Cu-catalyzed enantioselective alkylarylation of vinylarenes enabled by chiral binaphthyl-box hybrid ligands

Article abstract of DOI:10.1021/jacs.0c09008

Transition-metal-catalyzed radical relay coupling reactions have recently emerged as one of the most powerful methods to achieve difunctionalization of olefins. However, there has been limited success in applying this method to asymmetric catalysis using an effective chiral ligand. Herein we report the Cu-catalyzed enantioselective alkylarylation of vinylarenes using alkylsilyl peroxides as alkyl radical sources. This reaction proceeds under practical reaction conditions and affords chiral 1,1-diarylalkane structures that are found in a variety of bioactive molecules. Notably, a highly enantioselective reaction was accomplished by combining chiral bis(oxazoline) ligands with chiral binaphthyl scaffolds.

Full text of DOI:10.1021/jacs.0c09008

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Cu-Catalyzed Enantioselective Alkylarylation of Vinylarenes Enabled
by Chiral Binaphthyl−BOX Hybrid Ligands
Shunya Sakurai, Akira Matsumoto, Taichi Kano, and Keiji Maruoka*
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ABSTRACT: Transition-metal-catalyzed radical relay coupling reactions have recently emerged as one of the most powerful
methods to achieve difunctionalization of olefins. However, there has been limited success in applying this method to asymmetric
catalysis using an effective chiral ligand. Herein we report the Cu-catalyzed enantioselective alkylarylation of vinylarenes using
alkylsilyl peroxides as alkyl radical sources. This reaction proceeds under practical reaction conditions and affords chiral 1,1-
diarylalkane structures that are found in a variety of bioactive molecules. Notably, a highly enantioselective reaction was
accomplished by combining chiral bis(oxazoline) ligands with chiral binaphthyl scaffolds.
he difunctionalization of olefins is one of the most
study, we hypothesized that the generation of alkyl radicals
(INT-1) from ASPs and a CuI catalyst in the presence of
vinylarenes could give the corresponding benzyl radicals (INT-
2). The subsequent cross-coupling of INT-2 with arylboronic
acids under the influence of a CuII catalyst and a well-designed
chiral ligand could furnish 1,1-diarylalkane structures in an
enantioselective manner (Figure 2a).
T
powerful methods to create complex organic molecules in
a single step.1 In recent years, a number of methods for the
dicarbofunctionalization of olefins under transition-metal
catalysis have been developed.2 The alkylarylation of vinyl-
arenes via radical relay coupling is practically attractive because
it enables the facile and modular synthesis of 1,1-diary-
lalkanes,3 which are found in a variety of pharmaceuticals and
bioactive molecules (Figure 1).4−6 Several attempts to achieve
To test our hypothesis, we initially conducted reactions
using ASP 1a, methyl 4-vinylbenzoate (2a), and 4-
fluorophenylboronic acid (3a) with a Cu/bipyridyl catalyst
system. While the use of 1.0 equiv of 2a provided 4a′, the two-
component C(sp3)−C(sp2) coupling product from 1a and 3a,
as the major product, the use of 3.0 equiv of 2a afforded the
desired product 4a in 61% yield with the formation of 4a′
sufficiently suppressed. We also confirmed that the unreacted
vinylarene 2a could be recovered (see the Supporting
Information (SI) for details). Next, we examined some chiral
ligands to realize an asymmetric catalytic system as shown in
Figure 2b. Neither chiral ligand L18 nor L29 promoted a highly
enantioselective reaction, and other bidentate or tridentate
ligands furnished 4a with less than 48% ee (see Table S2 for
details). While low enantioselectivities were observed in the
case of the indanyl-substituted bis(oxazoline) (BOX) ligands9
L3 (20% ee) and L4 (32% ee), the structure of the cyclic
backbone was found to affect the enantioselectivity. We then
tested chiral BOX ligand L5,3b which contains a cycloheptyl
moiety on the backbone, and discovered that it provided 4a
with moderate ee (56% ee). These results indicate that the
introduction of a simple cyclic alkane structure onto the
backbone of a chiral BOX ligand was still insufficient to achieve
Figure 1. Pharmaceuticals and bioactive molecules with chiral 1,1-
diarylalkane structures.
the asymmetric alkylarylation of vinylarenes using transition-
metal catalysts and chiral ligands have already been reported.
However, the number of successful examples with high
enantioselectivity remains low, and these are limited to specific
structures such as 2-trifluoromethylated 1,1-diarylethanes.3b
To address this issue, we postulated that one of the most
crucial reasons for the limited number of examples reported to
date might be the lack of an effective chiral ligand scaffold for
the construction of a variety of 1,1-diarylalkane structures with
high enantioselectivity. Herein we report the design of novel
chiral ligands that enable a highly regio- and enantioselective
Cu-catalyzed synthesis of chiral 1,1-diarylalkanes.
Received: August 26, 2020
We recently reported Cu-catalyzed C(sp3)−C(sp2) bond
formations using alkylsilyl peroxides (ASPs),7 which are bench-
stable and easy-to-handle alkyl radical precursors, and
arylboronic acids via a radical process.7g On the basis of that
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A

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Figure 2. Working hypothesis and initial studies.
Figure 3. (a) Novel design of chiral binaphthyl−BOX hybrid ligands.
(b) Single-crystal X-ray diffraction analysis of CuBr2·L6 and CuBr2·
L7.
high enantioselectivity. Therefore, we envisioned that the
introduction of another steric factor onto the cyclic backbone
could change the asymmetric environment surrounding the
reactive site, which would in turn provide the desired 1,1-
diarylalkane structure in a more enantiomerically enriched
form. In this context, we chose chiral 2,2′-dimethyl-1,1′-
binaphthalene derivatives,10 which are readily prepared from a
variety of chiral BINOL derivatives, to form the new backbone
and developed a series of novel chiral binaphthyl−BOX (BN−
BOX) hybrid ligands (Figure 3a).11 A notable feature of our
ligand design is that the steric environment of the chiral
backbone can be modified flexibly by the introduction of
substituents at the 3- and 3′-positions of the binaphthyl moiety
or partial reduction of the binaphthyl skeleton. To the best of
our knowledge, such chiral BN−BOX hybrid ligands have not
yet been studied in asymmetric cross-coupling reactions.11
To confirm what steric effects, if any, arise from the
modulation of the substituents at the 3,3′-positions of the
binaphthyl moiety, we synthesized the two novel chiral BN−
BOX hybrid ligands L6 and L7, and prepared their respective
complexes with CuBr2 (Figure 3b). Single-crystal X-ray
diffraction analysis of CuBr2·L6 and CuBr2·L7 revealed that
their steric environments differ significantly from each other
and that of a previously reported crystal structure of a CuBr2·
chiral indanyl-substituted BOX ligand complex.9b
a b c
, ,
Table 1. Optimization of the Reaction Conditions
a
b
Reactions were performed on a 0.2 mmol scale based on 3a. Yields
1
To check their potential for asymmetric catalysis, we
subsequently applied L6 and L7 to a Cu-catalyzed three-
component radical relay coupling reaction of 1a, 2a, and 3a
(Table 1). We were pleased to see that the use of L6 and L7
afforded 4a with better enantioselectivities (66% ee and 76%
ee, respectively) than when L5 was used (56% ee). We then
extended the series of chiral BN−BOX hybrid ligands and
tested them to identify the most suitable ligand structure. The
were determined by H NMR spectroscopy using 1,1,2,2-tetrachloro-
c
ethane as an internal standard. Enantiomeric excesses were
d
determined by chiral HPLC. Deviations: Cu(OTf)·1/2benzene
(0.01 mmol) was used instead of Cu(MeCN)4BF4, and the reaction
was performed in 1,4-dioxane (2.0 mL) for 3 h without K2CO3.
Isolated yield. 4a′: 6% NMR yield. N.D.: not determined.
B
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Communication
Table 2. Substrate Scope
use of L8 bearing an (R)-1,1′-binaphthyl moiety and L9
bearing an (S)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl
moiety produced 4a with lower enantioselectivities (16% ee
and 52% ee, respectively) than when L7 was used. The
reaction using L10, which contains longer alkoxy groups at the
3- and 3′-positions of the binaphthyl moiety compared with
L7, was found to be less enantioselective (53% ee). On the
basis of these results, we chose L7 as the optimal ligand
structure for the present reaction. We also investigated the
reactions using L11 and L12, both of which do not contain a
binaphthyl backbone. As expected, these ligands showed
significantly lower enantioselectivities than L7, confirming
the importance of the binaphthyl backbone for the creation of
an efficient asymmetric environment. Using L7 as chiral ligand,
we optimized the other reaction conditions and found the use
of Cu(OTf)·1/2benzene as the Cu source and 1,4-dioxane as
the solvent in the absence of any additive to constitute the
optimal conditions (83% yield, 88% ee; see the SI for
details).12
using 1a and 2a. The use of phenylboronic acid (3b) and para-
substituted arylboronic acids bearing an electron-donating
methoxy group (3c) or an electron-withdrawing bromo group
(3d) afforded the corresponding products 4b−d in high yields
(74−89%) with high enantioselectivities (83−89% ee). It was
also possible to use m-tolylboronic acid (3e) in this reaction,
which afforded 4e in 70% yield with 82% ee. Then we
attempted to expand the scope of the vinylarenes by using
substrates substituted with esters or amide at the para position
(2b−d). The introduction of a tert-butyl ester did not affect
the enantioselectivity (4f, 88% ee), whereas the presence of a
phenyl ester moiety improved the selectivity (4g, 93% ee). The
reaction with a vinylarene having N,N-dimethylaminocarbonyl
substitution at the para position also proceeded smoothly,
albeit with a slightly lower enantioselectivity (4h, 70% ee). The
use of other para-substituted vinylarenes 2e−h with 3c gave
the desired products 4i−l with good to high enantioselectiv-
ities (73−81% ee). We next applied meta-substituted vinyl-
arenes 2i−l to the reaction using 1a and 3c as coupling
partners. In the case of 3-vinylacetophenone (2i), the reaction
using BOX ligand L13 without a binaphthyl backbone under
the standard conditions provided the corresponding product
4m with low enantioselectivity (42% ee). On the other hand,
replacement of the chiral ligand with L7 led to a significant
increase in the enantioselectivity (68% ee). Although there is
With the optimized reaction conditions in hand, we
investigated the substrate scope of the reaction using a variety
of ASPs 1, vinylarenes 2, and arylboronic acids 3 (Table 2; a
detailed list of the combinations of 1−3 and corresponding
products 4 is shown in Table S8).13 Initially, we examined the
effect exerted by the substituents on the arylboronic acids
C
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still room for improvement, these results further support the
effectiveness of our designed BN−BOX hybrid ligand L7. An
electron-withdrawing chloro group and a weak electron-
donating methyl group were tolerated in the reaction, as was
a strong electron-donating methoxy group at the meta position
of the vinylarene (4n−p, 77−81% ee). Nonsubstituted styrene
(2m) was also applicable under the reaction conditions (4q,
70% yield, 72% ee). Subsequently, we investigated the scope of
ASPs and discovered that both cyclic and acyclic ASPs could
be used. Cyclic ASPs (1b and 1c) provided the corresponding
products 4r and 4s with high enantioselectivities (88% ee and
92% ee, respectively). Moreover, the use of acyclic ASPs (1d−
f) resulted in the formation of various primary and secondary
alkyl radicals without a carbonyl moiety, affording 1,1-
diarylalkanes 4t−v with good to high enantioselectivities
(75−88% ee). Notably, our method was also applicable to the
enantioselective synthesis of 4w (52% yield, 55% ee), which
has anti-breast-cancer activity against MCF-7 breast cancer
cells. The use of ASP 1g containing a cyclopropylmethyl
moiety furnished ring-opened product 4x in 62% yield with
81% ee, indicating that this three-component coupling
proceeded via a radical process.
Figure 4. Transformations of 4a and 4d: (a) (i) NaBH4, MeOH, 0
°C; (ii) BF3·OEt2, HSiEt3, CH2Cl2, 0 °C to r.t.; 62% yield (in total,
one pot). (b) TsOH·H2O, IBX, DMSO, 85 °C; 54% brsm. (c)
Pd2(dba)3, Xantphos, pyrrolidone, Cs2CO3, 1,4-dioxane, 100 °C; 91%
yield.
During the investigation into the scope of vinylarenes, we
observed that the use of electron-rich vinylarene 2o under the
standard conditions provided benzylic alcohol 5 along with
4a′, whereas the desired 1,1-diarylalkane was not obtained
(Scheme 1a). Considering that electron-rich benzylic radicals
furnishing 4t in 62% yield with 88% ee. In addition,
desaturation of 4a by 2-iodoxybenzoic acid (IBX) provided
the corresponding α,β-unsaturated ketone 8 without decreas-
ing the enantiomeric excess. Furthermore, we also conducted
Pd/Xantphos-catalyzed amidation of the C(Ar)−Br bond
using 4d as a substrate.15 As expected, the desired product 9
was obtained in 91% yield with 83% ee.
Scheme 1. Reactions Using Vinylarene 2o or 2q
To show the applicability of chiral BN−BOX hybrid ligands
to the Cu-catalyzed enantioselective synthesis of 1,1-diary-
lalkane structures, we conducted the enantioselective δ-C−H
arylation of N-fluorotosylamide, in which benzyl radicals are
generated via an intramolecular hydrogen atom transfer
(HAT) process.16 The desired enantioselective δ-C−H
arylation of 10 proceeded smoothly to afford 11 in 87%
yield with 90% ee when L7 was used under slightly modified
reaction conditions (Scheme 2). When L5 was used instead,
Scheme 2. Application of BN−BOX Hybrid Ligands to
Another Enantioselective Cu Catalysis
are readily oxidized to benzylic cations,6 we suppose that
single-electron oxidation of benzylic radical 6 by CuII and
subsequent nucleophilic addition of the silanoxide derived
from the ASP to the benzylic cation intermediate 7 gave
benzylic alcohol 5 faster than the formation of the three-
component radical coupling product. In addition, the
formation of a considerable amount of 4a′ would be attributed
to the relatively slow addition of the nucleophilic alkyl radical
to electron-rich vinylarene 2o (see the SI for details). As an
alternative method, we applied 4-vinylphenyl trifluorometha-
nesulfonate (2q) as a p-oxygen-substituted vinylarene instead
of 2o.14 The desired reaction using 2q proceeded to give the
product 4y, albeit in moderate yield and enantioselectivity
(Scheme 1b).
11 was obtained in 75% yield with 63% ee. These results
demonstrate the versatility of BN−BOX hybrid ligands for the
enantioselective cross-coupling reaction of benzyl radicals with
arylboronic acids to construct chiral 1,1-diarylalkane structures.
In summary, we have developed a highly enantioselective
three-component radical relay coupling of alkylsilyl peroxides,
vinylarenes, and arylboronic acids. In this study, we designed a
novel set of binaphthyl−bis(oxazoline) (BN−BOX) hybrid
ligands and demonstrated their applications in a versatile
fashion to Cu-catalyzed couplings for the asymmetric
construction of 1,1-diarylalkane structures. We are convinced
that these BN−BOX hybrid ligands will find applications in a
broad range of asymmetric transition-metal-catalyzed reactions.
The synthetic utility of the obtained 1,1-diarylalkane
products was successfully demonstrated for the transforma-
tions of 4a and 4d as shown in Figure 4. The benzoyl moiety of
4a was reduced to a simple alkane in a one-pot deoxygenation,
D
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Org. Chem. 2017, 2017, 5821−5851. (h) Li, Z.-L.; Fang, G.-C.; Gu,
Q.-S.; Liu, X.-Y. Recent advances in copper-catalysed radical involved
asymmetric 1,2-difunctionalization of alkenes. Chem. Soc. Rev. 2020,
49, 32−48. (i) Siu, J. C.; Fu, N.; Lin, S. Catalyzing Electrosynthesis: A
Homogeneous Electrocatalytic Approach to Reaction Discovery. Acc.
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Further investigations of applications of the Cu/BN−BOX
hybrid ligand system are currently in progress in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09008.
■
sı
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Experimental procedures and spectral data (PDF)
Crystallographic data of CuBr2·L6 (CIF)
Crystallographic data of CuBr2·L7 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
́
́
Garcia-Domínguez, A.; Quiros, M. T.; Mondal, R.; Cardenas, D. J.;
Nevado, C. Ni-Catalyzed Reductive Dicarbofunctionalization of
Nonactivated Alkenes: Scope and Mechanistic Insights. J. Am.
Chem. Soc. 2019, 141, 13812−13821. (e) Campbell, M. W.;
Compton, J. S.; Kelly, C. B.; Molander, G. A. Three-Component
Olefin Dicarbofunctionalization Enabled by Nickel/Photoredox Dual
Catalysis. J. Am. Chem. Soc. 2019, 141, 20069−20078. (f) Diccianni,
J.; Lin, Q.; Diao, T. Mechanisms of Nickel-Catalyzed Coupling
Reactions and Applications in Alkene Functionalization. Acc. Chem.
Res. 2020, 53, 906−919. (g) Derosa, J.; Apolinar, O.; Kang, T.; Tran,
V. T.; Engle, K. M. Recent developments in nickel-catalyzed
intermolecular dicarbofunctionalization of alkenes. Chem. Sci. 2020,
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Keiji Maruoka − Department of Chemistry, Graduate School of
Science and Graduate School of Pharmaceutical Sciences, Kyoto
University, Kyoto 606-8502, Japan; School of Chemical
Engineering and Light Industry, Guangdong University of
Technology, Guangzhou 510006, China; orcid.org/0000-
0002-0044-6411; Email: maruoka.keiji.4w@kyoto-u.ac.jp
Authors
Shunya Sakurai − Department of Chemistry, Graduate School of
Science, Kyoto University, Kyoto 606-8502, Japan
Akira Matsumoto − Graduate School of Pharmaceutical
Sciences, Kyoto University, Kyoto 606-8501, Japan;
orcid.org/0000-0002-3719-8597
Taichi Kano − Department of Chemistry, Graduate School of
Science, Kyoto University, Kyoto 606-8502, Japan;
orcid.org/0000-0001-5730-3801
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Catalyzed Intermolecular Trifluoromethylarylation of Alkenes:
+
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Angew. Chem., Int. Ed. 2020, 59, 8047−8051.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09008
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge financial support via JSPS
KAKENHI Grants JP26220803, JP17H06450 (Hybrid Catal-
ysis), and JP18J22096. S.S. is thankful for the Grant-in-Aid for
JSPS Fellowships for Young Scientists. The authors also truly
appreciate Mr. Yamato Omatsu and Dr. Yoshiyuki Mizuhata
(Institute for Chemical Research, Kyoto University, Japan) for
X-ray diffraction analysis of CuBr2·L6 and CuBr2·L7.
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