Application of a C2-symmetric copper carbenoid in the enantioselective hydrosilylation of dialkyl and aryl-alkyl ketones

Article abstract of DOI:10.1021/ja209187a

We report excellent reactivity and enantioselectivity of a C ₂-symmetric copper-bound N-heterocyclic carbene (NHC) in the hydrosilylation of a variety of structurally diverse ketones. This catalyst exhibits extraordinary enantioselctivity in th

Full text of DOI:10.1021/ja209187a

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Application of a C2-Symmetric Copper Carbenoid in the
Enantioselective Hydrosilylation of Dialkyl and ArylꢀAlkyl Ketones
Abigail Albright and Robert E. Gawley*
Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, United States
S Supporting Information
b
ABSTRACT: We report excellent reactivity and enantio-
selectivity of a C2-symmetric copper-bound N-heterocyclic
carbene (NHC) in the hydrosilylation of a variety of struct-
urally diverse ketones. This catalyst exhibits extraordinary
enantioselctivity in the reduction of such challenging sub-
strates as 2-butanone and 3-hexanone. Even at low catalyst
loading (2.0 mol %), the reactions occur in under an hour at
room temperature and often do not require purification beyond
catalyst and solvent removal. The scope of this transforma-
tion was investigated in the reduction of 10 arylꢀalkyl and
alkylꢀalkyl ketones.
he asymmetric hydrosilylation of prochiral ketones yielding
enriched silylethers or alcohols is an attractive alternative to
T
asymmetric hydrogenation, avoiding the use of expensive pre-
cious metal catalysts and occurring under very mild conditions.1
The first catalytic ketone hydrosilylation was effected with
tris-(triphenylphosphine)-rhodium chloride in 1972,2 and this
transformation has since become an important route to access
the silyl ether and alcohol functionalities. Over the same period
of time, silanes have emerged as an important class of protecting
group for alcohols, fortuitously making the products of ketone
hydrosilylation—before hydrolysis—useful in their own right.
Furthermore, hydrosilylation generally occurs under mild reac-
tion conditions which avoid over-reduction of the substrate and
utilizes affordable and easy-to-handle reagents.3
Figure 1. Previously reported NHC-catalysts for asymmetric hydrosilylation.
Hydrosilylation catalysts are most frequently developed as
complexes of group 9 metals such as rhodium and iridium, although
recent advances have shown group 11 metals to be attractive (less
expensive) alternatives.4 In particular, stabilized copper hydride
species are powerful reducing agents for numerous reductive
transformations, among them hydrosilylation of ketones.5 Ter-
tiary phosphines are widely employed as ligands for hydrosilyla-
tion catalysts, particularly chiral ones, owing to their highly tunable
steric and electronic properties. Comparable in their attributes
but much less extensively employed are N-heterocyclic carbene
(NHC) ligands.6 The copper(I)-N,N0-bis-(2,6-diisopropylphe-
nyl)imidazol-2-ylidine (CuIPr) NHC, a number of its analogs,
and its cationic dimer, have shown promise in the hydrosilylation
of a wide variety of ketones.7
A handful of chiral NHC catalysts have been employed with
some success in the enantioselective hydrosilylation of prochiral
ketones; key examples are depicted in Figure 1.8ꢀ11 Whilesomearylꢀ
alkyl ketones can be reduced with excellent enantioselectivity
using these NHC hydrosilylation catalysts, the rhodium complex
developed by Gade is notable in that it can achieve moderate
Figure 2. ClꢀCuPhEt precatalyst.
enantioenrichment in the hydrosilylation of dialkyl ketones. The
enantioselective reduction of linear ketones remains an elusive
goal: the best selectivity achieved for the hydrosilylation of
2-butanone is 83:17 er.11,12
Of course, many enantioselective hydrosilylation catalysts not
containing NHC ligands can also be found in the literature.
Pioneering work by Nishiyama showed chiral bisoxazoline catalysts
to be effective in the asymmetric hydrosilylation of arylꢀalkyl
ketones.13 Ito was among the first to demonstrate the utility of
enriched silyl ethers as donors in cross coupling reactions.14 More
recently, Fu showed chiral P,N-ligands to be excellent catalysts
for asymmetric hydrosilylation of both aryl akyl and dialkyl ketones,
achieving the reduction of 2-octanone in 86:14 er.15
We recently disclosed the design and synthesis of three N-
heterocyclic carbene ligands that have a stereocenter γ to the
Received: September 29, 2011
Published: November 10, 2011
r
2011 American Chemical Society
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Table 1. Role of the Silane on the Time for 100% Conversion
and Enantioselectivity in Reactions Catalyzed by (R,R,R,R)-
CuPhEt
Table 2. Scope of (R,R,R,R)-CuPhEt-catalyzed
Hydrosilylation
* GC conversions.
Scheme 1. CuPhEt-catalyzed Hydrosilylation of Prochiral
Ketones
heterocyclic nitrogen.16 One of these, a C2-symmetric chiral
copper NHC (ClꢀCuPhEt, Figure 2), showed excellent activity
and enantioselectivity in the hydrosilylation of acetophenone.
The CuPhEt catalyst is air-stable and can be synthesized from
p-toluidine in five steps. We consider it a chiral analog of the widely
used ClꢀCuIPr catalyst.
We now report the highly enantioselective reduction of a variety
of arylꢀalkyl ketones and, more importantly, simple linear ketones.
The selectivity we observe with this class of substrates is excep-
tional, and it is achieved in less than an hour under very mild
reaction conditions at room temperature. Interestingly, CuPhEt
was found to be significantly more reactive than the CuIPr in the
hydrosilylation of acetophenone, achieving full conversion in a
fraction of the time (<1 h for CuPhEt vs 3ꢀ4 h for CuIPr).
Furthermore, the synthetic protocol in many cases makes use of a
highly volatile silane, which—though used in 3-fold excess—can
be easily removed under reduced pressure. The enantioenriched
silylether products are thus obtained without the need for extensive
purification.
We first investigated the effect of the silane reagent on the
enantioselectivity and percent conversion of 2-butanone to silyl
ethers of 2-butanol. The results are summarized in Table 1. We
observed that diethylsilane and diphenylsilane are more reactive
than triethylsilane, as indicated by more rapid consumption of
the ketone; triphenylsilane is unreactive with CuPhEt. This
observation is consistent with evidence in the literature suggest-
ing that hydrosilylation with trisubstituted silanes may be mec-
hanistically distinct from hydrosilylation with disubstituted silane
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reported herein for the reduction of dialkyl ketones is unmatched
by any asymmetric hydrosilylation or hydrogenation catalyst
reported to date.
’ ASSOCIATED CONTENT
S
Supporting Information. Spectroscopic and chromato-
b
graphic data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Figure 3. Predictive model for steric course of CuPhEt hydrosilylation.
S = small, L = large.
’ AUTHOR INFORMATION
reagents.17 Significantly, the disubstituted silanes produce a more
highly enantioenriched product than triethylsilane. Use of either
diphenyl- or diethylsilane provided for isolation of the silyl ether
of 2-butanol in 98:2 er. The dependence of enantioselectivity on
the silane reagent has been observed with chiral BINAP-copper-
(I) catalysts used for hydrosilylation.18 Also notable is the
chemoselectivity of the CuPhEt catalyst. The use of a dihydro-
silane reagent could lead to formation of the dialkoxy silane pro-
ducts, but di-sec-butoxysilanes were not detected in our experiments.
The optimized reaction conditions are detailed in Scheme 1.
Less volatile ketone substrates (Entries 1ꢀ5, Table 2) were hy-
drosilylated with diethylsilane, providing for easy removal of
excess silane during work up and obviating the need for chroma-
tographic purification of the product. To prevent loss of product
by evaporation, the more volatile dialkyl ketones (Entries 6ꢀ10,
Table 2) were converted to diphenylsilyl ethers instead.
CuPhEt shows a high degree of reactivity and enantioselec-
tivity in the hydrosilylation of a variety of arylꢀalkyl ketones and
simple linear ketones. 2-Butanone (entry 6) and 3-hexanone
(entry 10) are respectively reduced in 98:2 and 95:5 er! Remarkably,
hydrosilylation using CuPhEt is able to distinguish a methyl from
an ethyl and an ethyl from a propyl group.
The absolute configurations of the silyl ethers derived from
acetophenone, 2-butanone, 3-methyl-2-butanone, and 2-octanone
were assigned by CSP-GC coinjection of an authentic, enantio-
pure silyl ether, or by hydrolysis of the silyl ether to the corre-
sponding alcohol and comparison of optical rotation with an
authentic sample. The configuration of the silylethers was in all
cases found to be S via hydride addition to the Re face of the
ketone using (R,R,R,R)-CuPhEt. For the examples for which
an authentic enantiopure silane or alcohol was not available,
absolute configuration was assigned by analogy. A predictive
model, based on DFT calculations of an acetophenone complex
with CuPhEt-H is offered in Figure 3.16 This model is consistent
with modeling and kinetic studies recently reported by Bellemin-
Laponnaz et al.19
Corresponding Author
bgawley@uark.edu
’ ACKNOWLEDGMENT
We thank the National Science Foundation (CHE 1011788)
and the Arkansas Biosciences Institute for direct support of this
work. Core facilities were funded by the Arkansas Biosciences
Institute and the National Institutes of Health (P30 RR 031154).
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