Enantioselective Ni-Catalyzed Electrochemical Synthesis of Biaryl Atropisomers

Article abstract of DOI:10.1021/jacs.9b13117

A scalable enantioselective nickel-catalyzed electrochemical reductive homocoupling of aryl bromides has been developed, affording enantioenriched axially chiral biaryls in good yield under mild conditions using electricity as a reductant in an undivided cell. Common metal reductants such as Mn or Zn powder resulted in significantly lower yields in the absence of electric current under otherwise identical conditions, underscoring the enhanced reactivity provided by the combination of transition metal catalysis and electrochemistry.

Full text of DOI:10.1021/jacs.9b13117

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Communication
Enantioselective Ni-Catalyzed Electrochemical
Synthesis of Biaryl Atropisomers
Hui Qiu, Bin Shuai, Yun-Zhao Wang, Dong Liu, Yue-Gang Chen,
Pei-Sen Gao, Hong-Xing Ma, Song Chen, and Tian-Sheng Mei
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b13117 • Publication Date (Web): 11 May 2020
Downloaded from pubs.acs.org on May 11, 2020
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Enantioselective Ni-Catalyzed Electrochemical Synthesis of Biaryl Atro-
pisomers
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Hui Qiu,†,§ Bin Shuai,†,§ Yun-Zhao Wang,† Dong Liu,† Yue-Gang Chen,† Pei-Sen Gao,† Hong-
Xing Ma,†,‡ Song Chen,‡ and Tian-Sheng Mei*,†
†State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Insti-
tute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
‡School of Chemistry & Chemical Engineering, Yancheng Institute of Technology, Yancheng, Jiangsu 224051, China
Supporting Information Placeholder
Scheme 1. Enantioselective Biaryl Synthesis via Cross-
Coupling
ABSTRACT: A scalable enantioselective nickel-catalyzed
electrochemical reductive homocoupling of aryl bromides has
been developed, affording enantioenriched axially chiral biar-
yls in good yield under mild conditions using electricity as a
reductant in an undivided cell. Common metal reductants
such as Mn or Zn powder resulted in significantly lower yields
in the absence of electric current under otherwise identical
conditions, underscoring the enhanced reactivity provided by
the combination of transition metal catalysis and electro-
chemistry.
The construction of axially chiral biaryl compounds is im-
portant because they are essential structural units found in
ligands,1 organocatalysts,2 and natural products.3 Over the
past decade, various approaches have been developed to syn-
thesize atropisomeric biaryls,4 including transition metal-cat-
alyzed enantioselective synthesis via cross couplings between
an aryl halide and an arylmetal species5 the latter consisting of
organomagnesium,6 organozinc,7 organoboron,8 or or-
ganoindium reagents9 (Scheme 1a, left). Since arylmetal rea-
gents are typically prepared from the corresponding aryl hal-
ides, enantioselective reductive coupling of two aryl halides to
access axially chiral biaryls would provide an attractive step-
economical alternative. Although Ni-catalyzed reductive cou-
pling of two aryl halides using Mn, Zn, or Mg powders as re-
ducing agents has been extensively studied, enantioselective
variants are rare.10,11 As far as we know, the only example was
reported by Xu, Lin, and co-workers in 2010, wherein a chiral
BINOL-based monodentate phosphoramidite ligand was used,
but only modest enantioselectivity was achieved (up to 68%
ee).12 Alternatively, asymmetric oxidative homocoupling of 2-
naphthols is an useful method for the synthesis of simple
BINOLs (Scheme 1a, right).13 However, for 3,3’-Diaryl BINOLs
which have been recognized as preferred backbones for vari-
ous BINOL-based chiral ligands,14 the construction of which
via enantioselective oxidative coupling of 2-naphthols bearing
3-aryl substituents is rare. To the best of our knowledge, the
sole example was demonstrated by Katsuki and co-workers us-
ing an iron(salen) catalyst, but low ee values (47–74%) were
obtained without substituents present in the 3-position.15
General methods for providing both simple BINOLs and 3,3’-
diaryl substituted BINOLs is still lacking. Thus, the develop-
ment of a highly enantioselective Ni-catalyzed reductive cou-
pling of aryl halides to form biaryls with broad substrate scope
would provide a complementary and alternative method to
traditional cross-couplings and oxidative couplings for biaryl
synthesis.
Due to the need for more atom economical reaction plat-
forms to address growing global sustainability concerns and
awareness, the past decade has witnessed a renaissance in
electrochemical organic synthesis.16–18 As part of our ongoing
interest in merging cathodic reduction with transition metal
catalysis,19 we questioned whether enantioselective reductive
homocoupling of aryl halides could be achieved using electric
current as a reducing agent.20 Herein, we report the first ex-
ample of a Ni-catalyzed electrochemical enantioselective re-
ductive homocoupling of aryl bromides using chiral pyridine-
oxazoline ligands which affords biaryls in good yield and en-
antioselectivity using an undivided cell (Scheme 1b).21
At the outset, we surveyed various chiral ligands using 1-
bromo-2-methoxynaphthalene (1a) as the reaction partner
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and 10 mol % NiCl2•glyme as the catalyst under constant-cur-
standard. Enantioselectivities were determined by chiral
HPLC analysis.
1
rent electrolysis at 6 mA in the presence of one equivalent of
NaI in DMF in an undivided cell (Table 1). The Fu group
demonstrated that so-called pybox, box, and pyrox molecules
are privileged chiral ligands for Ni-catalyzed cross-coupling of
organometallic reagents with alkyl electrophiles.22 Unfortu-
nately, BINAP (L1), Ph-pybox (L2), i-Pr-box (L3), and i-Pr-biox
ligands (L4) did not lead to any significant amount of desired
biaryl product 3a; rather, starting material 1a was recovered
(Table 1). To our delight, i-Pr-6Me-pyrox ligand L5 resulted in
around 3% yield of desired product 3a in 15% ee. Encouraged
by this initial result, we systematically investigated the influ-
ence of pyridine and oxazoline ring substituents (L6–L15).23
An indane-fused oxazoline afforded the best enantioselectiv-
ity (L8 vs L5–L7), giving product 2a in 53% ee. Next, we inves-
tigated the pyridine ring substituent and found that other sub-
stituents including Et (L9), n-Pr (L10), cyclopropyl (L11), and
cyclopentyl (L12) all improved the enantioselectivity to ap-
proximately 83%. Since a benzyl group is more easily removed
than a methyl group, we next investigated the electrochemical
reductive coupling with substrate 1b. Interestingly, the enan-
tioselectivity is further improved and 90% ee was achieved us-
ing L12. Encouraged by these results, we prepared L13, L14 and
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3
4
5
6
7
8
9
L15 with different ring size in the pyridine substituent, but cy-
clohexyl-substituted L12 resulted in the best ee value (93%)
and 10% yield. The absolute configuration of 2b was assigned
as (R)-configuration (see Supporting Information for details).
Next, we optimized the reaction conditions using 1-bromo-
2-(benzyloxy)-1-naphthalene (1b) as the reaction partner and
L13 as the ligand to improve the reaction yield, as shown in
Table 2. The major byproduct in this electrochemical reduc-
tive coupling is debromination product 3b, which could be de-
rived from hydrolysis of the [ArNi] species. Accordingly, the
addition of 4 Å -molecular sieves significantly enhances the re-
action, as the desired product 2b is obtained in 65% isolated
yield and 93% ee (entry 2, Table 2) compared to just 10% yield
without molecular sieves (entry 1).24 Other desiccants such as
Na2SO4 and MgSO4 proved ineffective (entries 3 and 4). In ad-
dition, other Ni catalysts such as NiI2 and Ni(acac)2 resulted in
lower yields (entries 5 and 6). To our surprise, the use of
CH3CN as the reaction solvent resulted in lower yield and en-
antioselectivity (entry 7). Among the electrode materials we
tried, a sacrificial Fe anode is optimal (entries 8 and 9). Elec-
trolytes such as n-Bu4NI and n-Bu4NPF6 also resulted in di-
minished yields and enantioselectivities (entries 10 and 11). In
order to further diminish the moisture effect derived from the
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Table 1. Optimization of Chiral Liganda
Table 2. Reaction Optimization with Substrate 1ba.
aReaction conditions: 1b (0.30 mmol, 1.0 equiv), NiCl2•glyme
(10 mol%), L13 (12 mol%), NaI (0.3 mmol, 1.0 equiv), 4 Å MS
b
(250 mg) in DMF (5 mL) at 15 °C with 6 mA at 12 h. Yields
1
were determined by H NMR using mesitylene as an internal
standard. cEnantioselectivities were determined by chiral
d
e
HPLC analysis. Isolated yield. Reaction conditions: 1b (5.0
mmol, 1.0 equiv), NiCl2•glyme (10 mol%), L13 (12 mol%), NaI
(1.2 mmol, 0.24 equiv), 4 Å MS (250 mg) in DMF (20 mL) at 12
mA for 36 h.
aReaction conditions: 1a or 1b (0.30 mmol, 1.0 equiv.),
NiCl2•glyme (10 mol%), ligand (15 mol%), and NaI (0.3 mmol,
1.0 equiv.) in DMF (5 mL) at 15 °C for 12 h. Conversion and
1
yields determined by H NMR using mesitylene as internal
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Table 3. Substrate Scope
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a5 mmol scale reaction. bMn as reductant. c0.3 mmol scale. dReaction conditions: –10 °C and 1.0 equiv of NaI. L9 for 2o–2ac, L13 for
2b–2n, 2ad, and 2ae. eL4 is used instead of L9 or L13, 1.0 equiv n-Bu4BF4 is used instead of NaI.
reaction system, we scale up the reaction. Satisfied isolated
yield (81%) was achieved with slight erosion of enantioselec-
tivity (88% ee) when the reaction was performed on 5 mmol
scale at 12 mA for 36 h (entry 12). To our delight, decreasing
the temperature to 0 °C resulted in good yield (88%) and en-
antioselectivity (90% ee) (entry 13). Finally, control experi-
ments indicated that Ni catalyst and electrical current are
both essential for this reacton (entries 14 and 15). It is also
worth noting that the use of a stoichiometric amount of Mn
or Zn powder results in lower yields in the absence of electrical
current under otherwise identical conditions (entries 16 and
17).
With the optimized reaction conditions in hand, we inves-
tigated the generality and limitations of this electrochemical
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reductive homocoupling reaction. As shown in Table 3, naph-
Supporting Information for details), which indicates that the
Ni(II) catalyst is likely to be preferentially reduced in favor of
aryl halides in this electrochemical reductive coupling reac-
tion. Furthermore, the addition of 1p to 5 resulted in the loss
of the oxidation peak, indicative of a Ni(0)/Ni(I) redox couple,
indicating that oxidation addition of 1p to Ni(0) occurred
readily (Figure 1).25
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5
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thalenes substituted with a variety of functional groups such
as alkyl, ether, alkene, boron, ester, and chloro groups were
well tolerated under the electrochemical reductive coupling
condition, affording good yields and enantioselectivities (2b–
2n). More importantly, electrochemical homocoupling of
naphthyl bromides bearing 3-aryl substituents afforded biaryl
products with good yields and enantioselectivities (2o–2ac).
Thus, this electrochemical reductive coupling reaction pro-
vides a valuable alternative to the syntheses of simple BINOLs
and 3,3’-diaryl BINOLs. For comparison, the use of Mn as a
reducing agent typically resulted in lower yields (Table 3). The
direct comparison of the electrochemical condition with the
condition using metal reductants (Mn) clearly shows the su-
perior catalytic efficiency of this electrochemical variant (see
Table S11–16 in the Supporting Information for details). In ad-
dition, the structure of 2r was unambiguously verified by X-
ray analysis and absolute configuration of 2r was assigned as
(R)-configuration (see Supporting Information for details).
Looking beyond enantioselective BINOL synthesis, monoaryl
bromides afforded reasonable yields although with slightly di-
minished enantioselectivities (2ad and 2ae), while 2-phe-
nylester-functionalized bromonaphthalene 1af homocoupled
to give 2af in fair yield but significantly reduced enantioselec-
tivity. Lastly, homocoupling of 8-bromoquinoline resulted in
moderate yield of 2ag. Unprotected BINOLs are easily ob-
tained from the protected BINOLs by hydrogenation under
mild conditions. For example, free BINOL 4 can be obtained
upon hydrogenation of 2x in good yield without erosion of en-
antioselectivity as shown in Scheme 2.
6x10-5
a blank
b 5
5x10-5
9
g
c 5+1p (2 equiv)
f
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d 5+1p (6 equiv)
e 5+1p (10 equiv)
f 5+1p (20 equiv)
-2.02 V
-1.70 V
4x10-5
3x10-5
2x10-5
1x10-5
0
e
d
c
g
5+1p (30 equiv)
-1.52 V
b
-1.90 V
-1.54 V
a
-1.33 V
-1x10-5
-1.0
-1.5
-2.0
E (V) vs Ag/AgNO3/V
Figure 1. Cyclic voltammograms recorded on a glassy carbon
electrode (area = 0.03 cm2), The scan rate is 100 mVs-1: (a) DMF
containing 0.1 M n-Bu4NPF6; (b) DMF containing 0.1 M n-
Bu4NPF6, after addition of 2.5 mM 5; (c) DMF containing 0.1
M n-Bu4NPF6, after addition of 2.5 mM of 5 and 5 mM of 1p.
(d) DMF containing 0.1 M n-Bu4NPF6, after addition of 2.5 mM
of 5 and 15 mM of 1p. (e) DMF containing 0.1 M n-Bu4NPF6,
after addition of 2.5 mM of 5 and 25 mM of 1p. (f) DMF con-
taining 0.1 M n-Bu4NPF6, after addition of 50 mM of 5 and 15
mM of 1p. (g) DMF containing 0.1 M n-Bu4NPF6, after addition
of 2.5 mM of 5 and 75 mM of 1p.
Scheme 2. Synthesis of Chiral BINOL 4x.
Based on literature precedent25,26 and our results, a plausi-
ble mechanism is presented for this Ni-catalyzed electro-
chemical reductive coupling process (Scheme 4). Initially, the
Ni(II) catalyst is reduced to Ni(0) upon cathodic reduction.
After oxidative addition of an aryl bromide to Ni(0), aryl Ni(II)
species is formed, which may be reduced to an aryl Ni(I) com-
plex by another electrochemical reduction.25 Upon oxidative
addition followed by reductive elimination, biaryl product is
formed, along with the generation of Ni(I) species, which
could be reduced to Ni(0) by cathodic reduction and complete
the catalytic cycle.25 However, we could not rule out other
pathways at this stage.27
Scheme 3. Synthesis of Complex 5.
Scheme 4. Plausible Catalytic Cycle
In order to gain further insight into this electrochemical re-
ductive homocoupling reaction, we prepared the dimeric
[NiCl2(pyrox)]2 complex 5, the structure of which was unam-
biguously assigned by X-ray analysis (Scheme 3). In addition,
complex 5 showed three reductive peaks (–1.52 V, –1.70 V, and
–2.02 V vs. Ag/Ag+), corresponding to the successive for-
mation of nickel(I), nickel(0), and [nickel(0)pyrox]•ˉ species
(Figure 1).25 In contrast, the reduction potentials of substrate
1p are around -2.30 V and -2.64 V vs. Ag/Ag+ (See Figure S1 in
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(6) (a) Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. Asymmet-
ric Synthesis Catalyzed by Chiral Ferrocenylphosphine-Transi-
tion-Metal Complexes. 6. Practical Asymmetric Synthesis of 1,1′-
In summary, we have demonstrated the first example of a
Ni-catalyzed enantioselective electrochemical reductive cou-
pling of aryl bromides in an undivided cell at 0 °C, affording
axially chiral binol derivatives in good yield and enantiomeric
excess. The protocol is operationally simple and robust. Fur-
ther efforts to develop transition metal-catalyzed enantiose-
lective electrochemical reductive cross-couplings of aryl hal-
ides are currently underway in our laboratory.
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ASSOCIATED CONTENT
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Supporting Information
The Supporting Information is available free of charge on the
ACS
Publications
website.
Detailed experimental procedures and characterization of
new compounds (PDF)
(8) For selected recent examples, see: (a) Shen, D.; Xu, Y.; Shi,
S.-L. A Bulky Chiral N-Heterocyclic Carbene Palladium Catalyst
Enables Highly Enantioselective Suzuki–Miyaura Cross-Coupling
Reactions for the Synthesis of Biaryl Atropisomers. J. Am. Soc.
Chem. 2019, 141, 14938–14945. (b) Xu, G.; Fu, W.; Liu, G. D.; Sena-
nayake, C. H.; Tang, W. Efficient syntheses of korupensamines A,
B and michellamine B by asymmetric Suzuki-Miyaura coupling
reactions. J. Am. Chem. Soc. 2014, 136, 570−573. (c) Shen, X.; Jones,
G. O.; Watson, D. A.; Bhayana, B.; Buchwald, S. L. Enantioselec-
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Miyaura reaction: Substrate scope and quantum mechanical in-
vestigations. J. Am. Chem. Soc. 2010, 132, 11278−11287. (d) Zhang,
S.-S.; Wang, Z.-Q.; Xu, M.-H.; Lin, G.-Q. Chiral diene as the ligand
for the synthesis of axially chiral compounds via palladium-cata-
lyzed Suzuki-Miyaura coupling reaction. Org. Lett. 2010, 12, 5546
−5549.
(9) Mosquera, A.; Pena, M. A.; Pꢀrez Sestelo, J.; Sarandeses, L.
A. Synthesis of axially chiral 1,1′-binaphthalenes by palladium-
catalysed cross-coupling reactions of triorganoindium reagents.
Eur. J. Org. Chem. 2013, 2555−2562.
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Corpet, M.; Gosmini, C.; von Wangelin, A. J. Reductive Cross-Cou-
pling Reactions between Two Electrophiles. Chem. Eur. J. 2014, 20,
6828–6842.
(11) For selected examples on Ni-catalyzed reductive coupling
of two aryl halides, see: (a) Gong, C.; Huo, C.; Wang, X.; Quan, Z.
Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Bromides
with Pyrimidin-2-yl Tosylates. Chin. J. Chem. 2017, 35, 1366–1370.
(b) Ackerman, L. K. G.; Lovell, M. M. Weix, D. J. Multimetallic
catalyzed cross-coupling of aryl bromides with aryl triflates. Na-
ture 2015, 524, 454–457. (c) Iranpoor, N.; Panahi, F. Nickel-Cata-
lyzed One-Pot Deoxygenation and Reductive Homocoupling of
Phenols via C–O Activation Using TCT Reagent. Org. Lett. 2015,
17, 214–217. (d) Qian, Q.; Zang, Z.; Wang, S.; Chen, Y.; Lin, K.; Gong,
H. Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides.
Synlett 2013, 24, 619–624. (e) Buonomo, J. A.; Everson, D. A.; Weix,
D. J. Substituted 2,2'-Bipyrdidines by Nickel Catalysis: 4,4'-Di-
tert-butyl-2,2'-bipyridine. Synthesis 2013, 45, 3099–3102. (f) Gos-
mini, C.; Bassene-Ernst, C.; Durandetti, M. Synthesis of function-
alized 2-arylpyridines from 2-halopyrdidines and various aryl hal-
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G.-Q.; Hong, R. A New Reagent System for Modified Ullmann-
AUTHOR INFORMATION
Corresponding Author
mei7900@sioc.ac.cn
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was financially supported by the Strategic Priority
Research Program of the Chinese Academy of Sciences (Grant
XDB20000000), the NSF of China (Grants 21821002, 21772222,
and 91956112), and S&TCSM of Shanghai (Grants 17JC1401200,
and 18JC1415600, and 19YF1458500).
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