Enantioselective Preparation of Arenes with β-Stereogenic Centers: Confronting the 1,1-Disubstituted Olefin Problem Using CuH/Pd Cooperative Catalysis

Article abstract of DOI:10.1002/anie.202004414

Arenes with β-stereogenic centers are important substructures in pharmaceuticals and natural products. We have developed an asymmetric anti-Markovnikov hydroarylation of 1,1-disubstituted olefins by dual palladium and copper hydride catalysis as a conveni

Full text of DOI:10.1002/anie.202004414

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Accepted Article
Title: The Enantioselective Preparation of Arenes with β-Stereogenic
Centers: Confronting the 1,1-Disubstituted Olefin Problem Using
CuH/Pd Cooperative Catalysis
Authors: Zhaohong Lu and Stephen L. Buchwald
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10.1002/anie.202004414
Angewandte Chemie International Edition
RESEARCH ARTICLE
The Enantioselective Preparation of Arenes with β-Stereogenic
Centers: Confronting the 1,1-Disubstituted Olefin Problem Using
CuH/Pd Cooperative Catalysis
Zhaohong Lu and Stephen L. Buchwald*
[*]
Dr. Zhaohong Lu, Prof. Stephen L. Buchwald.
Department of Chemistry
Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, Massachusetts 02139
E-mail: sbuchwal@mit.edu
hydrometallation of 1,1-disubsituted olefins with subsequent
cross-coupling of the resulting organometallic intermediate.
We wondered whether a single-step, dual-catalytic approach
that combines asymmetric hydrometallation and cross-coupling
into one process might provide expanded access to arenes with
β-stereogenic centers. Such a process would improve on Yun’s
important report in several ways (Figure 1C).6 Besides
operational efficiency, one clear potential advantage is that, by
transmetallating directly from the metal involved in
hydrometallation (Cu) to the catalyst involved in cross-coupling
(Pd), the need to prepare, isolate and purify an organoboron
intermediate can be avoided. Further, since transmetallation
from branched alkyl pinacol boronates is often slow2d,7 or
requires harsh reaction conditions including the use of a strong
base8, avoiding the intermediacy of an aryl boronate ester
might also provide a method with improved functional-group
compatibility.
Abstract: Arenes with β-stereogenic centers are important
substructures in pharmaceuticals and natural products. Their
synthesis traditionally involves two separate and individually
challenging steps: enantioselective synthesis of a chiral main-group
organometallic complex and subsequent cross-coupling with an aryl
electrophile. We describe the development of asymmetric anti-
Markovnikov hydroarylation of 1,1-disubstituted olefins by dual
palladium and copper hydride catalysis as a convenient and
significantly more general alternative. This reaction is an efficient
one-step process that addresses several limitations of the stepwise
approaches. The use of cesium benzoate as a base and a common
phosphine ligand for both the Cu- and Pd-catalyzed processes
were important discoveries that allowed these challenging olefin
substrates to be efficiently transformed to products. A variety of aryl
bromide coupling partners, including numerous heterocycles, were
coupled with 1,1-disubstituted alkenes to generate arenes with β-
stereogenic centers. Finally, the effect of the level of olefin
substitution on reaction yield and enantioselectivity has been
investigated.
Introduction
Arenes with β-stereogenic centers are widely found in
biologically active drugs and natural products (Figure 1A)1. A
straightforward and convergent strategy for their synthesis
involves
the
cross-coupling
of
β-chiral
main-group
organometallics with aryl halides.2 These β-chiral nucleophiles
are typically made in one of two ways. First, an alkyl halide can
be metallated by a strongly reducing metal or by lithium-
halogen exchange, followed by further transmetallation (e.g., to
Sn, B, or Zn, Figure 1B)2c,2d. In such methods, the synthesis of
the chiral alkyl halide precursor is an additional challenge. A
second approach is the asymmetric hydrometallation of 1,1-
disubstituted olefins, which are relatively available starting
materials (Figure 1B)3,4
.
However, the stereoselective
functionalization of 1,1-disubstituted olefins has been a major
challenge5, and only three enantioselective methods for the
hydroboration of 1,1-disubstituted olefins have been reported.4
Most notably, Yun has accomplished the only highly
enantioselective catalytic hydroboration of 1,1-disubstituted
olefins, also demonstrating the further transformation of an
isolated β-chiral boronic ester product by Suzuki-Miyaura
coupling with bromobenzene.4c Thus, there have been no
general methods reported for the anti-Markovnikov asymmetric
1
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10.1002/anie.202004414
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RESEARCH ARTICLE
Figure 1. A) Representative bioactive molecules or natural product-
containing β-stereogenic arene motifs. B) Traditional stepwise strategy to
access β-stereogenic arenes. C) Our one-step transformation process to
access β-stereogenic arenes.
Recently, hydroarylation processes that involve the reaction
of olefins with metal hydride catalysts have attracted attention
from the synthetic chemistry community due to the mild
reaction conditions, high functional group tolerance, and broad
substrate scope.9 In 2014, we reported an enantioselective
anti-Markovnikov hydroamination of 1,1-disubstituted alkenes
catalyzed by CuH, which enabled the preparation of β-chiral
amines.10 In this process, the stereocenter was set through an
asymmetric hydrocupration of the alkene, a process which
generated a chiral alkylcopper intermediate. We considered
whether the same type of intermediate could also participate in
Pd-catalyzed cross-coupling. If successful, the net reaction
would be CuH/Pd-dual catalyzed asymmetric hydroarylation of
1,1-disubstituted alkenes, a transformation which has yet to be
realized in a single-step fashion.
Figure 2. Proposed catalytic cycles
Results and Discussion
We began our investigation by examining of the hydroarylation
of tert-butyldimethyl(3-methyl-2-methylenebutoxy)silane as a
model 1,1-disubstituted alkene. As expected, following
previously reported procedures optimized for terminal alkenes,
the desired coupling product was produced in low yield (Table 1,
entry 1, 13% yield, 95:5 er).6k A significant quantity of anisole
was observed, resulting from the reduction of 4-bromoanisole.
This was consistent with our hypothesis that the rate of
reduction might greatly exceed the rate of hydrocupration or
transmetallation under previous conditions.Replacement of
MePh2SiH with the more reactive silane Me(OMe)2SiH (DMMS)
or the use of several other commonly employed weak bases
(NaOPh, LiOMe, KOAc) failed to improve the outcome (entries
2–4). However, employing CsOAc as the base significantly
improved the yield and gave product with high
enantioselectivity (50% yield, 95:5 er). We hypothesize that this
effect might be due to the improved solubility of the salt, as well
as the low coordinating ability of the cesium cation, which might
accelerate salt metathesis of CsOAc with L*CuBr (X).14,15
Faster regeneration of LCuH might promote the formation of a
higher steady-state quantity of the alkylcopper nucleophile. In
turn, this should allow for more of the productive cross-coupling
reaction to occur rather than competing reduction of the
arylpalladium(II) species. The use of CsOBz, an even more
soluble Cs carboxylate, provided a slight further improvement in
yield (entry 6, 59%). The µ-dimer shown in Table 1 was more
effective than [Pd(cinnamyl)Cl]2 and Pd(OAc)2 as the Pd source
(entries 6–8). Evaluation of a variety of phosphine ligands for
Pd indicated that using DTBM-SEGPHOS (L1) as the ligand for
both the Pd- and Cu-catalyzed transformations, gave the best
yield (entry 11, 81% yield). We found that CuOAc is a better
copper source than the Cu(II) salt Cu(OAc)2 (entry 12). Finally,
the addition of PPh3 was not beneficial for this transformation
(entry 13).10
The proposed dual catalytic cycle is depicted in Figure 2. A
CuH catalyst I is the starting point for the mechanism and could
be generated in situ from an appropriate Cu salt, chiral ligand,
and silane. The enantioselective hydrocupration of 1,1-
disubstituted alkene II would be expected to proceed through
the transition state III with anti-Markovnikov regioselectivity,
forming a Cu(I) alkyl intermediate IV with the desired β-
stereogenic center.4c,10 At the same time, in the Pd catalytic
cycle, the oxidative addition of ligated Pd(0) complex V to an
aryl bromide would form the arylpalladium species VII. The
transmetallation of the Cu(I) alkyl intermediate IV with the
palladium species VII would generate the β-chiral palladium
alkyl complex VIII and L*CuBr (X). Reductive elimination from
VIII would furnish enantioenriched β-chiral arene IX, while
regenerating the Pd(0) species V and closing the Pd-catalyzed
cycle. Meanwhile, in the presence of base and silane the
reactive CuH catalyst I could be regenerated from X by a ligand
substitution/ꢀ-bond metathesis sequence.11 In order for a
successful cross-coupling reaction, the rates of the two catalytic
processes would need to be carefully matched. This is
particularly important in order to prevent undesired pathways
such as the direct reduction of the aryl bromide (VI), as
depicted by the red arrow in Figure 2.12
Compared to our previous work on CuH/Pd dual catalysis,
the challenges of rate-matching and preventing undesired
reduction were expected to be particularly prominent in the
current context. Although we have reported CuH/Pd dual
catalyst process for the enantioselective hydroarylation from
6j,6k
styrenes or terminal terminal alkenes
, the rate of
hydrocupration of 1,1-disubstituted alkenes is much slower in
comparison13. Thus, we expected that, under previously
developed conditions, the reduction of the aryl bromide might
be the major pathway. Further, due to the relatively hindered
and unactivated nature of branched alkylcopper species, it was
unclear whether the transmetallation to Pd would be as efficient
as in our earlier work. Below, we report the discovery of
optimized reaction conditions (different silane, ligand for Pd,
base, Pd source) that overcome these obstacles and
accomplish
the
anti-Markovnikov
enantioselective
hydroarylation of 1,1-disubstituted alkenes (Figure 1C), thus
allowing for the direct synthesis of arenes with β-stereogenic
centers under mild reaction conditions.
2
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10.1002/anie.202004414
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RESEARCH ARTICLE
Table 1. Optimization of the Pd/CuH-catalyzed enantioselective
Table 2. Scope of the aryl bromidesa
hydroarylation
aYields determined by 1H NMR of the crude reaction mixture using
mesitylene as an internal standard; enantioselectivity of the purified product
was determined by HPLC analysis on commercially available chiral stationary
phases (see Supporting Information for details); ND = not determined;
bMePh2SiH used as the silane; cCu(OAc)2 used as the Cu source.d8 mol%
PPh3 was used
aAll yields represent the average of isolated yields from two runs performed
with 1.0 mmol of alkene; enantioselectivity determined by chiral SFC.
Using the optimized olefin hydroarylation conditions, we
examined the scope of this reaction. As shown in Table 2, a
broad range of aryl bromides were effective coupling partners
in this protocol. Deprotection of the coupling products was
performed for ease of purification and determination of the
enantiomeric ratio. An advanced synthetic intermediate for the
synthesis of Aliskiren, which is used for the treatment for high
blood pressure,16 could be prepared using this method in good
yield and high enantioselectivity (3a, 61% yield, 95:5 er).
Compared to
a
previous synthesis of this advanced
intermediate based on Evans’ auxiliary (7 steps, 38% overall
yield, 99% ee), our catalytic approach is a viable alternative.
Chemoselective coupling with bromochlorobenzenes provided
products containing aryl chlorides, which could serve as a
handle for further functionalization (3b, 3c). An electron-
deficient aryl bromide proved to be effective in this
transformation, and an ester was also tolerated (3d, 67% yield,
94:6 er). A variety of heterocycles, including a pyridine (3e), a
quinoline (3f), a thiophene (3g), a carbazole (3h), a pyrimidine
(3i), and an indazole (3j), were suitable heteroaryl bromide
3
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10.1002/anie.202004414
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RESEARCH ARTICLE
coupling partners. For 3-bromoquinoline (2f), the low yield was
due to incomplete conversion of alkene, which was recovered
in 50% yield. Presumably, deactivation of the catalyst(s)
through coordination of the unhindered basic nitrogen present
in the quinoline is responsible.
conditions. Using an acetal-containing substrate (12a), the
hydroarylation product was formed with good enantioselectivity
(12b, 47%, 94:6 er).
Finally, to explore the possibility of catalyst-controlled
diastereoselectivity, we examined the use of opposite
enantiomers of L1 in reactions of each of two enantiopure chiral
alkenes (Table 3). Indeed, the olefin hydroarylation of (R)-
limonene provided the opposite major diastereomers when
using (R)-L1 vs. (S)-L1 giving the hydroarylation product in
12.3:1 dr (13b) and 1:11 dr (13c), respectively. However,
hydroarylation of Rotenone derivative proceeded with good
diastereoselectivity in the presence of (R)-L1 (14b, 12.3:1) but
poor diastereoselectivity in the presence of (S)-L1 (14c, 1:1.7).
Thus, while facial selection in the hydrocupration is primarily
dictated by the catalyst, substrate bias can still have a
significant effect in some cases.
To study the effects of olefin substitution on stereoselectivity
and yield,
a series of alkenes were coupled with 4-
bromoanisole following the optimized procedure. A free alcohol
(4a) was tolerated, but a significantly lower yield was obtained.
An increase in the difference in steric hindrance (5a, 1a, 6a, 7a
sequentially) between the two olefin substituents correlated
with an increase in enantioselectivity and with a slight decrease
in yield. For example, alkene 5a afforded hydroarylation
product in 70:30 er, while substrate 7a provided the coupling
product with >99:1 er. A trityl-protected 2-methylprop-2-en-1-ol
was arylated with moderate enantioselectivity (9b). Substrate
10a,
a
vinylsilane, produced
a
highly enantioenriched
hydroarylation product (10b) containing a silicon-substituted
stereogenic center. Another sterically encumbered vinylsilane
(11a) bearing a nitrile group can also be compatible with these
Table 3. Scope of 1,1-disubstituted alkenesa
aAll yields represent the average of isolated yields from two runs performed with 1.0 mmol of alkene; enantioselectivity determined by chiral SFC or chiral GC.
bworkup with TBAF (1.5 equiv) to deprotect (see supporting information Procedure B) c(S)-L1 was used instead of (R)-L1 for copper and palladium.
4
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10.1002/anie.202004414
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RESEARCH ARTICLE
Chem. Int. Ed. 2011, 50, 7079–7082; Angew. Chem. 2011, 123, 7217 –
7220.
Conclusion
[6]
(a) J. Huang, J. Chan, Y. Chen, C. J. Borths, K. D. Baucom, R. D.
Larsen, M. M. Faul, J. Am. Chem. Soc. 2010, 132, 3674–3675. (b) F.
Nahra, Y. Macé, D. Lambin, O. Riant, Angew. Chem. Int. Ed. 2013, 52,
3208–3212; Angew. Chem. 2013, 125, 3290–3294. (c) S. Vercruysse,
L. Cornelissen, F. Nahra, L. Collard, O. Riant, Chem. Eur. J. 2014, 20,
1834–1838. (d) F. Nahra, Y. Macé, A. Boreux, F. Billard, O. Riant,
Chem. Eur. J. 2014, 20, 10970–10981. (e) K. Semba, Y. Nakao, J. Am.
Chem. Soc. 2014, 136, 7567–7570. (f) K. B. Smith, K. M. Logan, W.
You, M. K. Brown, Chem. Eur. J. 2014, 20, 12032–12036. (g) K. M.
Logan, K. B. Smith, M. K. Brown, Angew. Chem. Int. Ed. 2015, 54,
5228–5231; Angew. Chem. 2015, 127, 5317–5320. (h) T. Jia, P. Cao,
B. Wang, Y. Lou, X. Yin, M. Wang, J. Liao, J. Am. Chem. Soc. 2015,
137, 13760–13763. (i) K. Semba, K. Ariyama, H. Zheng, R. Kameyama,
S. Sakaki, Y. Nakao, Angew. Chem. Int. Ed. 2016, 55, 6275–6279;
Angew. Chem. 2016, 128, 6383–6387. (j) S. D. Friis, M. T. Pirnot, S. L.
Buchwald, J. Am. Chem. Soc. 2016, 138, 8372–8375. (k) S. D. Friis, M.
T. Pirnot, L. N. Dupuis, S. L. Buchwald, Angew. Chem. Int. Ed. 2017,
56, 7242–7246; Angew. Chem. 2017, 129, 7348–7352..
In summary, we described the CuH/Pd-catalyzed asymmetric
hydroarylation of 1,1-disubstituted alkenes with anti-Markovnikov
regioselectivity under mild conditions. Notably, this method is
single-step process and uses the same ligand, DTBM-
SEGPHOS, as the ligand for both the Pd- and Cu-catalyzed
processes. This protocol provides a convenient and efficient way
to access β-chiral arenes, which are found in many drugs and
natural products. A wide range of aryl bromides, including
several heterocycle-containing substrates, can be used with
good efficiency and enantioselectivity. Various 1,1-disubstituted
alkenes have also been examined. Efforts toward expanding the
scope of Cu/Pd dual catalysis toward other classes of alkenes
are currently underway in our laboratory.
Acknowledgements
[7]
(a) S. N. Mlynarski, C. H. Schuster, J. P. Morken, Nature 2014, 505,
386–390. (b) M. Sato, N. Miyaura, A. Suzuki, Chem. Lett. 1989, 18,
1405–1408.
Research reported in this publication was supported by the
National Institutes of Health (R35GM122483). We also thank the
NIH for a supplemental grant for the purchase of supercritical
fluid chromatography equipment (GM058160-17S1). We thank
Drs: Alexander Schuppe, Richard Y. Liu, Scott McCann (MIT),
and Christine Nguyen for advice on the preparation of this
manuscript. We thank Dr. Richard Y. Liu for his helpful
discussions on this project. The content is solely the
responsibility of the authors and does not necessarily represent
the official views of the National Institutes of Health.
[8]
[9]
(a) C.-T. Yang, Z.-Q. Zhang, H. Tajuddin, C.-C. Wu, J. Liang, J.-H. Liu,
Y. Fu, M. Czyzewska, P. G. Steel, T. B. Marder, et al., Angew. Chem.
Int. Ed. 2012, 51, 528–532; Angew. Chem. 2012, 124, 543 –547. (b) K.
Yang, Q. Song, Green Chem. 2016, 18, 932–936.
(a) S. W. M. Crossley, C. Obradors, R. M. Martinez, R. A. Shenvi,
Chem. Rev. 2016, 116, 8912–9000. (b) X. Ma, S. B. Herzon, J. Am.
Chem. Soc. 2016, 138, 8718–8721. (c) X. Ma, H. Dang, J. A. Rose, P.
Rablen, S. B. Herzon, J. Am. Chem. Soc. 2017, 139, 5998–6007. (d) S.
L. Shevick, C. Obradors, R. A. Shenvi, J. Am. Chem. Soc. 2018, 140,
12056–12068.(e) S. A. Green, S. Vásquez-Céspedes, R. A. Shenvi, J.
Am. Chem. Soc. 2018, 140, 11317–11324. (f) S. D. Friis, M. T. Pirnot,
S. L. Buchwald, J. Am. Chem. Soc. 2016, 138, 8372–8375. (g) S. D.
Friis, M. T. Pirnot, L. N. Dupuis, S. L. Buchwald, Angew. Chem. Int. Ed.
2017, 56, 7242–7246; Angew. Chem. 2017, 129, 7348 –7352. (h) Y. He,
Y. Cai, S. Zhu, J. Am. Chem. Soc. 2017, 139, 1061–1064. (i) F. Chen,
K. Chen, Y. Zhang, Y. He, Y.-M. Wang, S. Zhu, J. Am. Chem. Soc.
2017, 139, 13929–13935. (j) J. Nguyen, A. Chong, G. Lalic, Chem. Sci.
2019, 10, 3231–3236. (k) L.-J. Xiao, L. Cheng, W.-M. Feng, M.-L. Li, J.-
H. Xie, Q.-L. Zhou, Angew. Chem. Int. Ed. 2018, 57, 461–464; Angew.
Chem. 2018, 130, 470 –473.
Conflict of interest
The authors declare no conflict of interest.
Keywords: enantioselective • hydroarylation • Cu/Pd dual
catalysis • single ligand
[1]
(a) D. Lednicer, The Organic Chemistry of Drug Synthesis:
Lednicer/Organic Chem Synthesis V7, John Wiley Sons, Inc.,
[10] S. Zhu, S. L. Buchwald, J. Am. Chem. Soc. 2014, 136, 15913–15916.
[11] Y.-M. Wang, N. C. Bruno, Á. L. Placeres, S. Zhu, S. L. Buchwald, J. Am.
Chem. Soc. 2015, 137, 10524–10527.
&
Hoboken, NJ, USA, 2007. (b) J. Chang, J. Reiner, J. Xie, Chem. Rev.
2005, 105, 4581–4609. (c) R. Wang, D. Liu, X. Li, J. Zhang, D. Cui, X.
Wan, Macromolecules 2016, 49, 2502–2510.
[12] H. Kotsuki, P. K. Datta, H. Hayakawa, H. Suenaga, Synthesis 1995,
1348–1350.
[2]
(a) N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Sato, A. Suzuki,
J. Am. Chem. Soc. 1989, 111, 314–321. (b) Norio. Miyaura, Akira.
Suzuki, Chem. Rev. 1995, 95, 2457–2483. (c) S. R. Chemler, D.
Trauner, S. J. Danishefsky, Angew. Chem. Int. Ed. 2001, 40, 4544–
4568. (d) R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev. 2011, 111,
1417–1492.
[13] G. Lu, R. Y. Liu, Y. Yang, C. Fang, D. S. Lambrecht, S. L. Buchwald, P.
Liu, J. Am. Chem. Soc. 2017, 139, 16548–16555.
[14] G. Dijkstra, W. H. Kruizinga, R. M. Kellogg, J. Org. Chem. 1987, 52,
4230–4234.
[15]
R. N. Salvatore, A. S. Nagle, K. W. Jung, J. Org. Chem. 2002, 67,
674–683.
[3]
[4]
(a) F.-M. Zhang, L. Peng, H. Li, A.-J. Ma, J.-B. Peng, J.-J. Guo, D.
Yang, S.-H. Hou, Y.-Q. Tu, W. Kitching, Angew. Chem. Int. Ed. 2012,
51, 10846–10850; Angew. Chem. 2012, 124, 11004 –11008. (b) M. M.
Midland, Y. C. Kwon, J. Org. Chem. 1981, 46, 229–230.
[16] E. Cini, L. Banfi, G. Barreca, L. Carcone, L. Malpezzi, F. Manetti, G.
Marras, M. Rasparini, R. Riva, S. Roseblade, et al. Org. Process Res.
Dev. 2016, 20, 270–283.
(a) S. Masamune, B. M. Kim, J. S. Petersen, T. Sato, S. J. Veenstra, T.
Imai, J. Am. Chem. Soc. 1985, 107, 4549–4551. (b) A. Z. Gonzalez, J.
G. Román, E. Gonzalez, J. Martinez, J. R. Medina, K. Matos, J. A.
Soderquist, J. Am. Chem. Soc. 2008, 130, 9218–9219. (c) W. J. Jang,
S. M. Song, J. H. Moon, J. Y. Lee, J. Yun, J. Am. Chem. Soc. 2017,
139, 13660–13663.
[5]
(a) S. McIntyre, E. Hörmann, F. Menges, S. P. Smidt, A. Pfaltz,
Advanced Synthesis
& Catalysis 2005, 347, 282–288. (b) S. J.
Roseblade, A. Pfaltz, Acc. Chem. Res. 2007, 40, 1402–1411. (c) Q.-H.
Xia, H.-Q. Ge, C.-P. Ye, Z.-M. Liu, K.-X. Su, Chem. Rev. 2005, 105,
1603–1662. (d) R. CorberáTn,hNi.sWa. Mrtsizcalre, Ai.sH.pHrooveteydca,teAndgebw.y copyright. All rights reserved.

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RESEARCH ARTICLE
Entry for the Table of Contents
We described the CuH/Pd-catalyzed enantioselective hydroarylation of 1,1-disubstituted alkenes with anti-Markovnikov
regioselectivity under mild conditions. Notably, the single ligand, DTBM-SEGPHOS, was used for both the Pd- and Cu-catalyzed
processes. β-Stereogenic arenes were accessed by this convenient and efficient single-step protocol. A wide range of aryl bromides,
including several heterocycle-containing substrates, can be used with good efficiency and enantioselectivity. Various 1,1-
disubstituted alkenes have also been examined.
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