One-pot multi-substrate enantioselective conjugate addition of diethylzinc to nitroalkenes

Article abstract of DOI:10.1016/S0040-4020(02)00574-4

A multi-substrate approach is used in the copper-phosphoramidite catalyzed enantioselective conjugate addition of diethylzinc to nitroalkenes, using up to nine different nitroalkenes in a one pot procedure. The 18 products (9 times 2 enantiomers of nine d

Full text of DOI:10.1016/S0040-4020(02)00574-4

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 5773±5778
One-pot multi-substrate enantioselective conjugate addition
of diethylzinc to nitroalkenes
p
Ate Duursma, Adriaan J. Minnaard and Ben L. Feringa
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen, Nijenborgh 4,
9
747 AG Groningen, The Netherlands
Received 22 March 2002; revised 21 May 2002; accepted 6 June 2002
AbstractÐA multi-substrate approach is used in the copper-phosphoramidite catalyzed enantioselective conjugate addition of diethylzinc to
nitroalkenes, using up to nine different nitroalkenes in a one pot procedure. The 18 products (9 times 2 enantiomers of nine different
nitroalkanes) can be analyzed by chiral CG in a single run since on overlap in the peaks is observed. The obtained enantioselectivities are
amongst the highest reported so far for the catalytic 1,4-addition of dialkylzinc reagents to nitroalkenes. q 2002 Elsevier Science Ltd. All
rights reserved.
1
4
1
. Introduction
higher atom economy, and using copper-phosphoramidite
catalysts in the 1,4-addition of diethylzinc to nitroalkenes
moderate to high enantioselectivities have been obtained
Conjugate addition reactions of dialkylzinc reagents to
Michael acceptors (e.g. enones) have reached a very high
level of enantioselectivity with copper catalysts based on
phosphoramidites, and more recently employing phosphites,
phosphonates and phosphines as chiral ligands.1 The
selectivities which can be obtained for acyclic substrates
with these catalysts is usually lower than for the cyclic
ones, though very recently Hoveyda et al. showed that a
copper-dipeptide phosphine catalyst gives high enantio-
1
5
16
by Sewald and Wendisch, Feringa and Versleijen et al.
1
7
and Alexakis and Benhaim (Scheme 1). Gennari and
co-workers have shown that a parallel library of sulfona-
mide ligands is able to generate moderate enantioselec-
tivities in the copper catalyzed conjugate addition of
diethylzinc to nitroalkenes. Hayashi et al. have recently
shown that the rhodium catalyzed addition of arylboronic
acids to cyclic nitroalkenes gives high enantioselectivities.
The use of alkenylboronic acids leads to a lower selectivity
however and only one example employing an acyclic
nitroalkene has been reported. Despite the progress in
enantioselective 1,4-addition to nitroalkenes the method-
ology is still limited and cannot be considered of general
use so far to prepare the valuable enantiomerically pure
nitroalkane building blocks. Since there is no unique cata-
lyst for all members of a substrate class, e.g. nitroalkenes,
rapid ®ne tuning of catalyst for a particular substrate is
necessary leading to tailor made catalysts. Several combi-
natorial methods have been developed for this purpose over
±5
1
8
6
,7
selectivities for both types of enones.
For acyclic
substrates chalcone is often used as the model enone but
nitroalkenes 1 are a more interesting class of substrates.
Nitroalkenes are suitable Michael acceptors due to the
strong electron-withdrawing nitro group. They can be
easily synthesized via the Henry condensation and many
1
9
8
9
substituted nitrostyrenes are commercially available.
Enantioselective addition of dialkylzinc reagents to
nitroalkenes leads to chiral nitroalkanes 2 and through
functional group transformations, such as reduction and
the Nef reaction, chiral amines and aldehydes can be
obtained. Nitroalkanes can also be used in a sequence
involving the Henry reaction with aldehydes followed by
reduction, leading to amino alcohols.
1
0
20
the last decade, most of them employing a set of parallel
reactions followed by a high throughput screening tech-
nique in which all reactions are analyzed individually.
1
1
21
A one-pot procedure employing a mixture of catalysts for
an enantioselective reaction is not feasible since the oppo-
site selectivities and different reaction rates of the catalysts
Enantioselective routes to chiral nitroalkanes have been
developed using stoichiometric amounts of chiral auxiliaries
or Ti-TADDOLates. Catalytic methods however, have
the advantage of low amounts of chiral auxiliaries and a
1
2,13
Keywords: combinatorial chemistry; asymmetric catalysis; phosphor-
amidities; copper; conjugate addition.
p
Corresponding author. Tel.: 131-50-3634278; fax: 131-50-3634296;
e-mail: feringa@chem.rug.nl
Scheme 1. Copper catalyzed 1,4 addition of dialkylzinc to nitroalkenes.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00574-4

5774
A. Duursma et al. / Tetrahedron 58 (2002) 5773±5778
Table 1. Retention times of aromatic nitroalkenes and nitroalkanes on chiral GC
a
a
Entry
Ar
GC retention time of 3 (min)
Conversion of 3 (%)
Product 4
GC retention time of 4 (min)
1
2
3
4
5
6
7
8
9
3a: furyl
3b: thienyl
3c: C
3d: 4-CH
3e: 4-F±C
3f: 4-CF O±C
3g: 4-CF ±C
3h: 4-CH O±C
3i: 4-B
29
50
52
64
69
77
79
94
174
100
100
100
100
100
100
100
100
100
4a: furyl
4b: thienyl
4c: C
4d: 4-CH3±C
4e: 4-F±C
4f: 4-CF O±C
4g: 4-CF ±C
4h: 4-CH O±C
4i: 4-B
10.7/11.0
22.8/23.4
24.4/25.2
36.2/37.5
39.9/40.7
41.1/42.4
44.9/46.2
59.2/60.2
77.6/78.5
6
H
5
6 5
H
3
±C
6
H
4
6 4
H
6
H
4
6 4
H
3
6
H
4
3
6 4
H
H
6 4
H
6 4
3
6
H
4
3
3
6
H
4
3
F
C
6
H
4
F 6 4
C H
a
Analysis on an A-TA column, see Section 4 for details.
will lead to unexplicable results. In 1998 Kagan introduced
the `one-pot multi-substrate' method by reducing mixtures
of up to seven different ketones in one pot with the Corey
substrate procedure is established. In this manuscript we
report the development of a one-pot multi-substrate pro-
cedure using up to nine different nitroalkenes followed by
analysis in a single chiral GC run. Moderate to high ees for
aromatic nitroalkanes using copper-phosphoramidite cata-
lysts were obtained whereas with these catalysts high ees
were found for aliphatic nitroalkanes.
2
2
oxazaborolidine (CBS) catalyst. Liskamp et al. used the
one-pot multi substrate method for the addition of diethyl-
2
3
zinc to a mixture of four aldehydes. With this method
the enantioselectivity of a catalyst of multiple substrates
can be screened without the need for (sophisticated) parallel
equipment. The absence of competing catalytic pathways
will allow an unambiguous interpretation of the results.
The utility of this procedure can be even more enhanced
when a single chiral GC or HPLC run can analyze the
products. The two basic requirements of such a system
are: (i) the product peaks in the chromatogram should not
overlap, and the product peaks in their turn not with the
peaks resulting from unconverted starting material, (ii) the
different substrates and products should not interfere
with each other during the reaction, for instance by auto-
2. Results and discussion
In the initial experiments single aromatic nitroalkenes 3a±i
were reacted with diethylzinc in toluene at 2458C under the
in¯uence of 2 mol% of a racemic copper phosphoramidite
catalyst to give complete conversion to racemic nitroalkanes
4a±i in 3 h (Table 1). The enantiomer separation of the nine
products with chiral GC showed that the retention times of
the enantiomers of the nine nitroalkanes are suf®ciently
different to allow separation in a single GC run. Since
these reactions are not known to show autocatalytic
2
4
catalysis. A major advantage is that different catalysts can
be evaluated with the same setup once such a multi-
1
7
effects, the above mentioned conditions for a one-pot
multi-substrate procedure are met. A one-pot multi-
substrate experiment with the nine nitroalkenes 3a±i and
racemic phosphoramidite A under the same conditions as
the individual experiments revealed that that was indeed the
case. Since not all catalysts might give complete conversion
the retention times of the starting materials were also
determined and to our delight the peaks did not overlap
and only in one case overlap with a product peak was
found (3f entry 6 and 4i entry 9). The starting materials
are however easily removed after the reaction by a quick
Table 2. Phosphoramidite ligands (absolute con®guration)
®ltration of the concentrated reaction mixture with an apolar
solvent through a short path of silica.
With this established one-pot multi-substrate procedure,
2
5
eight phosphoramidites (A±H, Table 2) were tested as
chiral ligands in the copper catalyzed enantioselective
conjugate addition of diethylzinc to nitroalkenes 3a±i. In
a typical experiment, 2.25 mmol of a mixture of nine
nitroalkenes (3a±i, 0.25 mmol each) was reacted with
diethylzinc and 2 mol% of catalyst in toluene at 2458C.
Lower temperatures led to a lower reaction rate whereas
higher temperatures were detrimental to the ee. This also

A. Duursma et al. / Tetrahedron 58 (2002) 5773±5778
Table 3. Ees (%) of aromatic nitroalkanes in the one-pot multi-substrate Table 4. Addition of diethylzinc to aliphatic nitroalkenes
procedure
5775
Ligand
A
B
C
D
E
F
G
H
Product:
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
I
42
48
33
44
47
45
57
42
54
5
4
1
46
49
32
34
30
26
6
56
66
57
71
77
62
70
64
48
75
63
16
52
44
52
48
38
30
56
46
60
43
38
35
35
41
36
27
36
13
13
15
21
19
13
34
18
Product 6
Ee (%) E
Ee (%) F
a
35
35
28
23
37
27
31
59
55
63
61
52
69
63
9
8
0
2
87
38
20
72
Absolute con®gurations were not determined
a
4
8% according to Ref. 15, 2% according to Ref. 17.
a
a
9
0 (83:17)
90 (84:16)
holds for the use of other solvents like THF, DCM and Et O.
2
With all eight ligands complete conversion was obtained
within three hours. After workup and ®ltration, the reaction
mixture was analyzed by chiral GC (Fig. 2) and the ees
obtained for the products 4a±i are shown in Table 3. In
order to prove that there was no in¯uence of the different
reactions upon each other, excluding autocatalysis, different
b
54
±
a
cis:trans ratio.
Not tested.
b
2
2
reaction rates or concentration effects, the reactions were
also performed separately with ligand E, which resulted in
no difference in ee or conversion in comparison to the
combinatorial reaction. In the ®rst experiment, with
enantiopure phosphoramidite ligand A, moderate ees were
obtained, ranging from 33% for 4c to 57% for 4g. Ligand B,
paring TADDOL phosphoramidites G and H, but no
improvement was observed going from a mono- to bidentate
31
ligand. As can be concluded from Table 3, there is no clear
2
6
correlation between the electronic effect of a variety of
substituents on the para position of the arene moiety of
the substrate and the ee.
an excellent ligand for enantioselective hydrogenations,
does not lead to a high selectivity in the present reaction.
A more bulky amine moiety in the ligand seemed to be
important in order to obtain higher enantioselectivities and
therefore ligands C±F, derived from bis(1-phenylethyl)-
amine, were tested. The amine part of the ligand is not
only important for the level of enantioselectivity; its
absolute con®guration also dictates the direction of the
enantioselectivity. Ligands A, B, and E give the same
major enantiomers in the products whereas for ligand D it
The position of the substituent on the aromatic ring was
investigated using ortho-, meta- and para-tri¯uoromethyl-
substituted nitrostyrene (3j, k and g) and the copper catalyst
based on ligand E, resulting in 79, 53 and 52% ee for the
corresponding nitroalkanes 4j, k and g, respectively (Fig. 1).
This result implies that steric factors might play a larger role
than electronic ones in the enantiodetermining step.
2
7
is reversed. The octahydro-BINOL based ligand C raised
the ee only slightly to 35 % for 4c, but with ligands E and F
moderate to high enantioselectivities were obtained. Like in
Next to aromatic nitroalkenes also four aliphatic nitro-
alkenes were tested as substrates in the enantioselective
conjugate addition (Table 4). Since ligands E and F showed
the highest selectivities in the addition to aromatic nitro-
alkenes, these were selected for the reactions with 5a±d.
For products 6a±c high ees and complete conversions
were reached with both ligands, but ligand E gave slightly
better results. Nitroalkane 6a, obtained with 90% ee, is
particularly interesting since it provides access to b-amino
alcohols after deprotection and reduction. In our hands 6b is
2
8
the case of the conjugate addition to enones the diastereo-
meric ligands D and E display a matched/mismatched
combination where the latter is also the matched one for
the conjugate addition reactions to nitroalkenes, e.g. 32
and 59% ee for 4c, respectively. The ees obtained for
1
4,15
4
phoramidite F, which contains the atropisomeric bisphenol
a±i are the highest reported so far with ligand E.
Phos-
2
9
30
moiety, reported by Alexakis, gives even higher
enantioselectivities for almost all products, leading to 77%
for 4c. For 4b 71% ee is obtained, whereas only moderate
ees have been reported until now for this substrate. The
in¯uence of a bidentate ligand was investigated by com-
obtained with 82% ee using ligand E, despite a reported
result of 94% ee.
17,²
1
8
In the case of 6c a cis/trans mixture
of products is obtained in good yield with a high ee of 90%
for both diastereomers. The 83/17 ratio of the cis and trans
isomers can be converted to a 11/89 ratio in favor of the
thermodynamically more stable trans form, by treatment
with 1 equiv. of DBU at room temperature without loss of
3
2
enantiomeric excess.
²
Figure 1. Tri¯uoromethyl-substituted aromatic nitroalkanes.
Several attempts to reproduce the literature results failed in our hands.

5776
A. Duursma et al. / Tetrahedron 58 (2002) 5773±5778
3
. Conclusions
amidite A dissolved in 3 mL of dry toluene. After stirring
0 min at room temperature 1.0 mmol of nitroalkene was
added to the clear solution. The reaction mixture was cooled
to 2458C and 1.5 mL of Et Zn (1.5 mmol, 1.0 M solution in
2
hexanes) was added. The reaction mixture was stirred at
2458C for 3 h and then poured into 10 mL of saturated
3
In conclusion we have shown that phosphoramidites are
excellent ligands for the enantioselective conjugate addition
of diethylzinc to nitroalkenes. In a one-pot multi-substrate
procedure moderate to high ees have been obtained for a
mixture of nine different aromatic nitroalkanes. The bene®ts
of such a procedure are a considerable reduction of time in
the screening and optimization of catalysts. Other catalytic
systems that lead to these products, such as the enantio-
selective conjugate reduction of nitroalkenes, can also be
evaluated in this way. In the reaction with aliphatic nitro-
alkenes good yields and high ees can be obtained by using
bis(1-phenylethyl)amine derived phosphoramidite ligands,
and applications of these reactions are currently under
investigation.
aqueous NH Cl and diluted with 10 mL of ethyl acetate.
4
The aqueous layer was extracted twice with 10 mL of
ethyl acetate and the combined organic layers were dried
over Na SO , concentrated and puri®ed with column
2
4
3
3
chromatography.
4.2.1. 2-(1-Nitromethyl-propyl)-furan (4a). According to
general procedure A, 139 mg (1.0 mmol) of 3a gave 69 mg
(0.4 mmol, 41% yield) of 4a after column chromatography
(pentane/diethyl ether 9:1 R 0.8) as a colorless oil. Spectral
f
1
2,17
data were in accordance with literature.
4. Experimental
4.2.2. 2-(1-Nitromethyl-propyl)-thiophene (4b). Accord-
ing to general procedure A, 155 mg (1.0 mmol) of 3b gave
82 mg (0.4 mmol, 44% yield) of 4b after column chroma-
4
.1. General
tography (pentane/diethyl ether 9:1 R 0.8) as a colorless oil.
f
1
2
Toluene was distilled from sodium. All reactions were
carried out under nitrogen atmosphere using dried glass-
ware. Chromatography: Merck silica gel Type 9385 230±
Spectral data were in accordance with literature.
4.2.3. (1-Nitromethyl-propyl)-benzene (4c). According to
general procedure A, 149 mg (1.0 mmol) of 3c gave 75 mg
(0.4 mmol, 42% yield) of 4c after column chromatography
1
13
4
00 mesh, TLC: Merck silica gel 60 F254. H and C NMR
spectra were recorded on a Varian Unity 300 (300 and
5 MHz, respectively) using CDCl as solvent. Chemical
7
(pentane/diethyl ether 9:1 R 0.8) as a colorless oil. Spectral
f
3
1
2,17
shifts are reported in ppm with the solvent resonance as
the internal standard (CHCl : d 7.25 for H, CDCl : d
data were in accordance with literature.
1
3
3
1
3
7.0 for C). Data are reported as follows: chemical shift,
7
4.2.4. 1-Methyl-4-(1-nitromethyl-propyl)-benzene (4d).
According to general procedure A, 163 mg (1.0 mmol) of
3d gave 106 mg (0.5 mmol, 55% yield) of 4d after column
chromatography (pentane/diethyl ether 9:1 Rf 0.8) as
a colorless oil. Spectral data were in accordance with
multiplicity (sˆsinglet, dˆdoublet, tˆtriplet, qˆquartet,
brˆbroad, mˆmultiplet), coupling constants (Hz), and inte-
gration. Nitroalkenes were commercially available (3a±k
and 5c, Aldrich) or synthesized (5a, b and d). Phosphor-
amidite ligands were synthesized according to a literature
1
2,17
literature.
2
5
procedure. Enantiomer separation of compounds 4a±i and
k was performed on a HP 5890A gas chromatograph
equipped with an Astec A-TA column (30 m£0.25 mm),
helium as the carrier gas (1.0 mL/min) with an oven
temperature of 1208C, heated to 1308C with 108C/min
after 10 min, then to 1508C with 108C/min after 27 min
and ®nally to 1708C with 108C/min after 20 min. Retention
times for 4a±i are given in Table 1, for 4k 39.2 and
4.2.5. 1-Fluoro-4-(1-nitromethyl-propyl)-benzene (4e).
According to general procedure A, 167 mg (1.0 mmol) of
3e gave 105 mg (0.5 mmol, 53% yield) of 4e after column
chromatography (pentane/diethyl ether 9:1 R 0.8) as a
f
1
colorless oil. H NMR d: 7.13 (m, 2H), 7.01 (m, 2H),
4.52 (m, 2H), 3.36 (m, 1H), 1.69 (m, 2H), 0.82 (t, Jˆ
1
3
7.5 Hz, 3H); C NMR d: 163.6 (s), 134.9 (s), 129.0 (d),
128.9 (d), 115.9 (d), 115.6 (d), 80.6 (t), 45.2 (d), 26.1 (t),
11.4 (q); HRMS Calcd for C H NO F 197.0851. Found
40.5 min. Enantiomer separation of compounds 6b and 6c
was performed on the same equipment with an oven
temperature of 1058C for 6b, retention times 57.7 and
1
0
12
2
197.0856.
5
9.7 min, and an oven temperature of 1008C for 6c, reten-
tion times 18.3 and 19.0 min for the cis isomer and 20.4 and
2.8 min for the trans isomer. Enantiomer separation of
4.2.6. 1-(1-Nitromethyl-propyl)-4-tri¯uoromethoxy-ben-
zene (4f). According to general procedure A, 233 mg
(1.0 mmol) of 3f gave 110 mg (0.4 mmol, 42% yield) of
2
compounds 4j, 6a and 6d was performed on a HP 5890A
gas chromatograph equipped with a Supelco b-dex 120
column (30 m£0.25 mm), helium as the carrier gas
4f after column chromatography (pentane/diethyl ether 9:1
R 0.8) as a colorless oil. H NMR d: 7.20 (m, 5H), 4.55 (m,
1
f
1
3
(
1.0 mL/min). At an oven temperature of 1308C, retention
2H), 3.38 (m, 1H), 1.70 (m, 2H), 0.83 (t, Jˆ7.5 Hz, 3H); C
NMR d: 148.4 (s), 138.0 (s), 128.9 (d), 121.2 (d), 118.6 (s),
80.3 (t), 45.2 (d), 26.1 (t), 11.4 (q); HRMS Calcd for
C H NO F 263.0769. Found 263.0760.
times of 33.8 and 34.4 min for 4j, and at an oven tempera-
ture of 1008C, retention times of of 34.9 and 36.0 min for 6a
and 48.4 and 49.4 min for 6d.
1
1
12
3 3
4
.2. General procedure A
4.2.7. 1-(1-Nitromethyl-propyl)-4-tri¯uoromethyl-ben-
zene (4g). According to general procedure A, 217 mg
(1.0 mmol) of 3g gave 106 mg (0.4 mmol, 43% yield) of
Synthesis of racemic nitroalkanes 4a±i, 6a±d. In a Schlenk
ask 7.2 mg (0.02 mmol) of CuOTf was ¯ame-dried, and
together with 16.6 mg (0.04 mmol) of racemic phosphor-
¯
4g after column chromatography (pentane/diethyl ether
9:1 R
2
1
0.8) as a colorless oil. H NMR d: 7.60 (d,
f

A. Duursma et al. / Tetrahedron 58 (2002) 5773±5778
5777
Jˆ8.1 Hz, 2H), 7.32 (d, Jˆ8.1 Hz, 2H), 4.58 (m, 2H), 3.44
and then triethylamine (2.0 equiv.) was added dropwise
over 15 min and the reaction mixture was stirred for an
additional 30 min at 2108C. The resulting mixture was
poured into CH Cl and washed with two portions of
1
3
(
m, 1H), 1.74 (m, 2H), 0.84 (t, Jˆ7.5 Hz, 3H); C NMR d:
1
43.4 (s), 127.9 (d), 125.9 (d), 125.8 (s), 80.1 (t), 45.7 (d),
6.1 (t), 11.4 (q); HRMS Calcd for C H NO F 247.0819.
Found 247.0822.
2
1
1
12
2
3
2
2
saturated aqueous NH Cl. The aqueous layers were
4
extracted with two portions of CH Cl and the combined
2
2
4
.2.8. 1-Methoxy-4-(1-nitromethyl-propyl)-benzene (4h).
According to general procedure A, 179 mg (1.0 mmol) of
h gave 114 mg (0.5 mmol, 55% yield) of 4h after column
organic layers were washed with brine, dried over MgSO4
and concentrated. The residue was puri®ed by column
chromatography.
3
chromatography (pentane/diethyl ether 9:1 Rf 0.5) as
a colorless oil. Spectral data were in accordance with
literature.
4.3.1. (E)-3,3-Dimethoxy-1-nitro-propene (5a). Accord-
ing to general procedure B, 3.12 g (30 mmol) of glyoxal
dimethylacetal (5.12 g of a 60% aqueous solution) gave
2.94 g (20 mmol, 67% yield) of 5a after column chroma-
1
2
4
.2.9. 1-Bromo-4-(1-nitromethyl-propyl)-benzene (4i).
According to general procedure A, 228 mg (1.0 mmol) of
i gave 121 mg (0.5 mmol, 47% yield) of 4i after column
tography (pentane/ethyl acetate 10:1 R 0.4) as a light
f
1
2
yellow oil. H NMR d: 7.17 (dd, Jˆ13.5, 1.5 Hz, 1H),
13
chromatography (pentane/diethyl ether 9:1 R 0.8) as a
f
7.00 (dd, Jˆ13.5, 3.3 Hz, 1H), 5.08 (dd, Jˆ3.3, 1.5 Hz,
1
colorless oil. H NMR d: 7.46 (dd, Jˆ8.6, 1.8 Hz, 2H),
1H) 3.31 (s, 6H); C NMR d: 142.4 (d), 136.3 (d), 97.9
(d), 52.9 (q); MS (CI1) 165 [M1NH ] ; Anal. Calcd for
1
7
.07 (d, Jˆ8.6 Hz, 2H), 4.53 (m, 2H), 3.32 (m, 1H), 1.68
4
1
3
(
m, 2H), 0.82 (t, Jˆ7.5 Hz, 3H); C NMR d: 138.2 (s),
C H NO : C, 40.82; H, 6.17; N, 9.52. Found C, 40.60; H,
5
9
4
1
1
2
31.9 (d), 129.2 (d), 121.3 (s), 80.3 (t), 45.4 (d), 26.0 (t),
1.4 (q); HRMS Calcd for C H NO Br 257.0050. Found
57.0044.
6.04; N, 9.38.
7
2
9
1
0
12
4.3.2. (E)-(-2-Nitro-vinyl)-cyclohexane (5b). According to
general procedure B, 3.00 g (26 mmol) of cyclohexane-
carboxaldehyde gave 2.22 g (14 mmol, 55% yield) of 5b
after column chromatography (pentane/ethyl acetate
4
.2.10. 1-(1-Nitromethyl-propyl)-2-tri¯uoromethyl-ben-
zene (4j). According to general procedure A, 217 mg
1.0 mmol) of 1-(2-nitro-vinyl)-3-tri¯uoromethyl-benzene
14 mg (0.4 mmol, 46% yield) of 4j after column chromato-
(
1
20:1 R 0.8) as a light yellow oil. Spectral data were in
accordance with literature.
f
3
4
graphy (pentane/diethyl ether 9:1 R 0.5) as a colorless oil.
f
1
H NMR d: 7.70 (m, 1H), 7.57 (m, 1H), 7.37 (m, 2H), 4.56
d, Jˆ11.1 Hz, 2H), 3.87 (quint, Jˆ11.1 Hz, 1H), 1.81 (m,
4.3.3. (E)-1-Nitro-hept-1-ene (5d). According to general
procedure B, 3.00 g (30 mmol) of hexanal gave 3.43 g
(
2
1
3
H), 0.81 (t, Jˆ10.8 Hz, 3H); C NMR d: 132.3 (s), 127.5
(12 mmol, 40% yield) of 5d after column chromatography
(
(
d), 127.4 (d), 126.8 (d), 126.6 (d), 121.4 (s), 80.2 (t), 40.4
d), 26.3 (t), 11.2 (q); HRMS Calcd for C H NO F
(pentane/ethyl acetate 20:1 R 0.8) as a light yellow oil.
Spectral data were in accordance with literature.
f
3
4
1
1
12
2
3
2
47.0819. Found 247.0831.
4
.3.4. 1,1-Dimethoxy-2-nitromethyl-butane (6a). Accor-
4
.2.11. 1-(1-Nitromethyl-propyl)-3-tri¯uoromethyl-ben-
ding to general procedure A, 147 mg (1.0 mmol) of 5a
gave 114 mg (0.6 mmol, 64% yield) of 6a after column
chromatography (pentane/ethyl acetate 3:1 R 0.6) as a
colorless oil. Spectral data were in accordance with litera-
ture.
zene (4k). According to general procedure A, 217 mg
1.0 mmol) of 1-(2-nitro-vinyl)-2-tri¯uoromethyl-benzene
gave 110 mg (0.4 mmol, 45% yield) of 4k after column
(
f
1
7
chromatography (pentane/diethyl ether 9:1 R 0.8) as a
f
1
colorless oil. H NMR d: 7.45 (m, 4H), 4.58 (m, 2H),
.41 (m, 1H), 1.72 (m, 2H), 0.84 (t, Jˆ7.5 Hz, 3H);
1
3
3
NMR d: 140.4 (s), 131.0 (d), 129.4 (d), 125.8 (s), 80.1 (t),
C
4.3.5. (1-Nitromethyl-propyl)-cyclohexane (6b). Accord-
ing to general procedure A, 155 mg (1.0 mmol) of 5b gave
112 mg (0.6 mmol, 61% yield) of 6b after column chroma-
tography (ethyl acetate/dichloromethane 1:1 R 0.8) as a
4
2
5.7 (d), 26.1 (t), 11.4 (q); HRMS Calcd for C H NO F
11 12 2 3
47.0819. Found 247.0834.
f
colorless oil. Spectral data were in accordance with litera-
ture.
1
7
4
.3. General procedure B
Synthesis of nitroalkenes 5a, b and d. According to a
4.3.6. 1-Ethyl-2-nitro-cyclohexane (6c). According to
general procedure A, 127 mg (1.0 mmol) of 5c gave
107 mg (0.7 mmol, 68% yield) of 6c after column chroma-
3
4
slightly modi®ed literature procedure, potassium tert-
butoxide (0.05 equiv.) was added to a stirred solution of
aldehyde (1.0 equiv.), nitromethane (1.5 equiv.), THF
tography (pentane/diethyl ether 20:1 R
oil. Spectral data were in accordance with literature.
0.8) as a colorless
f
1
7
(
3.0 equiv.) and tert-butanol (2.8 equiv.) at 08C. The stirred
mixture was allowed to warm to room temperature over 2 h
and stirred overnight. The mixture was poured into water
and extracted with three portions of diethyl ether. The
combined organic layers were washed with brine, dried
4.3.7. 3-Nitromethyl-octane (6d). According to general
procedure A, 143 mg (1.0 mmol) of 5d gave 82 mg
(0.5 mmol, 47% yield) of 6d after column chromatography
1
over MgSO and concentrated to give the crude b-nitro-
4
(pentane/ethyl acetate 3:1 R 0.8) as a colorless oil. H NMR
d: 4.30 (d, Jˆ7.2 Hz, 2H), 2.14 (m, 1H), 1.35 (m, 10H), 0.88
f
alcohol, which was dehydrated without further puri®cation.
Tri¯uoroacetic anhydride (1.05 equiv.) was added to a solu-
tion of b-nitroalcohol (1.0 equiv.) in CH Cl (18 equiv.) at
1
(m, 6H); C NMR d: 79.2 (t), 38.7 (d), 31.7 (t), 30.6 (t),
3
25.8 (t), 23.8 (t), 22.4 (t), 13.9 (q), 10.3 (q); HRMS Calcd for
C H19NO 173.1416. Found 173.1426.
9 2
2
2
2
108C. The resulting solution was stirred for exactly 2 min,

5778
A. Duursma et al. / Tetrahedron 58 (2002) 5773±5778
8
. Barrett, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86, 751±
62.
. Knochel, P.; Seebach, D. Synthesis 1982, 1017±1018.
7
9
1
1
1
0. Brown, B. R. The Organic Chemistry of Aliphatic Nitrogen
Compounds; Oxford University: Oxford, 1994; pp 443±469.
1. Blicke, F. F.; Faust, J. A.; Warzynski, R. J.; Gearien, J. E.
J. Am. Chem. Soc. 1945, 67, 205±207.
Figure 2. One-pot multi-substrate chiral GC chromatogram for 4a±i.
2. Sch aÈ fer, H.; Seebach, D. Tetrahedron 1995, 51, 2305±2324.
4
.4. General procedure C
13. Enders, D.; Syrig, R.; Raabe, G.; Fern a ndez, R.; Gasch, C.;
Lassaletta, J.-M.; Llera, J.-M. Synthesis 1996, 48±52.
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1341±1344.
One-pot multi-substrate reactions. In a Schlenk ¯ask
6.2 mg (0.045 mmol) of CuOTf2 was ¯ame-dried and
together with 0.09 mmol of phosphoramidite dissolved in
mL of dry toluene. After 30 min of stirring at room
1
3
16. Versleijen, J. P. G.; Van Leusen, A. M.; Feringa, B. L.
Tetrahedron Lett. 1999, 40, 5803±5806.
temperature 0.25 mmol of each nitroalkene (3a±i) was
added to the clear solution. The reaction mixture was cooled
to 2458C and 3.4 mL of Et Zn (3.4 mmol, 1.0 M solution in
2
hexanes) was added. The reaction mixture was stirred at 08C
for 3 h and then poured into 10 mL of saturated aqueous
NH Cl and diluted with 10 mL of ethyl acetate. The aqueous
4
17. Alexakis, A.; Benhaim, C. Org. Lett. 2000, 2, 2579±2581.
18. Ongeri, S.; Piarulli, U.; Jackson, R. F. W.; Gennari, C.; Eur
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19. Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc.
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layer was extracted twice with 10 mL of ethyl acetate and
the combined organic layers were dried over Na SO ,
concentrated and ®ltered through a short path of silica
with pentane/diethyl ether 9:1 to give the mixture of nine
nitroalkanes (4a±i) as a clear colorless oil, which was
analyzed by chiral GC (Fig. 2).
20. Reetz, M. T. Angew. Chem. Int. Ed. 2001, 40, 284±310.
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1998, 120, 9180±9187.
2
4
22. Gao, X.; Kagan, H. B. Chirality 1998, 10, 120±124.
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2
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Acknowledgements
This project was funded by the National Research School
Combination Catalysis (NRSCC). Ing. M. B. van Gelder is
acknowledged for his help with GC separations.
2
2
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