Intermolecular Palladium(0)-Catalyzed Atropo-enantioselective C-H Arylation of Heteroarenes

Article abstract of DOI:10.1021/jacs.9b12299

Atropisomeric (hetero)biaryls are motifs with increasing significance in ligands, natural products, and biologically active molecules. The straightforward construction of the stereogenic axis by efficient C-H functionalization methods is extremely rare an

Full text of DOI:10.1021/jacs.9b12299

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Communication
Intermolecular Palladium(0)-Catalyzed Atropo-
enantioselective C–H Arylation of Heteroarenes
Qui-Hien Nguyen, Shu-Min Guo, Titouan Royal, Olivier Baudoin, and Nicolai Cramer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12299 • Publication Date (Web): 22 Jan 2020
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Intermolecular Palladium(0)-Catalyzed Atropo-enantioselective C–H
Arylation of Heteroarenes
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Qui-Hien Nguyen,†,# Shu-Min Guo,‡,# Titouan Royal,‡ Olivier Baudoin,‡* and Nicolai Cramer†*
†Laboratory of Asymmetric Catalysis and Synthesis, Institute of Chemical Sciences and Engineering, Ecole
Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
‡University of Basel, Department of Chemistry, St. Johanns-Ring 19, 4056 Basel, Switzerland
Supporting Information Placeholder
coupling methodology requires the use and availability of two
pre-functionalized substrates.
ABSTRACT: Atropisomeric (hetero)biaryls are motifs with
increasing significance in ligands, natural products and
biologically active molecules. The straightforward construction
of the stereogenic axis by efficient C–H functionalization
methods is extremely rare and challenging. An intermolecular
and highly enantioselective C–H arylation of relevant
heteroarenes providing an efficient access to atropisomeric
(hetero)biaryls is reported. The use of a Pd(0) complex
equipped with H8-BINAPO as chiral ligand enables the direct
functionalization of a broad range of 1,2,3-triazoles and
pyrazoles in excellent yields and selectivities of up to 97.5:2.5
er. The method also allows for an atroposelective double C–H
arylation for the construction of two stereogenic axes with
>99.5:0.5 er.
A
Bioactive Molecules
Natural Products
Ligands
Cl
Cl
O
HN
Ph
Ph
Br
Cl
Br
Br
C6F5
N
N
NH2
N
OtBu
CO2H
Me
Br
F
PPh2
N
N
N
H
NH2
202W92
N
OMe
BI224436
StackPHOS
Rivularin D3
(Na-channel binder) (HIV integrase inhibitor)
B
Yamaguchi & Itami (2012, 2013):14
Me
O
O
Me
10 mol% PdII(OAc)2, TEMPO
S
S
N
N
iPr
iPr
Me
Me
10 mol%
O
27%, 86:14 er
+
iPr
B(OH)2
5 mol% FePc, air
iPr
N
iPr
10 mol%
Atropisomerism is the time-dependent chirality arising from
an impediment of free rotation about an axis in a molecule.
Such axially chiral molecules are an important source of
stereoinduction in asymmetric catalysis,1 as well abundantly
found in natural products.2 Recently, the use of atropisomeric
(hetero)biaryl motifs with ortho substituents to lock biaryl
bond rotation has garnered attention and is a current trend in
drug discovery.3 These molecules frequently display enhanced
stereochemical recognition of biological targets compared to
their achiral counterparts.4 Representative examples of
atropisomeric (hetero)biaryls in ligands (StackPHOS),5 natural
products (Rivularin D3)6 and bioactive molecules (202W92,7
BI224368) are depicted in Figure 1A. Given the relevance of this
motif, significant efforts have been dedicated to their
asymmetric synthesis.9 Catalytic approaches belong to four
strategies: (i) enantioselective de novo synthesis of an aromatic
ring,10 (ii) central-to-axial chirality transfer,11 (iii) locking a
pre-existing axis,12 and (iv) enantioselective formation of a
(hetero)biaryl linkage. The asymmetric construction of the
biaryl axis is straightforward in terms of retrosynthetic
disconnection, but remains challenging in practice. The high
steric demands of the substrates required to block rotation
around the axis reduces their chemical reactivity. In this
respect, the Suzuki–Miyaura coupling has achieved high levels
of enantiocontrol and good reactivity.13 However, the cross-
-O
S+
61%, 80.5:19.5 er
Pd
OAc
4-tol
AcO
This work:
POPh2
PPh2
R3
 up to 97%
 up to 97.5:2.5 er
 32 examples
R3
R2
Br
+
H
L*
10 mol% Pd0(dba)2
PivOH, Cs2CO3, CH3CN
R1
N
R1
R2
N
X
N
N
X
Figure 1. (A) Compounds with atropisomeric heterobiaryl C–C
linkage. (B) Intermolecular atropo-enantioselective C–H
functionalization approach.
Complementarily, the enantioselective direct C–H arylation of
(hetero)arenes – while being more atom-efficient and direct –
remains
challenges become quickly apparent from the two reported
cases proceeding both in modest yields and enantioselectivities
(Figure 1, B). In 2012, Yamaguchi and Itami reported two
examples of an oxidative Pd(II)-catalyzed coupling proceeding
in 27% yield and 86:14 er.14a One year later, they reported
another ligand and oxidant providing 61% yield and 80.5:19.5
er for the same substrate.14b A highly atropo-enantioselective –
a very underdeveloped field. The underlying
but intramolecular
–
synthesis of axially chiral
1
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dibenzazepinones by a Pd(0)-catalyzed C–H arylation was
13–18). Notably, a broad screen of carboxylic acid additives
revealed that they have negligible impact on the
enantioselectivity of this transformation (see SI). An increased
concentration (0.67 M) improved the isolated yield of 3aa to
93% keeping the er at 95:5 (Entry 19). The absolute
configuration of product 3aa was determined by X-ray
crystallography to be P (Scheme 1).28
reported by Cramer in 2018.15 The void of efficient
intermolecular atropo-enantioselective methods is in stark
contrast to the rapid recent developments of asymmetric C–H
functionalization technology.16 Given the long-standing
interest in asymmetric C–H functionalizations of our
laboratories,17 this challenged us to develop an intermolecular
Pd(0)-catalyzed C–H arylation of electron-deficient
heteroarenes constructing the heterobiaryl axis atropo-
enantioselectively.
a
1
2
3
4
5
6
7
8
Table 1. Optimization of the Intermolecular
Atroposelective C–H Arylationa
9
Despite being
a common motif in biologically active
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10 mol% Pd(dba)2
L*
H
compounds and usage as bioisostere and pharmacophore,18 the
atropisomeric behavior of 1,2,3-triazoles is rarely
investigated.19 Therefore, we selected 1-methyl-4-phenyl-1H-
1,2,3-triazole (1a) and 1-bromo-2-methoxynaphthalene (2a)
as suitable model substrates. 1,2,3-Triazoles are readily
accessible by Cu-catalyzed azide-alkyne cycloadditions20 and
OMe
Ph
20 mol%
Me
Ph
+
N
PivOH, Cs2CO3
Solvent, 80°C, 40 h
Me
OMe
N
N
N
Br
N
3aa
N
1a
2a
( )
OR
O
O
OMe
OMe
PPh2
5
O
CO2H
non-stereoselective Pd(0)-catalyzed C–H arylations have been
PAr2
P(Xyl)2
PPh2
reported.21 The racemization barrier (ΔG‡
)
of 3aa was
22
enant
measured to be 32.4 kcal/mol in MeCN (see SI for details). This
provides sufficient stability for the coupling products bearing
four ortho-substituents around the heterobiaryl axis to
withstand prolonged periods of heating at 80–100°C without
significant racemization (Eq 1).
L1
L2
(R=Me, Ar=Ph)
(R=iPr, Ar=3,5-Xyl)
L5
L3
L4
O
X
O
O
POPh2
PPh2
MeO
MeO
POPh2
PPh2
POPh2
PPh2
POPh2
PPh2
X
O
o
h
OMe
L7
L6
(X=CH2) (=81.7 )
L11
L10
(=80.4o)h
2a
Trac
cat. Pd0
L*
OMe
Ph
OMe
Ph
o
h
(=79.5o)h
Br
N
(=86.1o)h
L8
(X=C2H4) (=82.4 )
+
(1)
H
o
h
Me
Me
L9
(X=CF2) (=80.7 )
N
N
N
T<Trac
Me
Ph
N
N
N
G‡enant = 32.4 kcal/mol
N N
3aa
ent-
1a
3aa
conc.
[M]
entry L*
solvent
% yieldb
% erc
A brief initial screening revealed that Pd(dba)2 with MOP
(L1)23 as ligand and pivalic acid as co-catalyst provided a very
reactive catalytic system giving 3aa in an excellent 95% yield
and a proof of principle enantioselectivity of 67.5:32.5 (Table
1, Entry 1). Efforts to increase the sterics of L1 replacing phenyl
with 3,5-xylyl groups as well as exchanging methoxy for
isopropoxy (L2) had virtually no effect on the
enantioselectivity of 3aa (entry 2). Variations of the dihedral
angle of the ligand backbone, represented by L313c and L4,
marginally improved the selectivity for L3 (Entry 3) but largely
reduced it for L4 (Entry 4). A bifunctional phosphine ligand
with an attached carboxylic acid group (L5) developed by
Baudoin24 slightly improved the enantioselectivity to 73:27
(Entry 3). BINAPO (L6) improved the enantioselectivity for
3aa to 78.5:21.5 albeit with a reduced yield of 36% (Entry 6).
A switch to acetonitrile as solvent further improved the er to
85.5:14.5 with a significantly increased yield of 65% (Entry 7).
Different bisphosphine monoxides (BPMOs)25 such as
SEGPHOSO (L7), SYNPHOSO (L8), DIFLUORPHOSO (L9),
MeOBIPHEPO (L10) and H8-BINAPO (L11) were prepared
through a modified Grushin protocol in a single step.26 Notably,
the BPMO ligand type preferentially provided the opposite
enantiomer compared to the MOP ligands. The
enantioselectivity of 3aa progressively improved from L7 to
L11 (Entries 7–12). H8-BINAPO (L11) performed best in terms
of selectivity (95:5 er) and reactivity (79% yield) (Entry 12).
This finding correlates with the very recently reported results
from Larrosa on Pd(0)-catalyzed arylations of (η6-
arene)chromium complexes.27 The observed enantioselectivity
roughly correlates to the dihedral angle θ of the ligand, with a
larger θ providing a higher enantioselectivity (Figure S1).
Subsequent optimizations confirmed acetonitrile as the best
solvent and Cs2CO3 outperformed other carbonates (entries
1
L1
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
MeCN
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
95
76
98
91
88
36
65
57
34
26
62
79
59
53
48
40
33
<5
93g
67.5:32.5
67.5:32.5
71.5:28.5
53.5:46.5
73:27
2
L2
3
L3
4
5d
L4
L5
6
L6
78.5:21.5
85.5:14.5
12.5:87.5
12:88
7
L6
8
L7
MeCN
9
L8
MeCN
10
11
12
13
14
15
16
17
18e
19f
L9
MeCN
10.5:89.5
10:90
L10
L11
L11
L11
L11
L11
L11
L11
L11
MeCN
MeCN
95:5
EtCN
94.5:5.5
92.5:7.5
92:8
DME
tBuOMe
2-MeTHF 0.33
89.5:10.5
90:10
dioxane
MeCN
0.33
0.33
0.67
-
MeCN
95:5
a50 μmol 1, 75 μmol 2, 5 μmol Pd(dba)2, 10 μmol L*, 15 μmol
PivOH, 75 μmol Cs2CO3. bDetermined by 1H-NMR with
trichloroethene as internal standard. cDetermined by HPLC
d
e
with a chiral stationary phase. Without PivOH. With K2CO3.
fDouble scale. gIsolated yield. hCalculated biaryl dihedral angle
θ of L* in DFT-optimized PdCl2L* complexes (see SI for details).
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With the aforementioned conditions, the scope of the
10 mol% Pd(dba)2
L11
H
1
2
3
4
5
6
7
8
transformation was investigated (Scheme 1). We first focused
on different bromonaphthalenes. Variation of the alkoxy group
OR3 ortho to the stereogenic axis of the products had little effect
on both the reactivity and the enantioselectivity of the reaction
(3aa–3ad). Bulkier groups (OiPr and OBn) required higher
reaction temperature (90°C) and extended reaction times to
retain high yields. The selectivity of 3ae remained very high
(95.5:4.5 er), whereas it dropped to 91.5:8.5 er for 3af due to a
slow racemization at 90°C. The introduction of a further
substituent at C6 of the naphthalene (3ag–3ai) had little
influence on the reactivity and the stereoselectivity of the
process. Noteworthily, the naphthalene ring is not required for
the enantioselectivity. Indeed, tetrahydrobromonaphthalene
2j and bromocresol derivative 2k delivered coupling products
3aj and 3ak in good yield and excellent enantioselectivity.
Moreover, bromopyridine 2l was well arylated giving 3al in
good yield albeit a reduced 80:20 er. We next investigated the
scope for the 1,2,3-triazole coupling partner 2y. Modifications
of the aryl substituent of the 1,2,3-triazole were well tolerated
and delivered coupling products 3xa and 3xe in consistently
good yield and high atropo-enantioselectivity. The exceptions
were the o-tolyl (1b) and 1-naphthyl groups (1j) where the
increased steric demand of the substituent lowered the
enantioselectivity of products 3ba, 3be and 3je. In contrast,
triazoles bearing a 2-naphthyl (1i) or thienyl unit (1k) reacted
smoothly, with usual excellent atroposelectivity (3ie, 3ke).
Replacing the aryl substituent of the triazole by an aliphatic
group (iPr) had no influence on the reactivity and resulted in
the formation of 3la in 77% yield albeit with a reduced er of
82.5:17.5. Product 3na, bearing a methyl group at the C4
position of the triazole was formed with similar enantiomeric
ratio. Increasing the size of the nitrogen substituent (Me to Bn)
did not impact the enantiomeric ratio, forming 3ma in 93:7 er
with 62% yield. X-ray crystallographic analysis of 3la and 3ma
confirmed the absolute configurations of these two cases to be
P.28 Moreover, conducting the reaction with 1a and 2a at 10-
fold scale provided 3aa in 72% yield and 93.5:6.5 er.
OR3
R2
20 mol%
R1
R2
+
N
PivOH, Cs2CO3
MeCN, 80°C, 40 h
R1
OR3
N
N
N
Br
2y
N
N
3xy
1x
3aa
(R=Me)
93%, 95:5 er
72%, 93.5:6.5 erb
95%, 94.5:5.5 er
96%, 96.5:3.5 er
) 97%, 95:5 er
3ab
3ac
3ad
3aec
3afc
(R=Et)
(R=Pr)
(R=
OR
Ph
Me
R
N
N
N
(R=iPr)
83%, 95.5:4.5 er
81%, 91.5:8.5 er
9
(R=Bn)
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
3aa
X-ray structure of
3ag
3ah
3ai
(R=OMe) 98%, 93.5:6.5 er
(R=CO2Me) 98%, 91.5:8.5 er
OMe
Ph
(R=CN)
88%, 94:6 er
Me
N
N
N
N
Me
Me
OiPr
Me
Me
OiPr
OMe
Ph
Ph
N
Ph
Me
N
N
N
N
N
N
N
N
3akc
3alc
3ajc
80%, 96:4 er
71%, 80:20 er
71%, 95.5:4.5 er
OiPr
R
OiPr
OMe
R
S
Me
Me
N
N
Me
N
N
N
N
N
3kec
3bec
3dec
3fec
3gec
3hec
N
N
(R=2-Me) 81%, 65.5:34.5 er
(R=4-Me) 89%, 95.5:4.5 er
(R=4-Ph) 59%, 94.5:5.5 er
(R=4-CF3) 87%, 97:3 er
54%, 92:8 er
3ba
3ca
3da
3ea
(R=2-Me) 91%, 72.5:27.5 er
(R=3-Me) 98%, 95:5 er
(R=4-Me) 98%, 95:5 er
(R=4-OMe) 95%, 94.5:5.5 er
(R=4-F) 90%, 93.5:6.5 er
OiPr
OMe
iPr
OMe
Ph
OMe
Me
Me
Bn
Bn
Me
N
N
N
N
N
N
N
N
N
N
N N
3lac
3mac
3nac,d
77%, 82.5:17.5 er
62%, 93:7 er
31%, 81:19 er
3jec
82%, 67:33 er
OiPr
Scheme 1. Scope for Atroposelective Intermolecular
1,2,3-Triazole Arylationa
Me
N
N
N
3iec
91%, 95:5 er
3la
X-ray structure of
3ma
X-ray structure of
a0.1 mmol 1x, 0.15 mmol 2y, 10 mol% Pd(dba)2, 20 mol% (S)-
H8-BINAPO, 30 mol% PivOH, 150 mol% Cs2CO3, MeCN (0.67 M),
80°C, 40 h; isolated yield. bOn a 1.0 mmol scale of 1. c90°C, 60 h.
d
ent-L11 was employed. Absolute configurations assigned by
analogy to 3la and 3ma.
The applicability of the transformation was challenged with
related azoles (Scheme 2). We turned towards pyrazoles
representing important building blocks for pharmaceuticals
and agrochemicals.29 Pleasingly, pyrazoles with electron-
withdrawing groups at the 3-position underwent smooth and
highly enantioselective C–H arylation. 3-Carbonitrile pyrazole
1p was smoothly arylated with bromonaphthalene 2a and
bromocresol 2k, forming 3pa and 3pk in excellent yields and
enantioselectivities. The high atroposelectivity was maintained
with an ester or a CF3 group on the pyrazole instead of the
nitrile substituent (3oa, 3qa). Moreover, the arylation of 2-
phenylimidazo[1,2-a]pyrimidine (1r), conducted at 100°C in
dioxane, resulted in formation of the desired coupling product
3qa in 50% yield and 68:32 er. Isomeric arylation product 3qa’
was detected in low levels and as racemic mixture. While the
general feasibility of atroposelective C–H arylation of
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heteroaromatics is herein proven with triazoles and pyrazoles,
this example indicates that further tailored ligand and catalyst
systems are required for other cases.
To obtain further insights on the reaction mechanism and the
critical steps of the catalytic cycle, the initial reaction rates (0–
4 h reaction time) of protiated (1a) and deuterated (1a-D1)
triazole substrates were compared (Scheme 4). Independent
experiments performed with ligand L1 provided a kH/kD value
of 1.8. This value indicates that the C–H bond cleavage is the
rate-limiting step of this reaction.31 In addition, the structure of
the carboxylic acid co-catalyst had an influence on the rate (the
reaction was ca. 4 x faster with PivOH) but not on the
enantioselectivity (Table S1). Taken together, these results
indicate that the C–H activation step mainly operates through
the concerted metallation-deprotonation mechanism and is
rate-limiting.32,33 Moreover, the effect of the ligand dihedral
angle on the enantioselectivity tends to indicate that reductive
elimination is the enantio-determining step of the reaction.
1
2
3
4
5
6
7
8
Scheme 2. Atroposelective Arylation of Pyrazoles and
Imidazo[1,2-a]pyrimidinea
10 mol% Pd(dba)2
H
OR3
R2
L11
20 mol%
R1
R2
+
N
PivOH, Cs2CO3
MeCN, 80°C, 40 h
R1
OR3
N
X
Y
Br
2y
X Y
3xy
9
1x
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
Me
Me
OiPr
OMe
OMe
Ph
OMe
Ph
Ph
Me
Ph
Me
Me
N
N
N
N
N
N
N
N
CN
3pkb
(82%, 97.5:2.5 er)
CF3
CN
CO2Et
3pa
(97%, 97:3 er)
3qa
(49%, 94:6 er)
Scheme 4. Deuterium Kinetic Isotope Effect
3oa
(47%, 95.5:4.5 er)
H
OiPr
Me
Ph
OMe
OMe
N
+
Me
Ph
N
N
Ph
N
N
N
Ph
1a
N
N
N
N
OiPr
N
N
3rac
(50%, 68:32 er)
3ra'
3ae
Br
2e
parallel kinetics
(11%, 50:50 er)
Pd(dba)2/L1 cat.
a0.1 mmol 1, 0.15 mmol 2, 10 μmol Pd(dba)2, 20 μmol L11, 30
μmol PivOH, 0.15 mmol Cs2CO3, 0.67 M in MeCN at 80 °C for 40
30 mol% CsOPiv, Cs2CO3
CH3CN (1a) or CD3CN (1a-D1)
D
90 °C, 0-3 h
Me
Ph
OiPr
c
N
h; isolated yield. b90°C for 60 h. 100°C for 40 h in dioxane.
N
N
Me
Ph
kH/kD = 1.8
N
Absolute configurations assigned by analogy to 3la and 3ma.
1a-D1
N
N
3ae
To probe the limits of the transformation,
a double
atroposelective13f C–H arylation of 1,5-dibromo-2,6-
dimethoxynaphthalene 2m and triazole 1a was performed
(Scheme 3). The reaction cleanly proceeded at 80°C, delivering
the double C–H activation product 3am possessing two
stereogenic axes30 in 76% yield (based on limiting 2m) with an
outstanding enantioselectivity of >99.5:0.5. Notably, no meso-
isomer was observed, but compound 3ag arising from one C–H
arylation event and hydrodebromination of the second C–Br
bond was formed in 14% yield and 93:7 er. X-ray analysis of
3am allowed determination of the configuration of the axes to
be M,M,28 consistent with the fact that ent-L11 was used for this
reaction.
In conclusion, we report
a
highly enantioselective
intermolecular C–H arylation of medicinally relevant
heteroarenes providing an efficient access to atropisomeric
(hetero)biaryls. A Pd(0) complex equipped with H8-BINAPO as
chiral ligand enabled the arylation of a broad range of 1,2,3-
triazoles in excellent yields and selectivities of up to 97:3 er.
Besides triazoles, pyrazoles were arylated in high yields and
excellent atropo-enantioselectivity. Moreover, the method was
equally well suited for a stereoselective double arylation
allowing the construction of two stereogenic axes with
>99.5:0.5 er. The level of enantiocontrol seemed to be linked to
the biaryl dihedral angle of the employed bisphosphine
monoxide ligand. Mechanistic investigations indicated C–H
activation as the rate-determining but not enantio-determining
step. This provides a foundation to identify the origin of the
selectivity in this process and to further extend the application
potential of atroposelective C–H functionalization.
Scheme 3. Double Intermolecular Atroposelective C–H
Arylation
H
N
N
Me
Ph
N
N
Ph
MeO
Me
N
N
MeO
+
20 mol% Pd(dba)2
L11
1a
(2.0 equiv.)
ASSOCIATED CONTENT
40 mol% ent-
+
OMe
Ph
PivOH, Cs2CO3
MeCN, 80°C, 65 h
OMe
Br
Me
Supporting Information
N
Me
Ph
MeO
N
N
N
N
3am
N
The Supporting Information is available free of charge on the
ACS Publication website.
3ag
14%, 93:7 er
OMe
Br
76%, >99.5:0.5 er
2m
(1.0 equiv.)
Experimental procedures and characterization data (PDF)
X-ray crystallographic cate for 3aa, 3la, 3ma and 3am (CIF)
Coordinates for DFT-optimized PdCl2L* complexes (XYZ)
AUTHOR INFORMATION
Corresponding Author
*olivier.baudoin@unibas.ch
3am
X-ray structure of
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(8) (a) Fader, L. D.; Malenfant, E.; Parisien, M.; Carson, R.; Bilodeau,
*nicolai.cramer@epfl.ch
F.; Landry, S.; Pesant, M.; Brochu, C.; Morin, S.; Chabot, C.; Halmos, T.
Bousquet, Y.; Bailey, M. D.; Kawai, S. H.; Coulombe, R.; LaPlante, S.;
Jakalian, A.; Bhardwaj, P. K.; Wernic, D.; Schroeder, P.; Amad, M.;
Edwards, P.; Garneau, M.; Duan, J.; Cordingley, M.; Bethell, R.; Mason, S.
W.; Bös, M.; Bonneau, P.; Poupart, M.-A.; Faucher, A.-M.; Simoneau, B.;
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2
3
4
5
6
7
8
Author Contributions
# Q.-H. N. & S.-M. G. contributed equally to this work.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the SNF (no. 157741) and the
University of Basel. S.-M. G. thanks the China Scholarship
Council for a scholarship. We thank Dr. R. Scopelliti and Dr. F.
Fadaei Tirani (EPFL) for the X-ray crystallographic analysis of
compounds 3aa, 3la, 3ma and 3am.
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crystallographic data and can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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terphenyl ligands with two atropisomeric axes. Angew. Chem. Int. Ed.
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S. I. Origins of regioselectivity of the palladium-catalyzed (aromatic)C–
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POPh2
PPh2
R3
 33 examples
R3  up to 97%
 up to 97.5:2.5 er
Br
+
L*
H
R1
R2
cat. Pd0(dba)2, PivOH
Cs2CO3, CH3CN, 80 °C
R1
R2
N
N
N
X
N
X
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