Copper(II)-Catalyzed Asymmetric Photoredox Reactions: Enantioselective Alkylation of Imines Driven by Visible Light

Article abstract of DOI:10.1021/jacs.8b09251

Asymmetric photoredox catalysis offers exciting opportunities to develop new synthetic approaches to chiral molecules through novel reaction pathways. Employing the first-row transition metal complexes as the chiral photoredox catalysts remains, however, a formidable challenge, although these complexes are economic, environmentally friendly, and often exhibit special reactivities. We report in this Article the development of one class of highly efficient asymmetric/photoredox bifunctional catalysts based on the copper(II) bisoxazoline complexes (Cu^II-BOX) for the light-induced enantioselective alkylation of imines. The reactions proceed under very mild conditions and without a need for any other photosensitizer. The simple catalytic system and readily tunable chiral ligands enable a significantly high level of enantioselectivity for the formation of chiral amine products bearing a tetrasubstituted carbon stereocenter (36 examples, up to 98% ee). Overall, the Cu^II-BOX catalysts initiate the radical generation, and also govern the subsequent stereoselective transformations. This strategy utilizing chiral complexes comprised of a first-row transition metal and a flexible chiral ligand as the asymmetric photoredox catalysts provides an effective platform for the development of green asymmetric synthetic methods.

Full text of DOI:10.1021/jacs.8b09251

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Article
Copper(II)-Catalyzed Asymmetric Photoredox Reactions:
Enantioselective Alkylation of Imines Driven by Visible Light
Yanjun Li, Kexu Zhou, Zhaorui Wen, Shi Cao, Xiang Shen, Meng Lei, and Lei Gong
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 16 Oct 2018
Downloaded from http://pubs.acs.org on October 16, 2018
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Copper(II)-Catalyzed
Asymmetric
Photoredox
Reactions:
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Enantioselective Alkylation of Imines Driven by Visible Light
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Yanjun Li, Kexu Zhou, Zhaorui Wen, Shi Cao, Xiang Shen, Meng Lei, Lei Gong*
Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of
Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian
361005, China.
E-mail: gongl@xmu.edu.cn
ABSTRACT
Asymmetric photoredox catalysis offers exciting opportunities to develop new
synthetic approaches to chiral molecules through novel reaction pathways.
Employing the first-row transition metal complexes as the chiral photoredox
catalysts remains however a formidable challenge although these complexes are
economic, environmentally friendly and often exhibit special reactivities. We report in
this paper the development of one class of highly efficient asymmetric/photoredox
bifunctional catalysts based on the copper(II) bisoxazoline complexes (CuII-BOX) for
the light-induced enantioselective alkylation of imines. The reactions proceed under very
mild conditions and without a need for any other photosensitizer. The simple catalytic
system and readily tunable chiral ligands enable a significantly high level of
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enantioselectivity for the formation of chiral amine products bearing a tetrasubstituted
carbon stereocenter (36 examples, up to 98% ee). Overall, the CuII-BOX catalysts initiate
the radical generation, and also govern the subsequent stereoselective
transformations. This strategy utilizing chiral complexes comprised of a first-row
transition metal and a flexible chiral ligand as the asymmetric photoredox catalysts
provides an effective platform for development of green asymmetric synthetic methods.
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INTRODUCTION
Visible-light photoredox catalysis has been developed into a powerful tool to construct
carbon-carbon or carbon-heteroatom bonds in organic synthesis.1 Through high-energy
intermediates such as radicals and radical ions, unique reactions that are unavailable under
thermal conditions can be accessed. Significant advances have been achieved in this field
by employing ruthenium(II), iridium(III) complexes or organic dyes as photoredox
catalysts.2
In contrast, the use of first-row transition metal complexes such as copper species has
been much less frequently reported.3–7 Beside the aspects of relatively shorter excited-state
lifetimes and weaker visible-light absorption, an inherent drawback of copper complexes
as photoredox catalysts is that the low reduction potentials of CuIICuI might impede the
closure of a photocatalytic cycle.4 Very recently, an appealing strategy involving light-
accelerated homolysis (CuII-X CuII-Y CuI + Y‧) has been developed to address this
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problem, and opens up new avenues for copper-based photocatalysis.8
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On the other hand, asymmetric catalysis promoted by visible light is emerging as an
attractive synthetic strategy for chiral organic molecules. However, achieving a high level
of enantioselectivity in the photoredox reactions remains a remarkable challenge.9 In the
limited success that has been reported, the solutions typically rely on the dual catalysis
involving a ruthenium or iridium-based photocatalyst and a chiral co-catalyst, which often
contains one or more precious metals.10 Bifunctional catalysis employing a chiral-at-
iridium or rhodium complex as both the asymmetric catalyst and photocatalyst has also
been developed by Meggers and other groups recently.11,12 Although use of a single chiral
complex of a first-row transition metal as the asymmetric photocatalyst would be
economically attractive and environmentally friendly, it has been scarcely explored.13–15
An impressive pioneering work by Fu et al. disclosed light-promoted enantioselective C-
N cross-couplings by a copper(I) catalyst containing a chiral phosphine ligand.13 Even
more recently, a nickel(II)-DBFOX-catalyzed enantioselective photoredox reaction of α,β-
unsaturated carbonyl compounds and α-silylamines was developed in our laboratory.14
These studies revealed that chiral complexes of first-row transition metal exhibit special
features and reactivities in photochemical reactions beyond the role as inexpensive
alternatives to ruthenium or iridium-based photocatalysts. Therefore, development of new
chiral photocatalysts or applications based on the first-row transition metals would be of
great value and in high demand.
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Herein, we disclose the development of one class of copper(II) bisoxazoline
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complexes (CuII-BOX) as asymmetric/photoredox bifunctional catalysts in the light-
induced enantioselective alkylation of imines (Scheme 1). Without the need of any other
photosensitizer and under very mild conditions, the copper-catalyzed photochemical
reactions afforded a range of chiral amine products containing a tetrasubstituted carbon
stereocenter with good to excellent enantioselectivities.
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R1
R'
N
R'
R1
R3
HN
O
O
Cu(BF4)2/BOX
N
BF3K
+
R3
Ar
N
COR2
36 examples
CHCl3, -20 C
blue LEDs
Ar
COR2
[CuII]
R
R
up to 98% ee
[CuII-BOX]
[CuII-BOX]
R1
[CuII-BOX]
R3
R3
HN
Photoredox
Catalysis
Asymmetric
Catalysis
[imine-CuII-BOX]
Ar
COR2
• chiral photoredox catalysts of first-row transition metal
• light-active copper(II) catalysts
• radical pathway providing with high ees • broad scope for both cyclic and acyclic imines
Scheme 1. Strategy of using a single CuII-BOX complex as the chiral photoredox
bifunctional catalyst.
 RESULTS AND DISCUSSION
Initial experiments. In our primary studies on catalyst selection, we found that
several chiral copper(II) bisoxazoline complexes (CuII-BOX) exhibited obvious absorption
in the visible-light region. In particular, absorption in the range of 400–550 nm, attributed
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to metal-ligand-charge-transfer (MLCT), was one of the key features required for a visible-
light photocatalyst. In combination with their readily tunable chiral environment, redox-
active metal center and the established photoactivities of their reduced states–copper(I)
species,4 we assumed that these chiral copper(II) complexes might be potential candidates
for the development of asymmetric photoredox catalysis based on the first-row transition
metals.
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Accordingly, we developed a model catalytic system using in-situ generated copper(II)
bisoxazoline complexes as the catalyst, benzyl trifluoroborate 2a as the radical precursor,
and an α-carbonyl imine 1a as the coupling partner.16 The α-carbonyl adjacent to the C=N
bond of the imine substrate was thought to be able to act as a directing group for the
asymmetric induction.17 Such a photochemical reaction would lead to the development of
an inexpensive method for radical-based enantioselective alkylation of imines under mild
and convenient conditions.18
In an initial experiment, the mixture of substrate 1a, 2a, premixed copper salt
Cu(BF4)2∙H2O (10 mol%) and ligand L1 (11 mol%) in chloroform was stirred at 25 °C in
argon under irradiation with a 24 W blue LEDs lamp. The desired product (3a) was
produced in quantitative yield and with 74% ee (Table 1, entry 1). In the absence of the
blue LEDs lamp, stirring in the dark at room temperature (entry 2) or 80 °C (entry 3),
removing the ligand (entry 4) or the copper salt (entry 5), the reaction failed to proceed.
Addition of another photosensitizer such as [Ru(bpy)3](PF6)2 dramatically accelerated the
reaction (2 h, 100% conversion, entries 6–7), implying a light-induced pathway. Water was
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well-tolerated in the system (entry 8) while protic additive such as methanol led to the
lower reaction rate and slightly reduced enantioselectivity (entry 9).
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Table 1. Initial experiments and optimization of reaction conditionsa
Cl
O
O
N
O
O
S
S
BF3K
[M] L*
/
NH
+
Cl
argon
light source
CO2Et
CO2Et
3a
1a
2a
Bn
N
Bn
N
R2
R3
O
O
O
O
O
O
Ph
Ph
N
N
N
N
R1
R1
Ph
Ph
L9
L8
1
2
3
L1
L2
L3
L4
L5
L6
L7
: R = Ph, R = R = Me
1
2
3
: R = iPr, R = R = Me
1
2
3
: R = Bn, R = R = Me
O
O
PPh2
PPh2
1
2
3
N
: R = Ph, R = Me, R = Bn
1
2
3
N
N
: R = Ph, R = R = Bn
1
2
3
Ph
Ph
: R = Ph, R = R = CH2Ph(4-tBu)
L10
1
2
3
L11
: R = Ph, R = R = CH2Ph[4-(1-Ad)]
entry
metal salt
ligand T (°C) light source t (h)
conv.
(%)b
ee
(%)c
74
1
2
3
4
5
Cu(BF4)2∙H2O L1
Cu(BF4)2∙H2O L1
Cu(BF4)2∙H2O L1
Cu(BF4)2∙H2O none
25
25
80
25
25
25
blue LEDs
none
6
quant.
12
12
12
12
2
0
0
0
0
n.a.
n.a.
n.a.
n.a.
73
none
blue LEDs
blue LEDs
blue LEDs
none
L1
6 d Cu(BF4)2∙H2O L1
quant.
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7 d
none
none
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
red LEDs
12
6
15
6
22
quant.
93
92
quant.
0
0
<5
37
76
quant.
quant.
quant.
52
19
<5
0
0
33
n.a.
73
68
69
70
n.a.
n.a.
n.d.
50
77
78
84
85
62
-57
n.d.
n.a.
n.a.
84
8 e Cu(BF4)2∙H2O L1
9 f Cu(BF4)2∙H2O L1
10
Cu(OTf)2
L1
11 Cu(MeCN)4BF4 L1
12
13
6
10
11
12
13
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Ni(OTf)2
Fe(OTf)3
L1
L1
21
21
6
6
6
6
6
6
6
6
6
6
6
6
3
3
12
21
14 Cu(BF4)2∙H2O L2
15 Cu(BF4)2∙H2O L3
16 Cu(BF4)2∙H2O L4
17 Cu(BF4)2∙H2O L5
18 Cu(BF4)2∙H2O L6
19 Cu(BF4)2∙H2O L7
20 Cu(BF4)2∙H2O L8
21 Cu(BF4)2∙H2O L9
22 Cu(BF4)2∙H2O L10
23 Cu(BF4)2∙H2O L11
24 Cu(BF4)2∙H2O L7
25 Cu(BF4)2∙H2O L7
26g Cu(BF4)2∙H2O L7
27g Cu(BF4)2∙H2O L7
28g Cu(BF4)2∙H2O L7
29g Cu(BF4)2∙H2O L7
UV lamps
blue LEDs
blue LEDs
blue LEDs
blue LEDs
quant.
quant.
quant.
99
85
87
89
89
-20
-40
aReaction conditions: 1a (0.10 mmol), 2a (0.15 mmol), metal salt (10 mol%), ligand (11
mol%), CHCl3 (5 mL), indicated temperature, indicated light source, under argon, see more
details for the screening of solvent and light source in ESI. bconversion determined by 1H-
NMR. cee value determined by chiral HPLC. din the presence of 2 mol% [Ru(bpy)3](PF6)2.
ein the presence of 10 equiv. H2O. fin the presence of 10 equiv. MeOH. greaction performed
with a concentration of 0.030 M (based on 1a). n.d. = not determined, n.a. = not applicable.
Other metal salts were also tested in this reaction and it was found that the cuprous
salt Cu(MeCN)4BF4 provided similar results (entry 11), while Ni(OTf)2 and Fe(OTf)3
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failed in generating the product (entries 12, 13). Ligand screening experiments showed that
the chiral BOX ligands with different substituents R1, R2 and R3 remarkably affected the
conversion and enantioselectivity (entries 14–19). For example, L2 (R1 = iPr) only
provided trace amounts of the product, while L3 (R1 = Bn) resulted in 37% conversion and
50% ee (entries 14, 15). Ligand L4–6 with two side chains (R2, R3) gave a slightly
improved the enantioselectivity (entries 16–18). Such side-chain effects of chiral BOX
ligands have been intensively investigated by Tang et al. and others.19 According to these
results, a sterically more demanding ligand (L7) with adamantyl-modification was
designed and used in the reaction. This gave the best result, a quantitative conversion in 6
h, with 85% ee (entry 19). Other oxazoline-type ligands L8–10 led to both lower reaction
rates and enantioselectivities (entries 20–22). The chiral diphosphine ligand (L11) failed
to deliver any product (entry 23). In all cases, the catalytic outcomes were strongly
dependent on the light source. The reaction under irradiation with a 30 W red LEDs lamp
did not proceed (entry 24), while the same process with a 15 W UV light provided lower
conversion (entry 25). Ultimately, the enantioselectivity was further improved to 89% ee
by increasing the concentration of 1a to 0.030 M and reducing the temperature to -20 ℃
(entries 26–29).
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Substrate scope. With the best catalyst and reaction conditions in hand, we next
evaluated the reaction scope. A range of alkyl trifluoroborates bearing substituents with
different electronic and steric properties were examined (Scheme 2). Primary benzyl
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trifluoroborates with electron-withdrawing substituents on the phenyl ring gave products
3a–i with better enantioselectivity (87–94% ee), while those with an electron-donating
substituent resulted in products 3k, l with reduced ee values. Halogen and ester substituents
were well tolerated, offering the opportunity for further functionalization of the chiral
sultam products. Naphthalen-2-ylmethyl trifluoroborate (product 3m) and thiophen-3-
ylmethyl trifluoroborate (product 3n) were also compatible under the standard conditions.
Moreover, a secondary benzyl trifluoroborate provided product 3o as a 1:1 diastereomeric
mixture with moderate ee values (59% and 59% ee). The two diastereomers could be
readily separated by silica gel chromatography. A tertiary alkyl trifluoroborate also
afforded the product (3p) in a good yield but with a low enantioselectivity of 24% ee.
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R
R
O
O
O
O
N
Cu(BF4)2·H2O (10 mol%)
S
S
1
BF3K
R3
O
O
NH
R
L7
(11 mol%)
R1
R2
R2
+
N
N
R3
CHCl3, -20 °C
argon, 24 W blue LEDs
CO2Et
[CuII]
CO2Et
3a p
Ph
in-situ generated
R = adamantyl
Ph
CuII-L7

1a
2a p

10
11
12
13
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CO2Me
F
Br
Cl
O
O
O
O
O
O
O
O
S
S
S
S
NH
NH
NH
NH
CO2Et
CO2Et
3b
CO2Et
3c
CO2Et
3a
3d
12 h, 96% yield
10 h, 98% yield
12 h, 99% yield
12 h, 95% yield
89% ee
87% ee
89% ee
93% ee
F
CF3
O
O
O
O
O
O
O
O
S
S
S
S
NH
NH
NH
NH
CF3
F
CF3
CO2Et
CO2Et
CO2Et
CO2Et
3e
3g
3h
3f
15 h, 96% yield
21 h, 97% yield
12 h, 96% yield
12 h, 95% yield
93% ee
94% ee
90% ee
89% ee
Ph
OMe
O
O
O
O
O
O
O
O
S
S
S
S
NH
NH
NH
NH
Br
CO2Et
CO2Et
3k
CO2Et
CO2Et
3j
3l
3i
10 h, 98% yield
7 h, 99% yield
10 h, 98% yield
14 h, 97% yield
81% ee
60% ee
85% ee
90% ee
O
O
O
O
O
O
O
O
S
S
S
S
S
NH
NH
tBu
CO2Et
NH
NH
Me
CO2Et
CO2Et
CO2Et
3oa
48 h, 84% yield
3n
3p
3m
10 h, 98% yield
11 h, 88% yield
10 h, 98% yield
75% ee
24% ee
82% ee
1:1 d.r., 59%/59% ee
a
Scheme 2. Reaction scope of alkyl trifluoroborates. reaction 1a+2o3o was performed
at 25 °C due to the low reaction rate.
N-Sulfonylimines containing a distinct α-carbonyl group adjacent to the imino moiety
(products 3q–s), or those with an electron-donating substituent (products 3t, 3u), an
electron-withdrawing substituent within the benzenesulfonyl ring (products 3v–x), or a
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fused naphthalenesulfonyl moiety (products 3y, 3z) were all tested (Scheme 3). The chiral
sultams containing a tetrasubstituted carbon stereocenter20 were obtained in 92–98% yield
and with 82–94% ee. The reaction of a six-membered N-sulfonylimine also proceeded
smoothly, producing 3za in 95% yield and with 80% ee. However, replacement of the α-
carbonyl group next to the imine moiety by a methyl group led to zero product formation
(product 3zb).
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O
O
O
O
N
COOMe
COOMe
Cu(BF4)2·H2O (10 mol%)
BF3K
S
S
L7 (
11 mol%)
NH
+
MeOOC
COOMe
R1
R1
CHCl3, -20 C
argon, 24 W blue LEDs
R2
R2
1b m

2d
3q zb

COOMe
COOMe
O
O
S
O
O
O
O
O
O
S
S
S
NH
NH
NH
NH
CO2Et
3t
CO2Bn
CO2iPr
CO2Me
3q
Me
3s
3r
13 h, 92% yield
12 h, 93% yield
12 h, 95% yield
12 h, 97% yield
92% ee
88% ee
94% ee
90% ee
COOMe
COOMe
Cl
COOMe
COOMe
O
O
O
O
O
O
O
O
S
S
S
S
NH
NH
NH
NH
CO2Et
3u
14 h, 97% yield
CO2Et
3w
14 h, 98% yield
CO2Et
CO2Et
3x
14 h, 94% yield
MeO
F3C
F3CO
3v
12 h, 95% yield
86% ee
88% ee
86% ee
90% ee
COOMe
O
S O
NH
COOMe
COOMe
O
COOMe
O
O
O
O
O
O
S
S
S
NH
NH
NH
CO2Et
3za
17 h, 95% yield
80% ee
CO2Et
CO2Et
Me
3z
3y
3zb
no product
13 h, 96% yield
12 h, 98% yield
82% ee
89% ee
Scheme 3. Reaction scope of N-sulfonylimines.
Other α-carbonyl imines were examined in this system in attempt to evaluate the
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generality of the method. To our most interest, acyclic imines such as isatin-derived
ketimines worked well under the standard conditions and ligand L9 was identified as the
best ligand (Scheme 4). These reactions typically needed an extended irradiation time (32–
47 h) and produced the chiral 3-amino-3-alkyl oxindole (5a–h), a structure commonly
found in nature products,21 with higher enantiomer excess (96–98% ee).
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Bn
N
Bn
N
O
O
COOMe
L9
Cu(BF4)2·H2O (10 mol%) BocHN
NBoc
O
BF3K
L9
(11 mol%)
R1
+
MeOOC
R1
O
N
CHCl3, -20 °C
N
R2
4a–h
COOMe
R2
5a–h
argon, 24 W blue LEDs
2d
COOMe
COOMe
Cl
COOMe
BocHN
N
BocHN
BocHN
N
BocHN
Br
F
O
O
O
O
N
Bn
N
Bn
Bn
Bn
5a
5b
5d
5c
47 h, 77% yield
32 h, 84% yield
32 h, 88% yield
32 h, 80% yield
96% ee
96% ee
98% ee
96% ee
COOMe
COOMe
COOMe
COOMe
BocHN
N
BocHN
N
BocHN
N
BocHN
Me
MeO
O
O
O
O
N
Bn
Me
Bn
Bn
Me
5e
5h
5f
5g
39 h, 73% yield
35 h, 75% yield
45 h, 76% yield
45 h, 69% yield
96% ee
96% ee
96% ee
96% ee
Scheme 4. Application of the reaction to enantioselective benzylation of isatin-derived
ketimines.
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Probing the radical pathway. Several control experiments were conducted in an
effort to confirm the radical pathway (Scheme 5). First, introduction of air to the copper-
catalyzed reaction 1a+2d3d was found to completely inhibit the transformation to 3d,
instead affording an aldehyde side-product (6a) in 52% yield (Scheme 5a). Addition of
excess of the radical quencher 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) resulted in
a radical coupling product 6b in 62% yield (Scheme 5b). Interference with a radical
acceptor ethyl 2-((phenylsulfonyl)methyl)acrylate led to the formation of a mixture of 3d
(31%), 6c (44%) and a self-coupling product 6d (5%) (Scheme 5c). These outcomes
strongly indicate that an alkyl radical is involved in the catalytic process. The reaction
1a+2d3d was monitored by electron paramagnetic resonance spectroscopy (EPR) with
5,5-dimethyl-1-pyrroline N-oxide (DMPO) and the corresponding HRMS analysis, gave
results that further strengthen the conjecture (Scheme 5d).
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a) reaction in air
BF3K
Cu(BF4)2·H2O
CHO
O
O
N
(50 mol%)
S
L7
(55 mol%)
+
3d
+
9
CHCl3, 25 °C
CO2Et
blue LEDs, air, 12 h
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CO2Me
6a
CO2Me
2d
0% yield
1a
52% yield
b) interference with TEMPO
Cu(BF4)2·H2O
(50 mol%)
L7
O N
(55 mol%)
1a
+
2d
3d
+
MeO2C
TEMPO (2.5 eq)
CHCl3, 25 °C
0% yield
6b
62% yield
blue LEDs, argon, 12 h
c) interference with a radical acceptor
CO2Et
Cu(BF4)2·H2O
(50 mol%)
L7
(55 mol%)
3d
1a
+
2d
+
6c
44% yield
CO2Et
CO2Me
31% yield
SO2Ph
(2.5 eq)
MeO2C
+
CHCl3, 25 °C
CO2Me
blue LEDs, argon, 12 h
6d
5% yield
d) EPR study
O
1) standard conditions
N
blue LEDs,10 min
1a
+
2d
MeO2C
2)
N
O
6e
HRMS (ESI, m/z): calcd for
C15H21NO3 (M): 262.1443, found: 262.1446
Scheme 5. Control experiments to probe the existence of the alkyl radical.
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UV-Vis spectra. UV-Vis spectra were recorded to evaluate the light absorption of the
reaction components (Figure 1). The individual substrates 1a, 2a, chiral ligand L7, copper
salts Cu(BF4)2∙H2O and Cu(MeCN)4BF4 showed no obvious absorption in the visible light
region. However, complexes CuII-L7, CuII-L7-1a, CuI-L7 and CuI-L7-1a, which
potentially exist in the catalytic system, exhibited significant absorption enhancement in
the range of 400–550 nm. The broad signals at 600-800 nm in the UV/Vis absorption
spectra of CuII-L7 and CuII-L7-1a are attributed to d-d transitions of copper(II).22 These
results demonstrated that the combination of the copper with the BOX ligand leads to the
formation of species potentially active in visible light.
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Figure 1. UV-Vis spectras of the individual substrates 1a, 2a, chiral ligand L7, copper
salts Cu(BF4)2∙H2O, Cu(MeCN)4BF4, copper complexes CuI-L7 (generated in situ by
stirring a 1:1 mixture of Cu(MeCN)4BF4 and chiral ligand L7), CuI-L7-1a (generated in
situ by stirring a 1:1:1 mixture of Cu(MeCN)4BF4, chiral ligand L7 and substrate 1a), CuII-
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L7 (generated in situ by stirring a 1:1 mixture of Cu(BF4)2∙H2O and chiral ligand L7) and
CuII-L7-1a (generated in situ by stirring a 1:1:1 mixture of Cu(BF4)2∙H2O, chiral ligand
L7 and substrate 1a). All the samples were prepared as a 3.0 mM solution and used fresh
for the measurement.
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Cyclic voltammetry analysis. The cyclic voltammetry of substrates 1a, 2a, chiral
ligand L7 and copper complex CuI-L7 was measured under argon to estimate their redox
ability. As illustrated in Figure 2, the N-sulfonylimine (1a) exhibited a reversible
reduction/oxidation peak at E1/2 = -0.49 V (Ered(1a/1a∙–)), while the alkyl trifluoroborate 2a
showed an irreversible oxidation peak at +1.34 V (Eox(2a∙+/2a)). The chiral ligand (L7) did
not provide any obvious reduction/oxidation signals, revealing that the ligand itself was
redox-inert in the catalytic cycles. Moreover, reversible reduction/oxidation signals were
observed at E1/2 = +0.81 V for the copper complex CuI-L7 (Ered (CuII-L7/CuI-L7)),
suggesting that direct oxidation of 2a by the copper(II) complex is thermodynamically
unfavorable. Therefore, it was assumed that there must be some other pathway to achieve
single-electron oxidation of the alkyl trifluoroborate to generate the corresponding alkyl
radical.
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Figure 2. Cyclic voltammograms of 1a, 2a, L7 and CuI-L7 (generated in situ by stirring a
1:1 mixture of Cu(MeCN)4BF4 and chiral ligand L7) in MeCN (0.030 M) containing 0.1
M nBu4NBF4. Scan rate: 0.1 V/s. 1a: E1/2 = -0.49 V; 2a: Ep = +1.34 V; CuI-L7: E1/2
=
+0.81 V.
Investigations of single-electron oxidation of alkyl trifluoroborates by CuII.
Inspired by a recent reported from Rehbein, Reiser, et al.,8 we assumed that a ligand
exchange/light-accelerated homolysis of the copper(II) species might be involved in the
oxidation process. Accordingly, the chiral copper catalyst CuII-L undergoes fast ligand
exchange with alkyl trifluoroborate, generating the alkyl copper(II) intermediate, perhaps
through the hydroxide complex. Under irradiation with visible light, the alkyl copper(II)
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intermediate was excited. Ligand-metal-charge-transfer (LMCT) and homolysis led to the
formation of the CuI species and alkyl radical (Scheme 6).
8
9
X
X
X
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R
N
N
BF3K
N
N
H2O
- HX
N
N
CuII
CuII
CuII
R
X
- KBF3OH
OH
CuII-L
L
HRMS (ESI, m/z) calcd for
a crystal structure
of the dimer
C62H67CuN2O4 (M-X)+: 966.4397
N^N = = BOX
L
L7
)
found: 966.4395 ( =
LMCT
homolysis
blue LEDs
R
BF3K
N
N
direct intermolecular SET
CuI
X
R
2a•+ 2a
) = +1.34 V
II
I
Ered(Cu /Cu ) = ~ +0.81 V, Eox(
/
alkyl radical trapped and
consumption of CuII observed
Scheme 6. Proposed pathway for light-induced single-electron oxidation of the alkyl
trifluoroborates by the copper(II) catalyst.
To confirm this speculation, we carefully analyzed the catalytic system. First, a crystal
form of the copper hydroxide dimeric complex was obtained by mixing Cu(BF4)2∙H2O with
BOX ligand in a 1:1 ratio in chloroform. This demonstrated the ligand exchange process
perhaps going through the similar hydroxide intermediate (Figure 3). In addition, the
putative alkyl copper(II) intermediate was observed in the HRMS analysis of a mixture of
Cu(BF4)2∙H2O, ligand L7 and alkyl trifluoroborate 2d in chloroform.
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Figure 3. Ortep drawing of a CuII-BOX-OH dimeric complex [L6-Cu(H2O)μ-
(OH)]2(BF4)2 with 50% probability thermal ellipsoids.
A model reaction of alkyl trifluoroborate 2d and the catalyst CuII-L7 in chloroform
under irradiation of a blue LEDs lamp provided the self-coupling product 6d in 24% yield.
The reaction failed to proceed in the absence of the ligand or light, revealing that oxidation
of alkyl trifluoroborates to the corresponding alkyl radicals must go through a light-induced
pathway. In addition, a time-course UV-Vis absorption analysis showed that the broad
signal at 600-800 nm attributed to d-d transitions of CuII was significantly reduced under
irradiation with a blue LEDs lamp for only 0.5 h, suggesting consumption of the copper(II)
species in the photochemical reaction.
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8
Cu(BF4)2·H2O
(50 mol%)
BF3K
MeO2C
L7
(55 mol%)
CO2Me
CHCl3, 25 °C
argon, 20 h
9
6d
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CO2Me
blue LEDs: 24% yield.
blue LEDs (no ): 0% yield.
in the dark: 0% yield.
2d
L7
Scheme 7. Evidences for light-induced oxidization of alkyl trifluoroborate by CuII.
Mechanistic proposal. With this better understanding of the key step for the light-
initiated radical generation, we propose a plausible mechanism of the copper(II)-catalyzed
asymmetric photochemical reaction (Scheme 8). Catalyst CuII-L oxidizes the
trifluoroborate substrate 2 to the radical A through a ligand exchange/light accelerated
homolysis process. On the other hand, imine substrate 1 or 4 undergoes fast ligand
exchange with CuII-L and affords the intermediate complex B. The nucleophilic alkyl
radical A proceeds with radical addition to the C=N double bond of complex B in an
enantioselective fashion and transformation to radical C.23 Such copper(II)-stabilized N
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radical species have been reported by the group of Liu.24 Reduction of C by CuI-L affords
monocationic complex D, followed by protonation and ligand exchange to release chiral
product 3 or 5 and regenerated intermediate complex B. The effective asymmetric
induction can be explained by radical attack from the sterically less hindered side of the
copper-coordinated imine (Figure 4).25,26 The proposed transition state is consistent with
an observed R-configuration in the products 3a–za. Overall, the copper catalyst serves as
a bifunctional catalyst which is involved in both the photoredox process and the
asymmetric catalysis.
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1
4
or , H2O
R3
+
Ar
N
chiral product
L-CuII
SET
R1
or
3
5
CuI-L
R2
O
R1
D
R3
N
R3
A
2+
Ar
N
Ar
CuII-L
BF3K
L-CuII
R1
R2
4
2
R2
O
O
CuII-L
B
R3
N
2+
1
or
Ar
ligand exchange-
light accelerated homolysis
L-CuII
R1
R1
R2
A
O
C
Scheme 8. A proposed reaction mechanism.
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Si-face open
R1
Figure 4. A proposed transition state simulated by CYLview 1.0.
Alternative pathways to initiate the radical generation can also be considered. For
example, pentacoordinated copper(II) bisoxazline complexes are also well known.27 It is
possible that a pentacoordinated copper(II) complex of the type L-CuII(imine)-R forms,
which undergoes light-accelerated homolysis to afford R radical followed by attack on the
coordinated imine. In the radical transformation process, the radical chain propagation
pathway can be excluded by the quantum yield estimation (Φ = 0.27).
Transformation of the products. Finally, we investigated the further conversion of
the products (Scheme 9). For example, product 3i (90% ee) can be readily converted into
a polycyclic benzosultam compound 7 with retention of the enantiomeric excess through a
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copper-catalyzed intramolecular cross coupling of the C-N bond. The crystal structure of
7 revealed its absolute configuration to be R. Reduction of product 3g (94% ee) followed
by treatment with trichloromethyl carbonochloridate and trimethylamine in THF led to the
formation of compound 8 in 62% yield and with 93% ee. These polycyclic chiral sultams
are important building blocks present in many bioactive compounds and synthetic
intermediates for some nature product synthesis.28
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a)
O O
O O
CuI, K2CO3
DMEDA
S
N
S
NH
Br
PhMe, 50 °C
CO2Et
CO2Et
3i
7
crystal structure
98% yield, 90% ee
90% ee
7
of
O O
O
S
N
b)
O O
S
O
1) LiAlH4, THF, 60 °C, 6 h
NH
CF3 2) ClCOOCCl3, Et3N, THF
CO2Et
F3C
8
3g
62% yield, 93% ee
94% ee
Scheme 9. Transformation of the products.
 CONCLUSIONS
In summary, we have developed a highly efficient asymmetric photoredox catalysis
based on readily available copper(II)-BOX complexes. The copper catalysts were
employed in the enantioselective alkylation of imines driven by visible light and exhibited
high catalytic efficiency for both the photo-activation and asymmetric induction. The
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simple catalytic system and fine-tunable chiral ligands enabled a significantly high level of
enantioselectivity for the formation of a range of chiral amines containing a tetrasubstituted
carbon stereocenter (36 examples, up to 98% ee). The mechanistic studies revealed that a
ligand exchange/light-accelerated homolysis pathway might be engaged to overcome
the low oxidizability of the Cu(II) complexes. The strategy of utilizing chiral complexes
comprised of a first-row transition metal and flexible chiral ligand as bifunctional chiral
photocatalysts provide an effective platform for development of green asymmetric
synthetic methods. Further investigations on reaction mechanisms and applications are in
progress in the laboratory.
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 ASSOCIATED CONTENT
Supporting Information
Experimental procedures, compound characterization data, NMR spectrums, chiral HPLC
traces, and crystallographic data. This material is available free of charge on the ACS
Publications website at DOI: xx xxx. Crystallographic data for copper complex [L6-
Cu(H2O)μ-(OH)]2(BF4)2 and compound 7 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC 1842575 and
1844995, respectively.
 AUTHOR INFORMATION
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Corresponding Author
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*gongl@xmu.edu.cn
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ORCID
Lei Gong: 0000-0002-4478-6880
Notes
The authors declare no competing financial interest.
 ACKNOWLEDGEMENTS
We gratefully acknowledge funding from the National Natural Science Foundation of
China (grant no. 21572184, 21472154), the Natural Science Foundation of Fujian Province
of China (grant no. 2017J06006), and the Fundamental Research Funds for the Central
Universities (grant no. 20720160027). We thank Ms. Dandan Chen at Xiamen University
for her assistance in geometry optimization of the transition state.
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