Articles

https://doi.org/10.1038/s41929-019-0247-1

Asymmetric construction of atropisomeric biaryls

via a redox neutral cross-coupling strategy
Liang-Wen Qi1,3, Shaoyu Li   1,2,3, Shao-Hua Xiang   1,2, Jun (Joelle) Wang   1* and Bin Tan   1*

Atropisomerically enriched biaryl frameworks are ubiquitous in many fields of chemistry. Enantioselective aryl–aryl cross-
coupling provides the most straightforward entry to atropisomeric biaryls, with remarkable application potential in the field
of chemical science. However, their development is hindered due to the lack of convenient and pragmatic protocols. Here, we
report a method for the asymmetric synthesis of a myriad of 2-amino-2′-hydroxy-1,1′-binaphthyl (NOBIN) and 1,1’-binaph-
thyl-2,2’-diamine (BINAM) derivatives in excellent yields and enantioselectivities via a redox-neutral cross-coupling protocol.
Two complementary systems were devised employing a chiral phosphoric acid–salt complex or Ni(OTf)2/chiral bis(oxazoline)
ligand catalytic system for accessing atropisomeric NOBIN and BINAM derivatives, respectively. This work provides an alterna-
tive avenue to enantioenriched biaryls, and provides the capability to explore the synthetic and catalytic potentials of NOBIN-
and BINAM-based frameworks.

A
tropisomerically enriched biaryl frameworks are abun-
dantly featured in a wide range of natural products1, phar-
maceuticals2 and bioactive molecules3. They also constitute
the enantiopure building blocks for axially chiral hosts in the reso-
lution of racemic amino acids via host–guest chemistry4 as well as
stereogenic fluorescent sensors for highly enantioselective and sen-
sitive recognition of chiral amino alcohols, α-hydroxycarboxylic
acids and amino acid derivatives5. Furthermore, material scien-
tists exploit axially chiral frameworks as stationary phases for
enantioselective separation6, dopants in liquid-crystalline materi-
als7, chiroptical molecular switches8, microporous soluble poly-
mers9 and interlocked nanotubes10. They are, nevertheless, most
prominently prized as chiral ligands or catalysts in asymmetric
synthesis11–18 (Fig. 1a).
Their distinct structural features, together with the significance
of these biaryl core scaffolds, have galvanized the development of
highly efficient preparation methods. To this end, atroposelective
aryl–aryl cross-coupling is the most efficient and straightforward
route, as is evident from documentation of the diverse range of
transition-metal-catalysed protocols (Fig. 1b). These include con-
ventional transition-metal-catalysed cross-coupling reactions and
aryl C–H activation19–26 and oxidative C–H/C–H cross-couplings
enabled by a metal complex via a radical course27,28. Although a
direct C–H functionalization strategy negates the need to prefunc-
tionalize both coupling partners, it was rarely fruitful for enanti-
oselective construction of hindered biaryls before Colobert’s work26
due to the discord between the temperature tolerance of the rota-
tional axis and the high temperature required for C–H activation.
On the other hand, the oxidative aryl C–H/C–H cross-coupling
that proceeds via metal-induced radical formation suffers from
poor chemoselectivity and limited substrate scope for a stringent
redox potential difference between two coupling partners27,28. The
pursuit of a universal and robust catalytic approach to obtain opti-
cally active biaryls by designing and exploiting coupling technology
is therefore of great synthetic significance and would open the gate
for the development of enantioselective catalytic transformations.
To transcend these synthetic constraints, inverting the electronics
of an intrinsically nucleophilic aryl component to electrophilic for
chiral aryl C–H/C–H cross-coupling represents one ideal solution.
The interaction of a chiral electrophilic catalyst with a conjugated
functional group tethered to an arene was envisioned to further
enhance the electrophilicity of the aromatic ring and, at the same
time, impose steric hindrance to restrain the plausible 1,2-addition
(Fig. 1d). However, the realization of this redox-neutral aryl–aryl
cross-coupling poses a formidable challenge, given that control of
the axial chirality often requires mild reaction conditions. In this
regard, our recent research endeavour showed that the azo group is
an adequate activating and directing group for aryl C–H functional-
ization29. Moreover, the azo functionality could deliver the nitrogen
functionality for the high-value biaryls 2-amino-2′-hydroxy-1,1′-
binaphthyl (NOBIN) and 1,1’-binaphthyl-2,2’-diamine (BINAM).
Aside from the abovementioned oxidative aryl C–H/C–H cross-
coupling via metal-induced radical formation, the synthesis of
enantioenriched NOBIN from BINOL still requires a lengthy syn-
thetic route30. On the other hand, with the exception of the works
by List31 and Kürti32 that afford enantiopure BINAMs via exquisite
organocatalytic [3,3]-diaza Cope rearrangement from mostly sym-
metrical 2,2′-hydrazonaphthalene (Fig. 1c), a versatile synthetic
protocol with wider substrate range remains to be demonstrated.
In line with our research goal to devise concise and pragmatic
synthetic methods for high-value axial chiral frameworks, we there-
fore embarked on the exploration of azo-tethered aryl substrates
for the asymmetric construction of NOBIN and BINAM deriva-
tives in a redox-neutral cross-coupling. Driven by recent prog-
ress33–38 and our understanding of asymmetric biaryl synthesis39,
we here detail a highly efficient chiral phosphoric acid (CPA)–salt
complex or Ni(OTf)2/chiral bis(oxazoline) (BOX) ligand-catalysed
redox-neutral cross-coupling of 2-naphthols or 2-naphthylamines
with azonaphthalene derivatives, providing a wide range of opti-
cally active NOBIN and BINAM derivatives with excellent yields
and enantiocontrol. Moreover, the valuable NOBINs and BINAMs
were afforded via facile cleavage of the N–N bond with high

1
Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, China. 2Academy for Advanced
Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, China. 3These authors contributed equally: Liang-Wen Qi and Shaoyu Li.
*e-mail: wang.j@sustc.edu.cn; tanb@sustc.edu.cn

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Articles NATurE CATAlysIs

a OR
Cl HN NH2·HCl O CO2H
O O

Cl NH
HO OH O
i
Pr O O O
H H H O O
OH O N N N
N H H
CHO OH H N N N N CO2Bn O O
HN H H O
HO O O O O
OH O O O
OH CHO HO2C
HO NH2 O CO2H
OH
i
Pr (–)-Gossypol OH Vancomycin

Natural product Pharmaceutical Bioactive molecule Host–guest chemistry

Ph Ph

NH OH O CH3 OMe
O N
O O N OR
OH N O
OH O O N O
RO N
H O
OH Polymer N
N CH3 OMe
R = C8H17, C10H21, C12H25, C14H29
Ph Ph
Chiral stationary phase
Fluorescent sensor Liquid-crystalline material Chiroptical switch

O O O O
O O OH PPh2 NH2 NH2
N
N H H N OH PPh2 OH NH2
N O O
O O O
O
n BINOL BINAP NOBIN BINAM

Microporous soluble polymer Interlocked nanotube Chiral ligands and catalysts

N

b c

Y R1 R1
[M] R1 NH Chiral phosphoric acid catalyst NH2
R2
+
R1 Chiral ligand R2 NH NH2
[3,3]-Sigmatropic rearrangement
X R2 R2

d
Key point:

2 Nucleophilic
4 H2N
NHR A 1 OH
NH2 B OH H
H 3 H Aryl umpolung strategy
st

H
taly

NH2 NH2
Ca

Redox-neutral Redox-neutral R N
N
cross-coupling cross-coupling Electrophilic
BINAM NOBIN

Fig. 1 | Axially chiral biaryl molecules and reaction development. a, Representative applications of optically active biaryls. b, Metal-catalysed asymmetric
cross-coupling for the construction of optically active biaryls. c, Asymmetric organocatalytic benzidine rearrangement by List and Kürti. d, Our designed
umpolung strategy for asymmetric cross-coupling of aryls.

enantioretention. This work is expected to provide an avenue for desired product 3a was formed in less than 20% yield for most exam-
rapid construction of NOBIN- and BINAM-based frameworks with ined CPAs when the reactions were conducted with 2-naphthol 2a
synthetic and catalytic potentials. in CH2Cl2 at room temperature. Furthermore, the enantioselectivity
was no higher than 47% e.e. with CPA1, suggesting CPA alone was
Results not sufficiently competent for this transformation (Table 1, entry 1).
Reaction development. First reported by the groups of Akiyama Inclusion of Lewis acids led to reduced enantioselectivity due to the
and Terada in 200440,41, uncovering the utility of CPAs has long been strong background reactions. Interestingly, reversed stereoselectiv-
part of our ongoing research efforts. Considering the adequacy of ity was observed when ScCl3, YbCl3 and particularly ZnCl2 were
these Brønsted acid catalysts in azo group activation, the proposed used, hinting at a CPA–Lewis acid interaction (Table 1, entries 2 and
organocatalytic atroposelective synthesis of NOBIN commenced 3). At this stage, we recognized the following issues: poor solubility
using azonaphthalene 1a as the electrophile. Intriguingly, by-prod- of ZnCl2 in organic solvents could prevent an effective Lewis acid–
ucts (3a-1 and 3a-2, Supplementary Table 1) predominated and the CPA interaction, and both ZnCl2 and CPA could compete to facilitate

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Table 1 | Optimization of the reaction conditions for CPA–salt-catalysed asymmetric cross-coupling

H
OH N
Catalyst, Lewis acid N CO2Me
+ H
N OH
N CO2Me CH2Cl2, temp.

1a, 0.11 mmol 2a, 0.1 mmol 3a

(S)-C1: Ar = 4-PhC6H4 Ar
Ar (S)-C2: Ar = 4-CF3C6H4
Ar
(S)-C3: Ar = 3,5-(CF3)2C6H3 O O
O O (S)-C4: Ar = 1-naphthyl P Ca
P O O O O
O OH P Ca (S)-C5: Ar = 2-naphthyl
O O (S)-C6: Ar = 9-phenanthryl
Ar (S)-C7: Ar = 9-anthryl Ar
Ar 2
(S)-C8: Ar = 4-(2-naphthyl)C 6H4 (R)-C9
2 Ar = 2-naphthyl
CPA1: Ar = 4-PhC6H4

Entry Lewis acid Catalyst Temperature (°C) Yield (%) e.e. (%)
1 – CPA1 rt <20 47
2 YbCl3 CPA1 rt <20 −5
3 ZnCl2 CPA1 rt <20 −10
4 ZnCl2 C1 rt 45 −25
5 ZnCl2 + AgBArF C1 rt 75 −33
6a Zn(BArF)2(CH3CN)6 C1 rt 86 −55
7a Zn(BArF)2(CH3CN)6 C1 0 82 −28
8 a
Zn(BArF)2(CH3CN)6 C1 60 87 −72
9a Zn(BArF)2(CH3CN)6 C1 80 87 −70
10b Zn(BArF)2(CH3CN)6 C1 rt 87 −75
11c Zn(BArF)2 C1 rt 88 −77
12 c
Zn(BArF)2 C2 rt 87 −62
13c Zn(BArF)2 C3 rt 75 −35
14c Zn(BArF)2 C4 rt 72 −20
15c Zn(BArF)2 C5 rt 91 −89
16 c
Zn(BArF)2 C6 rt 81 −40
17c Zn(BArF)2 C7 rt 85 −58
18c Zn(BArF)2 C8 rt 97 −86
19c Zn(BArF)2 C9 rt 55 −44
20 c,d
Zn(BArF)2 C5 0 93 −92
Conditions: Lewis acid (5 mol%), catalyst (6 mol%) and CH2Cl2 (6 ml) were added to a Schlenk tube under argon. After stirring at room temperature (rt) for 1 h, 1a and 2a were added and the reaction was
carried out at rt for 20 h. Isolated yield was provided and e.e. was determined by chiral HPLC analysis. aC1 (6 mol%), Zn(BArF)2(CH3CN)6 (5 mol%) and CH2Cl2 (6 ml) were added to a Schlenk tube under
argon. After stirring at 50 °C for 2 h, 1a and 2a were added. bPre-treatment of catalyst: Zn(BArF)2(CH3CN)6 (5 mol%) and C1 (6 mol%) were mixed in DCE (10 ml) for 1 h at 60 °C. Solvent was then removed
at 60 °C and this process was repeated twice to give the freshly prepared catalyst. cPre-treated catalyst: Zn(BArF)2(CH3CN)6 (5 mol%) and C1 (6.5 mol%) were used. dConducted in 8 ml CH2Cl2 at 0 °C.

the reaction, leading to difficult stereocontrol. Correspondingly,
AgBArF (10 mol%) was reacted with ZnCl2 (5 mol%) to generate
soluble Zn(BArF)2 in situ and CPA–Ca (6 mol%), imposing neg-
ligible background reaction at room temperature, was enlisted as
the chiral catalyst. Although improved chemical yield and enanti-
oselectivity were indeed observed, the instability of AgBArF hin-
dered its practicality (Table 1, entries 4 and 5). We resorted to using
the pre-prepared Zn(BArF)2(CH3CN)6 as the Lewis acid instead.
Gratifyingly, 3a was formed with 86% yield and 55% e.e. at room
temperature (Table 1, entry 6). Notably, the reaction at 0 °C gener-
ated 3a with 28% e.e., while 72% and 70% e.e. values were obtained
from those at 60 °C and 80 °C, respectively; suggesting the exchange
of CPA–Ca and Zn(BArF)2(CH3CN)6 had to occur at higher tem-
perature (Table 1, entries 7–9). To substantiate this hypothesis and
eliminate any unwanted background reaction promoted by excess
CPA–Ca at temperatures above 40 °C, this exchange procedure
was pre-conducted at 60 °C in 1,2-dichloroethane (DCE) and the
model reaction with this pre-generated catalyst gave 3a in 75% e.e.
at room temperature (Table 1, entry 10). Subsequent studies with
CPA–Ca loadings found that a combination of 6.5 mol% CPA–Ca
and 5 mol% Zn(BArF)2(CH3CN)6 was able to deliver 3a in 77% e.e.
and 88% yield (Table 1, entry 11). Following these trials, we set out
to refine the reaction conditions by screening various CPAs, and
(S)-C5, with a methyl-spiro backbone, stood out as the best catalyst
in the context of stereoselectivity (Table 1, entries 12–19). A lower
reaction concentration at 0 °C further improved the chemical yield
to 93% with 92% e.e. (Table 1, entry 20).
Substrate generality. With the optimal reaction conditions in hand,
we probed the substrate generality using a broad range of azonaph-
thalene and 2-naphthol derivatives. Overall, all tested substrates
gave the desired non-C2-symmetrical biaryls in synthetically use-
ful yields and enantioselectivities, which were hardly attainable via
conventional oxidative cross-coupling (Fig. 2). Swapping the methyl

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Ar
Zn(BArF)2(CH3CN)6 (5 mol%) R2 H
OH N
(S)-C5 (6.5 mol%) N CO2 R1 O O
R2 + R3 H P Ca
N OH O O
N CO2R1 DCM (8 ml), 0 °C
3–20 h R3
Ar
2
1 2 3 (S)-C5
Ar = 2-naphthyl

a Substrate scope of azonaphthalenes

Me MeO
H H H H H
N N N N N
N CO2Et N CO2iPr N CO2Bn N CO2Me N CO2Me
H H H H H
OH OH OH OH OH

3b, 88% yield, 91% e.e. 3c, 84% yield, 92% e.e. 3d, 93% yield, 89% e.e. 3e, 97% yield, 92% e.e. 3f, 80% yield, 87% e.e.

Ph Br NC Cl
H H H H H
N N N N N
MeO N CO2Me N CO2Me N CO2Me N CO2Me N CO2Me
H H H H H
OH OH OH OH OH

3g, 85% yield, 84% e.e. 3h, 99% yield, 90% e.e. 3i, 86% yield, 90% e.e. 3j, 84% yield, 86% e.e. 3k, 99% yield, 81% e.e.

b Substrate scope of 2-naphthols

H H H H H
N N N N N
N CO2Me N CO2Me N CO2Me N CO2Me N CO2Me
H H H H H
Me OH OH OH MeO OH OH

Me Me MeO
3l, 84% yield, 91% e.e. 3m, 99% yield, 91% e.e. 3n, 99% yield, 91% e.e. 3o, 82% yield, 90% e.e. 3p, 82% yield, 84% e.e.

H H H H H
N N N N N
N CO2Me N CO2Me N CO2Me N CO2Me N CO2Me
H H H H H
OH Ph OH OH Br OH OH

Ph Br
3q, 70% yield, 90% e.e. 3r, 78% yield, 87% e.e. 3s, 70% yield, 83% e.e. 3t, 72% yield, 90% e.e. 3u, 80% yield, 92% e.e.

H
H H H H N
N N N N N CO2Me
N CO2Me N CO2Me N CO2Me N CO2Me H
H H H H OH
AcO OH OH OH OH

NC OHC MeO2C
CO2Me
3v, 85% yield, 90% e.e. 3w, 73% yield, 95% e.e. 3x, 70% yield, 93% e.e. 3y, 85% yield, 90% e.e. 3z, 85% yield, 87% e.e.

c Phenol as the nucleophile and modifications of both coupling partners

H Me Br Me MeO
N H H H H
N CO2Me N N N N
H N CO2Me N CO2Me N CO2Me N CO2Me
MeO OH H H H H
OH OH OH OH

Me Br Me Me
OMe
3aa, 99% yield, 75% e.e. 3ab, 90% yield, 90% e.e. 3ac, 79% yield, 92% e.e. 3ad, 99% yield, 93% e.e. 3ae, 98% yield, 92% e.e.

Br Ph Me Br
H H H H H
N N N N N
MeO N CO2Me N CO2Me N CO2Me N CO2Me N CO2Me
H H H H H
OH OH OH OH OH

Me Me Me Br Me
3af, 95% yield, 91% e.e. 3ag, 99% yield, 93% e.e. 3ah, 99% yield, 94% e.e. 3ai, 78% yield, 90% e.e. 3aj, 87% yield, 89% e.e.

Fig. 2 | Substrate generality for CPA-salt catalysed asymmetric cross-coupling. Reaction conditions: 1 (0.11 mmol), 2 (0.10 mmol) and the freshly
prepared catalyst (5 mol%) in CH2Cl2 (8 ml) at 0 °C. a, Substrate scope of azonaphthalenes. b, Substrate scope of 2-naphthols. c, Modifications of both
coupling partners.

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SA SA
Ni(OTf)2 (10 mol%) R1 H
NHR3 N O O
L10 (15 mol%) N CO2Me
R1 + H
N R2 N N
N CO2Me DCM, 0 °C, 4–72 h NHR3
R2 Cy L10 Cy
1 4 5 SA = 3,5-(MeO)2C6H3

a Substrate scope of azonaphthalenes

Me Ph Br
H H H H H
N N N N N
N CO2Me N CO2Me MeO N CO2Me N CO2Me N CO2Me
H H H H H
NHBn NHBn NHBn NHBn NHBn

5a, 99% yield, 94% e.e. 5b, 98% yield, 91% e.e. 5c, 94% yield, 89% e.e. 5d, 96% yield, 91% e.e. 5e, 99% yield, 93% e.e.
Gram-scale : 99% yield, 94% e.e.

b Substrate scope of 2-naphthylamines

H H H H H
N N N N N
N CO2Me N CO2Me N CO2Me N CO2Me N CO2Me
H H H H H
NHBn NHBn NHBn NHBn NHBn

Me Ph Br MeO2C Ac
5f, 99% yield, 92% e.e. 5g, 99% yield, 92% e.e. 5h, 96% yield, 91% e.e. 5i, 98% yield, 93% e.e. 5j, 70% yield, 91% e.e.

H H H H
N N N N
N CO2Me N CO2Me N CO2Me N CO2Me
H H H H
Me NHBn MeO NHBn Br NHBn NHBn

5k, 99% yield, 94% e.e. 5l, 99% yield, 95% e.e. 5m, 99% yield, 94% e.e. 5n, 99% yield, 91% e.e.

c Variation of amine protecting group and modifications of both coupling partners

Me
5o, R3 = 4-ClC6H4CH2, 99% yield, 94% e.e. H H
H N
N 5p, R3 = 4-MeOC6H4CH2, 99% yield, 94% e.e. N
N CO2Me N CO2Me N CO2Me
H H H
5q, R3 = 4-PhC6H4CH2, 99% yield, 93% e.e. H
NHR3 N NHBn
5r, R3 = allyl, 66% yield, 90% e.e.
5s, R3 = propargyl, 63% yield, 90% e.e. Me
5t, 93% yield, 93% e.e. 5u, 98% yield, 91% e.e.

Br Br Me Ph
H H H H H
N N N N N
N CO2Me MeO N CO2Me N CO2Me N CO2Me N CO2Me
H H H H H
NHBn MeO NHBn NHBn NHBn Br NHBn

Br Me MeO2C
5v, 96% yield, 91% e.e. 5w, 94% yield, 87% e.e. 5x, 98% yield, 92% e.e. 5y, 98% yield, 91% e.e. 5z, 98% yield, 90% e.e.

Fig. 3 | Substrate scope of BINAM derivatives via Ni(OTf)2/SaBOX-catalysed asymmetric cross-coupling. Reaction conditions: 1 (0.10 mmol),
4 (0.12 mmol), Ni(OTf)2 (10 mol%) and L10 (15 mol%) in CH2Cl2 (4 ml) at 0 °C. a, Substrate scope of azonaphthalenes. b, Substrate scope of
2-naphthylamines. c, Modifications of both coupling partners.

moiety on the ester with an ethyl or isopropyl group provided the
adduct 3b or 3c in marginally lower yields, while the e.e. value of
3d was slightly reduced with benzyl ester. The substituents on the
naphthalene ring of azonaphthalene exerted negligible influence on
the reaction outcome (3e–3k). When methyl, phenyl or bromide
was appended at the C6 position of the substrate, excellent yields
and e.e. values were observed (3e, 3h and 3i). The introduction
of a methoxy group at the C6 or C7 position, on the other hand,
gave products 3f and 3g with e.e. values of 87% and 84%, respec-
tively. Of note, a C3 substitution resulted in an obvious decline of
the enantioselectivity (3k). Further assessments revealed that all
tested 2-naphthols with varied functionalities and substitution

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SA SA

Ni(OTf)2 (10 mol%) R2 H H O O H

OH N
L12 (15 mol%) N CO2R1
R2 + R3 H N N
N OH
N CO2R1 NaHCO3, CHCl3, rt 6–16 h
H H
R3 L12
1 2 3 SA = f-tBuC 6H4

a Verifying the method's generality

Me Ph
H H H H H H
N N N N N N
N CO2iPr N CO2Me N CO2Me N CO2Me N CO2Me N CO2Me
H H H H H H
OH OH OH MeO OH Br OH AcO OH

3c, 99% yield, 93% e.e. 3e, 98% yield, 91% e.e. 3h, 96% yield, 91% e.e. 3o, 99% yield, 92% e.e. 3t, 94% yield, 92% e.e. 3v, 98% yield, 91% e.e.

b Improvement from previous results

H H H H H H
N N N N N N
N CO2Bn MeO N CO2Me N CO2Me N CO2Me N CO2Me N CO2Me
H H H H H H
OH OH OH Ph OH OH MeO OH

MeO
OMe
3d, 98% yield, 93% e.e. 3g, 98% yield, 91% e.e. 3p, 99% yield, 92% e.e. 3r, 98% yield, 91% e.e. 3s, 96% yield, 86% e.e.a 3aa, 96% yield, 94% e.e.b

c New substrates explored

Ph Me Br
H H H H H
N N N N N
N CO2Me MeO N CO2Me N CO2Me N CO2Me MeO N CO2Me
H H H H H
OH MeO OH Me OH Br OH Br OH

Ph
3ak, 91% yield, 90% e.e. 3al, 98% yield, 91% e.e. 3am, 94% yield, 91% e.e.c 3an, 96% yield, 90% e.e.c 3ao, 98% yield, 90% e.e.

Fig. 4 | Substrate scope of NOBIN derivatives via Ni(OTf)2/SaBOX-catalysed asymmetric cross-coupling. Reaction conditions: 1 (0.10 mmol),
2 (0.12 mmol), NaHCO3 (0.05 mmol), Ni(OTf)2 (10 mol%) and L12 (15 mol%) in CHCl3 (4 ml) at room temperature. aConducted in 20 ml CHCl3.
b
3 equiv. of 2 was used. cConducted at 15 °C. a, Verifying the generality of the method. b, Improvement from previous results. c, New substrates explored.

patterns could undergo effective transformations to furnish atro-
pisomers 3l–3z. Interestingly, a C3 methyl-substituted substrate
exhibited commendable compatibility, as evident by the excellent
yield and selectivity offered in 3n, while most other products were
furnished in lower yields, ranging from 70% to 85% (3l, 3o–3z).
2-Naphthols bearing electron-withdrawing functionalities such as
cyano, aldehyde and ester groups underwent the cross-coupling
reaction to afford compounds 3×−3z with excellent stereocontrol.
Remarkably, a substituted phenol in place of 2-naphthol was also a
suitable nucleophilic partner, giving 3aa in quantitative yield, albeit
in only 75% e.e. The synthesis of axially chiral adducts 3ab–3aj was
performed using substituted azonaphthalene and 2-naphthol part-
ners. Experimental data from 3ad–3ah further attested to our pre-
vious observation that a C3 methyl-substituted naphthol substrate
performed well under the reaction conditions.
Subsequently, the generality and limitations of our protocol were
further evaluated by adopting 2-naphthylamine as the nucleophile
to assemble enantioenriched BINAM derivatives. Disappointingly,
extensive efforts in a massive parallel screening of conditions were
unsuccessful in obtaining good stereocontrol. The best result (74%
yield and 53% e.e.) was obtained for the current CPA–salt complex-
based catalytic mode when the reaction was performed in CH2Cl2
at −30 °C with 10 mol% of CPA with a methyl-spiro backbone
(Ar = 3,5-Ph2C6H3). Considering the capability of Lewis acids to
activate the azo group and the innate difference between 2-naph-
thylamine and 2-naphthol, we turned to the Lewis acid and chiral
ligand for a model atroposelective transformation of 1a and ben-
zyl-protected 2-naphthylamine 4a (for details see Supplementary
Table 6). A meticulous examination of various reaction parameters
identified that a combination of 10 mol% of Ni(OTf)2 and 15 mol%
of sidearm-modified bis(oxazoline) (SaBOX) ligand L10 exhibited
the best catalytic activity with respect to the overall reaction out-
come. This 10 h reaction in CH2Cl2 could form the anticipated prod-
uct 5a in quantitative yield with up to 94% e.e. at 0 °C.
The optimal reaction conditions were then applied to synthesize
a variety of BINAM derivatives. As depicted in Fig. 3, the influence
of the substitution on the azonaphthalene 1 was initially investigated
and it was apparent that the position and electronics of the substitu-
ents exerted very limited effect, affording 5b–5e in excellent yields
and enantioselectivities. Similar results were obtained with the
introduction of substituents on 2-naphthylamines, giving BINAM
derivatives 5f–5n in near-quantitative yields and e.e. values exceed-
ing 90%. This chemistry was also well accommodated by other
benzyl-type protecting groups to generate 5o–5q and 5t with excel-
lent results, while the employment of allyl- and propargyl-protected
2-naphthylamines gave rise to 5r and 5s correspondingly in reduced
chemical yields but similar levels of stereoinduction. The flexibility
in the substituents on both coupling partners increased the product
range to also include 5u–5z with satisfactory enantioselectivities.
Notably, 5u–5w were amenable precursors for C2-symmetrical sub-
stituted BINAMs through facile deprotection and N–N bond cleav-
age steps. The near-quantitative chemical yields obtained for most

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NATurE CATAlysIs Articles
a Synthetic transformations

R1 R1 H
N
NH2 Raney-Ni, H2 (1 atm) N CO2Me Raney-Ni, H2 (30 bar) NH2
H
OH MeOH/KOH aq., 60 °C OH MeOH, rt, 8 h OH
R2 R2
86% yield, 93% e.e.
6 3 7, R1 = H, R2 = H
6a, R1 = R2 = H, 92% yield, 93% e.e.
H Raney-Ni, H2 (1 atm)
N
6g, R1 = MeO, R2 = H, 92% yield, 91% e.e. N CO2Me Ultrasound NH2
H
NHBn MeOH, 50 °C, 18 h NH2
6l, R1 = H, R2 = Me, 94% yield, 92% e.e.

6ak, R1 = R2 = Ph, 88% yield, 90% e.e.

5a, 94% e.e. 8, 82% yield, 94% e.e.

b Mechanistic studies
31P NMR ESI–HRMS of catalyst

O O Zn
O PO
645.1333
646.1329
2

645.6342 647.1330

646.6336

O O Ca 645.4722
O PO 645.7182 646.4698

645.0 645.5 646.0 646.5 647.0

2 m /z
2+ CPA–Ca + Zn(BArF)2

Zn 633.1492
CPA–Ca + Zn(BArF)2 O O O O (BArF)2
O PO P
O O
Ca

633.6514
634.1532
2+
634.5711
635.0729
Ca
CPA–Ca + Ca(BArF)2 O O O O 633.0 633.5 634.0 634.5 635.0 635.5
O PO P
O O
(BArF)2
m /z
Ca
CPA–Ca + Ca(BArF)2
659.1135

2+ 657.1151 658.1157

CPA–Zn + Zn(BArF)2 Zn
O O O O
(BArF)2
OPO P
O O 658.6173
Zn
659.2179

657.6197

657.2658 657.9369

657.0 657.5 658.0 658.5 659.0

m /z
7 –8 –9 –10 –11 –12 –13 –14 –15 –16 -
CPA–Zn + Zn(BArF)2
f1 (ppm)

Fig. 5 | Synthetic transformations and mechanistic studies. a, Synthetic transformations of NOBIN and BINAM derivatives. (b, Mechanistic investigations
for CPA–salt complex-based catalytic system.

biaryl products demonstrate the practicality of this method. Also, a
gram-scale reaction delivered 5a in analogous yield and enantiose-
lectivity, implying that this protocol should be well suited for large-
scale chemical production. The absolute configuration of 5o was
determined by X-ray crystallographic analysis after recrystallization
and those of other products in Fig. 3 were assigned by analogy.
We next investigated the compatibility and superiority of
this Ni/chiral BOX ligand system to construct NOBIN deriva-
tives with respect to the CPA–salt complex-based catalytic sys-
tem. Although these conditions were first found inapplicable for
the 2-naphthol nucleophile, exciting results were obtained after
switching the chiral ligand and reaction solvent and including
NaHCO3 as the base. The best results (99% yield and 93% e.e.)
were secured with the reaction conducted in CHCl3 at room
temperature. For the gram-scale reactions, no deterioration of
reaction outcome was observed under standard conditions, and
a slightly lower e.e. (91%) was only observed with 2.5 mol% cata-
lyst loading (Supplementary Fig. 2). Selected substrates with
diverse ester groups as well as substitutions on azonaphthalene 1
and 2-naphthol 2 were examined, all of which accomplished the
reaction in stereoselectivities similar to those with the previous
CPA–salt complex but with higher yields (3c, 3e, 3h, 3o, 3t and
3v). This method also complemented the former approach by
enhancing the stereochemical outcome for substrates formed in
poorer enantioselectivities (3d, 3g, 3p, 3r, 3s and 3aa). Finally,
five additional highly enantioenriched NOBIN derivatives were
prepared with excellent stereocontrol, highlighting the expedi-
ency and breadth of this protocol (Fig. 4).

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Articles NATurE CATAlysIs

Table 2 | Control experiments

H
OH N
Catalyst N CO2Me
+ H
N OH
N CO2Me CH2Cl2 (8 ml), 0 °C, 2 days

1a, 0.11 mmol 2a, 0.10 mmol 3a

Entry Catalyst system Yield (%) e.e. (%)

1 Ca(CPA)2 (10 mol%) – –
2 Zn(CPA)2 (10 mol%) 15 38
3 Ca(CPA)2 (3 mol%) Zn(CPA)2 (10 mol%) 10 70
4 Zn(BArF)2 (5 mol%) Zn(CPA)2 (6.5 mol%) 95 70
5 Ca(BArF)2 (5 mol%) Ca(CPA)2 (6.5 mol%) 18 36
6 Zn(BArF)2 (5 mol%) Ca(CPA)2 (6.5 mol%) 93 92
Conditions: The catalyst (entries 1–2) or its solution (entries 3–6) was added to the solution of 1a (0.11 mmol) and 2a (0.10 mmol) in CH2Cl2 at 0 °C. The reaction was then carried out at 0 °C for 2 days.
Pre-treatment of catalyst (entries 3–6): the two catalysts were mixed in DCE (10 ml) for 1 h at 60 °C, the solvent was then removed at 60 °C. This process was repeated twice to give the freshly prepared
catalyst, which was dissolved in 2 ml of CH2Cl2 to form its solution.

Ni(OTf)2 + SaBOX

1
NOBIN (3) [NiL*]2+ 2 –OTf

Chirality transfer

2+
2+ O
H OMe
N
N O
H H O R N
O Ni N
Ni
L* N O
N R
C
OMe A

2 + Base

Base O +

O O [Base-H]+ –OTf
[Base-H]+ –OTf R N
Ni N
N O
N R
OMe
B

Fig. 6 | Plausible mechanism for Ni-catalysed asymmetric cross-coupling. The catalytic cycle involes stereocontrol nucleophilic aromatic substitution and
a rearomatization process along with central-to-axial chirality conversion.

Synthetic transformations. The transfer of axial chirality com-
pleted with high fidelity when several NOBIN derivatives (3a, 3g, 3l
and 3ak) were converted to corresponding NOBINs 6 in good yields
via N–N bond cleavage in basic conditions with Raney nickel cata-
lyst under a 1 atm hydrogen atmosphere. Notably, NOBIN 6a could
be further hydrogenated to an analogue 7 in one pot with syntheti-
cally useful yield and enantioselectivity when the reaction was car-
ried out under higher pressure under neutral conditions (Fig. 5a).
Similarly, enantiopure BINAM 8 was obtained in 82% yield with
high enantioretention (94%) from 5a. The absolute configuration of
3a was assigned as (S) by comparing the chiral HPLC spectrum with
that of commercially available (S)-NOBIN. Those of other products
3 were assigned analogously.
Mechanistic studies. To acquire detailed mechanistic insights, a
series of control experiments were performed. First, a nonlinear
relationship between the enantiopurity of the catalyst and product
was observed, implying the generation of an active species contain-
ing two chiral phosphate anions and precluding single metal (Zn or
Ca) phosphate complex catalysis with a BArF counterion (for details
see Supplementary Fig. 3)31,42,43. Furthermore, the lack of product
formation with the CPA–Ca catalyst at 0 °C was consistent with the
negligible background reaction below room temperature. The pres-
ence of CPA–Zn (10 mol%) alone furnished 3a in 15% yield with
38% e.e. At the same time, the increased stereoselectivity of 70% e.e.
obtained with 3 mol% CPA–Ca and 10 mol% CPA–Zn implied for-
mation of the Ca–CPA–Zn complex, vital for chirality induction.

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NATurE CATAlysIs
The low yield was attributed to the poor solubility of the salts in
CH2Cl2 when the BArF counterion was absent. Additionally, reac-
tion with Zn(CPA)2 and Zn(BArF)2 afforded the target product
in 95% yield with 70% e.e., but only 18% yield and 36% e.e. were
achieved with Ca(CPA)2 and Ca(BArF)2 as co-catalyst. The most
optimal results (92% e.e. and 93% yield) were obtained when using a
mixture of 6.5 mol% Ca(CPA)2 and 5 mol% Zn(BArF)2 as co-catalyst
(catalyst ratio of the optimized conditions) (Table 2). Pronounced
variation of the chemical shifts in 31P NMR (ZnCa(CPA)22+,
−11.88 ppm; Ca2(CPA)22+, −11.46 ppm; Zn2(CPA)22+, −8.13 ppm) as
well as ESI-HRMS analysis of the freshly prepared catalyst showing
a peak of m/z 645.1333 bearing two positive charges further point to
ZnCPA2Ca2+ as the coordination mode of the active catalyst (Fig. 5b).
Based on the experimental results from the Ni(OTf)2/chiral
BOX ligand catalytic system and reference to preceding mechanistic
investigations of Ni-catalysed asymmetric reactions44–48, a plausible
catalytic cycle was outlined in Fig. 6. This reaction is thought to
commence with coordination of compound 1 with the nickel(ii) and
SaBOX ligand complex in a bidentate fashion, giving rise to species
A, with enhanced electrophilicity on the aromatic ring. Subsequently,
the deprotonated 2-naphthol 2 approaches A from the apical posi-
tion, which points away from the indane group of the BOX ligand
for minimal steric repulsion and sits parallel to the naphthalene ring
of 1a due to π–π stacking (species B). Compound 2 then performs
nucleophilic attack on activated azonaphthalene from the Si face to
generate C bearing two adjacent central chiralities. An efficient cen-
tral-to-axial chirality conversion featuring a rearomatization process
via C–H bond cleavage and N–H/O–H bond formation gives the
desired thermodynamically stable compound 3.
Conclusions
In summary, this work signifies a major departure from transition-
metal based cross-coupling reactions to generate a myriad of unex-
plored NOBIN and BINAM derivatives in excellent yields and
enantiopurities through a rationally designed redox-neutral cross-
coupling strategy. First, a CPA–salt complex-based system catalysed
the asymmetric redox-neutral cross-coupling of azonaphthalenes
and 2-naphthols to yield NOBIN derivatives in which mechanistic
studies credited a ZnCPA2Ca2+ complex as the actual active catalyst.
Complementarily, optically pure BINAM derivatives were prepared
from 2-naphthylamines with a Ni(OTf)2 and chiral BOX ligand
catalytic system. This Lewis acid catalysis approach was applicable
to 2-naphthol substrates by marginal modification of the reaction
conditions, allowing access to even more NOBIN derivatives with
improved chemical yields and enantioselectivities, thereby comple-
menting the former. Adept enantioretentive chemical transforma-
tions on the obtained products to NOBINs and BINAMs through
Raney nickel-catalysed hydrogenation showed the synthetic utility of
our protocols. This work is expected to give new impetus to the explo-
ration of these axially chiral molecules in terms of both synthesis and
application. Furthermore, our forays into the direct redox neutral
cross-coupling strategy would open up new vistas for the asymmetric
construction of other biaryls with unmined application potentials.
Methods
Materials. Chemicals were purchased from commercial suppliers and used without
further purification unless otherwise stated.
Synthesis of (S)-3 by CPA–Ca/Zn(BArF)2. Pre-treatment of catalyst:
Zn(BArF)2(CH3CN)6 (51 mg, 0.025 mmol) and CPA–Ca (39 mg, 0.0325 mmol) were
mixed in DCE (30 ml) for 1 h at 60 °C. The solvent was then removed in vacuo at
60 °C and this process was repeated twice to give the freshly prepared catalyst, which
was dissolved in 10 ml of DCM to form 2.5 mM l−1 catalyst. Standard synthetic
procedure: 2-naphthol 2 (0.1 mmol) was added to a solution of freshly prepared
catalyst (5 mol%) and compound 1 (0.11 mmol) in CH2Cl2 (8 ml) at 0 °C. The mixture
was then stirred at 0 °C for 3–20 h. After completion of the reaction (monitored
by thin-layer chromatography, TLC), the solution was directly purified by flash
chromatography on silica gel to afford the corresponding NOBIN derivatives (S)-3.
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Articles
Synthesis of (S)-3 by Ni(OTf)2/SaBOX. A mixture of Ni(OTf)2 (3.6 mg,
0.01 mmol), bisoxazoline L12 (9.3 mg, 0.015 mmol) and NaHCO3 (4.2 mg,
0.05 mmol) in CHCl3 (4 ml) was stirred at room temperature overnight under a
nitrogen atmosphere. Compound 1 (0.1 mmol) and 2-naphthol 2 (0.12 mmol) were
then added to the reaction. The mixture was stirred at room temperature until TLC
indicated that compound 1 had disappeared. The reaction mixture was directly
purified by flash chromatography on silica gel to afford the corresponding NOBIN
derivatives (S)-3.
Synthesis of (R)-5 by Ni(OTf)2/SaBOX. A mixture of Ni(OTf)2 (3.6 mg,
0.01 mmol) and BOX L10 (9.3 mg, 0.015 mmol) in CH2Cl2 (4 ml) was stirred at
room temperature overnight under a nitrogen atmosphere. The reaction was
cooled to 0 °C for 15 min and compound 1 (0.1 mmol) and 2-naphthylamine 4 were
added to the reaction. The mixture was stirred at 0 °C until TLC indicated that
compound 1 had disappeared. The reaction mixture was directly purified
by flash chromatography on silica gel to afford the corresponding BINAM
derivatives (R)-5.
Data availability
The X-ray crystallographic coordinates for structures of 3a-2 and 5o reported in
this Article have been deposited at the Cambridge Crystallographic Data Centre
(CCDC) under deposition numbers CCDC 1846849 (3a-2) and 1846841 (5o).
These data can be obtained free of charge from http://www.ccdc.cam.ac.uk/data_
request/cif. Experimental procedures and characterization of the new compounds
are available in the Supplementary Information. All other data are available from
the authors upon reasonable request.
Received: 5 September 2018; Accepted: 5 February 2019;
Published: xx xx xxxx
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Acknowledgements
The authors acknowledge financial support from the National Natural Science
Foundation of China (grants nos. 21772081, 21825105, 21702092 and 21801117),
Shenzhen Nobel Prize Scientists Laboratory Project (C17213101) and Shenzhen Special
Funds for the Development of Biomedicine, Internet, New Energy and New Material
Industries (JCYJ20170412151701379 and KQJSCX20170328153203). We dedicate this
paper to the memory of L.-R. Jin.
Author contributions
B.T. and J.W. conceived and directed the project. L.-W.Q. and S.L. designed and
performed experiments and prepared the Supplementary Information. S.-H.X. helped
collect some new compounds and in analysing the data. B.T., J.W. and S.-H.X. wrote the
paper. All authors discussed the results and commented on the manuscript.
Competing interests
The authors declare no competing interests.
Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/
s41929-019-0247-1.
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