Asymmetric Hydroarylation of Vinylarenes Using a Synergistic Combination of CuH and Pd Catalysis

Article abstract of DOI:10.1021/jacs.6b04566

Detailed in this Communication is the enantioselective synthesis of 1,1-diarylalkanes, a structure found in a range of pharmaceutical drug agents and natural products, through the employment of copper(I) hydride and palladium catalysis. Judicious choice of ligand for both Cu and Pd enabled this hydroarylation protocol to work for an extensive array of aryl bromides and styrenes, including β-substituted vinylarenes and six-membered heterocycles, under relatively mild conditions.

Full text of DOI:10.1021/jacs.6b04566

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Communication
Asymmetric Hydroarylation of Vinylarenes Using a
Synergistic Combination of CuH and Pd Catalysis
Stig D. Friis, Michael T. Pirnot, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04566 • Publication Date (Web): 27 Jun 2016
Downloaded from http://pubs.acs.org on June 27, 2016
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Asymmetric Hydroarylation of Vinylarenes Using a Synergis-
tic Combination of CuH and Pd Catalysis
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Stig D. Friis, Michael T. Pirnot and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Supporting Information Placeholder
with high stereospecificity, ultimately leading to an enan-
tioenriched coupling product. Using this approach, we
anticipated that a suitable combination of Cu and Pd
catalysts would allow for the enantioselective coupling of
styrenes with aryl bromides to form 1,1-diarylalkanes, a
biologically active structure
ABSTRACT: Detailed in this report is the enantioselec-
tive synthesis of 1,1-diarylalkanes, a structure found in a
range of pharmaceutical drug agents and natural prod-
ucts, through the employment of copper(I) hydride
(CuH) and palladium (Pd) catalysis. Judicious choice of
ligand for both copper and palladium enabled this hy-
droarylation protocol to work for an extensive array of
aryl bromides and styrenes, including β-substituted vi-
nylarenes and six-membered heterocycles, under rela-
tively mild conditions.
Scheme 1. A) Enantioselective access to 1,1-
diarylalkanes via Pd and Cu catalysis; B) Pro-
posed catalytic cycle for enantioselective hy-
droarylation of styrenes.
A)
Me
LPd
L*CuH
L*Cu
Palladium-catalyzed cross coupling has proven to be a
successful and reliable method for carbon−carbon bond
construction. Among the many substrate classes em-
ployed in this field, stoichiometric organometallic rea-
gents (e.g., Mg, Zn, Sn reagents) are traditionally used as
coupling partners in palladium chemistry due to their
propensity for facile transmetalation, and much success-
ful work has been realized with the use of these reagents
to generate functionalized arenes.1 Drawbacks associated
with the use of stoichiometric organometallic reagents,
including their possible sensitivity toward air/water,
promiscuity towards undesired pathways of reactivity,
and necessity to preform them before their use in cross
coupling, has inspired methods avoiding their interme-
diacy.2
X
Ar
Me
Y
styrene
enantioenriched
1,1-diaryl alkane
Y
B)
VI
L*Cu
III
Me
LPd Br
Ar
ArBr (V)
Ph
Ph
II
copper
palladium
catalytic
cycle
catalytic
cycle
L*CuH (I)
LPd (IV)
R3SiOR,
MBr
L
Me
Ph
VIII
Me
L*CuBr (IX)
Pd
Ar
R3SiH,
MOR
Ar
Ph
VII
1,1-diaryl alkane
Recent advances in copper chemistry have demonstrat-
ed that nucleophilic alkylcopper(I) species can be gener-
ated catalytically via olefin insertion and successfully
intercepted with a range of electrophiles.3,4 As an alter-
native to stoichiometric organometallic reagents, we
questioned whether an copper(I) alkyl intermediate of
this nature could be generated catalytically and exploited
in a palladium-catalyzed cross-coupling process to yield
the corresponding sp2−sp3 cross-coupled product
(Scheme 1). Importantly, we sought a chiral CuH cata-
lyst that would effect an enantioselective olefin hydrocu-
pration to form a stereodefined copper(I) intermediate,
which would undergo transmetalation with palladium
common in both pharmaceuticals and natural products.5
Enantioenriched 1,1-diarylalkanes have previously been
prepared through the stereospecific cross coupling of
enantioenriched benzylic electrophiles.6,7 A nickel-
catalyzed stereoconvergent coupling of racemic benzylic
8
alcohols with arylzinc reagents has also been reported.
Methods that employ prochiral substrates include
asymmetric hydrogenation of 1,1-diarylalkenes9 and
conjugate addition of arylmetal nucleophiles to cin-
namaldehyde derivatives.10 Our approach represents a
highly modular alternative for the enantioselective syn-
thesis of this class of compounds. Moreover, aryl bro-
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mides and vinylarenes are widely available reagents or
feedstock chemicals and are therefore nearly ideal cou-
pling partners.11
tioselectivity of the purified product was determined by
chiral HPLC; ND = not determined; Cu(OAc)2 used as
the Cu source; c CuOAc used as the Cu source.
1
2
3
b
Pioneering efforts by several researchers have demon-
strated the synergistic potential of Cu and Pd catalysis.12
More recently, Nakao13 and Brown14 have both reported
the diastereoselective borylarylation of styrene deriva-
tives using both Cu and Pd in catalytic quantities, while
Liao15 demonstrated the enantioselective boroallylation
of vinylarenes using a similar system. At the outset of this
project, the use of CuH and Pd catalysis in a cooperative
manner for hydrofunctionalization was unknown. How-
ever, a report detailing the Pd/Cu-catalyzed hydroaryla-
tion of styrenes to furnish racemic 1,1-diaryl alkanes was
recently published.16
IV would oxidatively add to the aryl bromide V to form
complex VI. As the key step in this process, the dual cat-
alytic cycle converges via a stereospecific transmetalation
of organocopper III with palladium species VI to form
chiral palladium(II) alkyl complex VII.19 Stereoretentive
reductive elimination furnishes enantioenriched 1,1-
diarylalkane VIII and regenerates palladium(0) species
IV. Considering previous reports with CuH catalysis, we
reasoned that salt metathesis of Cu(I) halide IX with
base would be required to regenerate CuH catalyst I.20
We believed that the success of our strategy was predi-
cated on three issues: i) competitive reduction of aryl
halide V via a metal hydride species would need to be
suppressed; ii) choice in ligand would enable productive
reactivity of each metal species while not deactivating
the other; iii) the rate of each metal cycle would need to
be matched so as to avoid unproductive side reactions.
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Scheme 1.B details our proposed dual catalytic cycle for
enabling the described transformation. Formation of
active CuH catalyst I would occur through the use of a
Cu(I) or Cu(II) salt, chiral ligand, and silane. Enantiose-
lective hydrocupration of olefin II would form stereode-
fined Cu(I) benzylic intermediate III.17,18 In the second
catalytic cycle, ligated palladium(0)
The optimization of an enantioselective hydroarylation
process for styrene and 4-bromoanisole is detailed in
Table 1. Examination of several silanes (entries 1−5)
indicated that methyldiphenylsilane (MePh2SiH) was the
optimal silane tested when combined with sodium trime-
thylsilanolate (NaOTMS), providing a moderate yield
and high level of enantioselectivity for the desired prod-
uct (entry 4, 58% yield, 83% ee). NaOTMS was a
uniquely effective base for this chemistry and little to no
product was observed with LiOTMS and KOTMS.21
Testing several biarylphosphine ligands (entries 4, 6, and
7) showed that a modest increase in yield was observed
when using BrettPhos as a secondary ligand (entry 6,
66% yield, 85% ee). Employing [Pd(cinnamyl)Cl]2 as the
source of palladium for this reaction resulted in im-
proved reactivity while not significantly affecting the
enantioselectivity of the process (entry 10, 75% yield,
88% ee). A range of Cu(I) and Cu(II) salts were exam-
ined, and a slight improvement was observed using
CuOAc as the source of copper (entry 11, 84% yield,
90% ee). Evaluation of a variety of chiral bisphosphines
demonstrated that DTBM-SEGPHOS was an excellent
ligand for this transformation with many other ligands
giving significantly lower yield and enantioselectivity of
the desired product.22
Table 1. Optimization of the Pd/Cu-catalyzed enanti-
oselective hydroarylation of styrene.a
Br
Pd source (4 mol% Pd)
L (4.4 mol%), Cu source (6 mol%)
MeO
Me
(R)-DTBM-SEGPHOS (6.6 mol%)
1.5 equiv
+
NaOTMS (2 equiv), silane (2 equiv)
THF [1M], 40 °C, 20 h
MeO
1.0 equiv
entry
ee
silane
Pd source
L
% yield
1b
2b
14
2
88
Et3SiH
Pd(OAc)2
Pd(OAc)2
L2
L2
L2
L2
L2
L3
L4
L3
L3
L3
L3
i-Pr3SiH
ND
3b
19
58
0
85
Me2PhSiH
MePh2SiH
Ph2SiH2
Pd(OAc)2
4b
83
--
Pd(OAc)2
5b
Pd(OAc)2
6b
66
61
45
63
75
84
85
85
ND
86
88
90
MePh2SiH
MePh2SiH
MePh2SiH
MePh2SiH
MePh2SiH
MePh2SiH
Pd(OAc)2
7b
Pd(OAc)2
8b
Pd2(dba)3
9b
Pd(COD)Cl2
[Pd(cinnamyl)Cl]2
[Pd(cinnamyl)Cl]2
10b
11c
With the optimized conditions in hand, we turned to-
ward examining the substrate scope of the aryl bromide
coupling partner (Table 2 and Table 3).23 Electron-rich
aryl bromides (2a and 2n) worked well in this reaction,
while 4-bromobenzonitrile and aryl bromides with acidic
protons were not compatible with the reactions condi-
tions. A range of functional groups, including ethers
(such as 2a, 2i, 2h, 2k, and 2n), an ester (2c), a thi-
oether (2d), an amine (2h), a carbamate (2l), an aryl
chloride (2l), and an amide (2l), were all tolerated in this
protocol. Employing ortho-substituted aryl bromides as
viable substrates required a slightly higher reaction tem-
OMe
O
PCy2
i-Pr
MeO
i-Pr
PR2
O
O
PAr2
PAr2
i-Pr
i-Pr
O
i-Pr
i-Pr
Ar = 3,5-(t-Bu)2-4-MeOC6H2
(R)-DTBM-SEGPHOS (L1)
XPhos (L2)
R = Cy, BrettPhos (L3)
R = t-Bu, t-BuBrettPhos (L4)
aYields determined by GC analysis of the crude reaction
mixture using tetradecane as an internal standard; enan-
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perature and longer reaction times to provide the prod- lower level of yield and stereoselectivity (23% yield, 61%
1
uct (3n) in good yield and high enantiopurity. Im-
portantly, a variety of brominated heterocycles, such as
pyridines (e.g., 2b and 2m), quinolines (2f and 2t), a
pyrimidine (2h), a pyridazine (2i), and an azaindole (2j),
were competent coupling partners. In addition, a five-
membered brominated heterocycle was effective (2o).
Certain aryl bromides, such as 4-bromoisoquinoline (2e)
and 5-bromo-1-methylindole (2g), resulted in moderate
yields but poor to modest enantioselectivities (76% yield,
27% ee and 68% yield, 56% ee, respectively).24 Charac-
terization of 3i via X-ray crystallography revealed the
absolute configuration of the stereocenter. This data,
combined with the sense of stereoinduction observed
with our method for CuH-catalyzed hydroamination of
styrenes,3d suggests that the proposed Cu-to-Pd
transmetalation step occurs with retention of configura-
tion (see Supporting Information for details).25,26
ee). This might be indicative of the configurational sta-
bility of the RCu intermediate. Finally, β-substituted
styrenes can be utilized in this transformation, affording
good yields and reasonable levels of enantioselectivity
(1s and 1t). Due to a more challenging hydrocupration
step, a lower palladium catalyst loading (1 mol% Pd) was
required for β-substituted styrenes, presumably to slow
down competitive reduction of the aryl bromide and
match the rate of the two productive catalytic cycles. In
addition, a slightly elevated reaction temperature and
use of dimethylphenylsilane (Me2PhSiH) as the reduct-
ant was required to achieve good results with this class of
olefins.
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Table 3. Scope of the styrene coupling partner with
various heteroaryl and aryl bromides.a
R
Ar
1
CuOAc (6 mol%), [Pd(cinnamyl)Cl]2 (2 mol%)
R
Table 2. Scope of the aryl bromide coupling partner.a
1.0 equiv
+
(R)-DTBM-SEGPHOS (6.6 mol%), BrettPhos (4.4 mol%)
(Het)ArBr (2)
NaOTMS (2 equiv), MePh2SiH (2 equiv), THF [1M]
35 °C, 18 h
CuOAc (6 mol%), [Pd(cinnamyl)Cl]2 (2 mol%)
(Het)Ar
Ar'
(Het)ArBr (2)
1.5 equiv
+
Me
(R)-DTBM-SEGPHOS (6.6 mol%), BrettPhos (4.4 mol%)
3
1.5 equiv
NaOTMS (2 equiv), MePh2SiH (2 equiv), THF [1M]
35 °C, 18 h
(Het)Ar
Ph
Ph
3
1
Me
Me
OMe
Me
Me
1.0 equiv
3m
3nb,c
Me
Me
Me
F3CO
N
EtO2C
Ph
Ph
90%, 89% ee
87%, 95% ee
Ph
N
Me
Me
3a
85%, 89% ee
3c
3o
3pb
3b
MeO
F
O
88%, 97% ee
82%, 90% ee
Me
Me
Me
S
O
CF3
Ot-Bu
S
Ph
66%, 93% ee
23%, 61% ee
Ph
Ph
Me
3eb
3qb
3d
3f
Me
3r
N
N
F
94%, 97% ee
Me
76%, 27% ee
Me
99%, 97% ee
Fe
N
N
Me
N
N
N
N
Ph
Et
N
Ph
Boc
N
Ph
73%, 97% ee
91%, 96% ee
N
N
N
3gb
3h
3i
MeO
3sd
Et
3td
O
Me
OMe
68%, 56% ee
Me
98%, 90% ee
68%, 92% ee
Me
Me
Ph
MeO
Boc
Ph
Cl
N
N
N
Ph
MeO
78%, 87% ee
93%, 86% ee
N
N
3j
3k
3l
O
85%, 98% ee
92%, 86% ee
97%, 95% ee
aAll yields represent the average of isolated yields from
two runs performed with 1 mmol of alkene, enantioselec-
aAll yields represent the average of isolated yields from
two runs performed with 1 mmol of styrene, enantiose-
b
tivity determined by chiral SFC; 2 equiv of Me2PhSiH
used as the silane, and the reaction was run at 45 °C;
cReaction was run for 40 h; d0.5 mol% of
[Pd(cinnamyl)Cl]2 used with 1.1 mol% BrettPhos L3, 2
equiv of Me2PhSiH used as the silane, and the reaction
was run at 45 °C.
b
lectivity determined by chiral SFC; Average of isolated
yields from three runs.
The scope of arylalkene coupling partner was then eval-
uated with a selection of aryl bromides (Table 3). Ortho-
substituted styrenes were well tolerated in this chemistry
(1m and 1n). Electron-rich arylalkenes productively
coupled with good levels of yield and enantioselectivity
(for example entry 1o, 66% yield, 93% ee), while an
electron-deficient styrene (entry 1p) produced a much
In conclusion, we report the enantioselective Pd/Cu-
catalyzed hydroarylation of styrenes to form 1,1-
diarylalkanes, a valuable structure in medicinal chemis-
try. This procedure performs well for a variety of aryl
bromides, including six-membered heterocycles, to form
3
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Yun, J. Angew. Chem. Int. Ed. 2009, 48, 6062. (b) Saxena, A.; Choi, B.;
the respective products in generally good yields and with
high levels of enantioselectivity. A range of vinylarenes,
including ortho- and β-substituted styrenes, were also
productively coupled in this hydroarylation reaction.
Extending this chemistry to other substrates classes is
currently being explored in our laboratory.
Lam, H. W. J. Am. Chem. Soc. 2012, 134, 8428. (c) Miki, Y.; Hirano,
K.; Satoh, T.; Miura, M. Angew. Chem. Int. Ed. 2013, 52, 10830. (d)
Zhu, S.; Niljianskul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135,
15746. (e) Pirnot, M. T.; Wang, Y. M.; Buchwald, S. L. Angew. Chem.
Int. Ed. 2016, 55, 48.
(4) For selected examples of generating alkyl copper(I) intermedi-
ates via borylcupration see: (a) Ito, H.; Kosaka, Y.; Nonoyama, K.;
Sasaki, Y.; Sawamura, M. Angew. Chem. Int. Ed. 2008, 47, 7424. (b)
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137, 6460.
(5) For references on various pharmaceuticals and biologically ac-
tive molecules containing 1,1-diarylalkanes refer to: (a) McRae, A. L.;
Brady, K. T. Expert Opin. Pharmacotherapy 2001, 2, 883. (b) Heydorn,
W. E. Expert Opin. Invest. Drugs 1999, 8, 417. (c) Hills, C. J.; Winter, S.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information
is available free of charge on the ACS Publications website.
Crystallographic data for 3i (CIF)
Experimental procedures and characterization data for all
compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*sbuchwal@mit.edu
Notes
(6) For general reviews on stereoselective transition-metal cross
coupling see: (a) Swift, E. C.; Jarvo, E. R. Tetrahedron 2013, 69, 5799.
(b) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Chem. Rev. 2015,
115, 9587.
The authors declare the following competing financial in-
terest(s): MIT has obtained patents for some of the ligands
that are described in this Communication from which
S.L.B. and former/current co-workers receive royalty pay-
ments.
(7) For representative examples of transition metal-catalyzed stereo-
specific cross coupling to synthesize enantioenriched 1,1-
diarylalkanes, see: (a) Imao, D.; Glasspoole, B. W.; Laberge, V. S.;
Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024. (b) Taylor, B. L.
H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011,
133, 389. (c) Zhou, Q.; Srinivas, H. D.; Dasgupta, S.; Watson, M. P.
J. Am. Chem. Soc. 2013, 135, 3307. (d) Yonova, I. M.; Johnson, A. G.;
Osborne, C. A.; Moore, C. E.; Morrissette, N. S.; Jarvo, E. R. Angew.
Chem. Int. Ed. 2014, 53, 2422. (e) Konev, M. O.; Hanna, L. E.; Jarvo,
E. R. Angew. Chem. Int. Ed. 2016, 55, 6730.
ACKNOWLEDGMENT
Research reported in this publication was supported by
the National Institutes of Health under award number
GM46059. We thank the National Institutes of Health
for a supplemental grant for the purchase of supercritical
fluid chromatography (SFC) equipment under award
number GM058160-17S1. M.T.P. thanks the National
Institutes of Health for a postdoctoral fellowship
(1F32GM113311). The content is solely the responsibil-
ity of the authors and does not necessarily represent the
official views of the National Institutes of Health. S. D.
F. thanks the Danish Council for Independent Research:
Natural Sciences and the Carlsberg Foundation for
postdoctoral fellowships. We thank Professor Shaolin
Zhu and Yuli He for preliminary investigations, Dr. Pe-
ter Mueller for X-ray crystallographic data, and Drs.
Yiming Wang and Jeffrey S. Bandar for their advice on
the preparation of this manuscript. We thank a reviewer
for insightful mechanistic suggestions.
(8) Do, H.-Q.; Chandrashekar, E. R. R.; Fu, G. C. J. Am. Chem. Soc.
2013, 135, 16288.
ꢀ
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REFERENCES
(1) For general reviews on palladium-catalyzed cross-coupling with
organometallic reagents, see: (a) Jana, R.; Pathak, T. P.; Sigman, M.
S. Chem. Rev. 2011, 111, 1417. (b) Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons, Inc.: New
York, USA, 2002; pp. 215−994.
(2) For selected examples of reductive Pd-catalyzed cross-coupling
to form sp2−sp3 products, see: (a) Gligorich, K. M.; Cummings, S. A.;
Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 14193. (b) Iwai, Y.; Gli-
gorich, K. M.; Sigman, M. S. Angew. Chem. Int. Ed. 2008, 47, 3219. (c)
Gligorich, K. M.; Iwai, Y.; Cummings, S. A.; Sigman, M. S. Tetrahe-
dron 2009, 65, 5074.
(16) Semba, K.; Ariyama, K.; Zheng, H.; Kameyama, R.; Sakaki,
S.; Nakao, Y. Angew. Chem. Int. Ed. 2016, 55, 6275.
(3) For selected examples that purportedly generate aliphatic cop-
per(I) species via hydrocupration see: (a) Noh, D.; Chea, H.; Ju, J.;
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(17) For computational studies exploring the regioselectivity of al-
bromoisoquinoline (1e) have indicated that increasing the palladium
catalyst loading increases the enantioselectivity of product 3e, a phe-
nomenon we generally observed with other substrates and that is
consistent with a unimolecular epimerization event competing with
kene insertion with analogous copper(I) boryl complexes, see: Dang,
L.; Zhao, H.; Lin, Z.; Marder, T. B. Organometallics 2007, 26, 2824.
(18) For a study regarding alkene insertion of stoichiometric cop-
per(I) boryl complexes, see: Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P.
Organometallics 2006, 25, 2405.
(19) For evidence of the transmetalation between an alkylcopper spe-
cies and palladium to be stereospecific, see: (a) ref. 14. (b) ref. 16.
(20) (a) Tsuda, T.; Hashimoto, T.; Saegusa, T. J. Am. Chem. Soc.
1972, 94, 658. (b) Wang, Y.-M.; Bruno, N. C.; Placeres, Á. L.; Zhu,
S.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 10524.
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bimolecular
transmetalation.
The
hydroarylation
of
4-
bromoisoquinoline (1e) and 3-bromoquinoline (1f) with styrene in one
reaction vessel also resulted in diminished enantioselectivity of quino-
line product 3f (see Supporting Information for details and additional
experiments).
(25) Recent reports on the Pd/Cu-catalyzed boryl- and hydroarylation
of styrene derivatives have indicated that retention or inversion of
configuration can occur during the purported transmetalation step
see: (a) ref. 14. (b) ref. 16.
(26) Deuterium-labeling and computational studies for the CuH-
catalyzed hydroboration of styrene derivatives indicate that hydrocu-
pration occurs through cis-addition, and boryl transmetalation is ste-
reoretentive. The sense of stereoinduction with (R)-DTBM-
SEGPHOS for CuH-catalyzed hydroboration, hydroamination, and
hydroarylation is the same see: Noh, D.; Yoon, S. K.; Won, J.; Lee, J.
Y.; Yun, J. Chem. Asian J. 2011, 6, 1967 and red. 3d.
9
(21) Trimethylsilanoate bases have previously been found to be effi-
cient bases in palladium-catalyzed cross-coupling chemistry. For a
representative example see: Denmark, S. E.; Tymonko, S. A. J. Org.
Chem. 2003, 68, 9151.
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(22) Refer to the Supporting Information for an extensive list of lig-
ands, bases, and copper sources examined.
(23) Running the reaction in an oil bath heated to 35 °C appeared to
give a slight increase in enantioselectivity and yield and was used for
subsequent hydroarylation reactions reported in this paper.
(24) These two entries gave variable yield and enantioselectivity, 3e:
69-81% yield, 19-34% ee, 3g: 52-82%, 49-65% ee. Studies with 4-
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