A Bulky Chiral N-Heterocyclic Carbene Palladium Catalyst Enables Highly Enantioselective Suzuki-Miyaura Cross-Coupling Reactions for the Synthesis of Biaryl Atropisomers

Article abstract of DOI:10.1021/jacs.9b08578

Axially chiral biaryl scaffolds are essential structural units in chemistry. The asymmetric Pd-catalyzed Suzuki-Miyaura cross-coupling reaction has been widely recognized as one of the most practical methods for constructing atropisomers of biaryls. However, longstanding challenges remain in this field. For example, substrate scope is often narrow and specialized, functional groups and heterocycles can lead to reduced reactivity and selectivity, bulky ortho-substituents are usually needed, and reported methods are generally inapplicable to tetra-ortho-substituted biaryls. We have developed an unprecedented highly enantioselective N-heterocyclic carbene (NHC)-Pd catalyzed Suzuki-Miyaura cross-coupling reaction for the synthesis of atropisomeric biaryls. These reactions enable efficient coupling of aryl halides (Br, Cl) or aryl triflates with various types of aryl boron compounds (B(OH)₂, Bpin, Bneo, BF₃K), tolerate a remarkably broad scope of functional groups and heterocycles (>41 examples), employ low loading of catalyst (0.2-2 mol %), and proceed under mild conditions. The protocol provided general and efficient access to various atropisomeric biaryls and heterobiaryls in excellent enantioselectivities (up to 99% ee) with no need of using bulky ortho-substituted substrates and was effective for the synthesis of tetra-ortho-substituent biaryls. Moreover, the method was successfully applied to the diastereo- and enantioselective synthesis of atropisomeric ternaphthalenes. Critical to the success of the reaction is the development and application of an extremely bulky C₂-symmetric chiral NHC, (R,R,R,R)-DTB-SIPE, as the ligand for palladium. To the best of our knowledge, this is the first highly enantioselective (>90% ee) example of a chiral NHC-metal-catalyzed C(sp²)-C(sp²) cross-coupling reaction.

Full text of DOI:10.1021/jacs.9b08578

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Article
A Bulky Chiral N-Heterocyclic Carbene Palladium Catalyst
Enables Highly Enantioselective Suzuki-Miyaura Cross-
Coupling Reactions for the Synthesis of Biaryl Atropisomers
Di Shen, Youjun Xu, and Shi-Liang Shi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08578 • Publication Date (Web): 28 Aug 2019
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A Bulky Chiral N-Heterocyclic Carbene Palladium Catalyst Enables
Highly Enantioselective Suzuki-Miyaura Cross-Coupling Reactions
for the Synthesis of Biaryl Atropisomers
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Di Shen,†,‡ Youjun Xu,‡ Shi-Liang Shi*,†
†State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
‡School of Pharmaceutical Engineering and Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of
Education), Shenyang Pharmaceutical University, Shenyang 110016, China
ABSTRACT: Axially chiral biaryl scaffolds are essential structural units in chemistry. The asymmetric Pd-catalyzed Suzuki-Miyaura
cross-coupling reaction has been widely recognized as one of the most practical methods for constructing atropisomers of biaryls.
However, longstanding challenges remain in this field. For example, substrate scope is often narrow and specialized, functional
groups and heterocycles can lead to reduced reactivity and selectivity, bulky ortho-substituents are usually needed, and reported
methods are generally inapplicable to tetra-ortho-substituted biaryls. We have developed an unprecedented highly enantioselective
N-heterocyclic carbene (NHC)-Pd catalyzed Suzuki-Miyaura cross-coupling reaction for the synthesis of atropisomeric biaryls. These
reactions enable efficient coupling of aryl halides (Br, Cl) or aryl triflates with various types of aryl boron compounds (B(OH)2, Bpin,
Bneo, BF3K), tolerate a remarkably broad scope of functional groups and heterocycles (>41 examples), employ low loading of catalyst
(0.2-2 mol%), and proceed under mild conditions. The protocol provided general and efficient access to various atropisomeric biaryls
and heterobiaryls in excellent enantioselectivities (up to >99% ee) with no need of using bulky ortho-substituted substrates and was
effective for the synthesis of tetra-ortho-substituent biaryls. Moreover, the method was successfully applied to the diastereo- and
enantioselective synthesis of atropisomeric ternaphthalenes. Critical to the success of the reaction is the development and application
of an extremely bulky C2-symmetric chiral NHC, (R,R,R,R)-DTB-SIPE, as the ligand for palladium. To the best of our knowledge,
this is the first highly enantioselective (>90% ee) example of a chiral NHC-metal catalyzed C(sp2)-C(sp2) cross-coupling reaction.
coupling partners. Although Suzuki-Miyaura coupling is one of
the most frequently utilized reactions in modern medicinal
chemistry, the atroposelective variant of this Nobel prize-
winning reaction has not been well-developed. In 2000, the
pioneering studies on Pd-catalyzed asymmetric Suzuki-
Miyaura reactions were disclosed by the groups of Buchwald8a
and Cammidge8c using KenPhos and a chiral ferrocene ligand,
respectively (Scheme 1A). Since then, important contributions
in this realm have been made from the group of Fernandez and
Lassaletta,8e-f Uozumi,8g,u Suginome,8h Senanayake,8s Tang,8i-j
Lin,8k and others,8m-t through the development of chiral ligands
including bishydrazones, a resin-supported phosphine, a
helically chiral polymeric phosphine, biaryl monophosphines,
and dienes. However, despite recent achievements,
longstanding challenges and significant limitations remain in
the field of enantioselective metal-catalyzed C(sp2)-C(sp2)
cross-couplings (Scheme 1B). First, the general construction of
heterobiaryls represents an unmet challenge. The use of
heterocyclic substrates poses additional challenges due to
problems associated with their strong coordination ability,9
weak reactivity or stability of reagents, and the reduced
configurational stability of the products.6a-d,r Second, a general
catalyst that allows the synthesis of atropisomeric biaryls with
a wide array of functional groups and substitution patterns is
highly desirable and remains unknown. Third, the preparation
of tetra-ortho-substituted biaryls through an asymmetric
Suzuki-Miyaura reaction is still challenging.8s Fourth, the high

INTRODUCTION
The axially chiral biaryl skeletons represent key structural
elements found in a wide variety of biologically active natural
products and drugs.1,2 These include gossypol, korupensamine
A, and BI-224436, a quinoline-based biaryl serves as the
allosteric HIV-1 integrase inhibitor.3 Moreover, atropisomeric
biaryls are widely present in many privileged ligands and
catalysts such as BINOL, BINAP, and QUINAP, and have
shown remarkable ability of stereoinduction in tremendous
asymmetric reactions catalyzed by organometallics and
organocatalysts (Figure 1).4
OH OMe
O
iPr
Me
OH
OH
OH
Me
Me
N
OH
OH
N
O
CHO
HO
PPh2
OH
HO
HO
NH
OH CHO
Me
O
N
Me
iPr
OH Me
Korupensamine A
(S)-QUINAP
HIV integrase inhibitor
(S)-BINOL
Gossypol
Figure 1. Examples of natural products and ligands bearing axially
chiral biaryls.
Accordingly, extensive effort has been devoted to the
synthesis of the axially chiral biaryl fragments in the past
decades.5,6 Among these reported methods, the Pd-catalyzed
Suzuki-Miyaura cross-coupling reaction7,8 has been recognized
as one of the most practical methods for constructing the
atropisomers because of the stability to moisture and oxygen
and easy availability of both organo-boron and aryl halide
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enantioselectivity outcomes commonly relied on the use of
scalable route to a novel bulky chiral NHC ((R,R,R,R)-DTB-
SIPE) and its successful application to a general, efficient, and
highly enantioselective Pd-catalyzed Suzuki-Miyaura reaction
for the synthesis of bi- and teraryl atropisomers with remarkably
broad scope and tolerance for functional groups and
heterocycles.
substrates possessing a bulky ortho-substituent,8 which led to
limited variations of the ortho-substituents. Furthermore,
reactions that performed with low catalyst loading under mild
conditions are still rare. Finally, we noted that only a limited
range of chiral phosphine ligands provide the products with
good enantioselectivity, and limits the further development of
enantioselective coupling reactions.
1
2
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4
5
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7
8

RESULTS AND DISCUSSION
Reaction Optimization And Ligand Design. We thus
Scheme 1. Pd-Catalyzed Asymmetric Suzuki-Miyaura
Cross-Coupling: Synthesis of Atropisomeric Biaryls
9
commenced
our
study
by
using
1-bromo-2-
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methoxynaphthalene (1a) and naphthalen-1-ylboronic acid (2a)
as model substrates for the synthesis of axially chiral biaryl (3a)
in the presence of palladium-NHC pre-catalysts at ambient
temperature. At first, the use of our previously reported ANIPE
ligand (L1) gave product 3a in nearly quantitative yield and
44% ee (Table 1, entry 1).
A. Representative chiral ligands for efficient Suzuki-Miyaura couplings:
O
O
H
R
tether
PS
N
P
NMe2
PCy2
tBu
N
MeO
OMe
PCy2
(S)-KenPhos
(R)-BI-DIME
resin-supported phosphine
57-92% ee8a
90-99% ee8j
88-99% ee8g
10 mol% catalyst
11 examples
Table 1. Reaction Optimizationa
bulky ortho-phosphonate
bulky ortho-substituent
Ph
N
Ph
N
Br
B(OH)2
H
Ar
[Pd(NHC)(3-cin)Cl] (0.5 mmol%)
base (2.0 equiv)
OMe
PQXPhos:
helically chiral polymer
Ar
N
N
OMe
+
H
solvent (0.2 M)
30 oC, 12 h
Ar = 3,5-Me-C6H3
diene
Ph
Ph
bis-hydrazone
1a
2a
3a
78-98% ee8h
70->98% ee8e
long reaction time
48-90% ee8k
Yield (%)b
Base
ee (%)c
Solvent
Entry
NHC
L1
L2
L3
L4
L5
L6
L7
L6
bulky ortho-phosphonate
moderate enantioselectivity
only simple substrate used
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
99
89
70
98
72
66
99
<2
44
74
80
54
84
96
40
nd
B. Current significant challenges and limitations:



Suppress coordination of heterocyclic substrates
General catalysts tolerant to various functional groups
Low catalyst loading and mild reaction conditions



Tetra-ortho-substituent biaryls
Bulky ortho-substituents needed
Limited type of chiral ligands
C. A novel NHC-Pd enables a general highly enantioselective Suzuki-Miyaura coupling
FG
NHC-Pd
(0.2-2 mol%)
85->99% ee
FG
X
R
R
Ar
R2
R1
+
9
L6
L6
L6
chexane
toluene
K2CO3
K2CO3
K2CO3
<2
59
73
nd
90
94
R4
R2
R3
R1
Ar
R4
R3
N
N
Het
wide scope
>41 examples
Y
10
11
Ar
Het
Ar
ANIPE or SIPE
X = Br, Cl, OTf Y = B(OH)2, Bneo
Bpin, or BF3K
this work
iPrOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
easily available and stable reagents
atropisomeric biaryls
12
13
14
15
16
L6
L6
L6
L6
L6
K2CO3
NaOH
76
<2
45
98
98
97
nd
97
96
97
In this context, we felt that the development of new chiral
ligand would be a fundamental strategy to address the
abovementioned problems. In particular, we envision that the
use of a highly electron-donating NHC ligand would form a
robust palladium catalyst10 to facilitate the oxidative addition of
aryl halides and to suppress the deactivating coordination of
substrates, thus resulting in the tolerance to various
heterocycles and functional groups. However, the
enantiocontrol of NHC-Pd-catalyzed C(sp2)-C(sp2) cross-
coupling is notoriously difficult.8p-r,11 Indeed, the best
enantioselectivity so far obtained is 80% ee, despite several
decades of effort from the chemical community to develop more
selective ligand.8p In this regard, we recently developed a family
of C2-symmetric chiral NHC,12 namely ANIPE and SIPE type
ligands (Scheme 1C).13 We envisage that the modular nature of
our NHCs would allow the introduction of bulky and tunable
C2-symmetric substituents on nitrogen to enhance the level of
enantiocontrol. Moreover, the sterically demanding property of
these NHCs is expected to accelerate the critical elementary
reductive elimination step. As part of our continuing efforts in
NHC-metal catalysis, we disclose herein the development of a
KOtBu
K3PO4
KOH
ANIPE type ligands
L1
L2
L3
(Ar = Ph), (R,R,R,R)-ANIPE
Ar
(Ar = 3,5-Xyl), (R,R,R,R)-DM-ANIPE
Ar
t
N
N
N
(Ar = 3,5- Bu-C6H3), (R,R,R,R)-DTB-ANIPE
Ph
Ar
Ar
Ar
N
SIPE type ligands
Ph
Ar
N
N
L4
L5
L6
(Ar = Ph), (R,R,R,R)-SIPE
Ar
Ph
(Ar = 3,5-Xyl), (R,R,R,R)-DM-SIPE
Ph
t
(Ar = 3,5- Bu-C6H3), (R,R,R,R)-DTB-SIPE L7
(R,R,R,R)-IPE
Ar
b
aReactions were performed on a 0.1 mmol scale. Determined by
NMR analysis using crude samples. cDetermined by HPLC
analysis with a chiral stationary phase.
Using a bulkier DM-ANIPE ligand (L2) with 3,5-xylyl groups
on the sidearm phenyl groups afford 3a in 74% ee (entry 2).
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Sterically more demanding DTB-ANIPE possessing 3,5-di-tert-
benzooxazolidinone8i-j
previously
used
for
optimal
1
butyl phenyl groups (L3) further improved the
enantioselectivity to 80% (entry 3). Next, we examined our
recently disclosed SIPE type ligand. The use of saturated SIPE
(L4) having the same N-substituents with L1 gave 3a in
quantitative yield and 54% ee (entry 4). Bulkier DM-SIPE
ligand (L5) shown dramatically increased enantioselectivity of
84% (entry 5). Based on these observations, we concluded that
SIPE type ligands were superior to the corresponding ANIPE
type ligands in terms of enantioselectivity. The higher
enantioselectivity stems from the incorporation of a bulkier
flanking group to the ligands. Therefore, we anticipated that an
extremely bulky DTB-SIPE ligand (L6) should be promising to
improve the level of enantiocontrol. However, the preparation
of L6 turned out to be problematic (Scheme 2). Although we
could prepare the corresponding chiral aniline11j in a 13.4 gram-
scale employing very low loading of rhodium catalyst (0.3
mol%), a typical synthetic route to the carbene precursor (an
imidazolium salt, L6/HCl) involving a diimine intermediate
resulted in very low yield. Eventually, we were able to
efficiently synthesize L6/HCl in gram-scale through a newly
designed route using a bis-oxalamide intermediate.14 As we
expected, the use of L6 did significantly improve the
enantioselectivity to 96% ee, although the yield was moderate
due to the formation of hydrodebromination byproduct (entry
6). Unsurprisingly, the less bulky unsaturated IPE ligand (L7)
gave 3a in very low enantioselectivity of 40% (entry 7).
stereoinduction are not necessary for our protocol. For example,
the chiral ortho-hydroxyl biaryls, important structures
commonly existed in numerous natural products, were obtained
in high enantioselectivities without the assistance of a special
bulky protection8j, but using simple ether protecting groups (3c,
3d) or non-protected substrates (3e-3h) even with lower loading
of catalyst (0.5 mol%). Remarkably, these mild conditions
tolerated a wide array of functional groups, including ethers
(3c), hemiacetals (3d), esters (3h), amides (3i), aldehydes (3j),
free anilines (3k), free phenols (3e-3h), ketones (3p), a
trifluoromethyl (3l), nitro (3n), cyano (3o) group and fluoride
(3m). In addition to aryl bromides, aryl chlorides (3v) and
triflates (3q) were competent coupling partners. For the aryl-
boron component, various bench-stable and commonly used
organoboron sources, including the boronic acids, pinacol and
neopentylglycol boronate esters (Bpin, Bneo), as well as the
potassium organotrifluoroborates, all delivered products in
excellent enantioselectivities and chemical yields (3r). These
expansions further highlighted the generality of the current
method.
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Encouraged by the above outcomes, we next surveyed the
scope of heteroaryl substrates. Due to their strong coordination
to metals and lower configurational stability of products, it's
much more challenging to achieve high levels of
enantiocontrol. Quinolines, core structures in bioactive
molecules and ligands, were chosen for evaluation. To our
delight, high to excellent levels of enantiocontrol were obtained
when we used bromo-quinoline and -isoquinoline substrates
with nitrogen atoms at all possible positions (3s-3y, 87-95%
ee). Moreover, bromoquinoline substrates were effective for
coupling with several different arylboronic acids (3z-4b). Aside
from quinoline and isoquinolines, other electron-deficient
heterocycles such as pyridines (4c) and quinazolines (4d), and
electron-rich heterocycles including carbazole (4e), indole (4f),
and benzothiophene (4g), were all compatible, affording
heterobiaryls in high yields and enantioselectivities. It bears
mentioning that challenging heterobiaryls with lower rotation
energy barriers, for example, 3y and 4g with less bulky 8-
quinoline and benzothiophene fragments, respectively, could be
generated in high enantioselectivities by conducting the
reaction at ambient temperature. Interestingly, a heteroaryl
bromide could be coupled with a heteroaryl boronate in
excellent yield and enantioselectivity (4h). Importantly, this
asymmetric coupling method could apply to the synthesis of
challenging tetra-ortho-substituted biaryls from both aryl and
heteroaryl bromides, furnishing products in excellent
enantioselectivities (4i-4l). Furthermore, a gram-scale reaction
(4 mmol) was successfully performed in the presence of very
low loading of catalyst (0.2 mol%) to deliver the product (3p)
in high yield and enantioselectivity as before, highlighting the
practicality of this method. Finally, the absolute configuration
of 3d was determined to be the (R)-form by X-ray
crystallographic diffraction analysis.
t
Importantly, a survey of solvents revealed that BuOH was a
superior solvent, as the hydrodebromination side reaction was
completely suppressed in these cases (entries 8-12). Finally,
through extensive screening of base effects, KOH was
identified as the most effective base affording product 3a in
97% ee and 98% yield (entries 13-16).
Scheme 2. Synthesis of a new NHC L6 and the pre-catalyst
1) NiCl2(dppp) ( 3 mol%)
NH2
2,6-dibromo-4-methylaniline
PEPPSI-IPr (2 mol%)
DIBAL (1.2 equiv)
0 oC to rt, 2 h
Ar
Ar
Ar
BPin
Ar
H
KOH (2.2 equiv)
THF, 100 oC, 15 h
87%
2) MeOBPin (1.5 equiv)
THF, 0 oC to 80 oC, 24 h
85%
(Ar = 3,5-tBu-C6H3
)
O
O
NH2
Ar
Ar
(NBD)2RhBF4 (0.3 mol%)
(1R,1'R, 2S, 2'S)-DuanPhos (0.36 mol%)
Ar
Ar
NH HN
(COCl)2 (0.5 equiv)
Et3N (1.02 equiv)
THF, rt, 12 h
97%
DCM/MeOH (1/10)
80 atm, 30 oC, 48 h
92%
Ar
Ar
prepared in 13.4 g-scale
(>99% ee)
bis-oxalamide
Ar
Ar
Ar
1) LiAlH4 (5.0 equiv)
NH4Cl(1.5 equiv)
THF, reflux, 24 h
Ar
NH HN
N
N
CH(OEt)3, 115 oC, 20 h
90%
2) BH3-Me2S (4.0 equiv)
toluene, reflux, 12 h
62%
Cl
Ar
Ar
Ar
N
Ar
L6/HCl
1.4 g prepared
Ar
iPr
iPr
1) KOtBu (0.9 equiv)
Ar
N
N
N
iPr
P
iPr
Cl
THF, rt, 4 h
tBu
tBu
Pd
N
H
Pd
Ar
H
P
Cl
2) [Pd(3-cin)(-Cl)]2
(0.5 equiv)
Ar
Cl
Ph
68%
Cl
PEPPSI-IPr
L6 3
Pd( )( -cin)Cl
(1R,1'R,2S, 2'S)-DuanPhos
Synthesis Of Axially Chiral Ternaphthalenes. To further
demonstrate the utility of our protocol, we applied it to the
synthesis of atropisomeric ternaphthalenes (Scheme 3).
Ternaphthalenes and oligonaphthalenes, which are higher
homologs of binaphthalene, have played essential roles in
supramolecular chemistry and materials science.15 However,
the asymmetric catalytic synthesis of these homologs has rarely
been reported, presumably due to the difficulty in control of
both diastereoselectivity and enantioselectivity.16 To our
Reaction Scope. With the optimized reaction conditions in
hand, we first examined the scope of this asymmetric cross-
coupling using simple bromoarene substrates. As shown in
Table 2, a wide variety of biaryl atropisomers were obtained
with high yields and excellent enantioselectivities (3a-3r, 85-
99% ee). Notably, large coordination groups at ortho-position
of haloarenes such as phosphonate8a,h,m-o, amide8b, or carbonyl-
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delight, the subjection of 1,4-dibromonaphthalene (5) and
boronic acids (6 or 7) to our coupling conditions smoothly
delivered the optically active ternaphthalenes (8 or 9) in
excellent enantioselectivity (>99% ee) and in high to excellent
ratio with their meso-isomers (8’ or 9’).
1
2
3
4
5
6
Table 2. Substrate Scopea
Ar
Br
B(OH)2



Excellent functional group compatibility
Tolerance to various types of heterocycles
Low catalyst loading and mild conditions



Tetra-ortho-substituents
Small ortho-substituents
Novel chiral NHC ligand
3
Ar
R3
R2
R1
N
N
R1
L6
[Pd( )( -cin)Cl] (1 mol%)
R3
R2
KOH (2.0 equiv)
tBuOH (0.2 M)
50 oC, 24 h
FG
Het
+
Ar
L6
Ar
Het
3-4
FG
7
8
t
, Ar = (3,5- Bu-C6H3)
1
2
(1.2 equiv)
9
functional group compatibility
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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60
OMe
b
Me
OBn
c
O
OEt
d
OH
HO
OH
ArBpin
b
d
d
3a
3b
3c
3d
3d
3e
3f
, 85%, 99% ee
, 91%, 97% ee
, 98%, 94% ee
, 92%, 90% ee
, 85%, 92% ee
X-ray structure of
, 76%, 97% ee
Me
Me
O
Me
Me
OEt
OH
HO
OH
CHO
NH2
CF3
NEt2
d
MeO
O
F
d
d
e
e
e
3g
3h
3i
3j
3k
3l
3m
, 89%, 92% ee
, 96%, 92% ee
, 98%, 91% ee
, 86%, 93% ee
, 81%, 90% ee
, 75%, 85% ee
, 81%, 91% ee
OMe
Me
Ar-B(OH)2 97%, 93% eeg
OMe
Me
OMe
Me
N
Me
Ar-Bpin
Ar-Bneo
Ar-BF3K
99%, 94% eeg
91%, 93% eeg
98%, 90% eee
OMe
Me
O
NO2
3n
CN
Ar-OTf
, 97%, 96% ee
ArBPin
f
d
f
3q
3r
3p
, 99%, 95% ee
3o
, 90%, 97% ee
, 95%, 95% ee
3s
, 60%, 90% ee
heteroaryl substrates
Me
Me
Me
OMe
Me
Me
N
OMe
N
N
N
N
N
N
ArBPin
f
Ar-Bpin
3v
, Ar-Br, 94%, 94% ee
Ar-Cl, 87%, 94% ee
f
c,f
f
3t
3u
3w
3x
3y
3z
, 92%, 96% ee
, 61%, 87% ee
, 88%, 93% ee
, 91%, 95% ee
, 84%, 94% ee
, 82%, 90% ee
N
Me
OR
OMe
Me
OMe
OMe
Me
Me
OMe
N
N
N
N
N
S
N
N
Me
Me
Ar-Bpin
e
4a
, R = Me, 98%, 95% ee
4b
f
c,f
4d
, 79%, 94% ee
4c
4e
4f
4g
4h
, 98%, 95% ee
, R = Et, 79 %, 92% ee
, 94%, 93%ee
, 93%, 99% ee
, 82%, 90% ee
, 97%, 86% ee
tetra-ortho-substituted biarylsb,f
gram-scale reaction
1.3 equiv
Me
3
L6
[Pd( )( -cin)Cl] (0.2 mol%)
Me
OMe
OMe
OMe
OMe
OBn
OMe
OMe
OMe
Me
KOtBu (1.3 equiv)
+
Br
B(OH)2
F
toluene/H2O (9:1, 0.25 M)
rt, 36 h
OMe
Me
N
Me
O
3p
, 1.15 g
99%, 95% ee
ArBPin
ArBPin
ArBPin
, 85%, 95% ee
ArBPin
54%, 94% ee
O
1.12 g (4 mmol)
4i,
4j,
4k
4l,
57%, 96% ee
62%, 92% ee
aYields of isolated products on a 0.2 mmol scale. b40 oC. c30 oC. d0.5 mol% catalyst, KOtBu (1.3 equiv), toluene/H2O (9:1), rt, 24 h. e2
mol% catalyst, Cs2CO3 (2.5 equiv), tBuOH/H2O (9:1), 60 oC, 24 h. f2 mol% catalyst. g0.5 mol% catalyst.
Scheme 3. Synthesis of Axially Chiral Ternaphthalenes
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1
2
3
4
5
6
B(OH)2
Me
OMe
OMe
OMe
OMe
Br
Br
Me
Me
Me
Me
B(OH)2
OMe
L6 3
KOH (5.0 equiv)
tBuOH (0.1 M)
50 oC, 24 h
Pd( )( -cin)Cl] (2 mol%)
left conditions
9'
= 91 : 9
b)
+
5
a)
+
+
+
9
60%,
:
8
8'
= 95 : 5
74%,
:
7
(3.6 equiv)
5
6
(3.6 equiv)
8,
>99% ee
8'
(meso)
9,
>99% ee
9'
(meso)
7
8
9
In conclusion, we have developed the first highly
enantioselective NHC-Pd catalyzed (Suzuki-Miyaura) C(sp2)-
C(sp2) cross-coupling reaction for the synthesis of
atropisomeric biaryls. A diverse variety of axially chiral biaryls,
Proposed Stereoinduction Models. To get insight into the
origin of excellent stereoinduction of the newly designed ligand,
we obtained the X-ray crystal structure of Pd(L6)(η3-cin)Cl
(Figure 2a).17 The steric map of this complex shows a
pronounced C2-symmetric binding pocket with two accessible
quadrants.18 Based on the X-ray crystal structure, we proposed
stereoinduction models for the oxidative addition and
transmetalation intermediates of L6-Pd complex, as shown in
Figure 2b. Notably, due to the steric repulsions between
coupling partners and the bulky 3,5-di-tert-butyl phenyl group
on the ligand, the reductive elimination would proceed through
the favored transition state (TM1), in which the two naphthyl
substituents occupy the two vacant quadrants provided by L6-
Pd complex, thereby furnishing biaryls 3d in the (R)-
configuration. These results are consistent with our initial
hypothesis that the bulkier C2-symmetric N-substituents on
NHCs would lead to a more efficient enantiodiscrimination and
facilitate the key reductive elimination step.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
heterobiaryls,
tetra-ortho-substituted
biaryls,
and
ternaphthalenes, were efficiently prepared in high yields with
excellent levels of enantiocontrol from readily available and
stable substrates. These reactions tolerate a remarkable scope of
heterocycles and functional groups, employ low catalyst
loading, and proceed under mild conditions. Key to the success
of the reaction was the development and application of a very
bulky C2-symmetric chiral NHC for the Pd catalyst. Efforts to
further explore this NHC-metal catalysis are underway in our
laboratory.

ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures, spectroscopic data, and NMR spectra of
all products (PDF)
a) Pd(L6)(η3-cin)Cl
Steric map (37.5 %VBur)
Crystallographic data for 3d (CCDC 1921079) (CIF)
Crystallographic data for Pd(L4)(η3-cin)Cl (CCDC 1921080)
(CIF)
Crystallographic data for Pd(L6)(η3-cin)Cl (CCDC 1921081)
(CIF)

AUTHOR INFORMATION
Corresponding Author
* shiliangshi@sioc.ac.cn
ORCID
b) Proposed stereoinduction models
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
N
N
N
N
Shi-Liang Shi: 0000-0002-0624-6824
Pd
Pd
OR
tBu
RO
Br
Br
tBu
tBu
tBu
tBu
Notes
tBu
tBu
tBu
OA2
OA1
The authors declare the following financial interests: A patent
(WO2019096209) for some of the ligands (including L6) in this
Communication has been filed.
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
N
N
N
N
N
N
N
N
Pd
OR
Pd
OR
Pd
Pd

ACKNOWLEDGMENT
RO
RO
tBu
tBu
tBu
tBu
tBu
TM3
tBu
tBu
tBu
tBu
tBu
This work is supported by the NSFC (grant nos. 21690074,
21871288, 91856111, 21821002), the “1000-Youth Talents Plan”,
and the CAS (grant no. XDB 20000000). We thank Prof. Yiming
Wang for proofreading this manuscript.
TM1
TM2
TM4
Reductive elimination
O
OEt

REFERENCES
3d
3d
X-ray structure of
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
CONCLUSIONS
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Application of
a
C2-Symmetric Copper Carbenoid in the
was also obtained, see SI for details.
Enantioselective Hydrosilylation of Dialkyl and Aryl-Alkyl Ketones.
J. Am. Chem. Soc. 2011, 133, 19680.
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(14) L6 was included in our patent, see: (a) Shi, S.-L.; Cai, Y.; Yang,
X.-T.; Li, F. WO2019096209 (publication date: May 23rd, 2019). (b)
During the preparation of this manuscript, a Ni-catalysis using L6
appeared: Diesel, J.; Grosheva, D.; Kodama, S.; Cramer, N. A Bulky
Organometallics
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(b)
https://www.molnac.unisa.it/OMtools/sambvca2.0/
TOC graphic
R3
R2
L6
-Pd (0.2~2 mol%)
85~>99% ee
R3
R2
R1
Y
>41 examples
Y = B(OH)2, Bneo
Bpin, or BF3K
Het
FG
Ar
+
X
Ar
N
N
aptroisomeric biaryls
R1
Ar
Ar
Het
FG
Broad scope &
tolerance to FG
and heterocycles
Ar = 3,5-tBu-C6H3
L6
)
(R,R,R,R)-DTB-SIPE (
X = Br, Cl, OTf
ACS Paragon Plus Environment