Enantioselective Three-Component Fluoroalkylarylation of Unactivated Olefins through Nickel-Catalyzed Cross-Electrophile Coupling

Article abstract of DOI:10.1021/jacs.0c03708

A nickel-catalyzed, enantioselective, three-component fluoroalkylarylation of unactivated alkenes with aryl halides and perfluoroalkyl iodides has been described. This cross-electrophile coupling protocol utilizes a chiral nickel/BiOx system as well as a pendant chelating group to facilitate the challenging three-component, asymmetric difunctionalization of unactivated alkenes, providing direct access to valuable chiral β-fluoroalkyl arylalkanes with high efficiency and excellent enantioselectivity. The mild conditions allow for a broad substrate scope as well as good functional group toleration.

Full text of DOI:10.1021/jacs.0c03708

Subscriber access provided by Uppsala universitetsbibliotek
Communication
Enantioselective Three-Component Fluoroalkylarylation of Unactivated
Olefins Through Nickel-Catalyzed Cross-Electrophile Coupling
Hai-Yong Tu, Fang Wang, Liping HUO, Yuanbo Li, Shengqing
ZHU, Xian ZHAO, Huan Li, Feng-Ling Qing, and Lingling Chu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03708 • Publication Date (Web): 11 May 2020
Downloaded from pubs.acs.org on May 11, 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
Enantioselective Three-Component Fluoroalkylarylation of Unactivated
Olefins Through Nickel-Catalyzed Cross-Electrophile Coupling
Hai-Yong Tu#, Fang Wang#, Liping Huo, Yuanbo Li, Shengqing Zhu, Xian Zhao, Huan Li, Feng-Ling
Qing, and Lingling Chu*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical
Engineering and Biotechnology, Center for Advanced Low-Dimension Materials, Donghua University, Shanghai 201620,
China
Supporting Information Placeholder
ABSTRACT:
A nickel-catalyzed, enantioselective, three-
component fluoroalkylarylation of unactivated alkenes with aryl
halides and perfluoroalkyl iodides has been described. This cross-
electrophile coupling protocol utilizes a chiral nickel/BiOx system
as well as a pendant chelating group to facilitate the challenging
three-component, asymmetric difunctionalization of unactivated
alkenes, providing direct access to valuable chiral -fluoroalkyl
arylalkanes with high efficiency and excellent enantioselectivity.
The mild conditions allow for a broad substrate scope as well as
good functional group toleration.
Transition metal-catalyzed dicarbofunctionalization of
alkenes has been proven as a powerful strategy to the rapid
generation of molecular complexity by simultaneously
forging two vicinal sp3 C–C bonds from abundant building
blocks in one single operation;1 however, enantioselective
control of the newly formed stereogenic centers,2 particularly
in three-component assembly mode, remains a formidable
challenge. The known examples of three-component
reactions densely rely on the asymmetric functionalization of
vinylarenes via a radical relay strategy, wherein intercepting
the putative benzylic radicals by chiral transition metal
catalysts is key.3, 4 Nevertheless, unactivated alkenes were not
applicable in this asymmetric radical protocol, presumably
because of lacking resonance stabilization for the in-situ
generated highly reactive alkyl radical species. Indeed,
asymmetric dicarbofunctionalization of unactivated alkenes
has been primarily restricted to intramolecular, two-
component assembly modes.5 To the best of our knowledge,
Figure
1.
Enantioselective,
three-component
1,2-
fluoroalkylarylation of unactivated alkenes via chelation-assisted
nickel catalysis.
coupling reactions of unactivated alkenes, forging two
consecutive sp3-hybridized carbon centers, with one sp3
prochiral center.8,
With a particular interest in the
9
introduction of fluoroalkyl groups because of their increasing
importance in medicinal agents,10 as well as the high
reactivity of perfluoroalkyl radicals,11 our group previously
developed an intermolecular, selective carboacylation of
unactivated alkenes with acyl chlorides and perfluoroalkyl
halides via a Ni-catalyzed cross-electrophile coupling,
incorporating the perfluoroalkyl and carbonyl groups over
unbiased double bonds under mild conditions.8j In this work,
a weak coordination effect between the pendant chelating
group and nickel species was found to be crucial to achieving
the challenging regio- and chemo-selectivity in three-
component cross-coupling reactions. Encouraged by these
results, we envisioned that whether it would be possible to use
a chiral ligand, assisted by a proper pendant
catalytic,
enantioselective,
three-component
difunctionalization of unactivated alkenes has not been
reported. Herein, we report an enantioselective 1,2-
fluoroalkylarylation of unactivated alkenes with aryl halides
and perfluoroalkyl iodides through a chelation-assisted
nickel-catalyzed cross-electrophile coupling6, which
demonstrates an example of the integration of three-
component dicarbofunctionalization of unactivated alkenes
with a high level of enantioselectivity for the first time.
Owing to the unique properties of nickel catalysts,7
recently, several research groups, including ours, have
established that nickel could enable three-component cross-
ACS Paragon Plus Environment

Journal of the American Chemical Society
failed to promote this three-component reaction under similar
Page 2 of 9
1
2
3
4
5
6
7
8
Table 1. Optimization of reaction conditionsa
conditions (Table S2 and S7). Therefore, we further screened
a series of chiral BiOx ligands, and found that BiOx ligands
containing longer alkyl chains offered higher yield and
enantioselectivity, and (R,R)-4-heptyl-BiOX (L5), originally
developed for Ni-catalyzed asymmetric reductive cross-
couplings,6e, 6h delivered product 4h with 87% yield and 94:6
er at room temperature (entries 2–5). Encouraged by this
result,6h we designed and synthesized a new (R,R)-5-nonyl-
BiOX ligand (L6) bearing alkyl chains with nine carbon
atoms, which to our disappointment provided the same er
with L5 (entry 6). Finally, conducting the reaction at lower
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
temperature (–10 C) slightly improved enantioselectivity,
furnishing 4 with 95:5 er in 76% yield (entry 7). A trace
amount of product was observed when employing Zn or
(tetrakis(dimethylamino)ethylene)12
as
a
variations from standard
TDAE
entry
yield
er
conditions
stoichiometric reductant (entry 8). Control experiments
further confirmed that all nickel catalyst, ligand, and Mn dust
were required for this asymmetric system (entry 9).
Employment of TMSCl, which could activate the surface of
Mn, as additive was important to ensure reproducibility for
this transformation (entry 10) (See Table S1–S11 for more
optimizations).
With optimal reaction conditions in hand, we began to
explore the generality of this asymmetric, three-component
1,2-fluoroalkylarylation of unactivated alkenes with respect
to aryl and heteroaryl halides. As shown in Scheme 1, a
variety of 5-bromopyrimidines bearing electron-withdrawing
and electron-donating groups all underwent the desired cross-
electrophile coupling smoothly, delivering the corresponding
chiral -fluoroalkyl arylalkanes with good to excellent yields
and high enantioselectivity (Products 4−11, 47%−96% yields,
up to 95:5 er); while pyrimidines with electron-donating
groups displayed lower efficiency (Products 10 and 11).
Moreover, electron-deficient pyridines and quinolines were
1
2
L1
21%
55%
24%
75%
87%
81%
76%
trace
0%
20:80
12:88
10:90
9:91
94:6
94:6
95:5
--
L2
3
L3
4
L4
L5
5
6
L6
7
-10 oC, instead of rt
Zn or TDAE, instead of Mn
w/o nickel, L5, or Mn
w/o TMSCl
8
9
--
10
66%
93:7
aReactions were carried out with alkene 1 (0.2 mmol), aryl
bromide 2 (0.1 mmol), C4F9I (0.2 mmol), NiCl2•glyme (10
mol%), chiral ligand (12 mol%), TMSCl (0.01 mmol), Mn (0.25
mmol), DME [0.5 M], rt, 24 h. Yields were determined by GC
using an internal standard. The er values were determined by
HPLC on a chiral stationary phase.
also
viable
coupling
partners,
furnishing
1,2-
fluoroalkylarylation products in good yields and high ers
(Products 12−21, 50%−91% yields, up to 97:3 er). It should
be noted that ortho-substituents in pyrimidines and pyridines
were found to be crucial to achieving high enantioselective
control in this transformation, and simple 2-bromopyridine
was ineffective under the standard conditions. We surmised
that the presence of 2-substituent would prevent the undesired
coordination between nickel and nitrogen atom of
heterocycles. Additionally, this catalytic protocol
demonstrated excellent chemoselectivity, as exclusive
reactivity toward bromides over chlorides was observed in the
cases of multiple halogenated heteroarenes (Products 7, 14,
16, 19−21). Moreover, electron-deficient aryl bromides also
worked well to give the three-component coupling products
in good yields and high ers (Products 26−29, 72%−88%
yields, up to 98:2 er). Notably, simple recrystallization from
hot ethanol furnished product 29 in 96% ee. The mild reaction
conditions were well compatible with a wide range of
important functionalities, including CF3, chloride, thioether,
sulfone, cyano, ketone, and ester, offering useful handles for
further synthetic manipulations (Products 4−29).
Nevertheless, electron-neutral and -rich aryl iodides showed
lower reactivity in this catalytic protocol, furnishing the final
directing group, to facilitate the stereocontolled radical/nickel
combination step, thus fulfilling catalytic enantioselective
control in the intermolecular three-component version of
unactivated alkenes.
With this idea in mind, we began our investigations by
evaluating unactivated alkenes incorporated with different
types of directing groups. Pleasingly, we found that allylic
ester, the carbonyl group of which could interact with nickel
species via a six-membered-chelated ring, was a promising
non-conjugated alkene substrate for this enantioselective,
three-component dicarbofunctionalization reaction (See
Table S1). Employing the catalyst combination of
NiCl2•DME and chiral bioxazoline (Bn-BiOX, L1), reaction
of allyl ester 1 with 5-bromo-2-(trifluoromethyl)pyrimidine 2
and C4F9I in the presence of stoichiometric Mn and catalytic
TMSCl afforded the desired 1,2-fluoroalkylarylation product
4 in 21% yield with an encouraging 20:80 (S:R) enantiomeric
ratio (er) (Table 1, entry 1). Several pendant directing groups
such as carbonates, carbamates and benzoates, afforded
decreased ers with varied yields (Table S1). Screening of
chiral ligands indicated that only BiOx ligands4d, 6e, 6h were
effective, while other commonly employed chiral ligands all
ii
ACS Paragon Plus Environment

Page 3 of 9
Journal of the American Chemical Society
products with moderate yields and ers (Products 30−32, 1-chloro-2-iodotetrafluoroethane proceeded smoothly to
1
2
75%−80% yields, up to 89:11 er).
afford product 39, via selective cleavage of C–I bond, in 66%
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Scope of aryl halides. Reaction conditions: alkene 1 (0.2 mmol), aryl bromide (0.1 mmol), C4F9I (0.2 mmol), NiCl2•glyme
o
(10 mol%), L5 (12 mol%), TMSCl (0.01 mmol), Mn (0.25 mmol), DME [0.5 M], -10 C, 24 h. Isolated yields. The er values were
determined by HPLC on a chiral stationary phase. aConducted at 0 oC. bConducted at room temperature. cWith aryl iodide. Indole = 1-
methyl-1H-indole.
Next, we examined the scope of the fluoroalkyl yield and 93:7 er. Moreover, ethyl difluoroiodoacetate also
precursors. As depicted in Scheme 2, a wide array of underwent this asymmetric three-component protocol
perfluoroalkyl iodides (from C2 to C10) could be employed as smoothly (Product 40, 77% yield, 90:10 er). Pleasingly, we
competent C-radical precursors, leading to the corresponding also found that tertiary alkyl iodides could be employed as
enantioenriched fluoroalkyl-containing motifs in moderate to effective nonfluorinated C-radical precursors to afford the
high yields and high ers (Products 33−38, 50%−88% yields, 1,2-alkylarylated products 41 and 42 with 96:4 ers, albeit in
up to 96:4 er). While reaction efficiency decreased to a small relatively low yields (45% and 37% yield, respectively).13
extent as the fluoroalkyl carbon chains grew longer, probably
Finally, we also examined the reactivity of unactivated
due to the lower solubility of larger perfluoroalkyl iodides in alkenes under the optimal conditions (Scheme 2). Allyl esters
the current system (Products 37 and 38). The reaction with derived from different indole-3-carboxylic acids all
iii
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Scope of alkenes and alkyl halides. Reaction conditions: alkene (0.2 mmol), aryl bromide (0.1 mmol), alkyl halide (0.2 mmol),
NiCl2•glyme (10 mol%), L5 (12 mol%), TMSCl (0.01 mmol), Mn (0.25 mmol), DME [0.5 M], -10 oC, 24 h. Isolated yields. The er values
were determined by HPLC on a chiral stationary phase. Conducted at 0 C. Conducted at room temperature. Indole = 1-methyl-1H-
a
o
b
indole
via K2CO3 in MeOH,14 affording the enantioenriched -
underwent the desired three-component coupling reaction in
good yields and high ers (Products 43−50, 63%−81% yields,
up to 96:4 er). Substituents on nitrogen atom or the indole ring
had no significant influence on the yield and
enantioselectivity of this transformation. Unprotected indole
was also well-tolerated under mild conditions (Product 43).
Interestingly, allyl esters incorporating other types of
directing groups, exemplified by benzoate, carbonate, and
carbamate, were also applicable in this system, albeit with
only moderate enantioselectivity (Products 51−53, 64%−83%
yields, up to 91:9 er). Nevertheless, 1,1-disubstituted alkenes
and 1,2-disubstituted internal alkenes were generally
ineffective (e.g. 54 and 55).
This asymmetric, three-component difunctionalization
protocol could be feasibly scaled up, yield and
enantioselectivity of product 4 on a gram scale were
comparable to a smaller scale (Scheme 3A). Furthermore, the
ester directing group of product 29 could be easily cleavage
fluoroalkyl--aryl alcohol 56 (96% ee) without racemization
(Scheme 3B). To further demonstrate the synthetic utility of
this asymmetric method, several diversifications of alcohol
56 were performed (Scheme 3B). -Fluoroalkyl alcohol was
easily converted to the corresponding alkyl chloride 57 (95%
ee) and bromide 58 (96% ee),15 versatile intermediates in
organic synthesis, in high yields without loss of
enantioselectivity. Substitutions of 56 with phenyl disulfide
and phthalimide afforded fluoroalkyl thiol 60 (95% ee) and
fluoroalkyl amide 59 (97% ee) in 99% and 85% yields,16
respectively. It should be noted that the absolute
configuration of compound 58 was assigned by X-ray
diffraction analysis and the configuration of the other
products was assigned by analogy (see SI for X-ray
diffraction data for 58).
To shed some light on the plausible mechanism of this
novel nickel-catalyzed enantioselective three-component
iv
ACS Paragon Plus Environment

Page 5 of 9
Journal of the American Chemical Society
fluoroalkylarylation reaction, we have conducted several
preliminary mechanistic experiments (Scheme 4). Since the
iodoperfluoroalkylation byproduct was detected in our
reactions,17 we performed a control reaction of alkene 1 with
C4F9I in the absence of aryl bromide, which gave the racemic
1
2
3
4
5
6
7
8
A) Large scale reaction:
O
Br
NiCl2· DME
indole
O
C4F9
O
L5
I
C4F9
indole
O
N
N
standard
condition
9
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CF3
2, 5 mmol
CF3
4, 1.86g
1, 2 equiv.
2.0 equiv.
C4F9
68%, 94:6 er
B) Product transformations:
C4F9
Cl
Cl
29
96% ee
K2CO3
MeOH
SO2Me
SO2Me
58, 99%, 96% ee
57, 82%, 95% ee
C4F9
OH
(X-ray)
O
C4F9
SPh
N
SO2Me
56, 83%, 96% ee
O
C4F9
SO2Me
60, 99%, 95% ee
MeO2S
59, 85%, 97% ee
Scheme 3. A) Large scale reaction; B) Cleavage of directing
group and product transformations. a. CCl4, PPh3, CH2Cl2; b.
CBr4, PPh3, CH2Cl2; c. PhSSPh, PBu3, THF; d. phthalimide,
PPh3, DIAD, THF.
Scheme 4. Preliminary mechanistic studies.
transformation.22 Nevertheless, further studies are required to
fully elucidate the possible reaction pathway.9f, 23
In conclusion, we have developed the first
enantioselective, three-component 1,2-fluoroalkylarylation
of unactivated alkenes with aryl halides and fluoroalkyl
iodides via a chelation-assisted Ni-catalyzed multicomponent
cross-electrophile coupling. The benign protocol allows for
the facile construction of a wide range of functionalized chiral
-fluoroalkyl arylalkanes with high efficiency and excellent
alkyl iodide 61 in 44% yield (Scheme 4A). Two-component
reaction of racemic 61 with aryl bromide 2 in the presence of
Ni(II)/(R,R)-L5 and Mn also furnished product 4 with
excellent yield and enantioselectivity (Scheme 4A).18
Moreover, the time courses for this reaction disclosed that the
conversion of alkene 1 into alkyl iodide 61 was achieved at enantioselectivity from readily available starting materials.
the beginning of the reaction, and then the final product 4 The pendant ester group plays a crucial role in achieving high
gradually formed as the consumption of intermediate 61, levels of enantioselectivity and efficiency in this three-
suggesting alkyl iodide was an on-cycle reactive intermediate component, asymmetric difunctionalization of unactivated
in this catalytic system (Fig. S1). On the other hand, the alkenes. Moreover, the chelating group could be readily
desired reaction was completely inhibited by TEMPO, and cleaved to give enantioenriched alcohols, further
TEMPO-C4F9 adduct 62 was observed via 19F NMR (Scheme transformations of which generate a series of chiral
4B). The radical probe reaction of diene 63 with aryl bromide fluoroalkyl-containing motifs that could be useful in the areas
2 and C4F9I resulted in the cyclized product 64 in 11% yield of pharmaceuticals and agrochemicals.
(cis/trans 20:1, 52:48 er)19 along with 71% yield of the
cyclized alkyl iodide 64’ (cis/trans 12:1)20 (Scheme 4C). ASSOCIATED CONTENT
These cis/trans ratios were consistent with the involvement of Supporting Information
a radical intermediate (Scheme 4C).9a,
To further The Supporting Information is available free of charge on the
19, 21
diagnose the importance of chelation effect for this ACS Publications website.
remarkable enantioselective control, we submitted 4-phenyl-
1-butene, a non-activated alkene without a chelation group, • Experimental details, analytical data, and NMR spectra for
into our standard condition, which only afforded the desired all new compounds; synthetic applications; effect of reaction
product 65 in 14% yield and 68:32 er, along with 56% yield parameters; mechanistic studies (PDF)
of alkyl iodide 65’ (Scheme 4D). We anticipated that the • X-ray crystallographic details for Compound 58 (CIF)
weak chelating effect of the pendant indole carbonate group
would be beneficial to the enantio-determining step of this AUTHOR INFORMATION
v
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 9
Am. Chem. Soc. 2019, 141 (5), 1887-1892; (f) Lin,
J.-S.; Li, T.-T.; Liu, J.-R.; Jiao, G.-Y.; Gu,
Q.-S.; Cheng, J.-T.; Guo, Y.-L.; Hong, X.; Liu,
Corresponding Author
*lingling.chu1@dhu.edu.cn
1
2
X.-Y.,
Cu/Chiral
Phosphoric
Acid-Catalyzed
3
4
5
6
7
8
9
Asymmetric Three-Component Radical-Initiated 1,2-
Dicarbofunctionalization of Alkenes. J. Am. Chem.
Soc. 2019, 141 (2), 1074-1083; (g) Sha, W.; Deng,
L.; Ni, S.; Mei, H.; Han, J.; Pan, Y., Merging
Photoredox and Copper Catalysis: Enantioselective
Radical Cyanoalkylation of Styrenes. ACS Catal.
2018, 8 (8), 7489-7494; (h) Zhang, Z. Q.; Meng,
Author Contributions
†
H.-Y.T. and F.W. contributed equally to this work.
ACKNOWLEDGEMENT
We thank the National Natural Science Foundation of China
(21991123, 21971036, 21702029), the “Thousand Plan”
Youth program, and the Fundamental Research Funds for the
Central Universities for financial support. We thank Ms. L.
Wei and Prof. Y.-B. Zhang for beneficial discussion on X-ray
determination of absolute configuration with support from
Analytical Instrumentation Center (# SPST-AIC10112914) at
ShanghaiTech University.
X. Y.;
Enantioselective
Sheng, J.;
Lan, Q.; Wang, X. S.,
Copper-Catalyzed 1,5-
Cyanotrifluoromethylation of Vinylcyclopropanes.
Org. Lett. 2019, 21 (20), 8256-8260.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4. For recent examples on catalytic, three-
component, asymmetric alkene difunctionalizations
enabled by other metals, see: (a) Stokes, B. J.;
Liao, L.; de Andrade, A. M.; Wang, Q.; Sigman, M.
S., A Palladium-Catalyzed Three-Component-Coupling
Strategy for the Differential Vicinal Diarylation
of Terminal 1,3-Dienes. Org. Lett. 2014, 16 (17),
4666-4669; (b) Gu, J.-W.; Min, Q.-Q.; Yu, L.-C.;
Zhang, X., Tandem Difluoroalkylation-Arylation of
Enamides Catalyzed by Nickel. Angew. Chem. Int. Ed.
2016, 55 (40), 12270-12274; (c) Xiong, Y.; Zhang,
G., Enantioselective 1,2-Difunctionalization of
1,3-Butadiene by Sequential Alkylation and Carbonyl
Allylation. J. Am. Chem. Soc. 2018, 140 (8), 2735-
2738; (d) Anthony, D.; Lin, Q.; Baudet, J.; Diao,
REFERENCES
1. For selected reviews, see: (a)
Merino, E.;
Nevado, C., Addition of CF3 across unsaturated
moieties: a powerful functionalization tool. Chem.
Soc. Rev. 2014, 43 (18), 6598-6608; (b) Dhungana,
R. K.; KC, S.; Basnet, P.; Giri, R., Transition
Metal-Catalyzed
Unactivated Olefins. Chem. Rec. 2018, 18 (9), 1314-
1340; (c) Giri, R.; Kc, S., Strategies toward
Dicarbofunctionalization of Unactivated Olefins by
Combined Heck Carbometalation and Cross-Coupling.
J. Org. Chem. 2018, 83 (6), 3013-3022; (d) Zhang,
J.-S.; Liu, L.; Chen, T.; Han, L.-B., Transition-
Dicarbofunctionalization
of
T.,
Nickel-Catalyzed
Asymmetric
Reductive
Diarylation of Vinylarenes. Angew. Chem. Int. Ed.
2019, 58 (10), 3198-3202.
5. (a) Watson, M. P.; Jacobsen, E. N., Asymmetric
Intramolecular Arylcyanation of Unactivated Olefins
via C−CN Bond Activation. J. Am. Chem. Soc. 2008,
130 (38), 12594-12595; (b) You, W.; Brown, M. K.,
Catalytic Enantioselective Diarylation of Alkenes.
J. Am. Chem. Soc. 2015, 137 (46), 14578-14581; (c)
Carmona, R. C.; Köster, O. D.; Correia, C. R. D.,
Chiral N,NꢀLigands Enabling Palladium-Catalyzed
Metal-Catalyzed
Three-Component
Difunctionalizations of Alkenes. Chem. Asian J.
2018, 13 (17), 2277-2291; (e) J. Derosa; V. T.
Tran; V. A. van der Puyl; Engle, K. M., Carbon–
Carbon π Bonds as Conjunctive Reagents in Cross-
Coupling. Aldrichimi. Acta 2018, 51, 21-32; (f)
Lin, J.; Song, R.-J.; Hu, M.; Li, J.-H., Recent
Enantioselective
Intramolecular
Heck–Matsuda
Carbonylation Reactions by Sequential Migratory and
CO Insertions. Angew. Chem. Int. Ed. 2018, 57 (37),
12067-12070; (d) Wang, K.; Ding, Z.; Zhou, Z.;
Kong, W., Ni-Catalyzed Enantioselective Reductive
Diarylation of Activated Alkenes by Domino
Cyclization/Cross-Coupling. J. Am. Chem. Soc. 2018,
140 (39), 12364-12368; (e) Tian, Z. X.; Qiao, J.
B.; Xu, G. L.; Pang, X.; Qi, L.; Ma, W. Y.;
Zhao, Z. Z.; Duan, J.; Du, Y. F.; Su, P.; Liu,
X. Y.; Shu, X. Z., Highly Enantioselective Cross-
Advances
in
the
Intermolecular
Oxidative
Difunctionalization of Alkenes. Chem. Rec. 2019, 19
(2-3), 440-451.
2. For selected reviews, see: (a) McDonald, R. I.;
Liu, G.; Stahl, S. S., Palladium(II)-Catalyzed
Alkene Functionalization via Nucleopalladation:
Stereochemical
Catalytic Applications. Chem. Rev. 2011, 111 (4),
2981-3019; (b) Coombs, J. R.; Morken, J. P.,
Pathways
and
Enantioselective
Catalytic Enantioselective Functionalization of
Unactivated Terminal Alkenes. Angew. Chem. Int. Ed.
2016, 55 (8), 2636-2649.
3. For recent examples on Cu-catalyzed three-
component, asymmetric alkene difunctionalizations,
see: (a) Wang, F.; Wang, D.; Wan, X.; Wu, L.;
Chen, P.; Liu, G., Enantioselective Copper-Catalyzed
Intermolecular Cyanotrifluoromethylation of Alkenes
via Radical Process. J. Am. Chem. Soc. 2016, 138
(48), 15547-15550; (b) Wu, L.; Wang, F.; Wan, X.;
Electrophile
Alkenes. J. Am. Chem. Soc. 2019, 141 (18), 7637-
7643; (f) Jin, Y.; Wang, C., Nickel-Catalyzed
Aryl-Alkenylation
of
Unactivated
Asymmetric Reductive Arylalkylation of Unactivated
Alkenes. Angew. Chem. Int. Ed. 2019, 58 (20), 6722-
6726; (g) Li, Y.; Ding, Z.; Lei, A.; Kong, W.,
Ni-Catalyzed
enantioselective
reductive
aryl-
alkenylation of alkenes: application to the
synthesis of (+)-physovenine and (+)-physostigmine.
Org. Chem. Front. 2019, 6 (18), 3305-3309; (h)
Zhang, Z. M.; Xu, B.; Wu, L.; Wu, Y.; Qian, Y.;
Wang, D.;
Chen, P.; Liu, G., Asymmetric Cu-
Catalyzed Intermolecular Trifluoromethylarylation
of Styrenes: Enantioselective Arylation of Benzylic
Radicals. J. Am. Chem. Soc. 2017, 139 (8), 2904-
2907; (c) Fu, L.; Zhou, S.; Wan, X.; Chen, P.;
Zhou, L.;
Liu, Y.; Zhang, J., Enantioselective
Dicarbofunctionalization of Unactivated Alkenes by
Palladium-Catalyzed Tandem Heck/Suzuki Coupling
Reaction. Angew. Chem. Int. Ed. 2019, 58 (41),
14653-14659.
6. For examples on Ni-catalyzed asymmetric reductive
cross-couplings, see: (a) Zhao, Y.; Weix, D. J.,
Enantioselective Cross-Coupling of meso-Epoxides
with Aryl Halides. J. Am. Chem. Soc. 2015, 137 (9),
3237-3240; (b) Cherney, A. H.; Kadunce, N. T.;
Reisman, S. E., Catalytic Asymmetric Reductive Acyl
Liu,
G.,
Enantioselective
Trifluoromethylalkynylation of Alkenes via Copper-
Catalyzed Radical Relay. J. Am. Chem. Soc. 2018, 140
(35), 10965-10969; (d) Wang, F.; Chen, P.; Liu,
G., Copper-Catalyzed Radical Relay for Asymmetric
Radical Transformations. Acc. Chem. Res. 2018, 51
(9), 2036-2046; (e) Wu, L. Q.; Wang, F.; Chen,
P. H.; Liu, G. S., Enantioselective Construction of
Quaternary All-Carbon Centers via Copper-Catalyzed
Arylation of Tertiary Carbon-Centered Radicals. J.
Cross-Coupling:
Synthesis
of
Enantioenriched
Acyclic α,α-Disubstituted Ketones. J. Am. Chem. Soc.
vi
ACS Paragon Plus Environment

Page 7 of 9
Journal of the American Chemical Society
2013, 135 (20), 7442-7445; (c)
Reisman, S. E., Nickel-Catalyzed
Reductive Cross-Coupling Between Vinyl and Benzyl
Electrophiles. J. Am. Chem. Soc. 2014, 136 (41),
14365-14368; (d) Kadunce, N. T.; Reisman, S. E.,
Cherney, A. H.;
Asymmetric
Engle, Keary M., Directed nickel-catalyzed 1,2-
dialkylation of alkenyl carbonyl compounds. Chem.
Sci. 2018, 9 (23), 5278-5283; (i) Derosa, J.;
1
2
3
4
5
6
7
8
Kleinmans, R.; Tran, V. T.; Karunananda, M. K.;
Wisniewski, S. R.; Eastgate, M. D.; Engle, K. M.,
Nickel-Catalyzed 1,2-Diarylation of Simple Alkenyl
Amides. J. Am. Chem. Soc. 2018, 140 (51), 17878-
17883; (j) Zhao, X.; Tu, H.-Y.; Guo, L.; Zhu,
S.; Qing, F.-L.; Chu, L., Intermolecular selective
carboacylation of alkenes via nickel-catalyzed
reductive radical relay. Nat. Commun. 2018, 9 (1),
3488; (k) Guo, L.; Tu, H.-Y.; Zhu, S.; Chu, L.,
Selective, Intermolecular Alkylarylation of Alkenes
via Photoredox/Nickel Dual Catalysis. Org. Lett.
2019, 21 (12), 4771-4776; (l) García-Domínguez, A.;
Mondal, R.; Nevado, C., Dual Photoredox/Nickel-
Catalyzed Three-Component Carbofunctionalization of
Alkenes. Angew. Chem. Int. Ed. 2019, 58 (35), 12286-
12290; (m) Shu, W.; Garcia-Dominguez, A.; Quiros,
M. T.; Mondal, R.; Cardenas, D. J.; Nevado, C.,
Ni-Catalyzed Reductive Dicarbofunctionalization of
Nickel-Catalyzed
Asymmetric
Reductive
Cross-
α-
Coupling between Heteroaryl Iodides and
Chloronitriles. J. Am. Chem. Soc. 2015, 137 (33),
10480-10483; (e) Poremba, K. E.; Kadunce, N. T.;
Suzuki, N.; Cherney, A. H.; Reisman, S. E., Nickel-
Catalyzed Asymmetric Reductive Cross-Coupling To
Access 1,1-Diarylalkanes. J. Am. Chem. Soc. 2017,
139 (16), 5684-5687; (f) Suzuki, N.; Hofstra, J.
9
L.;
Poremba, K. E.; Reisman, S. E., Nickel-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Catalyzed Enantioselective Cross-Coupling of N-
Hydroxyphthalimide Esters with Vinyl Bromides. Org.
Lett. 2017, 19, 2150-2153; (g)
Cherney, A. H.; Ordner, C. M.; Reisman, S. E.,
Hofstra, J. L.;
Synthesis of Enantioenriched Allylic Silanes via
Nickel-Catalyzed Reductive Cross-Coupling. J. Am.
Chem. Soc. 2018, 140 (1), 139-142; (h) Woods, B.
P.; Orlandi, M.; Huang, C. Y.; Sigman, M. S.;
Doyle, A. G., Nickel-Catalyzed Enantioselective
Reductive Cross-Coupling of Styrenyl Aziridines. J.
Am. Chem. Soc. 2017, 139 (16), 5688-5691.
7. For selected reviews, see: (a) Tasker, S. Z.;
Standley, E. A.; Jamison, T. F., Recent advances in
homogeneous nickel catalysis. Nature 2014, 509, 299;
(b) Ananikov, V. P., Nickel: The “Spirited Horse”
of Transition Metal Catalysis. ACS Catal. 2015, 5
(3), 1964-1971; (c) Choi, J.; Fu, G. C., Transition
metal–catalyzed alkyl-alkyl bond formation: Another
dimension in cross-coupling chemistry. Science 2017,
356 (6334), eaaf7230.
Nonactivated
Alkenes:
Scope
and
Mechanistic
Insights. J. Am. Chem. Soc. 2019, 141 (35), 13812-
13821.
9. For recent examples on Ni-catalyzed two-component
dicarbofunctionalizations of unactivated alkenes,
see: (a) Kuang, Y.; Wang, X.; Anthony, D.; Diao,
T.,
Ni-catalyzed
two-component
reductive
dicarbofunctionalization of alkenes via radical
cyclization. Chem. Commun. 2018, 54 (20), 2558-2561;
(b) Kadam, A. A.; Metz, T. L.; Qian, Y.; Stanley,
L.
M.,
Ni-Catalyzed
Three-Component
Alkene
Carboacylation Initiated by Amide C–N Bond
Activation. ACS Catal. 2019, 9 (6), 5651-5656; (c)
8. For recent examples on Ni-catalyzed three-
component dicarbofunctionalizations of unactivated
Jin,
Y.;
Wang,
C.,
Ni-catalysed
reductive
arylalkylation of unactivated alkenes. Chem. Sci.
2019, 10 (6), 1780-1785; (d) Zheng, S.; Gutiérrez-
Bonet, Á.; Molander, G. A., Merging Photoredox PCET
alkenes, see: (a)
Dhungana, R. K.; Kc, S.; Thapa, S.; Sears, J. M.;
Giri, R., Ni-Catalyzed Regioselective 1,2-
Shrestha, B.;
Basnet, P.;
with
Ni-Catalyzed
Cross-Coupling:
Cascade
Dicarbofunctionalization of Olefins by Intercepting
Heck Intermediates as Imine-Stabilized Transient
Metallacycles. J. Am. Chem. Soc. 2017, 139 (31),
Amidoarylation of Unactivated Olefins. Chem 2019, 5
(2), 339-352; (e) Law, C.; Meng, Y.; Koo, S. M.;
Morken, J. P., Catalytic Conjunctive Coupling of
Carboxylic Acid Derivatives with 9-BBN-Derived Ate
Complexes. Angew. Chem. Int. Ed. 2019, 58 (20),
6654-6658; (f) Lin, Q.; Diao, T., Mechanism of Ni-
Catalyzed Reductive 1,2-Dicarbofunctionalization of
Alkenes. J. Am. Chem. Soc. 2019, 141 (44), 17937-
17948; (g) Huang, D.; Olivieri, D.; Sun, Y.;
Zhang, P.; Newhouse, T. R., Nickel-Catalyzed
Difunctionalization
Initiated by Unstabilized Enolates. J. Am. Chem.
Soc. 2019, 141 (41), 16249-16254.
10. (a)
Fluorine
10653-10656; (b)
Nevado, C.,
García-Domínguez, A.;
Nickel-Catalyzed
Li, Z.;
Reductive
Dicarbofunctionalization of Alkenes. J. Am. Chem.
Soc. 2017, 139 (20), 6835-6838; (c) Derosa, J.;
Tran, V. T.; Boulous, M. N.; Chen, J. S.; Engle,
K.
M.,
Nickel-Catalyzed
of Alkenyl
β,γ-
Carbonyl
Dicarbofunctionalization
Compounds via Conjunctive Cross-Coupling. J. Am.
Chem. Soc. 2017, 139 (31), 10657-10660; (d) Thapa,
S.; Dhungana, R. K.; Magar, R. T.; Shrestha, B.;
Kc, S.; Giri, R., Ni-catalysed regioselective 1,2-
diarylation of unactivated olefins by stabilizing
Heck intermediates as pyridylsilyl-coordinated
transient metallacycles. Chem. Sci. 2018, 9 (4),
904-909; (e) Basnet, P.; Dhungana, R. K.; Thapa,
S.; Shrestha, B.; Kc, S.; Sears, J. M.; Giri, R.,
Ni-Catalyzed Regioselective beta,delta-Diarylation
of Unactivated Olefins in Ketimines via Ligand-
Enabled Contraction of Transient Nickellacycles:
Rapid Access to Remotely Diarylated Ketones. J. Am.
Chem. Soc. 2018, 140 (25), 7782-7786; (f) Basnet,
P.; Kc, S.; Dhungana, R. K.; Shrestha, B.; Boyle,
T. J.; Giri, R., Synergistic Bimetallic Ni/Ag and
Ni/Cu Catalysis for Regioselective gamma,delta-
Diarylation of Alkenyl Ketimines: Addressing beta-H
Elimination by in Situ Generation of Cationic Ni(II)
Catalysts. J. Am. Chem. Soc. 2018, 140 (46), 15586-
of
Unactivated
Alkenes
Müller, K.;
in Pharmaceuticals:
Faeh, C.; Diederich, F.,
Looking Beyond
Intuition. Science 2007, 317 (5846), 1881-1886; (b)
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur,
V., Fluorine in medicinal chemistry. Chem. Soc. Rev.
2008, 37 (2), 320-330.
11.
Studer, A., A “Renaissance” in Radical
Trifluoromethylation. Angew. Chem. Int. Ed. 2012,
51 (36), 8950-8958.
12. Anka-Lufford, L. L.; Huihui, K. M. M.; Gower,
N. J.; Ackerman, L. K. G.; Weix, D. J., Nickel-
Catalyzed Cross-Electrophile Coupling with Organic
Reductants in Non-Amide Solvents. Chem. Eur. J.
2016, 22 (33), 11564-11567.
13. Other tertiary alkyl iodides led to low yields,
while primary alkyl iodides didn’t react under the
standard conditions.
14. Kleman, P.; González-Liste, P. J.; García-
Garrido, S. E.; Cadierno, V.; Pizzano, A., Highly
Enantioselective Hydrogenation of 1-Alkylvinyl
Benzoates: A Simple, Nonenzymatic Access to Chiral
2-Alkanols. Chem. Eur. J. 2013, 19 (48), 16209-
16212.
15590; (g)
Kc, S.;
Basnet, P.;
Thapa, S.;
Shrestha, B.; Giri, R., Ni-Catalyzed Regioselective
Dicarbofunctionalization of Unactivated Olefins by
Tandem Cyclization/Cross-Coupling and Application
to the Concise Synthesis of Lignan Natural Products.
J. Org. Chem. 2018, 83 (5), 2920-2936; (h) Derosa,
J.; van der Puyl, V. A.; Tran, V. T.; Liu, M.;
vii
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 9
15. Boz, E.; Nemeth, A. J.; Ghiviriga, I.; Jeon,
K.; Alamo, R. G.; Wagener, K. B., Precision
Ethylene/Vinyl Chloride Polymers via Condensation
Polymerization. Macromolecules 2007, 40 (18), 6545-
6551.
16. (a) Han, Y.-C.; Zhang, Y.-D.; Jia, Q.; Cui,
J.; Zhang, C., Hypervalent-Iodine-Mediated Ring-
23. (a) Jones, G. D.; Martin, J. L.; McFarland,
C.; Allen, O. R.; Hall, R. E.; Haley, A. D.;
Brandon, R. J.; Konovalova, T.; Desrochers, P. J.;
Pulay, P.; Vicic, D. A., Ligand Redox Effects in the
Synthesis, Electronic Structure, and Reactivity of
an Alkyl−Alkyl Cross-Coupling Catalyst. J. Am. Chem.
1
2
3
4
5
6
7
8
Soc. 2006, 128 (40), 13175-13183; (b)
Lin, X.;
Contraction
Monofluorinated
Monofluorination
Five-Membered
Affording
Ring-Fused
Phillips, D. L., Density Functional Theory Studies
of Negishi Alkyl–Alkyl Cross-Coupling Reactions
Catalyzed by a Methylterpyridyl-Ni(I) Complex. J.
Org. Chem. 2008, 73 (10), 3680-3688; (c) Biswas,
S.; Weix, D. J., Mechanism and Selectivity in
Nickel-Catalyzed Cross-Electrophile Coupling of
Aryl Halides with Alkyl Halides. J. Am. Chem. Soc.
2013, 135 (43), 16192-16197; (d) Breitenfeld, J.;
Oxazolines. Org. Lett. 2017, 19 (19), 5300-5303; (b)
Raghavan S; L., R. C., Stereoselective carbon–carbon
bond formation via 1,2-asymmetric induction by a β-
substituent in the reaction of α-chloro sulfides
with organozinc reagents. Indian J. Chem. Sec B
2018, 57B, 327-339.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17.
Several
byproducts
including
the
Ruiz, J.;
Wodrich, M. D.; Hu, X., Bimetallic
hydroperfluoroalkylated and iodoperfluoroalkylated
alkane as well as C4F9-alkenes were detected in the
reaction.
18. (a) Everson, D. A.; Shrestha, R.; Weix, D. J.,
Nickel-Catalyzed Reductive Cross-Coupling of Aryl
Halides with Alkyl Halides. J. Am. Chem. Soc. 2010,
Oxidative Addition Involving Radical Intermediates
in Nickel-Catalyzed Alkyl–Alkyl Kumada Coupling
Reactions. J. Am. Chem. Soc. 2013, 135 (32), 12004-
12012; (e)
Catalyzed
Bromides: A Mechanistic Investigation. J. Am. Chem.
Soc. 2014, 136 (47), 16588-16593; (f) Mohadjer
Beromi, M.; Nova, A.; Balcells, D.; Brasacchio,
A. M.; Brudvig, G. W.; Guard, L. M.; Hazari, N.;
Vinyard, D. J., Mechanistic Study of an Improved Ni
Precatalyst for Suzuki–Miyaura Reactions of Aryl
Sulfamates: Understanding the Role of Ni(I) Species.
J. Am. Chem. Soc. 2017, 139 (2), 922-936; (g) Kc,
S.; Dhungana, R. K.; Shrestha, B.; Thapa, S.;
Khanal, N.; Basnet, P.; Lebrun, R. W.; Giri, R.,
Schley, N. D.; Fu, G. C., Nickel-
Negishi Arylations of Propargylic
132 (3), 920-921; (b)
Liang, Y.; Fu, G. C.,
Stereoconvergent Negishi Arylations of Racemic
Secondary Alkyl Electrophiles: Differentiating
between a CF3 and an Alkyl Group. J. Am. Chem. Soc.
2015, 137 (30), 9523-9526.
19.
Huang, L.;
Zhu, C.;
Yi, L.;
Yue, H.;
Kancherla, R.; Rueping, M., Cascade Cross-Coupling
of Dienes: Photoredox and Nickel Dual Catalysis.
Angew. Chem. Int. Ed. 2020, 59 (1), 457-464.
20. Helmecke, L.; Spittler, M.; Baumgarten, K.;
Czekelius, C., Metal-Free Activation of C–I Bonds
and Perfluoroalkylation of Alkenes with Visible
Light Using Phosphine Catalysts. Org. Lett. 2019,
21 (19), 7823-7827.
21. Shevick, S. L.; Obradors, C.; Shenvi, R. A.,
Mechanistic Interrogation of Co/Ni-Dual Catalyzed
Hydroarylation. J. Am. Chem. Soc. 2018, 140 (38),
12056-12068.
22. 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 (15), 4896-4899.
Ni-Catalyzed
Regioselective
Alkylarylation
of
Vinylarenes via C(sp3)–C(sp3)/C(sp3)–C(sp2) Bond
Formation and Mechanistic Studies. J. Am. Chem. Soc.
2018, 140 (31), 9801-9805; (h) Wang, X.; Ma, G.;
Peng, Y.; Pitsch, C. E.; Moll, B. J.; Ly, T. D.;
Wang, X.; Gong, H., Ni-Catalyzed Reductive Coupling
of Electron-Rich Aryl Iodides with Tertiary Alkyl
Halides. J. Am. Chem. Soc. 2018, 140 (43), 14490-
14497; (i)
Investigation of Enantioconvergent Kumada Reactions
of Racemic α-Bromoketones Catalyzed by
Yin, H.; Fu, G. C., Mechanistic
a
Nickel/Bis(oxazoline) Complex. J. Am. Chem. Soc.
2019, 141 (38), 15433-15440.
viii
ACS Paragon Plus Environment

Page 9 of 9
Journal of the American Chemical Society
1
2
3
4
TOC
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ix
ACS Paragon Plus Environment