. W.; Marsch, M. Chem.dEur. J.
1996, 2, 604.
8. For the conversion of nitroepoxides into oximes, see: (a) Baer, H. H.; Madumelu,
C. B.; Hanna, Z. S.; Potvin, P. G. Carbohydr. Res. 1979, 76, 141; (b) Saito, I.; Takami,
M.; Konoike, T.; Matsuura, T. Bull. Chem. Soc. Jpn. 1973, 46, 98.
4.5.8. (2R,4S,5R)-4-Methyl-5-(nitromethyl)-2-phenyl-1,3-dioxolane
17. 1H NMR (CD3CN)
d 7.26–7.21 (5H, m), 5.99 (1H, s), 4.79 (1H, q,
J¼6.5 Hz), 4.50 (2H, d, J¼6.5 Hz), 4.36 (1H, dq, J¼6.5 Hz), 1.08 (3H, d,
J¼6.5 Hz). 13C NMR (CD3CN)
d
138.92, 130.20, 129.88, 127.75, 102.18,
2924, 2854, 1556, 1452,
9. The hydrogenation reaction of nitroepoxide
decomposition.
8 using hydrogen resulted in
75.59, 75.22, 73.16, 13.20 ppm. IR (NaCl)
n
1376, 1093, 700 cmꢀ1
Acknowledgements
This work was financed by Bancaixa-UJI foundation (P11A2005-
.
10. Sohtome, Y.; Takemura, N.; Iguchi, T.; Hashimoto, Y.; Nagasawa, K. Synlett 2006,
144.
11. The stereochemistry of nitroepoxides 7 was assigned based on the coupling
constants (see Ref. 3a): J2,3 (syn)¼8.0 Hz and J2,3 (anti)¼6.5 Hz. Similar coupling
constants were observed for syn and anti isomers of 1-substituted 3-hydroxy-1-
nitroepoxides (Ref. 2d).
12. Kocienski, P.; Street, S. D. A. Synth. Commun. 1984, 14, 1087.
13. Johansson, R.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1984, 201.
14. The reversibility experiment was also carried out in the presence of nitroalkene
1, also nitroepoxide 8 was obtained and nitroalkene was recovered. Only trans-
nitroepoxide are observed as it is from the epoxidation reactions.
´
14). We thank Prof. Fernando Cossıo for helpful discussions.
Supplementary data
15. For conjugate addition of amides to non-substituted and
a-methyl-substituted
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.08.010.
g-methoxyenoates, see: (a) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.;
Kitahara, H. J. Am. Chem. Soc. 1992, 114, 7652; (b) Asao, N.; Shimada, T.; Sudo, T.;
Tsukada, N.; Yazawa, K.; Gyoung, Y. S.; Uyehara, T.; Yamamoto, Y. J. Org. Chem.
1997, 62, 6274. For epoxidation of a-methyl-substituted g-hydroxyenoates see
Ref. 3b.
References and notes
16. Preparation of tert-butyl hydroperoxide solution: Hill, J. G.; Rossiter, B. E.;
Sharpless, B. J. Org. Chem. 1983, 48, 3607–3608.
1. (a) Barrett, A. G. M.; Grabowski, G. G. Chem. Rev. 1986, 86, 751; (b) Barrett, A. G.
M. Chem. Soc. Rev. 1991, 20, 95; (c) Ono, N. The Nitro Group in Organic Synthesis;