Re-Evaluating the Nucleophilicity of Zinc Enolates in Alkylation Reactions
yields and dr.[15] These results, combined with other copper- Acknowledgments
catalyzed conjugate additions, suggest catalytic copper
enolates are not the active alkylation species. Consequently,
the lingering concept that zinc enolates serve as poor nu-
cleophiles should be re-evaluated (Scheme 1).
Financial support for this work was provided by Indiana Univer-
sity.
[
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Scheme 1. Alkylation of lithium enolate with crotyl bromide.
Conclusions
In summary, the allylic or benzylic alkylation of chiral
zinc enolates, resulting from an asymmetric copper-cata-
lyzed conjugate addition reaction of dialkylzinc, could be
performed with allylic or benzylic halides in reasonable
yields and high diastereoselectivities. The one-pot pro-
cedure avoids the use of additional transition-metal cata-
lysts, making the operation more environmentally friendly
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facile transformation runs counter to the common percep-
tion that zinc enolates are poor nucleophiles and provides
a platform for using sterically hindered allylic electrophiles
that were previously unviable even under palladium cataly-
sis.
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[
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Experimental Section
1
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Standard Procedure: To a flame-dried flask was added CuTC (1 mg,
0.0052 mmol), phosphoramidite ligand (5.6 mg, 0.0104 mmol) and
anhydrous toluene (0.4 mL) under a nitrogen atmosphere. This
mixture was stirred for 20 min at room temperature before cooling
to the desired temperature for an additional 20 min. Dialkylzinc
2
004, 126, 16559; c) A. Alexakis, C. Benhaim, S. Rosset, M.
Humam, J. Am. Chem. Soc. 2002, 124, 5262.
(
1.2 equiv.) was added to the cooled solution and stirred for an
additional 20 min. After the introduction of the enone (0.26 mmol,
equiv.), the reaction was stirred until complete consumption of
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1
starting material (usually 3 h) was indicated by TLC (hexanes/ethyl
acetate, 6:1). Following the complete consumption of starting mate-
rial, electrophile (1.2–1.5 equiv.) was added, and the reaction
warmed. Upon completion, the reaction mixture was filtered
through small silica plug before diluting with 10 mL of DCM and
1
999, 38, 3518; e) Y. Yamanoi, T. Imamoto, J. Org. Chem. 1999,
6
4, 2988; f) I. Chataigner, C. Gennari, U. Piarulli, S. Ceccarelli,
2
4
mL of water. The organic layer was dried with anhydrous MgSO ,
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916; g) A. Pfaltz, I. H. Escher, Tetrahedron 2000, 56, 2879.
[13] B. H. Lipshutz, M. R. Wood, R. Tirado, Org. Synth. 1999, 76,
252.
filtered, and concentrated in vacuo. The crude mixture was purified
by preparative TLC (hexanes/ethyl acetate, 6:1) to afford the de-
sired product.
[
14] S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard,
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15] See Supporting Information for reaction details.
Received: January 18, 2012
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures describing the synthesis of com-
pounds 6–8 and 10, as well as the characterization data are pro-
vided.
[
Published Online: February 21, 2012
Eur. J. Org. Chem. 2012, 1712–1715
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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