Enantioselective CuH-Catalyzed Reductive Coupling of Aryl Alkenes and Activated Carboxylic Acids

Article abstract of DOI:10.1021/jacs.6b03086

A new method for the enantioselective reductive coupling of aryl alkenes with activated carboxylic acid derivatives via copper hydride catalysis is described. Dual catalytic cycles are proposed, with a relatively fast enantioselective hydroacylation cycle followed by a slower diastereoselective ketone reduction cycle. Symmetrical aryl carboxyclic anhydrides provide access to enantioenriched α-substituted ketones or alcohols with excellent stereoselectivity and functional group tolerance.

Full text of DOI:10.1021/jacs.6b03086

Communication
pubs.acs.org/JACS
Enantioselective CuH-Catalyzed Reductive Coupling of Aryl Alkenes
and Activated Carboxylic Acids
Jeffrey S. Bandar, Erhad Ascic, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
Scheme 1. (a) Prior Work in Aryl Alkene Reductive Coupling
to Acyl Electrophiles; (b) Proposed Access to Chiral Ketones
or Alcohols; (c) Proposed Catalytic Cycles
ABSTRACT: A new method for the enantioselective
reductive coupling of aryl alkenes with activated carboxylic
acid derivatives via copper hydride catalysis is described.
Dual catalytic cycles are proposed, with a relatively fast
enantioselective hydroacylation cycle followed by a slower
diastereoselective ketone reduction cycle. Symmetrical aryl
carboxyclic anhydrides provide access to enantioenriched
α-substituted ketones or alcohols with excellent stereo-
selectivity and functional group tolerance.
he asymmetric construction of chiral ketones and alcohols
Tremains an important area of research in organic synthesis
due to the high utility of these functional groups.1 The reaction of
an alkene with an aldehyde, via catalytic hydroacylation or
reductive coupling, represents an attractive route to α-chiral
ketones and alcohols, respectively.2,3 These processes construct a
carbon−carbon bond (and corresponding stereogenic center)
while obviating the need for stoichiometric preformed organo-
metallic reagents. Impressive developments toward generalizing
these transformations have been reported although significant
limitations and challenges remain. For example, numerous
methods for highly enantioselective intermolecular alkene
hydroacylation have been reported; however, a metal-coordinat-
ing substituent on either the alkene or aldehyde component is
typically required.4 Pioneering work by Krische has led to
numerous methods for the asymmetric reductive coupling of
alkenes to carbonyls for relatively activated C−C π-systems, such
as electron-deficient alkenes, enynes, dienes, and allenes.3,5−7 In
contrast, stereoselective catalytic intermolecular reductive
coupling of aryl alkenes to carbonyls remains largely
undeveloped, likely a consequence of the lower reactivity of
these alkenes.8,9 Building upon an initial report by Miura,10
Krische developed a highly efficient Rh-catalyzed coupling of aryl
alkenes and anhydride reagents to selectively access branched
ketones in a racemic manner (Scheme 1a).9,11 We reasoned that
using a similar approach, namely, using a carboxylic acid
derivative as an aldehyde surrogate, the limitations described
above for hydroacylation and reductive coupling could be
addressed via copper(I) hydride (CuH) catalysis. We herein
report a CuH-catalyzed protocol for the reductive coupling of
aryl alkenes to activated carboxylic acids that, depending on the
reaction conditions, selectively yields enantioenriched ketones or
alcohols (Scheme 1b).
intermediates that are formed from hydrocupration of an alkene
substrate.12,13 As an expansion of this work, we recently reported
methods for the synthesis of enantioenriched carbo- and
heterocycles via intramolecular trapping of a putative organo-
copper intermediate with alkyl bromides and imines.14 We
reasoned that this strategy could be applied to the intermolecular
coupling of an alkene to an appropriately activated carboxylic
acid derivative to initially yield an α-chiral ketone, constituting a
formal hydroacylation process.15,16 Subsequent reduction of the
ketone would additionally yield an alcohol containing two
stereocenters. The proposed catalytic cycle (Scheme 1c)
proceeds via asymmetric Markovnikov hydrocupration of aryl
alkene 2 followed by electrophilic interception with an acyl
electrophile (1) to deliver enantioenriched ketone (3) and
L*CuX (7).17 σ-Bond metathesis of L*CuX (7) with a
hydrosilane is required to regenerate L*CuH (5). Under
We, as well as Hirano and Miura, have developed
enantioselective CuH-catalyzed hydroamination reactions that
proceed through catalytically generated chiral organocopper
Received: March 24, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b03086
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
appropriate conditions, reformed L*CuH (5) could perform a
highly diastereoselective 1,2-reduction of ketone 3 in the
reduction cycle to produce silyl ether 9. Ideally, these two
catalytic processes could be performed in the same reaction
vessel with a common electrophile, thus providing either
enantioenriched ketone or alcohol products, depending upon
the reaction conditions employed.
In the presence of a hydrosilane reductant, phosphine-ligated
CuH species are typically very active catalysts for the 1,2-
reduction of carbonyl functional groups, such as ketones and
aldehydes.18 This propensity for efficient carbonyl reduction
presents a major challenge in the development of the proposed
methodology (Scheme 1b), as hydrocupration of an alkene must
occur in the presence of a carbonyl electrophile. Variation of the
electronic, steric, and coordinating properties of the activating
group provides an opportunity to achieve the desired chemo-
selectivity. A highly stereoselective process is further contingent
on avoiding ketone racemization.
alcohol was still the major product (entry 7). Use of other biaryl-
based diphosphine ligands, such as (S)-BINAP (L2), did not
yield any product (entry 8), while monoaryl diphoshine (R,R)-
Me-DuPhos (L3) increased the yield to 45% with drastically
reduced stereoselectivity (entry 9). The trialkyl diphosphine
(S,S)-Ph-BPE (L4) proved to be the optimal supporting ligand,
increasing the yield to 77% with high selectivity (entry 10). The
yield was further increased to 91% when (S,S)-Ph-BPE was used
with added PPh3 (2.2 mol %) as a secondary ligand, yielding the
desired product in >20:1 dr and 94% ee (entry 11).19
The scope of the optimized coupling process was next
explored using symmetrical aryl carboxylic anhydrides (Table 2).
Many functional groups, such as esters (4b), nitriles (4c),
phenols (4d), substituted alkenes (4e), carbamates (4h), and
a
Table 2. Alcohol Synthesis Substrate Scope
We began our studies with an examination of the reductive
coupling of styrene (2a) to benzoyl electrophiles to yield chiral
alcohol product (4a). Based on our catalyst system for
enantioselective hydroamination, we initially employed a mixture
of Cu(OAc)2 (2 mol %), (S)-DTBM-SEGPHOS phosphine
ligand (L1, 2.2 mol %), and dimethoxymethylsilane (DMMS) in
THF.12 Most of the electrophiles examined (1a−f) failed to react
or underwent rapid reduction to form benzyl alcohol (Table 1,
entries 1−6). When benzoic anhydride (1g) was used, 25% of the
desired product was formed with high selectivity, but benzyl
Table 1. Optimization of Chiral Alcohol Synthesis via Styrene
a
Reductive Coupling with Benzoyl Electrophiles
a
All yields represent average isolated yields of two runs performed
1
with 1 mmol of alkene; dr determined by H NMR analysis of crude
reaction material. Reaction run at ambient temperature. 2.0 equiv of
anhydride used. 4 mol % catalyst used. Bz2O added over 4 h, H
NMR yield, product isolated and characterized as the acylated alcohol.
a
b
c
1
Yields and dr determined by H NMR analysis of crude reaction
d e
1
mixture; enantioselectivity determined of the purified alcohol product
after treatment with NH4F in MeOH.
B
DOI: 10.1021/jacs.6b03086
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Journal of the American Chemical Society
Communication
aryl halides (4k, 4m, and 4n), are compatible with this
transformation. With electron-neutral and electron-rich aryl
alkenes, alcohol products are typically formed in moderate to
good yield (45−88%) with >20:1 dr and >95% ee. However,
highly electron-deficient styrenes, such as 4-cyanostyrene (4c),
led to products in good yield but with low selectivity, possibly
due to racemization of the more acidic ketone intermediate
formed upon hydroacylation. ortho- and β-Substitution is
tolerated on the aryl alkene component (4i and 4j), but product
yields are decreased as direct anhydride reduction competes with
hydrocupration of these more encumbered alkene substrates. For
the anhydride component, electron-rich (4l), electron-poor
(4k), and ortho-substituted (4m) substrates are all competent
coupling partners. Furthermore, good yields and selectivities
were obtained with a range of substrates containing heterocyclic
fragments, including indoles (4f), pyrazoles (4g), piperazines
(4h), benzofurans (4o), furans (4p), and thiophenes (4q).
Under the current reaction conditions, alkyl carboxylic
anhydrides do not engage in the coupling reaction and are
instead directly reduced by the CuH catalyst, a current limitation
of this system.
A useful feature of this methodology is the ability to selectively
access chiral ketones or alcohols by controlling the relative rates
of hydroacylation and carbonyl reduction. We have qualitatively
observed that 1,2-reduction occurs more slowly than the
hydroacylation process, and when the reaction is conducted at
a lower temperature, ketone products can be isolated in good
yields.20 Scheme 2a shows several examples of this formal
enantioselective hydroacylation protocol. With styrene, ketones
are isolated with moderate to good enantioselectivity (77−89%
ee) (3a, 3c, and 3d). Employing the more electron-rich 4-
acetoxystyrene as a substrate enabled the respective ketone
product to be produced with high enantioselectivity (3b, 97%
ee).
At the outset of this project, we questioned whether the
chirality of the L*CuH catalyst would be matched for both
transformations (hydroacylation and 1,2-reduction). To examine
this aspect, chiral ketone 3a, which was produced in 89% ee using
(S,S)-Ph-BPE ligand, was reduced under the standard reaction
conditions using both antipodes of the Ph-BPE ligand.21 The
(S,S)-Ph-BPE system yielded alcohol in 97:3 dr with 97% ee,
while the use of (R,R)-Ph-BPE ligand delivered alcohol in 55:45
dr with 78 and 99% ee, respectively. These results indicate that a
matched/mismatched case is evident for ketone reduction and
that the ligand used is stereomatched for hydroacylation and
reduction. This phenomenon provides an opportunity for further
enantioenrichment of the final alcohol product, as demonstrated
with the typically high levels of enantiopurity (>90% ee)
observed for the alcohol products in Table 2.22
In summary, we have developed a new protocol for the
enantioselective reductive coupling of aryl alkenes with aryl
carboxylic anhydrides for selective access to either chiral ketones
or alcohols. This process is enabled through dual catalytic cycles
wherein a chiral L*CuH catalyst first promotes enantioselective
hydroacylation, while a slower diastereoselective ketone
reduction process delivers the alcohol product with further
enantioenrichment. A wide range of functional groups and
heterocycles are tolerated, and ongoing work is aimed at
expanding this methodology to less activated alkenes and
aliphatic carboxylic acids.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b03086.
■
S
Experimental procedures and characterization data for all
compounds (PDF)
Scheme 2. (a) Enantioselective Ketone Synthesis and (b)
a
Reduction
AUTHOR INFORMATION
Corresponding Author
*sbuchwal@mit.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
National Institutes of Health (GM46059). We thank the NIH for
a postdoctoral fellowship for J.S.B. (GM112197) and the Danish
Council for Independent Research, Technology and Production
Sciences for a postdoctoral fellowship for E.A. The content is
solely the responsibility of the authors and does not necessarily
represent the official views of the National Institutes of Health.
We also thank Drs. Michael Pirnot and Yiming Wang for advice
on the preparation of this manuscript.
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Journal of the American Chemical Society
Communication
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D
DOI: 10.1021/jacs.6b03086
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX