Catalytic Enantioselective Conjugate Reduction of β,β -Disubstituted Nitroalkenes

Article abstract of DOI:10.1002/anie.200352175

Efficient addition: Bisphosphane-Cu^I complexes catalyze the enantioselective reduction of β,β-disubstituted nitroalkenes, giving chiral β,β-disubstituted nitroalkanes in useful yields and selectivities (see scheme). The reaction can be carried out with as little as 0.1 mol % of complex, rendering the process among one of the more efficient methods for conjugate addition chemistry.

Full text of DOI:10.1002/anie.200352175

Angewandte
Chemie
Chiral Nitroalkanes
formed between CuCl, tol-binap, and NaOtBu. Under these
conditions, the reaction proceeded rather sluggishly: 5 mol%
of catalyst led to 18% conversion after 22 h at 258C.
Additionally, isomerization of 1 to the b,g-unsaturated nitro-
alkene (14%) was observed. We then investigated the catalyst
prepared from tol-binap and CuOtBu which we had originally
formulated for mechanistic studies in aldol addition chemis-
try. In the presence of 5 mol% of this catalyst, full conversion
of 1 into 2 (65% yield, 80% ee) within 18 h at room
Catalytic Enantioselective Conjugate Reduction
of b,b-Disubstituted Nitroalkenes**
Constantin Czekelius and Erick M. Carreira*
Optically active nitroalkanes are versatile precursors for a
wide range of useful building blocks for fine-chemical syn-
thesis. However, only a few effective methods for their
[
11]
temperature was observed [Eq. (2)].
Interestingly, at this
[
1–3]
preparation are available.
Despite recent advances in the
addition of dialkyl zinc reagents to a,b-unsaturated nitro-
olefins, the complementary method involving metal-catalyzed
enantioselective reduction of b,b-disubstituted nitroalkenes
[
2]
has not been reported. Herein we document such an
approach in which bisphosphane–Cu complexes (with tol-
stage the reduction appeared to be quite general as 2-methyl-
3-nitro-prop-2-en-1-ol provided the corresponding nitroal-
kane in 58% yield and 56% ee.
These results along with subsequent investigations led us
to the significant conclusion that the presence of NaCl inhibits
the activity of the Cu–phosphane complex, a premise which is
supported by the finding that the addition of various inorganic
[
4]
binap or josiphos ) catalyze the enantioselective reduction of
b,b-disubstituted nitroalkenes, giving optically active b,b-
disubstituted nitroalkanes in useful yields and selectivities
[
12]
[
5]
[
Eq. (1)]. Of additional mechanistic and practical impor-
salts (e.g. LiCl, NEt Cl, KCN) always leads to diminished
4
reaction rates.
We subsequently looked to variation of the silane
component in the reaction in an effort to increase turnover
[
13]
tance is the observation we have made regarding the
inhibitory effect of halides; thus, in their absence the
reductions can be carried out with as little as 0.1 mol% of
complex, rendering the process among one of the more
efficient methods for conjugate addition chemistry.
frequency and lower catalyst loading. We found that the use
of diphenylsilane or phenylsilane in the reaction resulted in
increased reaction rates, with the highest acceleration
observed when a combination of PMHS (0.1 equiv) and
phenylsilane (1.2 equiv) was employed. Nevertheless, under
these conditions, substantial amounts of 2-phenyl-propional-
We had previously reported that a complex prepared from
tol-binap and CuOtBu effectively catalyzes the addition of
dienolates to aldehydes involving a metalloenolate inter-
[
14]
dehydeoxime (38%) were isolated. However, the addition
of 1.2 equivalents of water to the reaction mixture resulted in
[
6]
[15]
mediate. A related complex derived from tol-binap, CuCl,
complete suppression of this overreduction. An important
and NaOtBu mediates the enantioselective reduction of a,b-
consequence of these conditions is the fact that in the
presence of tol-binap and josiphos, the catalyst loadings can
be further substantively decreased to the level of 0.1 mol%
[Eq. (1), Table 1].
[
7,8]
unsaturated esters and ketones.
As part of our ongoing
investigations of copper–phosphane complexes for asymmet-
ric synthesis, we have tested such systems in the reduction of
b,b-disubstituted nitroalkenes, which are not only easily
prepared (i.e., addition of N O to alkenes and subsequent
As shown in Table 1 aromatic and aliphatic substrates are
reduced to give adducts in useful selectivity. Both protected
and unprotected alcohol functionalities as well as heterocyclic
substrates are tolerated. The reduction of E and Z olefins
(Table 1, entries 7 and 8) resulted in the formation of opposite
2
4
[
1,9]
elimination ) but also whose reductions are unprecedented
[
10]
in small-molecule catalysis.
In our initial investigations on the reduction of (E)-1-
nitro-2-phenyl-1-propene (1) with PMHS, we employed the
published procedure for the preparation of the catalyst
[
17]
enantiomers with similar high levels of enantioselectivity.
This observation is in accordance with those in conjugate
[
8a,18]
reductions of unsaturated carbonyls.
The nitroalkane products provide entry to valuable chiral
amines that are otherwise not easily accessed. In this respect,
[
*] Prof. Dr. E. M. Carreira, C. Czekelius
Laboratorium für Organische Chemie
ETH Hönggerberg, HCI H335
reduction of 2 (Pd/C, H ) serves to exemplify the convenience
2
[19]
with which amines can be accessed in high yield [Eq. (3)].
8093 Zürich (Schwitzerland)
In conclusion, we have developed a novel copper-cata-
lyzed, asymmetric reduction of substituted nitroolefins that
Fax: (+41)1-632-1328
E-mail: carreira@org.chem.ethz.ch
[
**] This research was supported by Sumika Fine Chemicals, Japan. C.C.
was supported by a fellowship of the Fonds der Chemischen
Industrie (Germany).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 4793 –4795
DOI: 10.1002/anie.200352175
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4793

Communications
Table 1: Conjugate reduction in the presence of CuOtBu, PMHS, and PhSiH3.
Entry
1
Substrate
Product
Ligand
Catalyst [mol%]
t [h]
Yield [%]
ee [%]
(S)-tol-binap
0.1
0.1
24
24
60
77
78
88
(S,R)-josiphos
2
(S,R)-josiphos
S,R)-josiphos
1
0.1
5
24
89
88
90
90
(
3
4
(S,R)-josiphos
(S,R)-josiphos
1
5
94
90
1
1
12
12
83
86
94
92
5
6
(S,R)-josiphos
(S)-tol-binap
1
1
0.3
5
5
24
60
66
55
86
90
86
(
(
S,R)-josiphos
S,R)-josiphos
[
[
b]
b]
7
8
(S)-tol-binap
S,R)-josiphos
1
0.1
5
24
76
81
66
86
(
[
[
b]
b]
(S,R)-josiphos
S,R)-josiphos
1
0.1
5
24
82
77
68
66
(
9
(S,R)-josiphos
(S,R)-josiphos
(S,R)-josiphos
1
1
1
12
12
12
55
72
75
72
90
84
1
1
0
1
[
a] Reactions were run at 0.2m of olefin in toluene with PhSiH (1.2 equiv), PMHS (0.1 equiv), and water (1.2 equiv) at room temperature. [b] See
3
reference [16].
provides access to optically active b,b-disubstituted nitro-
alkanes. Importantly, we have documented means by which
such reductions can be carried out under operationally
convenient conditions with as little as 0.1 mol% of catalyst
such catalytic processes. Further work is continuing with the
aim of better understanding the mechanism of the reaction
and ultimately identifying ligands that lead to further
improvement in the selectivity.
(
CuOtBu, tol-binap, or josiphos). The method described
represents the first such report, ultimately providing access to
optically active amines. Given the increased importance of
copper-catalyzed processes for asymmetric synthesis, of addi-
tional significance is the observation that halides can inhibit
Received: June 23, 2003 [Z52175]
Keywords: asymmetric catalysis · copper · hydrosilylation · nitro
.
compounds · reduction
4
794
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 4793 –4795

Angewandte
Chemie
[
15]We believe that in the presence of water, the first formed silyl
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were obtained as single isomers in most cases (E for entries 1, 2,
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[
8
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[
[19]It was shown by analysis of the Mosher amide that no erosion of
enantiomeric purity occurred in the course of the reduction.
[
4]josiphos = 1-[2-(diphenylphosphanyl)ferrocenyl]ethyldicyclo-
hexylphosphane
[
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