Retention or inversion in stereospecific nickel-catalyzed cross-coupling of benzylic carbamates with arylboronic esters: Control of absolute stereochemistry with an achiral catalyst

Article abstract of DOI:10.1021/ja311783k

Stereospecific coupling of benzylic carbamates and pivalates with aryl- and heteroarylboronic esters has been developed. The reaction proceeds with selective inversion or retention at the electrophilic carbon, depending on the nature of the ligand. Tricyclohexylphosphine ligand provides the product with retention, while an N-heterocyclic carbene ligand provides the product with inversion.

Full text of DOI:10.1021/ja311783k

Communication
pubs.acs.org/JACS
Retention or Inversion in Stereospecific Nickel-Catalyzed Cross-
Coupling of Benzylic Carbamates with Arylboronic Esters: Control of
Absolute Stereochemistry with an Achiral Catalyst
Michael R. Harris,† Luke E. Hanna,† Margaret A. Greene,† Curtis E. Moore,‡ and Elizabeth R. Jarvo*,†
†Department of Chemistry, 4114 Natural Sciences 1, University of California, Irvine, California 92697, United States
‡Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, MC 0358, La Jolla, California
92093, United States
S
* Supporting Information
Scheme 1. Control of Product Stereochemistry in
Stereospecific Reactions
ABSTRACT: Stereospecific coupling of benzylic carba-
mates and pivalates with aryl- and heteroarylboronic esters
has been developed. The reaction proceeds with selective
inversion or retention at the electrophilic carbon, depend-
ing on the nature of the ligand. Tricyclohexylphosphine
ligand provides the product with retention, while an N-
heterocyclic carbene ligand provides the product with
inversion.
he mechanisms of alkyl cross-coupling reactions are hard-
Twired with implications for the stereochemical outcome at
the reactive center.1 Simple changes to the reaction conditions
do not typically perturb the inherent bias for racemization,
retention, or inversion at the reactive center. For example,
palladium-catalyzed reactions of alkyl electrophiles are typically
stereospecific and proceed with inversion at the stereogenic
center,2,3 while nickel-catalyzed reactions of alkyl halides
proceed with racemization at the electrophilic carbon4 and
judicious use of a chiral catalyst permits stereoconvergent
reactions.5 Overcoming the intrinsic preference of a reaction
that typically proceeds with inversion at the stereogenic center
to make it proceed with retention is quite unusual and requires
a significant change to the mechanism of the transformation.
For stereospecific reactions, special cases using α-chiral
transmetalating agents have been reported in which modification
of the reaction conditions or substrate structure can affect a
switch in the sense of the absolute stereochemistry.6 Trans-
metalation typically occurs with retention at the stereogenic
center;7,8 select examples that proceed with inversion have been
reported.9 In seminal contributions, Hiyama demonstrated that
palladium-catalyzed couplings of alkylsilanes could proceed
with retention or inversion, depending on the reaction
conditions.10 Recently, the Suginome group has developed
stereodivergent reactions of α-(acetylamino)benzylboronic
esters that are controlled by the choice of additive to afford
either retention or inversion selectively (Scheme 1a).11,12
In this communication, we demonstrate catalyst control of
the stereochemical course with respect to the electrophilic
partner in a cross-coupling reaction. Stereospecific nickel-
catalyzed cross-coupling reactions of benzylic alcohol deriva-
tives typically proceed with inversion at the electrophilic
carbon.13,14 Here we report nickel-catalyzed cross-coupling of
benzylic esters in which the achiral ligand structure dictates
whether the reaction proceeds with retention or inversion
(Scheme 1b). Use of SIMes, an N-heterocyclic carbene (NHC)
ligand, affords inversion, while PCy3 gives retention. To the
best of our knowledge, these results constitute the first cross-
coupling reactions of alkyl electrophiles that undergo two
distinct stereospecific mechanistic pathways to provide either
retention or inversion at the electrophilic carbon.
In previous work, we established the synthesis of
enantioenriched triarylmethanes by stereospecific nickel-cata-
lyzed cross-coupling of ethers with aryl Grignard reagents.13b
The triarylmethane moiety is present in medicinal chemistry
targets, natural products, and synthetic materials.15,16 Despite
recent advances in the preparation of racemic triarylmethanes,17
there are few methods for their enantioselective synthesis.18 As
part of our ongoing interest in developing nickel-catalyzed
stereospecific reactions of alkyl electrophiles, we chose to
examine cross-coupling reactions of arylboronic esters for
triarylmethane synthesis. The functional group tolerance and
ready availability of a wide range of boronic esters makes them
attractive coupling partners.
Received: December 3, 2012
Published: February 18, 2013
© 2013 American Chemical Society
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We began by examining a range of benzylic alcohol
derivatives (Table 1). Our initial reaction conditions resulted
reaction was consistent across the range of esters and
carbamates that we examined: PCy3 and SIMes reliably
afforded opposite enantiomers of the product (Table 1, entries
8−11, 15, and 16).23 Under the optimal reaction conditions,
addition of n-BuOH was found to the improve stereochemical
fidelity when either ligand was used (cf. entries 13−16).
Having optimized the reaction conditions for stereospecfic
synthesis of either enantiomer of the product, we turned our
attention to the scope of the reaction with respect to the
boronic ester (Table 2). Electron-donating and -withdrawing
Table 1. Optimization of the Reaction Conditions
a
Table 2. Scope with Respect to Arylboronic Esters
a
b
PCy3 (20 mol %); SIMes (11 mol %). Isolated yields after column
c
chromatography. Enantiospecificity (es) = (eeproduct/eestarting material) ×
100%.
in modest conversion of carbonate (S)-3 and low enantiospe-
cificity (es) (entry 1).19 To our surprise, in contrast to the
Kumada coupling, the product, (R)-2, resulted from retention at
the electrophilic carbon. An improvement to 43% es was
observed when the solvent was changed from toluene to
tetrahydrofuran (THF) (entry 2). Alcohol additives further
improved the yield and stereochemical fidelity of the reaction,
with n-BuOH providing the highest es (87%; entry 4). More
sterically encumbered alcohols provided more modest improve-
ments, while water and the electron-deficient alcohol
trifluoroethanol proved detrimental to the reaction (entries 3,
5, and 7). The enantiospecificity of the reaction showed a
marked dependence on the identity of the leaving group. While
the use of pivalate (S)-4 in the cross-coupling reaction resulted
in lower enantiomeric excess of the product (entry 8), the
benzoate and carbamate derivatives (S)-5 and (S)-1 showed a
significant increase in product ee, providing 91 and 95% es,
respectively (entries 10 and 12). An additional small improve-
ment in yield and es resulted from using a 1:1 THF/toluene
mixture as the solvent (cf. entries 12 and 15).
a
All data are averages of two experiments, unless otherwise indicated.
b
c
PCy3 (20 mol %); SIMes (11 mol %). Isolated yields after column
d
chromatography. Determined by chiral supercritical fluid chromatog-
raphy (SFC). Data were obtained from a single experiment.
e
substituents on the arylboronic ester were well-tolerated under
the reaction conditions (entries 1−8), which are mild and allow
for broad functional group tolerance. Boronic esters containing
ketone, free alcohol, and carbamate functional groups all
coupled in good yield and es (entries 9−14). Boronic esters
containing heterocyclic groups, including pyrimidine, furan, and
indole, underwent smooth cross-coupling (entries 15−20). The
reaction conditions developed for the formation of either
enantiomer of 2 were general across the range of boronic esters
that we examined: of 20 examples, 18 provided high es.
Therefore, either enantiomer of a given product can be
obtained from the same enantiomer of the starting material
through the use of the appropriate ligand, PCy3 or SIMes.
We examined other ligands20 under the reaction conditions
and found that the NHC ligand SIMes21 afforded comparable
yields and enantiospecificity of 2, but the major product was the
S enantiomer, resulting from inversion at the electrophilic
carbon.22 Catalyst control of the stereochemical outcome of the
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Author Contributions
We set as our goal the cross-coupling of oxidative addition
partners that do not include a naphthylene moiety. These
electrophiles are typically less reactive in cross-coupling
reactions13c and were found not to be competent for
triarylmethane synthesis via Kumada coupling.13b Indeed,
neither the corresponding carbamates nor the use of PCy3 as
ligand provided acceptable yields of product. However,
benzhydril pivalates underwent smooth cross-coupling under
our optimized reaction conditions when SIMes was used as the
ligand (Table 3). Efficient cross-coupling was achieved for
‡C.E.M. solved the X-ray structure of the compound in Table 2,
entry 19 (S enantiomer).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NIH NIGMS (R01GM100212),
the University of California Cancer Research Coordinating
Committee, the University of California (Chancellor’s Fellow-
ship to M.R.H.), the Ford Family Foundation (predoctoral
fellowship to M.R.H.), and DOE (GAANN PA200A120070 to
L.E.H.). We thank Frontier Scientific for generous donations of
boronic acids. Dr. Joseph Ziller and Dr. John Greaves are
acknowledged for X-ray crystallographic and mass spectrometry
data, respectively.
a
Table 3. Scope of Oxidative Addition Partners
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data, including
X-ray crystallographic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
erjarvo@uci.edu
■
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