Communication
Enantioselective Cross-Coupling of meso-Epoxides with Aryl Halides
Yang Zhao and Daniel J. Weix*
Department of Chemistry, University of Rochester, Rochester, New York 14627-0216, United States
S
* Supporting Information
would be possible because more sterically hindered catalysts
ABSTRACT: The first enantioselective cross-electrophile
coupling of aryl bromides with meso-epoxides to form
trans-β-arylcycloalkanols is presented. The reaction is
catalyzed by a combination of (bpy)NiCl2 and a chiral
titanocene under reducing conditions. Yields range from
57 to 99% with 78−95% enantiomeric excess. The 30
examples include a variety of functional groups (ether,
ester, ketone, nitrile, ketal, trifluoromethyl, sulfonamide,
sulfonate ester), both aryl and vinyl halides, and five- to
seven-membered rings. The intermediacy of a carbon
radical is strongly suggested by the conversion of
cyclooctene monoxide to an aryl [3.3.0]bicyclooctanol.
were poorly reactive.
On the basis of the work of Gansauer,14 we initially examined
̈
several different chiral titanocene catalysts (2,15 3, and 4; Scheme
2) and found that menthol-derived catalyst 4, first reported by
a
Scheme 2. Enantioselective Arylation of Cyclohexene Oxide
he opening of epoxides with carbon nucleophiles is a useful
Ttransformation in organic synthesis because of the
availability of epoxides and the versatility of the alcohol
products.1 The enantioselective opening of meso-epoxides
forms two new, adjacent stereocenters, and highly selective
catalysts have been reported for a variety of heteroatom
nucleophiles,1,2 carbon monoxide,3 and cyanide.1,4 In contrast,
the enantioselective coupling of aryl and vinyl nucleophiles with
meso-epoxides has proven to be more challenging.5,6 The best
results to date are with aryllithium reagents and stoichiometric7
or catalytic8 amounts of chiral ligands (Scheme 1A).9 In general,
a more functional-group-tolerant procedure would be a useful
advance, suggesting a cross-electrophile approach.10
a
Reactions were run with 1.0:2.0:0.1:0.1:0.1 Et3N·HCl/Mn0/titano-
cene/NiCl2(dme)/bipyridine in DMPU with stirring for 12 h at rt.
Assay yields (GC area %) are shown, with an isolated yield in
parentheses. Enantiomeric excesses were determined by chiral-phase
GC or SFC analysis.
Kagan,16 provided the highest yield and enantioselectivity. These
conditions proved general for a variety of meso-epoxides and aryl
halides (Scheme 3). As expected, the enantioselectivity of the
product was primarily determined by the epoxide and not by the
electronics of the aryl halide. For example, products 5, 7, 8, 9, and
10 were all obtained with enantioselectivities of 5% ee. While
ortho-substituted aryl halides did not couple well with
cyclohexene oxide under catalysis by titanocene 4, the use of a
smaller titanocene catalyst (1) or a less hindered epoxide
(cyclopentene oxide; Scheme 4) provided yields of up to 85%
(products 6, 18, 19).
Scheme 1. Enantioselective Arylation of meso-Epoxides
Better enantioselectivities were obtained from more planar
epoxides. For example, a reaction with cyclohexadiene monoxide
(14) was more selective than the same reaction with cyclohexene
oxide (5). Only the trans diastereomer of the product was
observed regardless of the epoxide. Finally, cis-stilbene oxide was
found to be unreactive under these conditions.
We report here that the combination of an achiral nickel
catalyst with a chiral titanium catalyst can enantioselectively
couple aryl halides with meso-epoxides in high yield (Scheme
1B). While we had previously demonstrated that the radical
generated from titanium(III)-mediated epoxide opening11 could
be intercepted by arylnickel intermediates (Scheme 1B),12,13 it
was not clear that an enantioselective version of the catalysis
Although most of these reactions were set up on a 0.5 mmol
scale in a nitrogen-filled glovebox for convenience, the chemistry
Received: February 20, 2015
Published: February 25, 2015
© 2015 American Chemical Society
3237
J. Am. Chem. Soc. 2015, 137, 3237−3240