Copper-Catalyzed Asymmetric Radical 1,2-Carboalkynylation of Alkenes with Alkyl Halides and Terminal Alkynes

Article abstract of DOI:10.1021/jacs.0c03130

A copper-catalyzed intermolecular three-component asymmetric radical 1,2-carboalkynylation of alkenes has been developed, providing straightforward access to diverse chiral alkynes from readily available alkyl halides and terminal alkynes. The utilization of a cinchona alkaloid-derived multidentate N,N,P-ligand is crucial for the efficient radical generation from mildly oxidative precursors by copper and the effective inhibition of the undesired Glaser coupling side reaction. The substrate scope is broad, covering (hetero)aryl-, alkynyl-, and aminocarbonyl-substituted alkenes, (hetero)aryl and alkyl as well as silyl alkynes, and tertiary to primary alkyl radical precursors with excellent functional group compatibility. Facile transformations of the obtained chiral alkynes have also been demonstrated, highlighting the excellent complementarity of this protocol to direct 1,2-dicarbofunctionalization reactions with C(sp²/sp³)-based reagents.

Full text of DOI:10.1021/jacs.0c03130

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE
Article
Copper-Catalyzed Asymmetric Radical 1,2-Carboalkynylation
of Alkenes with Alkyl Halides and Terminal Alkynes
Xiao-Yang Dong, Jiang-Tao Cheng, Yu-Feng Zhang, Zhong-Liang Li, Tian-Ya Zhan, Ji-
Jun Chen, Fu-Li Wang, Ning-Yuan Yang, Liu Ye, Qiangshuai Gu, and Xin-Yuan Liu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03130 • Publication Date (Web): 25 Apr 2020
Downloaded from pubs.acs.org on April 25, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 9
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Copper-Catalyzed Asymmetric Radical 1,2-Carboalkynylation of Al-
kenes with Alkyl Halides and Terminal Alkynes
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
†,‡,§
‡,§
‡,§
||, §
‡
‡
Xiao-Yang Dong, Jiang-Tao Cheng, Yu-Feng Zhang, Zhong-Liang Li, Tian-Ya Zhan, Ji-Jun Chen, Fu-
‡
‡
||
||
*,‡
Li Wang, Ning-Yuan Yang, Liu Ye, Qiang-Shuai Gu, and Xin-Yuan Liu
†
School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, China
‡
Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of
Science and Technology, Shenzhen 518055, China
||Academy for Advanced Interdisciplinary Studies and Department of Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China
Supporting Information Placeholder
ABSTRACT: A copper-catalyzed intermolecular three-component
asymmetric radical 1,2-carboalkynylation of alkenes has been devel-
oped, providing straightforward access to diverse chiral alkynes from
readily available alkyl halides and terminal alkynes. The utilization of
a cinchona alkaloid-derived multidentate N,N,P-ligand is crucial for
the efficient radical generation from mildly oxidative precursors by
copper and the effective inhibition of the undesired Glaser coupling
side reaction. The substrate scope is broad, covering (hetero)aryl-,
alkynyl-, and aminocarbonyl-substituted alkenes, (hetero)aryl and alkyl as well as silyl alkynes, and tertiary to primary alkyl radical precursors
with excellent functional group compatibility. Facile transformations of the obtained chiral alkynes have also been demonstrated, highlighting
2
3
the excellent complementarity of this protocol to direct 1,2-dicarbofunctionalization reactions with C(sp /sp )-based reagents.
As our continuous research interest in copper-catalyzed asymmet-
INTRODUCTION
6
ric radical reactions, we have recently developed a copper-catalyzed
3
7
The intermolecular three-component asymmetric 1,2-dicarbo-
functionalization of alkenes has recently attracted increasing atten-
tion owing to its high synthetic convergency with readily available
starting materials for rapid assembly of carbon skeletons (Scheme
enantioconvergent Sonogashira C(sp )–C(sp) coupling reaction.
Critical to the success of the reaction is the development of a chiral
alkaloid-derived multidentate N,N,P-ligand for both enhancing the
reducing capability of copper catalyst and inhibiting the Glaser cou-
1
,2
8
1
A). Given the fact that chiral alkynes are versatile synthons for
pling side reaction (Scheme 1C). Thus, mildly oxidative alkyl hal-
2
3
3
many other C(sp /sp )-based functionalities, the enantioselective
1,2-carboalkynylation of alkenes represents a useful and appealing
strategy in asymmetric organic synthesis. However, this strategy has
been significantly underdeveloped and only recently did Liu et al.
achieve an asymmetric 1,2-trifluoromethylalkynylation of alkenes.
ides and side-reaction-prone terminal alkynes were highly enanti-
oselectively coupled together via trapping alkyl radicals with the pre-
II
sumed chiral Cu –alkyne complex. Since alkyl halides and terminal
9
alkynes both are widespread building blocks in organic synthesis,
we envisioned a copper-catalyzed asymmetric radical 1,2-carboal-
kynylation of alkenes direct with these two readily available reagents
(Scheme 1D). The success of this method would not only allow ex-
peditious access to diverse chiral alkynes but also offer complemen-
tary approaches to direct asymmetric 1,2-dicarbofunctionalization
4
(Scheme 1B). In this work, the efficient trap of in situ generated
II
benzylic radical with chiral Box(bisoxazoline)Cu –alkynyl species is
crucial for subsequent enantioselective C–C bond formation, which
represents a general strategy pioneered by Fu and others. Notably,
the reaction was demonstrated to be compatible with only the
5
2
3
of alkenes using C(sp /sp )-based reagents. Several factors have
thwarted the development of such a strategy: (1) The relatively dif-
ficult radical generation from alkyl halides by copper catalysts with
(MeO)
3
Si-prefunctionalized alkynes and the Togni’s reagent as the
4
nucleophiles and the radical precursor, respectively, the cost and
availability of which arguably impedes its wide application in asym-
metric synthesis. Therefore, the development of robust catalyst for a
broadly applicable atom- and step-economic asymmetric 1,2-car-
boalkynylation of alkenes from readily available building blocks is
highly desirable.
1
0
most of common chiral ligands; (2) The inhibition of easily occur-
8
ring copper-catalyzed Glaser homocoupling of terminal alkynes;
(3) The problematic chemoselectivity between radical addition to
terminal alkenes and alkynes owing to the inherently high reactivity
1
1
of radical species. Herein, we describe the development of a mild
ACS Paragon Plus Environment

Page 3 of 9
Journal of the American Chemical Society
copper(I)/cinchona alkaloid-derived N,N,P-ligand catalytic system
to afford the desired products 4–25 in good yields and excellent ee.
Many functional groups, such as methoxyl (5–7), phenoxyl (8), ace-
toxyl (9), halo (15–19), trifluoromethyl (20), cyano (21), formyl
(22), acetyl (23), and methoxylcarbonyl (24) groups, were well tol-
erated under the reaction conditions. Furthermore, alkenes bearing
polycyclic aryl rings were also compatible with the reaction to give
26–28 in moderate to good yield with excellent enantioselectivity.
Noteworthy is that many alkenes that contain medicinally relevant
heterocycles, such as benzo[d][1,3]dioxole, pyrazole, furan, benzo-
furan, thiophene, benzo[b]thiophene, pyridine, quinoline, and thia-
zole, all underwent the current reaction smoothly to deliver the cor-
responding products 27–35, respectively, in 46–91% yields with 83–
96% ee. Interestingly, besides (hetero)aryl alkenes, the reaction of
an aminocarbonyl-substituted alkene also proceeded to provide the
corresponding product 36 in 20% yield and 81% ee. More signifi-
cantly, the conjugated eneyne was also a suitable substrate to afford
1
2
3
4
5
6
7
8
9
for a general asymmetric intermolecular three-component radical
1,2-carboalkynylation of alkenes with alkyl halides and terminal al-
kynes.
Scheme 1. Intermolecular 1,2-Carboalkynylation of Alkenes
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Table 1. Screening of Reaction Conditions for Model Reaction
t
O Bu
Br
[Cu] (10 mol%)
L (15 mol%)
Cs2CO3 (2.0 equiv.)
O
3
a
t
O Bu
+
Solvent, rt
O
NC
NC
1
a
2a
4, 72%, 93% ee
OMe
N
OMe
N
NC
CN
N
N
4
' 0%
CN
NH PAr2
NH PPh2
O
O
t
L3
L1 (Ar = 3,5- Bu2C6H3)
L2 (Ar = Ph)
t
O Bu
O
L4 (Ar = 3,5-(CF3)2C6H3)
L5 (Ar = 4-PhC6H4)
4
"
NC
RESULTS AND DISCUSSION
Yield (%)b Ee
4
Entry
[Cu]
L
Solvent
Et
Reaction Development. Based on the above-mentioned pro-
posal, we began to investigate the three-component asymmetric re-
action of easily available styrene 1a, alkyne 2a and t-butyl α-bro-
moisobutyrate 3a (Table 1). After extensive screening of reaction
conditions, we were pleased to find that the chiral cinchona alkaloid-
derived N,N,P-ligands were remarkably effective in radical genera-
tion and inhibition of the Glaser coupling side reaction leading to 4'
4'' (%)c
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuTc
L2
L2
L2
2
O
42
31
45
50
52
20
68
66
67
76
71
67
70
76
16
43
20
12
14
15
18
32
27
8
72
69
74
70
70
77
77
94
94
94
93
94
93
94
93
CH
3
CN
EtOAc
L2 1,4-dioxane
L3 1,4-dioxane
L4 1,4-dioxane
L5 1,4-dioxane
L1 1,4-dioxane
L1 1,4-dioxane
L1 1,4-dioxane
L1 1,4-dioxane
L1 1,4-dioxane
L1 1,4-dioxane
L1 1,4-dioxane
(
Table 1). In addition, the desired reaction was disfavored with lig-
ands bearing electron-deficient P-aryl rings and the most sterically
bulky ligand L1 gave rise to the highest enantioselectivity. In con-
trast, the enantioselectivity only slightly changed among different
solvents or copper salts. Notably, the reaction solvent significantly
affected the ratio between the desired alkene addition product 4 and
the undesired alkyne addition product 4'' and 1,4-dioxane gave the
highest ratio. We finally identified the best reaction conditions in
terms of cost efficiency as follows: the reaction of 1a, 2a, and 3a in a
molar ratio of 1.5:1.0:1.2 in the presence of 7.5 mol% CuOAc and
d
9
1
1
1
1
1
0e
e
1
12
8
15
4
e
2
e
3
Cu(CH
3
CN)
4
PF
6
e
4
CuOAc
CuOAc
e,f
1
5
L1 1,4-dioxane 72
4
aReaction conditions: 1a (0.10 mmol), 2a (0.15 mmol), 3a (0.12
mmol), [Cu] (10 mol%), L (15 mol%), and Cs
2
CO
3
(2.0 equiv.) in sol-
7.5 mol% L1 provided 4 in 72% yield and 93% ee in 1,4-dioxane at
b
vent (1.0 mL) at room temperature for 24 h under argon. Yield of 4 and
room temperature (Table 1, entry 15).
1
4
'' was based on H NMR analysis of the crude product using 1,3,5-tri-
With the optimized reaction conditions in hand, the substrate
scope of alkenes for this asymmetric transformation was then inves-
tigated (Table 2). Various styrene-type alkenes, including those hav-
ing monosubstituted phenyl rings with electron-neutral, -rich, or -
deficient functional groups at different positions (ortho, meta or
para) and a disubstituted phenyl ring, were suitable for this reaction
methoxybenzene as an internal standard, and that of 4' was based on
c
d
GC-MS analysis. Ee values based on HPLC analysis. 1a (0.12 mmol),
e
2
a (0.10 mmol), 3a (0.12 mmol). 1a (0.15 mmol), 2a (0.10 mmol), 3a
0.12 mmol). CuOAc (7.5 mol%), L (7.5 mol%).
f
(
ACS Paragon Plus Environment

Journal of the American Chemical Society
with Togni’s reagent 3h (Table 2) as the radical precursor to afford
Page 4 of 9
a,b,c
Table 2. Substrate Scope of Alkene
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the product 38 in good yield, albeit with low ee. These results are
currently under further optimization in our lab. Unfortunately, the
1,1- and 1,2-disubstituted alkenes are currently inapplicable to the
carboalkynylation (see Scheme S1 in the Supporting Information).
Encouraged by the above results, we next switched our attention
to evaluate the scope of alkynes (Table 3). Thus, under the standard
conditions, a series of aryl alkynes possessing phenyl rings with dis-
tinct electronic and steric properties and a naphthalene ring as well
as a ferrocene ring all worked well to give 39–54 in moderate to good
yield with excellent ee. Many functional groups, such as methoxyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
(
41–43), halo (45–48), methoxylcarbonyl (49), formyl (50), nitro
51), and pinacolborato (52), survived the reaction conditions. The
absolute configuration of 53 was determined to be R by X-ray crys-
tallographic analysis (Table 3 and Figure S1 in the Supporting Infor-
mation). Furthermore, heteroaryl alkynes, such as 3-pyridinyl-, 2-
thiophenyl-, and 3-imidazo[1,2-b]pyridazinyl-substituted acety-
lenes, were also viable substrates for this reaction to deliver 55–57
in 48–68% yield with 93–96% ee. Notably, a series of alkyl alkynes
underwent the current reaction smoothly to give products 58–67 in
good yield and high ee. And a wide range of functional groups, such
a,b,c
Table 3. Substrate Scope of Alkyne
aReaction conditions: 1 (0.30 mmol), 2a (0.20 mmol), 3a (0.24
mmol), CuOAc (7.5 mol%), L1 (7.5 mol%), and Cs CO (0.40 mmol)
2
3
b
c
in 1,4-dioxane (2.0 mL). Isolated yield. The ee value was determined
d
by HPLC. N,N-diethylacrylamide (0.80 mmol) was used as the alkene
aReaction conditions: 1a (0.30 mmol), 2 (0.20 mmol), 3a (0.24
e
substrate. Togni’s reagent 3h was used as the radical precursor.
mmol), CuOAc (7.5 mol%), L1 (7.5 mol%), and Cs
in 1,4-dioxane (2.0 mL). Isolated yield. The ee value was determined
2
CO (0.40 mmol)
3
b
c
the carboalkynylation product 37 in 66% yield and 65% ee. With re-
gard to the unactivated aliphatic alkene, the reaction also worked
by HPLC.
ACS Paragon Plus Environment

Page 5 of 9
Journal of the American Chemical Society
as cyano (58), carbazole (59), carbamate (60), acetal (61), ester
64), primary alcohol (65), and even primary chloride (66), at dif-
Scheme 2. Synthetic Applications
1
2
3
4
5
6
7
8
9
(
ferent distances away from the reacting alkynes were compatible
with the reaction conditions. Most importantly, the industrially rel-
evant propyne, one key component of the readily available MAPP
(methylacetylene-propadiene propane) welding gas, was also a suit-
able substrate to give the desired product 67 in 66% yield and 95%
ee. Furthermore, trimethylsilyl acetylene also worked well to provide
68 in 90% yield and 96% ee.
a,b,c
Table 4. Substrate Scope of Alkyl Radical Precursors
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Mechanistic Studies. To gain insights into the reaction mecha-
nism, control experiments were conducted. First, the reaction of
copper phenylacetylide, 1a, and 3a proceeded smoothly in the pres-
ence of L1 to provide 39 in 80% yield and 96% ee, while no reaction
occurred in the absence of L1 (Scheme 3A). Thus, the ligand-coor-
dinated copper acetylide is likely the reductant of alkyl halides for
reaction initiation. The radical clock substrate 82 led to the ring-
opening product 83 under the standard reaction conditions
(
Scheme 3B). Thus, a radical pathway was likely involved, which was
further supported by the radical inhibition experiment with TEMPO
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl) (Scheme 3C).
(
Scheme 3. Control Experiments
aReaction conditions: 1a (0.30 mmol), 2a (0.20 mmol), 3 (0.24
mmol), CuOAc (10 mol%), L1 (15 mol%), and Cs
2
CO
3
(0.40 mmol)
b
c
in 1,4-dioxane (2.0 mL). Isolated yield. The ee value was determined
d
e
by HPLC. CuOAc (7.5 mol%), L1 (7.5 mol%). Yield was based on re-
covered 2a.
Synthetic Utility. To demonstrate the synthetic utility of this
method, we carried out further transformations of the prepared chi-
ral alkynes. As shown in Scheme 2, the complete hydrogenation of
chiral alkyne 59 provided 77 featuring a saturated aliphatic chain.
On the other hand, a highly stereoselective partial hydrogenation of
this chiral alkyne afforded Z-alkene 78. Besides, the trimethylsilyl
group of chiral alkyne 68 was readily removed to provide the corre-
sponding terminal alkyne, which further underwent copper-cata-
lyzed azide-alkyne cycloaddition (CuAAC) reaction to provide 1-
sulfonyl-1,2,3-triazole 79 in 90% yield and 96% ee. In addition, di-
rect oxidation of alkyne 68 to the corresponding carboxylic acid fol-
To investigate the possible binding mode of the N,N,P-ligand
lowed by reduction with LiAlH
4
successfully gave the chiral 1,5-diol
I
with Cu , we carried out the NMR experiments (Figure 1). The
8
0. Moreover, straightforward hydration of chiral alkyne 76 fur-
I
L2Cu complex was synthesized by mixing CuI and L2 in a 1:1 ratio
nished ketone 81 characterized by a β-chiral stereocenter. It is note-
worthy that no apparent loss of enantiopurity was observed during
all these transformations. Thus, this asymmetric radical 1,2-carboal-
kynylation of alkenes—when combined with one- or two-step fur-
ther manipulations—provides practical and excellent complemen-
tary approaches to direct asymmetric 1,2-dicarbofunctionalization
1
in CDCl
3
at room temperature. Its H NMR spectrum revealed ap-
parent downfield shifts of protons adjacent to the quinuclidine ni-
trogen compared with those of L2, indicating probable binding of
I
Cu with the quinuclidine moiety L2 in solution (see full NMR anal-
31
ysis in the Supporting Information). The P NMR experiments also
showed an apparent downfield shift (+2.4 ppm relative to that of
2
3
of alkenes using C(sp /sp )-based reagents.
I
L2), supporting probable binding of Cu with the phosphine moiety
in L2 in solution (see Figure S2 in the Supporting Information). The
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 9
complex formation was further supported by the observation of the
signals at m/z of 674.1969 and 676.1960, corresponding to the
masses of L2 Cu and L2 Cu , respectively (see Figure S3 in the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
3
I
65
I
Supporting Information). However, we cannot get further infor-
I
mation on other binding sites in L2 with Cu from the NMR experi-
ments.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. X-band EPR spectrum (9.26 GHz, 100K). Black: a mixture of
Cu(OAc) , L2, and 2a; Red: a reaction component of the standard
model carboalkynylation reaction.
2
Further kinetic analysis on the carboalkynylation reaction of 4-
fluorostyrene 1l was performed with alkyne 2a, alkyl halide 3a,
CuOAc and ligand L2. The reaction was found to be of first-order
dependence in alkene and catalyst, respectively (Figures 4A and 4B).
The rate dependence on alkyl halide was close to zeroth order,
demonstrating that the generation of radical species from alkyl hal-
ide was irrelevant to the rate-determining step(s) (Figure 4C). With
regard to alkyne, the reaction rate was firstly increased and then de-
creased following the increase of its concentration, indicating its
multifaceted roles in the reaction process (Figure 4D).
1
I
1
Figure 1. H NMR Studies of the L2Cu Complex. Red: H NMR of L2;
1
I
Blue: H NMR of L2Cu .
A series of cyclic voltammogram (CV) experiments were per-
formed to investigate the influence of the N,N,P-ligand on the redox
I
potential of Cu catalyst utilizing CuBr as the copper salt. The CV of
CuBr showed a quasi-reversible couple at +0.6 V (Figure 2). The
complex of L2CuBr was prepared by mixing CuBr, L2, and Cs
2
CO
3
in a 1:1:1 ratio, and the CV experiment showed a quasi-reversible
I
II
couple at −0.1 V, corresponding to the Cu /Cu redox couple (Fig-
ure 2). These experiments support our hypothesis that the multiden-
tate N,N,P-ligand could enhance the reducing capability of copper
catalyst.
Figure 2. Cyclic voltammograms of CuBr (red) and the L2CuBr com-
plex (blue). Conditions: 10 mM in CH
3
CN with 0.1 M Bu
4
NPF as elec-
6
Figure 4. Kinetic analysis of the 1,2-carboalkynylation of alkenes. (A)
Initial rate plot for determining the order in alkene. (B) Initial rate plot
for determining the order in catalyst. (C) Initial rate plot for determin-
ing the order in alkyl halide. (D) Initial rate plot for alkyne.
trolyte and a 100 mV/s scan rate using a glassy carbon working electrode
and a Pt counter electrode. Potentials were calibrated with Fc as an in-
ternal standard.
II
9
Since Cu has a d configuration, we carried out the electron par-
amagnetic resonance (EPR) experiment of the reaction mixture in
6,7
Based on these results and our previous reports, we proposed a
plausible reaction mechanism, shown in Scheme 4. In the presence
II
order to support the involvement of a Cu species. The sample was
I
of base, Cu , alkyne, and L1 react to form a monomeric intermediate
prepared by taking an aliquot from the standard model reaction in
glove box. The EPR spectrum of the reaction mixture is consistent
II. This complex may further react to afford the inactive polymeric
complex V in the presence of excessive terminal alkyne, thus result-
II
II
with that of a standard Cu complex, thus indicating that a Cu spe-
cies is likely involved (Figure 3).
13
I
ing in reaction inhibition. The Cu intermediate II reduces alkyl
II
2
halide 3 to generate a Cu complex III and a ·R radical possibly via
a single electron transfer process. The alternative halogen atom
transfer process is less likely based on the fact that 3b and 3c have
1
4
2
led to the same enantioselectivity (Table 4). Next, the ·R radical
selectively adds to alkene 1 to provide a prochiral alkyl radical IV,
ACS Paragon Plus Environment

Page 7 of 9
Journal of the American Chemical Society
which was stabilized by delocalization of the unpaired electron into
CONCLUSION
II
1
2
3
4
5
6
7
8
9
the adjacent (hetero)aromatic ring. Finally, radical IV and the Cu
In summary, we have developed a copper-catalyzed intermolecu-
lar three-component asymmetric radical 1,2-carboalkynylation of al-
kenes for expedite synthesis of structurally diverse chiral alkynes.
One striking feature of this method is the ready accommodation of
easily available terminal alkenes ((hetero)aryl-, alkynyl, and ami-
nocarbonyl-substituted) and alkynes ((hetero)aryl, alkyl, and silyl)
as well as various alkyl radical precursors (3°, 2°, and 1°). A multiden-
tate cinchona alkaloid-derived N,N,P-ligand was strategically em-
ployed to enhance the reducing power of copper. Thus, a variety of
mildly oxidative alkyl halides could be used as radical precursors and
the Glaser coupling side reaction was effectively inhibited. Im-
3
complex III undergo C(sp )–C(sp) bond formation to deliver the
I
enantioenriched products 4–76, while releasing the L1Cu complex
I for the next catalytic cycle. Notably, the direct coupling reaction
2
II
between the tertiary ·R radical and the Cu complex III was not ob-
served, probably due to the steric hindrance in the construction of
quaternary carbon centers.
Scheme 4. Proposed Mechanism
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
portantly, this reaction provides a general strategy for asymmetric
3
1
,2-dicarbofunctionalization with not only chiral C(sp )–C(sp) but
3
2
3
also chiral C(sp )–C(sp /sp ) bond formations when allied with fol-
low-up transformations. Further efforts for exploration of this cata-
lyst system in asymmetric radical reactions are ongoing in our labor-
atory.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org./
Experimental procedures, characterization of compounds, Schemes S1
and S2, Figures S1−S3 and crystallographic data of 53.
3
As for the enantiodetermining C(sp )–C(sp) bond formation, we
AUTHOR INFORMATION
Corresponding Author
have tentatively proposed the formation of Cu(III) species VI and
1
5
its subsequent reductive elimination (Scheme 5A; also see Scheme
S2 in the Supporting Information for alternative possible pathways).
Accordingly, two enantiodiscrimination transition states of penta-
*
liuxy3@sustech.edu.cn
ORCID
1
5
coordinated Cu(III) complexes leading to enantiomers of 4–76,
respectively, was deduced, as shown in Scheme 5B. The steric clash
between the relatively bulky (hetero)aryl group in substrate and the
P-3,5-di-tert-butylphenyl group in the ligand renders the si-TS unfa-
vorable. Thus, the favorable re-TS leads to the formation of products
of an R absolute configuration as experimentally observed. Nonethe-
less, we currently have no solid evidence to support this proposed
enantiodiscrimination mechanism and thus, are carrying out further
experimental and theoretical studies on this reaction.
Xin-Yuan Liu: 0000-0002-6978-6465
Author Contributions
§
These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support from the National Natural Science Foundation of
China (Nos. 21722203, 21831002, and 21801116), Natural Science
Foundation of Guangdong Province (No. 2018A030310083), Guang-
dong Provincial Key Laboratory of Catalysis (No. 2020B121201002),
Guangdong Innovative Program (2019BT02Y335), Shenzhen Special
Funds (No. JCYJ20180302180235837), Shenzhen Nobel Prize Scien-
tists Laboratory Project (No. C17783101) and SUSTech Special Fund
for the Construction of High-Level Universities (No. G02216303).
Scheme 5. Proposed Mechanism
REFERENCES
(1) For selected reviews, see: (a) Guo, H.-C.; Ma, J.-A. Catalytic Asym-
metric Tandem Transformations Triggered by Conjugate Additions. Angew.
Chem., Int. Ed. 2006, 45, 354–366. (b) Jensen, K. H.; Sigman, M. S. Mecha-
nistic Approaches to Palladium-Catalyzed Alkene Difunctionalization Reac-
tions. Org. Biomol. Chem. 2008, 6, 4083–4088. (c) McDonald, R. I.; Liu, G.;
Stahl, S. S. Palladium(II)-Catalyzed Alkene Functionalization via Nucleo-
palladation: Stereochemical Pathways and Enantioselective Catalytic Appli-
cations. Chem. Rev. 2011, 111, 2981–3019. (d) Plesniak, M. P.; Huang, H.-
M.; Procter, D. J. Radical Cascade Reactions Triggered by Single Electron
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 9
Transfer. Nat. Rev. Chem. 2017, 1, 0077. (e) Tian, Y.; Chen, S.; Gu, Q.-S.;
representative examples, see: (e) Binder, J. T.; Cordier, C. J.; Fu, G. C. Cat-
alytic Enantioselective Cross-Couplings of Secondary Alkyl Electrophiles
with Secondary Alkylmetal Nucleophiles: Negishi Reactions if Racemic
Benzylic Bromides with Achiral Alkylzinc Reagents. J. Am. Chem. Soc. 2012,
134, 17003–17006. (f) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Cat-
alytic Asymmetric Reductive Acyl Cross-Coupling: Synthesis of Enantioen-
riched Acyclic α,α-Disubstituted Ketones. J. Am. Chem. Soc. 2013, 135,
7442–7445. (g) Zhu, R.; Buchwald, S. L. Enantioselective Functionalization
of Radical Intermediates in Redox Catalysis: Copper-Catalyzed Asymmetric
Oxytrifluoromethylation of Alkenes. Angew. Chem., Int. Ed. 2013, 52,
12655–12658. (h) Mao, J.; Liu, F.; Wang, M.; Wu, L.; Zheng, B.; Liu, S.;
Zhong, J.; Bian, Q.; Walsh, P. J. Cobalt–Bisoxazoline-Catalyzed Asymmetric
Kumada Cross-Coupling of Racemic α-Bromo Esters with Aryl Grignard Re-
agents. J. Am. Chem. Soc. 2014, 136, 17662–17668. (i) Gutierrez, O.; Tellis,
J. C.; Primer, D. N.; Molander, G. A.; Kozlowski, M. C. Nickel-Catalyzed
Cross-Coupling of Photoredox-Generated Radicals: Uncovering a General
Manifold for Stereoconvergence in Nickel-Catalyzed Cross-Couplings. J.
Am. Chem. Soc. 2015, 137, 4896–4899. (j) Jin, M.; Adak, L.; Nakamura, M.
Iron-Catalyzed Enantioselective Cross-Coupling Reactions of α-Chloroes-
ters with Aryl Grignard Reagents. J. Am. Chem. Soc. 2015, 137, 7128–7134.
(k) Schmidt, J.; Choi, J.; Liu, A. T.; Slusarczyk, M.; Fu, G. C. A General,
Modular Method for the Catalytic Asymmetric Synthesis of Alkylboronate
Esters. Science 2016, 354, 1265–1269. (l) Wang, Z.; Yin, H.; Fu, G. C. Cata-
lytic Enantioconvergent Coupling of Secondary and Tertiary Electrophiles
with Olefins. Nature 2018, 563, 379–383.
(6) For a review, see: (a) Gu, Q.-S.; Li, Z.-L.; Liu, X.-Y. Copper(I)-Cata-
lyzed Asymmetric Reactions Involving Radicals. Acc. Chem. Res. 2020, 53,
170–181. For selected examples, see: (b) Lin, J.-S.; Dong, X.-Y.; Li, T.-T.;
Jiang, N.-C.; Tan, B.; Liu, X.-Y. A Dual-Catalytic Strategy to Direct Asym-
metric Radical Aminotrifluoromethylation of Alkenes. J. Am. Chem. Soc.
2016, 138, 9357–9360. (c) Ye, L.; Gu, Q.-S.; Tian, Y.; Meng, X.; Chen, G.-
C.; Liu, X.-Y. Radical Asymmetric Intramolecular α-Cyclopropanation of Al-
dehydes towards Bicyclo[3.1.0]hexanes Containing Vicinal All-Carbon
Quaternary Stereocenters. Nat. Commun. 2018, 9, 227. (d) Lin, J.-S.; Li, T.-
T.; Liu, J.-R.; Jiao, G.-Y.; Gu, Q.-S.; Cheng, J.-T.; Guo, Y.-L.; Hong, X.; Liu,
X.-Y. Cu/Chiral Phosphoric Acid-Catalyzed Asymmetric Three-Compo-
nent Radical-Initiated 1,2-Dicarbofunctionalization of Alkenes. J. Am. Chem.
Soc. 2019, 141, 1074–1083. (e) Ye, L.; Tian, Y.; Meng, X.; Gu, Q.-S.; Liu, X.-
Y. Enantioselective Copper(I)/Chiral Phosphoric Acid Catalyzed Intramo-
lecular Amination of Allylic and Benzylic C−H Bonds. Angew. Chem., Int. Ed.
2020, 59, 1129–1133.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Lin, J.-S.; Liu, X.-Y. Amino- and Azidotrifluoromethylation of Alkenes. Tet-
rahedron Lett. 2018, 59, 203–215. (f) Wang, K.; Kong, W. Recent Advances
in Transition Metal-Catalyzed Asymmetric Radical Reactions. Chin. J. Chem.
2
018, 36, 247–256. (g) Li, Z.-L.; Fang, G.-C.; Gu, Q.-S.; Liu, X.-Y. Recent
Advances in Copper-Catalysed Radical-Involved Asymmetric 1,2-Difunc-
tionalization of Alkenes. Chem. Soc. Rev. 2020, 49, 32–48. (h) Li, S.; Xiang,
S.-H.; Tab, B. Chiral Phosphoric Acid Creates Promising Opportunities for
Enantioselective Photoredox Catalysis. Chin. J. Chem. 2020, 38, 213−214.
(
2) For selected recent examples, see: (a) Liao, L.; Jana, R.; Urkalan, K.
B.; Sigman, M. S. A Palladium-Catalyzed Three-Component Cross-Cou-
pling of Conjugated Dienes or Terminal Alkenes with Vinyl Triflates and
Boronic Acids. J. Am. Chem. Soc. 2011, 133, 5784–5787. (b) Wu, X.; Lin, H.-
C.; Li, M.-L.; Li, L.-L.; Han, Z.-Y.; Gong, L.-Z. Enantioselective 1,2-Difunc-
tionalization of Dienes Enabled by Chiral Palladium Complex-Catalyzed
Cascade Arylation/Allylic Alkylation Reaction. J. Am. Chem. Soc. 2015, 137,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3476–13479. (c) Yamamoto, E.; Hilton, M. J.; Orlandi, M.; Saini, V.;
Toste, F. D.; Sigman, M. S. Development and Analysis of a Pd(0)-Catalyzed
Enantioselective 1,1-Diarylation of Acrylates Enabled by Chiral Anion Phase
Transfer. J. Am. Chem. Soc. 2016, 138, 15877–15880. (d) Derosa, J.; Tran,
V. T.; Boulous, M. N.; Chen, J. S.; Engle, K. M. Nickel-Catalyzed β,γ-Dicar-
bofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive
Cross-Coupling. J. Am. Chem. Soc. 2017, 139, 10657–10660. (e) Orlandi,
M.; Hilton, M. J.; Yamamoto, E.; Toste, F. D.; Sigman, M. S. Mechanistic
Investigations of the Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of
Benzyl Acrylates. J. Am. Chem. Soc. 2017, 139, 12688–12695. (f) Gao, P.;
Chen, L.-A.; Brown, M. K. Nickel-Catalyzed Stereoselective Diarylation of
Alkenylarenes. J. Am. Chem. Soc. 2018, 140, 10653–10657. (g) Xiong, Y.;
Zhang, G. Enantioselective 1,2-Difunctionalization of 1,3-Butadiene by Se-
quential Alkylation and Carbonyl Allylation. J. Am. Chem. Soc. 2018, 140,
2
735–2738. (h) Wang, K.; Ding, Z.; Zhou, Z.; Kong, W. Ni-Catalyzed En-
antioselective Reductive Diarylation of Activated Alkenes by Domino Cy-
clization/Cross-Coupling. J. Am. Chem. Soc. 2018, 140, 12364–12368. (i)
Anthony, D.; Lin, Q.; Baudet, J.; Diao, T. Nickel-Catalyzed Asymmetric Re-
ductive Diarylation of Vinylarenes. Angew. Chem., Int. Ed. 2019, 58, 3198–
3
202. (j) Zhang, Z.; Zhu, L.; Li, C. Copper-Catalyzed Carbotrifluorometh-
ylation of Unactivated Alkenes Driven by Trifluoromethylation of Alkyl
Radicals. Chin. J. Chem. 2019, 37, 452–456.
(3) (a) Pu, L. Asymmetric Alkynylzinc Additions to Aldehydes and Ke-
tones. Tetrahedron 2003, 59, 9873–9886. (b) Acetylene Chemistry Chemistry,
Biology and Material Science; Diederich, F.; Stang, P. J.; Tykwinski, R. R.,
Eds.; WILEY-VCH: Weinheim, 2005. (c) Li, L.; Rui, W. Recent Advance in
Asymmetric Alkynylation of Ketones. Curr. Org. Chem. 2009, 13, 1565–
(7) Dong, X.-Y.; Zhang, Y.-F.; Ma, C.-L.; Gu, Q.-S.; Wang, F.-L.; Li, Z.-
L.; Jiang, S.-P.; Liu, X.-Y. A General Asymmetric Copper-Catalysed So-
3
1
576. (d) Modern Alkyne Chemistry Catalytic and Atom-Economic Transfor-
nogashira C(sp )–C(sp) Coupling. Nat. Chem. 2019, 11, 1158–1166.
mations; Trost, B. M.; Li, C.-J., Eds.; Wiley-VCH: Weinheim, 2015. (e)
Chinchilla, R.; Nájera, C. Chemicals from Alkynes with Palladium Catalysts.
Chem. Rev. 2014, 114, 1783–1826. (f) Wang, Z.-X.; Bai, X.-Y.; Li, B.-J. Re-
cent Progress of Transition-Metal-Catalyzed Enantioselective Hydroal-
kynylation of Alkenes. Synlett 2017, 28, 509–514. (g) Le Vaillant, F.; Waser,
J. Alkynylation of Radicals: Spotlight on the “Third Way” to Transfer Triple
Bonds. Chem. Sci. 2019, 10, 8909–8923.
(8) For selected examples, see: (a) Glaser, C. Beiträge zur Kenntnifs des
Acetenylbenzols. Ber. Dtsch. Chem. Ges. 1869, 2, 422–424. (b) Kamata, K.;
Yamaguchi, S.; Kotani, M.; Yamaguchi, K.; Mizuno, N. Efficient Oxidative
Alkyne Homocoupling Catalyzed by a Monomeric Dicopper-Substituted
Silicotungstate. Angew. Chem., Int. Ed. 2008, 47, 2407–2410. (c) Singh, M.;
Singh, A. S.; Mishra, N.; Agrahari, A. K.; Tiwari, V. K. Benzotriazole as an
Efficient Ligand in Cu-Catalyzed Glaser Reaction. ACS Omega 2019, 4,
2418–2424.
(9) For selected reviews, see: (a) Li, C.-J. Cross-Dehydrogenative Cou-
pling (CDC): Exploring C−C Bond Formations beyond Functional Group
Transformations. Acc. Chem. Res. 2009, 42, 335–344. (b) Girard, S. A.;
Knauber, T.; Li, C.-J. The Cross-Dehydrogenative Coupling of Csp3–H
Bonds: A Versatile Strategy for C–C Bond Formations. Angew. Chem., Int.
Ed. 2014, 53, 74–100. (c) Díez-González, S. Copper(I)–Acetylides: Access,
Structure, and Relevance in Catalysis. Adv. Organomet. Chem. 2016, 66, 93–
141.
(4) Fu, L.; Zhou, S.; Wan, X.; Chen, P.; Liu, G. Enantioselective Trifluo-
romethylalkynylation of Alkenes via Copper-Catalyzed Radical Relay. J. Am.
Chem. Soc. 2018, 140, 10965–10969.
(
5) For selected reviews, see: (a) Cherney, A. H.; Kadunce, N. T.; Reis-
man, S. E. Enantioselective and Enantiospecific Transition-Metal-Catalyzed
Cross-Coupling Reactions of Organometallic Reagents To Construct C–C
Bonds. Chem. Rev. 2015, 115, 9587–9652. (b) Choi, J.; Fu, G. C. Transition
Metal–Catalyzed Alkyl-Alkyl Bond Formation: Another Dimension in
Cross-Coupling Chemistry. Science 2017, 356, eaaf7230. (c) Fu, G. C. Tran-
sition-Metal Catalysis of Nucleophilic Substitution Reactions: A Radical Al-
(10) For selected reviews, see: (a) Patten, T. E.; Matyjaszewski, K. Cop-
per(I)-Catalyzed Atom Transfer Radical Polymerization. Acc. Chem. Res.
1999, 32, 895–903. (b) Tang, S.; Liu, K.; Liu, C.; Lei, A. Olefinic C–H Func-
tionalization through Radical Alkenylation. Chem. Soc. Rev. 2015, 44, 1070–
1082. (c) Boyer, C.; Corrigan, N. A.; Jung, K.; Nguyen, D.; Nguyen, T.-K.;
ternative to S
N
1 and S 2 Processes. ACS Cent. Sci. 2017, 3, 692–700. (d)
N
Wang, F.; Chen, P.; Liu, G. Copper-Catalyzed Radical Relay for Asymmetric
Radical Transformations. Acc. Chem. Res. 2018, 51, 2036–2046. For selected
ACS Paragon Plus Environment

Page 9 of 9
Journal of the American Chemical Society
Adnan, N. N. M.; Oliver, S.; Shanmugam, S.; Yeow, J. Copper-Mediated Liv-
11613. (e) Wang, F.; Zhu, N.; Chen, P.; Ye, J.; Liu, G. Copper-Catalyzed
Trifluoromethylazidation of Alkynes: Efficient Access to CF -Substituted
1
2
3
4
5
6
7
8
9
ing Radical Polymerization (Atom Transfer Radical Polymerization and
Copper(0) Mediated Polymerization): From Fundamentals to Bioapplica-
tions. Chem. Rev. 2016, 116, 1803–1949. (d) Ouyang, X.-H.; Song, R.-J.; Li,
J.-H. Developments in the Chemistry of α-Carbonyl Alkyl Bromides. Chem.
3
Azirines and Aziridines. Angew. Chem., Int. Ed. 2015, 54, 9356–9360. (f) He,
Y.-T.; Wang, Q.; Zhao, J.; Liu, X.-Y.; Xu, P.-F.; Liang, Y.-M. The Copper-
Catalyzed Synthesis of β-Trifluoromethylated Acrylonitriles and Trifluoro-
methyl-Substituted 2H-Azirines. Chem. Commun. 2015, 51, 13209–13212.
(g) Xiang, Y.; Li, Y.; Kuang, Y.; Wu, J. Stereoselective Vicinal Difunctionali-
zation of Alkynes through a Three-Component Reaction of Alkynes, So-
dium Sulfinates, and Togni Reagent. Adv. Synth. Catal. 2017, 359, 2605–
2609. (h) Xiang, Y.; Li, Y.; Kuang, Y.; Wu, J. Vicinal Difluoroalkylation and
Aminosulfonylation of Alkynes under Photoinduced Conditions. Chem. -
Eur. J. 2017, 23, 1032–1035. (i) Zhu, X.; Ye, C.; Li, Y.; Bao, H. Iron-Cata-
lyzed Radical Decarboxylative Oxyalkylation of Terminal Alkynes with Alkyl
Peroxides. Chem. - Eur. J. 2017, 23, 10254–10258. (j) Israr, M.; Xiong, H.;
Li, Y.; Bao, H. Copper(I)-Catalyzed Cyanoperfluoroalkylation of Alkynes.
Org. Lett. 2019, 21, 7078–7083.
(12) Feng, Z.; Xiao, Y.-L.; Zhang, X. Transition-Metal (Cu, Pd, Ni)-Cat-
alyzed Difluoroalkylation via Cross-Coupling with Difluoroalkyl Halides.
Acc. Chem. Res. 2018, 51, 2264–2278.
(13) Zuidema, E.; Bolm, C. Sub-mol% Catalyst Loading and Ligand-Ac-
celeration in the Copper-Catalyzed Coupling of Aryl Iodides and Terminal
Alkyenes. Chem. Eur. J. 2010, 16, 4181–4185.
-
Asian J. 2018, 13, 2316–2332. For selected recent examples, see: (e) Nishi-
kata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. An Efficient Generation of a
Functionalized Tertiary-Alkyl Radical for Copper-Catalyzed Tertiary-Alkyl-
ative Mizoroki-Heck Type Reaction. J. Am. Chem. Soc. 2013, 135, 16372–
16375. (f) Zhang, X.; Yi, H.; Liao, Z.; Zhang, G.; Fan, C.; Qin, C.; Liu, J.; Lei,
A. Copper-Catalysed Direct Radical Alkenylation of Alkyl Bromides. Org. Bi-
omol. Chem. 2014, 12, 6790–6793. (g) Tang, C.; Zhang, R.; Zhu, B.; Fu, J.;
Deng, Y.; Tian, L.; Guan, W.; Bi, X. Directed Copper-Catalyzed Intermolec-
ular Heck-Type Reaction of Unactivated Olefins and Alkyl Halides. J. Am.
Chem. Soc. 2018, 140, 16929–16935. (h) Gockel, S. N.; Buchanan, T. L.;
Hull, K. L. Cu-Catalyzed Three-Component Carboamination of Alkenes. J.
Am. Chem. Soc. 2018, 140, 58–61. (i) Neff, R. K.; Su, Y.-L.; Liu, S.; Rosado,
M.; Zhang, X.; Doyle, M. P. Generation of Halomethyl Radicals by Halogen
Atom Abstraction and Their Addition Reactions with Alkenes. J. Am. Chem.
Soc. 2019, 141, 16643–16650.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
11) For a review on radical addition to terminal alkynes, see: (a) Gao,
P.; Song, X.-R.; Liu, X.-Y.; Liang, Y.-M. Recent Developments in the Trifluo-
romethylation of Alkynes. Chem. - Eur. J. 2015, 21, 7648–7661. For selected
examples, see: (b) Xu, T.; Cheung, C. W.; Hu, X. Iron-Catalyzed 1,2-Addi-
tion of Perfluoroalkyl Iodides to Alkynes and Alkenes. Angew. Chem., Int. Ed.
(14) Fantin, M.; Lorandi, F.; Gennaro, A.; Isse, A. A.; Matyjaszewski, K.
Electron Transfer Reactions in Atom Transfer Radical Polymerization. Syn-
thesis 2017, 49, 3311–3322.
2
014, 53, 4910–4914. (c) Xu, T.; Hu, X. Copper-Catalyzed 1,2-Addition of
(15) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.; Stahl, S.
S.; Liu, G. Enantioselective Cyanation of Benzylic C–H Bonds via Copper-
Catalyzed Radical Relay. Science 2016, 353, 1014–1018.
α-Carbonyl Iodides to Alkynes. Angew. Chem., Int. Ed. 2015, 54, 1307–1311.
(d) Li, Z.; García-Domínguez, A.; Nevado, C. Pd-Catalyzed Stereoselective
Carboperfluoroalkylation of Alkynes. J. Am. Chem. Soc. 2015, 137, 11610–
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 9
OMe
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R4
N
R1
R2
H
X
Cu(I)/L*
R4
R3
NH PAr2
R3
R2
R1
N
O
R
R
t
L* (Ar = 3,5- Bu2C6H3)
> 70 Examples Up to 99% yield Up to 98% ee
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment