Enantioselective CuH-Catalyzed Hydroallylation of Vinylarenes

Article abstract of DOI:10.1021/jacs.6b02527

The enantioselective, intermolecular hydroallylation of vinylarenes employing allylic phosphate electrophiles has been achieved through a copper hydride catalyzed process. The protocol described herein can be applied to a diverse set of vinylarene substrates and allows for the installation of the parent allyl group as well as a range of 2-substituted allylic fragments.

Full text of DOI:10.1021/jacs.6b02527

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Communication
Enantioselective CuH-Catalyzed Hydroallylation of Vinylarenes
Yi-Ming Wang, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02527 • Publication Date (Web): 04 Apr 2016
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Enantioselective CuH-Catalyzed Hydroallylation of Vinylarenes
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Yi-Ming Wang and Stephen L. Buchwald*
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Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Supporting Information Placeholder
ABSTRACT: The enantioselective, intermolecular hy-
droallylation of vinylarenes employing allylic phosphate
electrophiles has been achieved through a copper hydride-
catalyzed process. The protocol described herein can be
applied to a diverse set of vinylarene substrates and allows
for the installation of the parent allyl group as well as a
range of 2-substituted allylic fragments.
We anticipated that further advances in CuH chemistry
would enable the enantioselective formation of C—C
bonds in an intermolecular sense. In particular, we
reasoned that the use of allylic electrophiles would
permit the development of a hydroallylation process in
which simple styrenes and allylic electrophiles could be
brought together to form enantioenriched β-chiral
olefins. Previous methods to access these products have
generally required the use of either stoichiometric chiral
9
The creation of configurationally well-defined
stereogenic centers during the course of carbon-carbon
bond formation is of great importance for the synthesis
of complex organic molecules. Due to the synthetic
versatility of the olefin functional group, the
enantioselective installation of an allylic fragment has
long been regarded as a particularly valuable subset of
reagents or multistep synthetic sequences.
1
-3
stereoselective C–C bond-forming transformations.
Among the numerous transition metal-catalyzed
methods for enantioselective allylation, the copper-
catalyzed addition of organometallic reagents to allylic
electrophiles is distinguished by its applicability to non-
4
heteroatom-stabilized carbon nucleophiles.
As a
consequence, these methods can be readily applied to
the construction of C–C bonds remote from polar
functional groups in an enantioselective manner, a
process for which few other catalytic methods are
available.
In typical copper-catalyzed allylic
substitution reactions, the organocopper intermediate
undergoes addition to a prochiral allylic electrophile,
resulting in the formation of a stereocenter α to a double
Figure 1. Comparison between copper-catalyzed
allylic substitution and hydroallylation (A) and
postulated catalytic cycle (B).
bond.
In contrast, the addition of an α-chiral
organocopper species to an allylic electrophile to furnish
A postulated catalytic cycle for the proposed formal
hydroallylation process is shown in Figure 1B. In
analogy to previously reported CuH-catalyzed reactions,
insertion of the olefin into the ligated copper hydride
species L*CuH (I) would afford enantioenriched
benzylcopper species II. This could then be intercepted
by the allylic electrophile to furnish the organic product
and copper (pseudo)halide species III. Ligand exchange
of III with a metal alkoxide and σ-bond metathesis of
the resultant copper alkoxide IV with a hydrosilane
would regenerate I and complete the catalytic cycle. We
recognized that the undesired reactions of I with the
allylic electrophile or the β-chiral olefin product were
a β stereocenter has seldom been reported and would
5
represent a significant advance (Figure 1A).
Recently, our group has described the reactions of
copper hydride (CuH) catalysts with olefins as a means
of accessing putative chiral organocopper intermediates.
This approach avoids the preparation of a stoichiometric
organometallic reagent and allows for the use of mild,
functional group tolerant conditions. Using this strategy,
6
we developed several hydroamination reactions, an
7
asymmetric indoline synthesis, as well as an
intramolecular hydroalkylation protocol for the synthesis
8
of four to six membered carbo- and heterocycles.
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also possible and represented potential complications in
Table 1. Optimization of reaction conditions
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efforts to implement the proposed hydroallylation
process. In this manuscript, we report that the requisite
selectivity could indeed be achieved, permitting the
development of a highly enantioselective hydroallylation
reaction which affords a wide range of functionalized
and unfunctionalized β-chiral olefins with good to
excellent
yield
and
outstanding
levels
of
enantioselectivity.
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We initiated our investigation by examining the
reactivity of 4-phenylstyrene in the presence of common
allyl electrophiles under conditions similar to those
previously
developed
for
the
intramolecular
hydroalkylation reaction. When Ph-BPE was employed
as the supporting ligand, allyl chloride was found to
provide the desired product in moderate yield and with
excellent enantioselectivity, while allyl benzoate was
unreactive (Table 1, entries 1 and 2). Although
reactivity improved upon substitution of allyl chloride
with allyl diethylphosphate, the enantioselectivity
decreased significantly (entry 3). An evaluation of
different bisphosphine ligands at this point revealed that
the catalyst derived from Ph-BPE exhibited the best
reactivity, although that based on DTBM-SEGPHOS
provided product with higher enantiomeric excess
To evaluate the scalability of the current procedure, the
synthesis of 3e was conducted on a 5 mmol scale with
the catalyst loading reduced to 1 mol %. Under these
conditions, the desired product was isolated in
essentially unchanged yield and enantioselectivity (1.05
g of 3e isolated, 82% yield, 97% ee). Finally, the
connectivity and absolute configuration of 3h was
ascertained by X-ray crystallography. The observed
sense of stereoinduction was consistent with that of the
previously reported CuH-catalyzed indoline synthesis,
(entries 4-6). The enhanced enantioselectivity obtained
using allyl chloride as the substrate led us to postulate a
beneficial effect from the presence of chloride anion in
the reaction mixture. Indeed, the use a 1:1 complex of
7
, 13
which also utilized Ph-BPE as the supporting ligand.
a
Table 2. Scope of the Allylic Electrophile
11
copper(I) chloride and Ph-BPE provided product in
high yield and with excellent enantioselectivity. The
reactivity, however, was somewhat attenuated and a
1
2
higher reaction temperature was required (entry 7).
Switching from LiOMe to LiOt-Bu as the metal alkoxide
dramatically improved reactivity while maintaining a
high level of enantioselectivity (entry 8). Lastly, the use
of diphenylphosphate as the leaving group allowed the
desired product to be obtained in high yield and high
enantioselectivity at room temperature with a reduced
catalyst loading of 2 mol % (entry 12).
Having found reaction conditions that resulted in an
excellent outcome, we set out to investigate the scope of
the electrophilic component of this hydroallylation
protocol. In addition to the parent allyl group, a variety
of 2-substituted electrophiles could be handled. For
instance, substrates with alkyl groups of varying steric
demand were efficiently transformed (3b-3d). A chloro
group was also tolerated (3e), providing the desired
coupling product in high yield without reduction of the
vinyl chloride functional group. Moreover, electron-rich
a
Reactions were conducted on 0.5 mmol scale. The
yields reported are the average of two runs.
(3f) and electron-poor (3g) aryl substituents could be
incorporated. Heteroaryl substituents were similarly
feasible (3h and 3i). Regardless of the nature of the 2-
substituent, products were isolated in good to high yield,
and enantioselectivity found to be uniformly high (≥97%
ee) in all cases.
Subsequently, the scope of the olefin coupling partner
was surveyed. A range of olefin substrates could be
coupled to give the desired β-chiral olefin in moderate to
excellent yield and high enantioselectivity (≥90% ee).
Styrenes with a range of electronic properties could be
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of the electrophile. Upon subjecting a mixture of 4-
employed in this transformation to provide the
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respective products with good synthetic efficiency (3j-l).
Chlorinated styrenes (ortho and para) could also be used
to deliver products which are potentially amenable to
further functionalization through metal-catalyzed cross-
coupling reactions (3j and 3m). Moreover, a tert-butyl
ester (3o) and tertiary amide (3n) were readily
(trifluoromethyl)styene and the deuterated substrate to
CuH-catalyzed hydroallylation conditions, 3l-d2 was
obtained in high yield, with full deuterium incorporation
observed at the internal allylic positions, rather than the
terminal olefinic positions (eq 1). This result suggests
that substitution occurs through a S 2´-like process via
N
accommodated.
Highlighting the mildness and
attack of the postulated organocopper species at the 3-
position of the allylic phosphate.
functional group tolerance of this protocol, the presence
of a conjugated diene in 3o and a vinyl bromide in 3n
did not lead to the formation of undesired overreduction
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products.
Vinylheteroarenes were also explored as
substrates. Vinyl-substituted 2-aminopyrimidine (3p),
quinoline (3q), and carbazole (3r) substrates all proved
to be suitable coupling partners. A styrene with β
substitution was also found to react efficiently (3s).
Remarkably, the hydroallylation reaction could be
applied to vinylferrocene as well as a vinylsilane
derivative, providing rapid access to highly
enantioenriched ferrocene (3t) and alkylsilane (3u)
derivatives. In the case of the latter, the product was
isolated as a 10:1 mixture of regioisomers, with the
minor regioisomer formed from competitive allylation of
the terminal position of the vinylsilane.
In summary, an intermolecular, enantioselective
hydroallylation of vinylarenes has been developed. This
process was suitable for
a
wide range of
vinyl(hetero)arenes, allowing for the installation of
unsubstituted and 2-substituted allylic fragments in a
highly enantioselective manner.
Furthermore, the
reaction proceeds with relatively low catalyst loading,
and the mild conditions were suitable for substrates
containing a variety of functional groups. Efforts to
develop other broadly applicable hydroalkylation
protocols are currently under way.
a
Table 3. Scope of the Olefin Coupling Partner
ASSOCIATED CONTENT
Supporting Information. Experimental procedures,
characterization data for new compounds, and crystallo-
graphic data for 3h (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* sbuchwal@mit.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Research reported in this publication was supported by
the National Institutes of Health under award no.
GM46059. The content is solely the responsibility of
the authors and does not necessarily represent the offi-
cial views of the National Institutes of Health. Y.-M.W.
thanks the National Institutes of Health for a postdoctor-
al fellowship (GM112218). We thank Dr. Peter Mueller
for X-Ray crystallographic data and Drs. Michael Pirnot
and Aaron Sather for their advice on this manuscript.
a
Reactions were conducted on 0.5 mmol scale. The
b
yields reported are the average of two runs. Conducted
with 4 mol % catalyst at 35 °C.
To gain an understanding of the C–C bond forming
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.
.
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TOC graphic:
R'
R
R'
21 examples
L*CuH
Het
+
X
R
50 to 93% yield
90 to 99% ee
enantioselective
hydroallylation
Het
olefin
allylic electrophile
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ACS Paragon Plus Environment