Enantioselective copper-catalyzed conjugate addition of dialkyl zinc to nitro-olefins

Article abstract of DOI:10.1021/ol0059596

(equation presented) The copper-catalyzed asymmetric conjugate addition of dialkylzinc onto various nitro-olefins has been carried out with excellent results. An enantiomeric excess of up to 94% was obtained using 0.5% Cu(OTf)₂ and 1% of chiral

Full text of DOI:10.1021/ol0059596

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2579-2581
Enantioselective Copper-Catalyzed
Conjugate Addition of Dialkyl Zinc to
Nitro-Olefins
Alexandre Alexakis* and Cyril Benhaim
Department of Organic Chemistry, UniVersity of GeneVa, 30, Quai Ernest Ansermet,
1211 GeneVa 2, Switzerland
alexandre.alexakis@chiorg.unige.ch
Received April 18, 2000
ABSTRACT
The copper-catalyzed asymmetric conjugate addition of dialkylzinc onto various nitro-olefins has been carried out with excellent results. An
enantiomeric excess of up to 94% was obtained using 0.5% Cu(OTf)2 and 1% of chiral trivalent phosphorus ligand.
The copper-catalyzed conjugate addition of dialkyl zinc to
various enones1a was later extended to a range of other
Michael acceptors.1b As little as 0.5% of copper salt and 1%
trivalent phosphorus ligand were needed for high yields. Over
the course of the past few years we1a,2 and others3 have
reported the use of several chiral phosphorus ligands in the
enantioselective version of this reaction on enones. As an
extension to our previous work, we become interested in the
conjugate addition to nitro-olefins, which were excellent
substrates in the racemic version of this reaction.1b
it was possible to carry out the enantioselective conjugate
additions of diethyl zinc through the use of stoichiometric
amount of titanium TADDOLates5 as chiral Lewis acids.
During the course of our studies, a catalytic version was
disclosed by Sewald,6a on two examples 1 and 5, as well as
by Feringa,6b on benzylidene nitroacetates and nitrocou-
marins, both using the same chiral phosphorus ligand L5.3a
We report herein the results of our investigations on several
nitro-olefins 1-6, using various chiral phosphorus ligands
according to Scheme 1.
Being among the best Michael acceptors, nitro-olefins add
a range of functionalized nucleophiles.4 Seebach showed that
In the conjugate addition to enones, there is no single
ligand of wide efficiency. For example, L1 and L5 are
excellent for cyclohexenone,1c,3a whereas L6 affords the best
results for acyclic enones.1d For this reason, several structur-
ally different trivalent phosphorus ligands were tested. In
the present study, we shall see that L37 appears to be the
optimal choice for aryl nitro-olefins. The results obtained
with diethylzinc and a selection of most representative
ligands are shown in Table 1.
(1) (a) Alexakis A.; Frutos J. C.; Mangeney, P. Tetrahedron: Asymmetry
1993, 4, 2427-2430. (b) Alexakis, A.; Vastra, J.; Mangeney, P. Tetrahedron
Lett. 1997, 38, 7745-7748.
(2) (a) Alexakis, A.; Vastra, J.; Burton, J.; Mangeney, P. Tetrahedron:
Asymmetry 1997, 8, 3193-3196. (b) Alexakis, A.; Burton, J.; Vastra, J.;
Mangeney, P. Tetrahedron: Asymmetry 1997, 8, 3987-3990. (c) Alexakis,
A.; Vastra, J.; Burton, J.; Benhaim, C.; Mangeney, P. Tetrahedron Lett.
1998, 39, 4821-4824. (d) Alexakis, A.; Benhaim, C.; Fournioux, X.; van
den Heuvel, A.; Leveˆque, J.-M.; March, S.; Rosset, S. Synlett 1999, 1811-
1813.
(3) (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries,
A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620-2622. (b) Kno¨bel,
A. K. H.; Escher, I. H.; Pfaltz, A. Synlett 1997, 1429-1431. (c) Zhang,
F.-Y.; Chan, A. S. C. Tetrahedron: Asymmetry 1998, 9, 1179-1182. (d)
Mori, T.; Kosaka, K.; Nakagawa, Y.; Nagaoka, Y.; Tomioka, K. Tetrahe-
dron: Asymmetry, 1998, 9, 3175-3178. (e) Yamanoi, Y.; Imamoto, T. J.
Org. Chem. 1999, 64, 2988-2990. (f) Pamies, O.; Net, G.; Ruiz, A.; Claver,
C. Tetrahedron: Asymmetry 1999, 10, 2007-2014. (g) Yan, M.; Yang,
L.-W.; Wong, K.-Y.; Chan, A. S. C. Chem. Com. 1999, 11.
(4) (a) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979,
33, 1-18. (b) Barrett, A. G. M. Chem. Soc. ReV. 1991, 20, 95-127.
(5) Scha¨fer, H.; Seebach, D. Tetrahedron 1995, 51, 2305-2324.
(6) (a) Sewald, N.; Wendish, V. Tetrahedron: Asymmetry 1998, 9, 1341-
1344. (b) Versleijen, J. P. G.; van Leusen, A. M.; Feringa, B. L. Tetrahedron
Lett. 1999, 40, 5803-5806.
(7) Alexakis, A.; Burton, J.; Vastra, J.; Benhaim, C.; Fournioux, X.; van
den Heuvel, A.; Leveˆque, J.-M.; Rosset, S., submitted for publication.
10.1021/ol0059596 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/02/2000

Scheme 1
We have found that running the reactions in toluene at
Ligand L1, one of the best in the conjugate addition to
cyclohexenone,2c gave good to moderate ee’s on all of the
tested nitro-olefins (entry 1). It is worth noting that aryl-
substituted nitro-olefins (1-3) afford better results than the
alkyl-substituted ones (4-6). This trend in the two classes
of substrates will be noticed throughout all this study. In
the TADDOL series of ligands, L2 was among the best for
acyclic enones.7 However, only poor results were obtained
with nitro-olefins (entry 2).
The main surprise came from ligand L3. This ligand was
successfully used in the Rh-catalyzed hydrosilylation and
hydroformylation reactions.8 In our hands (entry 3), it appears
to be the ligand of choice for aryl-substituted nitro-olefins
-30 °C for 1-3 h, using 0.5 mol % of copper(II) triflate
and just 1 mol % of ligand, afforded the highest enantio-
selectivity along with high chemical yields (83-100%).
Other solvents, such as CH2Cl2, Et2O, or THF, gave lower
asymmetric induction, although the chemical yield remains
excellent. The optimum reaction temperature was found to
be -30 °C. Higher temperature is detrimental to the ee,
whereas lower temperature does not improve it, with
prohibitively long reaction time. Increasing the amount of
catalyst to 1% or 2% of (Cu(OTf)2) and 2% or 4% of L* is
useless. We have also checked that at -30 °C the reaction
does not proceed in the absence of catalyst.
Table 1. Reaction of Diethyl Zinc with Nitro-Olefins 1-6, with 0.5% Cu(OTf)2 and 1% Chiral Ligands L1-L9
nitro-olefin (yield, ee, conf)
entry
ligand
1a
2a
3b
4a
5a
6d
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
100%, 64, R
88%, 28, S
100%, 81, S
100%, 50, S
100%, 2, R
100%, 35, S
100%, 0
100%, 56, R
100%, 35, (+)
100%, 35, (+)
85%, 13, (-)
92%, 63, (-)
100%, 40, (+)
100%, 94, (+)
100%, 10, (+)
95%, 13, (-)
100%, 31, (+)
100%, 0
85%, 28, (-)
100%, 86, S
100%, 25, S
95%, 78, (-)
95%, 60, (+)
96%, 8, (-)
95%, 20, (-)
95%, 60, (-)
85%, 67, (+)
95%, 3, (+)
100%, 0
95%, 0
96%, 5, (-)
100%, 7, (+)
100%, 0
66%, 33, S
100%, 2, S
100%, 13, Sc
9a
9b
a The ee was determined by chiral GC on a LipodexE (25 mm × 0.25 mm) capillary column. b The ee was determined by chiral GC on a CP chirasil-Dex
(25 mm × 0.25 mm) capillary column. c The reaction was performed in CH2Cl2. d See comment in the text.
2580
Org. Lett., Vol. 2, No. 17, 2000

(1-3), with ee’s as high as 86% in the case of 2. It also
displays good enantioselectivity with two of the alkyl-
substituted substrates, 4 (ee 63%) and 6 (ee 60%). It was
reported that the 2-naphthyl-TADDOLs usually afford
increased stereoselectivities.8 However, in our case, ligand
L4 gave only moderate asymmetric induction (entry 4).
In addition to diethyl zinc, we also tested the reaction with
dibutyl zinc and dimethyl zinc on nitro-olefin 2 and with
ligand L3. Both reacted quantitatively, with 71% and 20%
ee, respectively. The lower ee with Me2Zn could be the result
of its lesser reactivity, since the reaction temperature had to
be rised to 0 °C.
Two ligands of the binaphthol series were tested. Ligand
L5 is among the best for conjugate addition to cyclic
enones.3a It was also used by Sewald on nitro-olefins 1 and
5.6 Under our above-mentioned conditions (entry 5), this
ligand appears to give the best results for alkyl-substituted
nitro-olefins (4-6). Thus, in the case of 4 it gave a better
result than L3 (94% instead of 63% ee) and was clearly much
better for nitro acetal 5 (60% ee). However, Sewald reported
a higher ee value in this case (86%). Repetition of this
experiment, using exactly Sewald’s conditions (12 times
more dilute),9 indeed increased the ee to the reported value.
The result on nitrostyrene 1 was also improved to almost
the reported one (42% instead of 48%). These results point
to the sensitivity of the copper-catalyzed conjugate addition
to the reaction conditions. However, the “high dilution effect”
could not improve any result with the other ligands. The other
binaphthol-based ligand, L6, was the most efficient for many
acyclic enones2d but did not give any good result with nitro-
olefins (entry 6).
The last ligands tested were representative of other classes
of ligands. Ligand L7 has been successfully employed for
the conjugate addition with stoichiometric lithium dialkyl
cuprate reagents,1a,10 and ligand L811 was the best one in
the tartrate-phosphite series.2b Neither, however, gave good
result with nitro-olefins (entries 7 and 8). Finally, a diphos-
phine ligand was also tested. Norphos L9 (entry 9) gave 44%
ee in the addition of diethyl zinc to cyclohexenone2a but only
2% ee (entry 9a) and 13% in CH2Cl2 (entry 9b) with nitro-
olefin 2.
Concerning the reactivity of nitro-olefins 1-6, we noticed
that the nitro acetal 5 was the most reactive, but no
improvement of ee could be gained by running the reaction
at -80 °C (although the yield was quantitative). On the other
hand, the trisubstituted 6 was the least reactive. The reaction
temperature had to be raised to 0 °C for complete conversion.
The crude adduct 1-nitro-2-ethyl cyclohexane was obtained
as a mixture of cis and trans isomers (80:20 ratio with,
respectively, 65% and 68% ee, for entry 5). This could be
isomerized into the trans (67% ee) isomer by treatment with
DBU at room temperature.
In addition to being truly catalytic, these results represent
the highest ee’s reported to date in the enantioselective
conjugate addition of alkyl groups to nitro-olefins. The scope
and limitations of this reaction is presently under investiga-
tion.
Acknowledgment. Financial supportfrom the Swiss Na-
tional Science Foundation (20-53967.98) is gratefully ac-
knowledged.
(8) (a) Seebach, D.; Hayakawa, M.; Sakaki, J.-I.; Schweizer, W. B.
Tetrahedron 1993, 49, 1711-1724. (b) Sakaki, J.-I.; Schweizer, W. B.;
Seebach, D. HelV. Chim. Acta 1993, 76, 2654-2665.
(9) We thank Prof. N. Sewald for providing us his detailed experimental
procedure.
(10) Alexakis, A.; Mutti, S.; Normant, J. F. J. Am. Chem. Soc., 1991,
113, 6332-6334.
(11) Bernard, D.; Burgada, R. Phosphorus 1974, 3, 187.
Supporting Information Available: Experimental pro-
1
cedure, H and 13C spectra, and GC chromatograms. This
material is available free of charge via Internet at http://
pubs.acs.org.
OL0059596
Org. Lett., Vol. 2, No. 17, 2000
2581