Convenient catalytic, enantioselective conjugate reduction of nitroalkenes using CuF2

Article abstract of DOI:10.1021/ol048035h

(Chemical equation presented) We document the use of a new catalyst system for the enantioselective conjugate reduction of nitroalkenes utilizing commercially available CuF₂ and the bis-phosphine JOSIPHOS as a ligand. This new protocol not only

Full text of DOI:10.1021/ol048035h

ORGANIC
LETTERS
2
004
Vol. 6, No. 24
575-4577
Convenient Catalytic, Enantioselective
Conjugate Reduction of Nitroalkenes
Using CuF2
4
Constantin Czekelius and Erick M. Carreira*
Laboratorium f u¨ r Organische Chemie, ETH Z u¨ rich, ETH H o¨ nggerberg,
HCI, H335, CH-8093 Z u¨ rich
carreira@org.chem.ethz.ch
Received September 27, 2004
ABSTRACT
We document the use of a new catalyst system for the enantioselective conjugate reduction of nitroalkenes utilizing commercially available
CuF and the bis-phosphine JOSIPHOS as a ligand. This new protocol not only facilitates ready access to a variety of optically active nitroalkanes,
2
but the results provide also new insight into copper-catalyzed reactions.
t
3,4
Optically active nitroalkanes are valuable building blocks
in organic synthesis. They can be processed to other useful
chiral intermediates in fine-chemical synthesis such as
amines, aldehydes, or acids and can be employed as
CuO Bu and the chiral bis-phosphine JOSIPHOS. Use of
this catalyst system can effect the preparation of optically
active â,â-disubstituted nitroalkanes with catalyst loadings
t
as low as 0.1 mol %. The use of CuO Bu can be a drawback
1
precursors to nitrile oxides in dipolar cycloaddition reactions.
to the broad application of this process, because it is sensitive
to oxygen and moisture. Thus, we have been interested in
evaluating an alternative catalyst system for enantioselective
reduction of nitroalkenes employing inexpensive, com-
mercially available copper salts that are conveniently handled.
In this communication, we report such a system in which
There have been recent reports of highly enantioselective
2
addition reactions of various C-nucleophiles to nitroalkenes.
We have documented a novel conjugate reduction of â,â-
disubstituted nitroalkenes employing a catalyst prepared from
(1) (a) The Nitro Group in Organic Synthesis; Ono, N.; Wiley-VCH:
the combination of a chiral bis-phosphine ligand and CuF
can be employed (eq 1). The ability to use CuF was rather
2
2
New York, 2001. (b) Nitroalkenes; Perekalin, V. V.; Lipina, E. S.;
Berestovitskaya, V. M.; Efremov, D. A. John Wiley & Sons: Chichester,
4
1
994. (c) Nitro CompoundssRecent AdVances in Synthesis and Chemis-
unexpected, as we have previously shown that halides inhibit
this process. Additionally, we disclose an unusual observation
wherein nitromethane is used as an additive and activator
for the enantioselective reduction of more electron-rich
nitroalkene substrates.
try: Organic Nitro Chemistry Series; Feuer, H., Nielsen, A. T., Eds.; VCH:
Weinheim, 1990. (d) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia
1
979, 33, 1-18. For the concept of polarity control and umpolung, see:
e) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239-258. (f)
Polarity Control for Synthesis; Ho, T.-L.; John Wiley & Sons: New York,
991.
2) (a) For a review, see: Berner, O. M.; Tedeschi, L.; Enders, D. Eur.
J. Org. Chem. 2002, 1877-1894. (b) Sch a¨ fer, H.; Seebach, D. Tetrahedron
995, 51, 2305-2324. (c) Sewald, N.; Wendisch, V. Tetrahedron: Asym-
(
1
(
1
metry 1998, 9, 1341-1344. (d) Ongeri, S.; Piarulli, U.; Jackson, R. F. W.;
Gennari, C. Eur. J. Org. Chem. 2001, 803-807. (e) Luchaco-Cullis, C.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192-8193. (f) Alexakis,
A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124,
5
262-5263. (g) Mampreian, D. M.; Hoveyda, A. H. Org. Lett. 2004, 6,
In our initial investigations of the enantioselective reduc-
tion of nitroalkenes, we had observed the inhibition of the
2829-2832. (h) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2003, 125, 3700-3701. (i) Li, H.; Wang, Y.; Tang, L.; Deng, L. J.
Am. Chem. Soc. 2004, 126, 9906-9907. (j) Choi, H.; Hua, Z.; Ojima, I.
Org. Lett. 2004, 6, 2689-2691. (k) Ishii, T.; Fujioka, S.; Sekiguchi, Y.;
Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558-9559.
(3) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42,
4793-4795; Angew. Chem. 2003, 115, 4941-4943.
1
0.1021/ol048035h CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/30/2004

t
3
reaction by chloride; this prompted us to use CuO Bu. Our
subsequent interest in developing a more convenient protocol
led us to examine the use of copper fluoride salts, as these
Table 1. Conjugate Reduction of Nitroalkenes Using a
a
Complex Prepared from CuF
2
have been demonstrated to function in a variety of catalytic
5
processes. A particularly attractive feature of CuF
2
is its
stability, allowing it to be conveniently handled. Of additional
importance, despite our observations with halides, we
anticipated that the fluorides would be compatible with the
process, because this halide would be sequestered from the
reaction mixture through its reaction with the silanes to form
compounds with strong Si-F bonds (ca. 135 kcal/mol).
2
When commercially available CuF and JOSIPHOS in
toluene along with phenylsilane, PMHS, and water were
utilized in the conjugate reduction of 2-phenyl-1-nitro-
propene, the formation of the desired nitroalkane was
observed, but the reaction did not go to completion (61%
conversion). Recent observations by Riant in the context of
copper fluoride bis-phosphine complexes as catalysts for
ketone hydrosilylation compelled us to examine purposefully
exposing our system to oxygen; however, the presence of
oxygen led to significant inhibition of the conjugate reduc-
6
tion. Optimization studies revealed that best results were
obtained when 1.5 equiv of phenylsilane were added por-
tionwise in two batches of 0.5 equiv and an additional 1.0
equiv after 12 h, respectively. Under these conditions, full
conversion was observed. Applying this optimized procedure,
we investigated the reduction of differently substituted
nitroalkenes. In all cases, use of 1 mol % catalyst provided
the nitroalkane products in useful yields and selectivity (eq
7
1, Table 1).
Although the protocol described above was effective for
a series of nitroalkenes, some substrates that had proven to
be successful in the earlier procedure involving CuO Bu now
a
t
Reaction conditions: PhSiH3 (1.5 equiv), PMHS (0.1 equiv), CuF2
1 mol %), JOSIPHOS (1.1 mol %), H2O (1.0 equiv), toluene, 16 h at room
(
failed to undergo reduction. In particular, the more electron-
rich substrates such as p-methoxyphenyl- or furanyl-
substituted nitroalkenes (Scheme 1) proved to be inert under
these conditions, and only traces of products were formed.
temperature.
8
addition of silyl dienolates to aldehydes. In this process, a
number of observations are consistent with a catalytically
active Cu(I) species: the isolation of dimeric dienolate
products that were the product of oxidative dimerization of
Scheme 1. Reduction of Nitroalkenes by Addition of
t
the starting enolate and the fact that CuO Bu was shown to
Nitromethane
be an effective catalyst. In our model for the enantioselective
conjugate reduction of nitroalkenes, we have worked under
the assumption that Cu(I) is also the active species. However,
in contrast to the dienolate chemistry, we had hypothesized
that it was the silane that effects the requisite reduction
(Cu(II) f Cu(I)). The inability to observe reduction of the
more electron-rich nitroalkenes led us to question this
(5) (a) Suto, Y.; Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki, M.
Org. Lett. 2003, 5, 3147-3150. (b) Oisaki, K.; Suto, Y.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5644-5645. (c) Agnelli, F.;
Sulikowski, G. A. Tetrahedron Lett. 1998, 39, 8807-8810.
(
6) (a) Sirol, S.; Courmarcel, J.; Mostefai, N.; Riant, O. Org. Lett. 2001,
3
, 4111-4113. (b) Courmarcel, J.; Mostefa ¨ı , N.; Sirol, S.; Choppin, S.;
Riant, O. Isr. J. Chem. 2001, 41, 231-240.
7) For the assignment of absolute stereochemistry, see ref 3.
(
In 1998, we investigated and documented the behavior of
different Cu(I) and Cu(II) catalysts in the enantioselective
(8) (a) Pagenkopf, B. L.; Kr u¨ ger, J.; Stojanovic, A.; Carreira, E. M.
Angew. Chem., Int. Ed. 1998, 37, 3124-3126. (b) Kr u¨ ger, J.; Carreira, E.
M. Tetrahedron Lett. 1998, 39, 7013-7016. (c) Kr u¨ ger, J.; Carreira, E. M.
t
J. Am. Chem. Soc. 1998, 120, 837-838. (d) For the preparation of CuO Bu,
(
4) JOSIPHOS
)
1-[2-(diphenylphosphino)ferrocenyl]ethyldicyclo-
see: Tsuda, T.; Hashimoto, T.; Saegusa, T. J. Am. Chem. Soc. 1972, 94,
658-659.
hexylphosphine; PMHS ) Poly(methylhydrosiloxane).
4576
Org. Lett., Vol. 6, No. 24, 2004

hypothesis. Our experience with dienolates prompted us to
consider that the generation of a nitronate in the reaction
and its subsequent oxidative dimerization could be respon-
sible for the generation of the active Cu(I) species. The
difference in acidity between the various nitroalkenes would
account for the absence of reaction with electron-rich
nitroolefins, as the active catalyst would never be generated.
To examine this new working hypothesis, an experiment
was designed in which the active catalyst generated from
the reduction of a reactive nitroalkene was subsequently
exposed to a more electron-rich nitroalkene. In the experi-
ment, a reaction mixture was set up incorporating the
act as modifying ligands in the catalyst complex. In the
second possibility, the difference between the two classes
of nitroalkenes is related to the ability of these to undergo
deprotonation and oxidative coupling. Importantly, in neither
scenario is the silane the active agent that provides initial
access to the active catalyst. Both modes of action would
be mechanistically interesting for the application of copper
fluoride complexes in further studies.
In summary, we document the use of a new catalyst system
for the enantioselective conjugate reduction of nitroalkenes
utilizing commercially available CuF
ligand. Fundamentally, the results we document disclose the
unique features of CuF in a process that is otherwise
2
and a bis-phosphine
requisite components for the catalytic reduction (CuF
2
,
2
ligand, phenylsilane, PMHS, and water) and 2-phenyl-1-
nitro-propene as a substrate. After stirring for 30 min, the
starting material had been consumed; subsequently, a 10-
fold excess of the previously unreactive 2-(p-methoxy-
phenyl)-1-nitro-propene was added. This substrate now
underwent reduction at a good rate.
To simplify the reaction protocol and generate a process
that was more amenable, we tested a procedure in which
nitromethane is added at the outset of the reaction mixture.
Indeed, a solution of the catalyst (1 mol %) and nitromethane
inhibited by halides and reveal the unusual effect of adding
nitromethane for initial catalyst activation. From a more
practical perspective, this new protocol allows for ready
access to a variety of optically active nitroalkanes. The
possibility to start from a commercially available, bench-
stable copper(II) salt and to generate a catalytically active
species in situ by addition of nitromethane facilitates the
reaction setup. Furthermore, this new protocol may find
additional application in other copper-catalyzed processes
in large-scale as well as in fine-chemical synthesis.
(
10 mol %) under otherwise identical conditions effected the
enantioselective reduction of previously unreactive substrates
Scheme 1). With this simplified, convenient protocol, the
Acknowledgment. We thank Sumika Fine Chemicals,
Japan (currently Sumitomo Chemical Co., Ltd), for generous
support.
(
products are isolated in useful yields and selectivity.
The results we have described imply at least two mecha-
nistically different explanations. In the first of these, in the
presence of nitromethane or 2-phenyl-1-nitro-propane a new
catalytically active species is generated that exhibits increased
reactivity such that more electron-rich substrates can be
effectively reduced. These nitrocompounds would need to
Supporting Information Available: Characterization
data and representative experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL048035H
Org. Lett., Vol. 6, No. 24, 2004
4577