Enantioselective Hydroalkenylation of Olefins with Enol Sulfonates Enabled by Dual Copper Hydride and Palladium Catalysis

Article abstract of DOI:10.1021/jacs.1c02117

The catalytic enantioselective synthesis of α-chiral olefins represents a valuable strategy for rapid generation of structural diversity in divergent syntheses of complex targets. Herein, we report a protocol for the dual CuH- and Pd-catalyzed asymmetric Markovnikov hydroalkenylation of vinyl arenes and the anti-Markovnikov hydroalkenylation of unactivated olefins, in which readily available enol triflates can be utilized as alkenyl coupling partners. This method allowed for the synthesis of diverse α-chiral olefins, including tri- and tetrasubstituted olefin products, which are challenging to prepare by existing approaches.

Full text of DOI:10.1021/jacs.1c02117

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Enantioselective Hydroalkenylation of Olefins with Enol Sulfonates
Enabled by Dual Copper Hydride and Palladium Catalysis
Alexander W. Schuppe, James Levi Knippel, Gustavo M. Borrajo-Calleja, and Stephen L. Buchwald*
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ABSTRACT: The catalytic enantioselective synthesis of α-chiral olefins represents a valuable strategy for rapid generation of
structural diversity in divergent syntheses of complex targets. Herein, we report a protocol for the dual CuH- and Pd-catalyzed
asymmetric Markovnikov hydroalkenylation of vinyl arenes and the anti-Markovnikov hydroalkenylation of unactivated olefins, in
which readily available enol triflates can be utilized as alkenyl coupling partners. This method allowed for the synthesis of diverse α-
chiral olefins, including tri- and tetrasubstituted olefin products, which are challenging to prepare by existing approaches.
he development of transition-metal-catalyzed methods
various electrophiles in catalytic hydrofunctionalization re-
actions43,44 led us to propose a complementary approach for
asymmetric olefin hydroalkenylation. As an alternative to
preformed stoichiometric organometallic reagents and vinyl
halides, which are generally prepared through multistep
sequences,45−47 we sought to leverage a copper hydride
(CuH) and Pd dual catalyst system (Figure 1A, bottom) to
effect the enantioselective hydroalkenylation of olefins. This
approach would utilize an in situ generated Cu(I)-alkyl species
(I) and widely available enol triflates (2). Although the
proposed synergistic CuH and Pd catalytic cycles involve
similar elementary steps to olefin hydroarylation (Figure
1B),48−52 we anticipated several unique challenges for the
dual-catalytic olefin hydroalkenylation (Figure 1C). It was
evident that the enol triflate (2) could undergo facile
hydrolysis or reduction to the corresponding olefin (V),
which may then be subject to further hydrofunctionalization
reactions. A similar outcome, such as reduction, olefin
isomerization, or oligomerization, is also conceivable for the
product (3) of this transformation. Therefore, construction of
the critical C−C bond of the α-chiral olefin would necessitate
the design of a synergistic catalyst system in which the rates of
key steps in both catalytic cycles, hydrocupration (1 → I),
oxidative addition (2 → II), transmetalation (I + III → IV),
and catalyst regeneration, are well aligned.
T
for enantioselective Csp3−Csp2 cross-coupling is a
vibrant area of research due to the ability of these reactions
to rapidly generate structural diversity through the strategic
construction of carbon−carbon bonds.1 Specifically, asymmet-
ric arylation and alkenylation reactions with alkylmetal
nucleophiles allow access to important substructures present
in many pharmaceuticals and biologically active natural
products. However, these approaches often necessitate the
use of stoichiometric quantities of organometallic reagents.2−6
Owing to the numerous subsequent functionalization reactions
olefins can undergo, the enantioselective installation of an
alkenyl fragment represents a particularly valuable synthon for
divergent synthesis.7,8 A conceptually straightforward way to
access α-chiral olefin products is through hydroalkenylation of
olefin precursors. Although numerous approaches for the
racemic hydroalkenylation of olefins exist,9−12 a general
method for the analogous asymmetric variant of this
transformation remains underdeveloped.
Pioneering work on enantioselective hydrovinylation, by
RajanBabu13,15−21 and others,14,22,23 demonstrated an atom-
economical coupling of ethylene with vinyl arenes. However,
attempts to expand this strategy to additional unactivated
olefins often led to mixtures of products.24 The prototypical
approach for asymmetric olefin hydroalkenylation, which
avoids these regioisomeric product mixtures, involves the
coupling of a preformed stoichiometric organometallic reagent
to an alkene (Figure 1A, top).25−27 To circumvent specific
limitations of these prior methods, Zhu and Gong recently
reported a NiH-catalyzed enantioselective migratory olefin
hydroalkenylation to prepare 1,2-disubstituted olefins from
alkenyl bromides and vinyl arenes (Figure 1A, middle).28
Complementary syntheses of enantioenriched 1,1-aryl, alkenyl
alkanes, including stereospecific reductive cross-coupling of
racemic benzylic halides and β-bromostyrenes,29−32 asymmet-
ric allylic alkylation,33−39 and stereospecific cross-coupling of
activated phenethyl derivatives,40−42 have also been developed.
Our group’s continued interest in exploring the propensity
of a stereodefined organocopper intermediate to engage
Accordingly, we focused on finding a suitable dual catalytic
system for the asymmetric olefin hydroalkenylation, using
styrene (1a) as a model substrate and 1-cyclohexenyl
trifluoromethanesulfonate (2a) as the alkenyl coupling partner
(Table 1). Utilizing our previously described conditions for
dual CuH/Pd-catalyzed hydroarylation of olefins in this
Received: February 23, 2021
Published: March 30, 2021
https://doi.org/10.1021/jacs.1c02117
J. Am. Chem. Soc. 2021, 143, 5330−5335
© 2021 American Chemical Society
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Table 1. Optimization of the Enantioselective
Hydroalkenylation of Styrene (1a) with Alkenyl Coupling
a
Partner (2)
a
Reaction conditions: 0.2 mmol styrene (1a) (1.0 equiv), alkenyl
coupling partner (2) (0.3 mmol, 1.5 equiv), yields were determined
by 1H NMR spectroscopy of the crude reaction mixtures, using
1,1,2,2-tetrachloroethane as internal standard. Enantiomeric ratio (er)
was determined by chiral supercritical fluid chromatography (SFC).
N.D.: not determined.
ligand scaffold, from dppbz (L4) to other bisphosphine or
biarylphosphine ligands, resulted in a substantially diminished
yield of the olefin hydroalkenylation adduct 3a (see entry 10
and Table SI2), further demonstrating the importance of
tuning the rates of the two catalytic cycles. When the reaction
was run in the absence of P1 (entry 11) or Cu and L1 (entry
12), minimal or no 3a was observed, respectively.
Figure 1. (A) Previous approaches to asymmetric olefin hydro-
alkenylation and our approach. (B) Proposed dual CuH/Pd catalytic
cycles. (C) Potential side reactions for the hydrofunctionalization
process involving an enol triflate (2).
Having established excellent reaction conditions for the
asymmetric olefin hydroalkenylation, we investigated the scope
of olefin products that could be prepared by this protocol
(Scheme 1). Cyclic, benzofused (3b), and heterocyclic (3g, 3j,
3p, and 3v) α-stereogenic olefin products could be accessed in
good yield and enantioselectivity. Additionally, tetrasubstituted
(3d, 3n), acyclic trisubstituted (3c, 3f, 3h, 3k, 3l, and 3m), and
1,1-disubstituted olefins (3i), which are challenging substrates
to prepare by complementary methods,25−28 were obtained in
high yield and enantiopurity. We were also able to synthesize a
cyclic 1,3-butadiene (3s) diastereoselectively (>20:1 dr)
through the use of a dienyl-triflate. When an E/Z-mixture
(6.5:1 E:Z) of the alkenyl coupling partner was utilized, the
olefin product was isolated as a single olefin isomer (3c). A
geometrically pure Z-alkenyl coupling partner resulted
exclusively in Z-3e in similar yield and enantioselectivity
(78%, 97:3 er) to E-3e. These experiments suggest that the
reaction of an E-alkenyl coupling partner outcompetes the
corresponding Z-substrate. Notably, despite 1,2- and 1,1-
disubstituted olefin products (3e, 3i) being common substrates
for copper hydride-catalyzed hydrofunctionalization reactions,
we detected no significant dimerization or oligomerization of
the product with excess enol triflate.
reaction system,48,49 we observed minimal hydroalkenylation
product 3a (see Table SI1−3 for further details on the reaction
optimization). Investigation of the optimal reaction conditions
identified the air-stable Pd-precatalyst, Pd(cinnamyl)(dppbz)-
(Cl) (P1), CuI, (S)-DTBM-SEGPHOS (L1), NaOTMS, and
Me2PhSiH as crucial to form 3a in high yield and
1
enantioselectivity (entry 1, 96% H NMR yield and 96:4 er).
An alternative ligand, (S)-DTBM-MeO-BIPHEP (L2), per-
formed with similar efficiency to L1 (entry 2). The use of a
vinyl bromide (2b) or iodide (2c) furnished 3a in moderate
yield but low enantioselectivity (entries 3, 4). However, when
the corresponding enol tosylate (2d) was employed in the
olefin hydroalkenylation, 3a was formed with increased
enantioselectivity and minimal reduction of the alkenyl
1
coupling partner (entry 5, 69% H NMR yield and 92:8 er).
Substituting L1 with L2 in conjunction with an enol tosylate
further increased the enantioselectivity (entry 6). This
suggested that enol tosylates may be suitable substrates for
the olefin hydroalkenylation if the analogous enol triflate
undergoes facile reduction or hydrolysis (see Table SI3 for
additional experiments comparing the efficiency of enol
triflates and tosylates). Evaluation of a series of Cu salts
demonstrated a dependence on the counterion (entries 7−9),
with CuBr and CuI performing similarly. Variation of the Pd
A variety of heterocycle-containing vinyl arene and enol
triflates could be coupled to yield the corresponding
hydroalkenylation products, including pyrimidine (3f), benzo-
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a
Scheme 1. Substrate Scope of the Asymmetric Markovnikov Hydroalkenylation of Vinyl Arenes
a
All yields represent the average of at least two isolated yields with 0.5 mmol of alkene (1); the corresponding enol triflate was used unless
1
otherwise noted, enantioselectivity determined by chiral SFC or HPLC. The yields in parentheses were determined by H NMR spectroscopy of
b
the crude reaction mixtures using 1,1,2,2-tetrachloroethane as an internal standard. An E:Z mixture (6.5:1) of the enol triflate was employed.
c
d
e
Enol tosylate was employed with 7.0 mol% L2. E-Vinyl bromide was employed with 7.0 mol% L2. Z-Vinyl bromide was employed with 7.0 mol
f
g
h
% L2 and 0.2 mmol of 1. Enol tosylate was employed under standard reaction conditions. 2.0 mol% P1. 3.0 mol% CuI, 3.5 mol% L1, and 3.0
mol% P1. 7.0 mol% L2.
i
thiophene (3g), furan (3h), thiomorpholine (3i), 7-azaindole
(3k), carbazole (3n), pyrazole (3o), pyridine (3p, 3t),
benzothiazole (3q), and quinoline (3v). Substrates containing
an ester (3g), aryl chloride (3l), thiomethyl (3m), carbamate
(3t, 3v), or a tertiary amine (3u) were well tolerated under the
reaction conditions and resulted in good yields and
enantioselectivities of the olefin products. However, when a
substrate bearing a ketal was employed, hydrolysis of the
corresponding product (3r) was observed, resulting in
diminished yield (37%). A sterically congested vinyl arene
containing an alkyl ortho-substitution was effectively converted
to a trisubstituted olefin (3h) in high yield and 95:5 er. While
electron-deficient vinyl arenes (3g, 3r) could be readily
converted to the hydroalkenylation products, an electron-rich
vinyl heteroarene (3j) necessitated a lower Pd-catalyst loading
to minimize competing reduction of the enol triflate.
1,2-Disubstituted olefin substrates, which have higher
barriers to hydrocupration relative to vinyl arenes,53,54 were
equally competent substrates for the hydrofunctionalization
reaction (3p−3r). A cinnamyl amine substituted with a basic
−NMe2 group furnished 3x with moderate enantioselectivity
(81:19 er). The enantiomeric ratio could be increased (92:8
er) by employing the corresponding enol tosylate and L2.
Moreover, when the −NBn2 derivative was employed under
analogous conditions, 3w was isolated with 99:1 er, suggesting
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that the pendant −NMe2 group present in 3x may be
competing as a ligand or slowing the transmetalation step.
In cases where highly activated enol triflates were employed,
such as 3d, 3i, and 3m, reduction of the alkenyl coupling
partner competed with the desired olefin hydroalkenylation
reaction. This undesired pathway could be suppressed by
utilizing the corresponding enol tosylate in conjunction with
L2. Contrary to our observation that unactivated vinyl halides,
such as 2b (Table 1), were poor substrates for this method, we
found that a β-bromostyrene provided an enantioenriched 1,2-
disubstituted α-stereogenic olefin with excellent yield and
selectivity (3e). Additionally, when cycloalkyl enol triflates
were utilized, the catalyst loading could be significantly
decreased (3o, 3q, 3t, and 3u). Employing an α-substituted
cyclic enol triflate resulted in an unexpected regioisomeric
mixture of the Markovnikov and anti-Markovnikov hydro-
alkenylation products (3n).
Scheme 2. Scope of the Anti-Markovnikov
Hydroalkenylation of Unactivated Olefins
a
To further demonstrate the utility of this enantioselective
olefin hydroalkenylation method, we subjected several
medicinally relevant molecules to the hydroalkenylation
reaction to afford derivatives of cholesterone (3s), loratadine
(3t), and chlorpromazine (3u). Pharmaceutical intermediates,
including a precursor to a Cephalon FASN inhibitor (3v)55
and 3x, could readily be synthesized with high enantioselec-
tivity by this approach. Subsequent hydrogenation of 3x to (S)-
gamfexine, an antidepressant,56 represents a net formal
enantiospecific Csp3−Csp3 coupling. The hydroalkenylation
process could be easily conducted on 5.0 mmol scale with vinyl
arene 1b and commercially available enol triflate 2a (eq 1).
Using reduced catalyst loading, 1.5 mol% Cu and Pd catalysts,
3y could be synthesized in 74% isolated yield with high
stereoselectivity (93:7 er).
a
All yields represent the average of at least two isolated yields with 0.5
b
mmol of alkene. 6.0 mol% CuI, 7.0 mol% ( )-L1, and 4.0 mol% P1
were used. 45 °C.
c
In summary, we have developed a method for asymmetric
olefin hydroalkenylation that allows access to a wide variety of
α-stereogenic olefins using widely available starting materials.
Our dual CuH- and Pd-catalyzed approach allowed entry to
olefin classes that are difficult to synthesize by complementary
strategies, including tri- and tetrasubstituted olefin products.
The reaction conditions tolerated a variety of medicinally
relevant substructures and enabled the synthesis of several
pharmaceutical intermediates. This protocol was expanded to
the anti-Markovnikov hydroalkenylation of unactivated olefins.
Given the general reactivity we observed while studying the
hydroalkenylation of vinyl arenes, we were interested in
extending the scope of this transformation to include
unactivated olefins. Typically, these products are accessed
using the B-alkyl Suzuki−Miyaura reaction, which represents a
robust way to couple olefins to alkenyl (pseudo)halides in a
regiospecific manner.57 However, these reactions rely on the
generation of stoichiometric quantities of alkyl-boron species
from olefin precursors, limiting their step and atom economy.
As an alternative, we reasoned that the catalytic generation of a
terminal organocopper species would allow us to extend our
protocol to the hydroalkenylation of unactivated olefins.
Without significant modification of the reaction conditions,
we could achieve a regioselective hydroalkenylation of terminal
olefins (Scheme 2). A variety of important structural elements
were tolerated in this process, including a basic quinuclidine
(6a), indole (6c), amide (6d), morpholine (6e), dioxolane
(6f), and thiopyrimidine (6h). This Csp3−Csp2 coupling
facilitated the synthesis of tetrasubstituted olefins (6b, 6g) and
a vinyl arene (6f). Further, this approach to generate vinyl
arenes may be a viable strategy for the synthesis of starting
materials for ensuing hydrofunctionalization reactions.43,44
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c02117.
■
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Experimental procedures and characterization data for
all new compounds including NMR spectra, SFC, and
HPLC traces (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Stephen L. Buchwald − Department of Chemistry,
Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States; orcid.org/0000-
0003-3875-4775; Email: sbuchwal@mit.edu
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Authors
Alexander W. Schuppe − Department of Chemistry,
Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States; orcid.org/0000-
0001-6002-9110
James Levi Knippel − Department of Chemistry,
Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States; orcid.org/0000-
0002-3867-4372
Gustavo M. Borrajo-Calleja − Department of Chemistry,
Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c02117
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
Arnold and Mabel Beckman Foundation for a postdoctoral
fellowship to A.W.S., the Swiss National Science Foundation
(SNSF) for a postdoctoral fellowship (P2GEP2-181266) to
G.M.B.-C., the National Science Foundation Graduate
Research Fellowship Program (1122374) to J.L.K., and the
National Institutes of Health (R35-GM122483 and Diversity
Supplement Fellowship R35-GM122483-03S to J.L.K.). We
thank the National Institutes of Health for a supplemental
grant for the purchase of SFC equipment (GM058160-17S1).
We thank Millipore-Sigma and Solvias for the generous
donation of biarylphosphine ligands and (S)-DTBM-MeO-
BIPHEP, respectively. We thank Dr. Yuxan Ye for the donation
of some of the enol triflates used in this study. We are grateful
to Drs. Veronika Kottisch, Simon Rössler, and Christine
Nguyen (MIT) for advice on the preparation of this
manuscript.
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