Asymmetric Ni-Catalyzed Radical Relayed Reductive Coupling

Article abstract of DOI:10.1021/jacs.0c05254

Alkene dicarbofunctionalizations enable the streamlined construction of aliphatic structures and have thus been the subject of intense research efforts. Despite significant progress, catalytic asymmetric variants remain scarce. Inspired by the advantages of reductive cross-coupling approaches, we present here a highly efficient asymmetric intermolecular Ni-catalyzed reductive dicarbofunctionalization of alkenes. Two distinct readily available electrophiles, namely, Csp2- and Csp3-halides, are added simultaneously across a variety of olefins (vinyl amides, vinyl boranes, vinyl phosphonates) at room temperature in a highly regio- and enantioselective manner. The reaction, devoid of sensitive organometallic reagents, takes advantage of an in situ generated chiral alkyl Ni(III)-intermediate to ensure a stereodefined outcome in the Csp3-Csp2 bond-forming reaction. An (l)-(+)-isoleucine chiral bisoxazoline ligand and the presence of coordinating sites on the alkene are key for the successful outcome in these asymmetric radical relayed reductive couplings (ARRRCs). Further, multiple transformations of the chiral amides obtained in this process showcase the potential of this new methodology for the straightforward assembly of chiral building blocks such as primary and secondary amines and oxazolines, highlighting its synthetic utility.

Full text of DOI:10.1021/jacs.0c05254

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Article
Asymmetric Ni-catalyzed Radical Relayed Reductive Coupling
XiaoFeng Wei, Wei Shu, Andrés García-Domínguez, Estibaliz Merino, and Cristina Nevado
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c05254 • Publication Date (Web): 29 Jun 2020
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Asymmetric Ni-catalyzed Radical Relayed Reductive Coupling
Xiaofeng Wei, Wei Shu, Andrés García-Domínguez, Estíbaliz Merino† and Cristina Nevado*
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Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich, CH 8057, Switzerland.
KEYWORDS Nickel, Asymmetric dicarbofunctionalization, Alkenes, Reductive coupling.
ABSTRACT: Alkene dicarbofunctionalizations represent streamline the construction of aliphatic structures and have thus been
the subject of intense research efforts. Despite significant progress, catalytic asymmetric variants remain scarce. Inspired by the
advantages of reductive cross-coupling approaches, we present here a highly efficient asymmetric intermolecular Ni-catalyzed
reductive dicarbofunctionalization of alkenes. Two distinct readily available electrophiles, namely Csp2- and Csp3- halides are added
simultaneously across a variety of olefins (vinyl amides, vinyl boranes, vinyl phosphates) at room temperature in a highly regio- and
enantioselective manner. The reaction, devoid of sensitive of organometallic reagents, takes advantage of an in situ generated chiral
alkyl Ni(III)-intermediate to ensure a stereodefined outcome in the Csp3-Csp2 bond forming reaction. An (L)-(+)-isoleucine chiral
bisoxazoline ligand and the presence of coordinating sites on the alkene are key for the successful outcome in these “Asymmetric
Radical Relayed Reductive Coupling” (ARRRC). Further, multiple transformations of the chiral amides obtained in this process
showcase the potential of this new methodology for the straightforward assembly of chiral building blocks such as primary and
secondary amines, oxazolines, etc. highlighting its synthetic utility.
amounts of an organo-lithium or –magnesium reagents to a
Introduction
vinyl borane, undergo arylation or alkylation in the β position
delivering, upon 1,2-rearrangement, the corresponding
alkylboronate esters with excellent levels of stereocontrol
Olefins represent excellent platforms for regio- and
enantioselective transformations. Because of their ubiquitous
presence in pharmaceuticals and orthogonal reactivity with
respect to carbonyls and other polar functional groups, they
have also been used in late-stage functionalization efforts.1 In
recent years, three-component alkene dicarbofunctionalizations
have triggered significant attention based on their unique ability
to streamline the assembly of complex aliphatic structures
through the simultaneous construction of two new C-C bonds
across the π system. Transition metals,2 in particular paladium3
and more recently nickel,4 have played a significant role in
developing catalytic versions of these transformations, the latter
enabling the utilization of a wide variety of Csp3-based partners.
Still, and despite significant progress, catalytic asymmetric
dicarbofunctionalizations of alkenes, in particular those dealing
with intermolecular three-component reactions,5 remain largely
underdeveloped. Remarkable examples by Liu and co-workers
showed that, in situ generated trifluoromethyl radicals undergo
addition across double bonds to produce intermediates which
are subsequently intercepted by chiral copper species to yield
efficient enantioselective trifluoromethylarylation and
cyanotrifluoromethylation reactions.6 Interestingly, oxidation
of such radical intermediates to the corresponding carbocations
was also recently harvested by Liu et al. to produce the
corresponding chiral perfluoroalkylarylated products in the
presence of a chiral phosphoric acid organocatalyst (Scheme
1A).7 Chiral phosphoric acids were also employed in a
photocatalyzed three component Minisci reaction recently
reported by Studer et al.8 In a different approach, Morken´s
group has taken advantage of well-established 1,2-metallate
rearrangements at Boron9 developing a series of Pd- and Ni-
catalyzed conjuctive cross-coupling reactions. Boron-ate
intermediates produced in situ by addition of stoichiometric
(Scheme 1B).10 Recently,
a
Ni-catalyzed asymmetric
dicarbofunctionalization of vinyl boranes using organozinc
reagents was also reported.10f Despite the profound impact of
these transformations, multiple challenges still lay ahead. First,
methods remain highly tailored to olefinic partners able to
stabilize the fast-paced radical/cationic intermediates involved
in these transformations.
A. Asymmetric Perfluoroalkylcarbofunctionalizations B. Asymmetric Dicarbofunct. via Boron-ates
R'
Nu
R'-M
cat.
Nu
E
R
+
E
CnFm
L2B

L2B
Ar
via:
Ar
cat.

Ar
via:
via:
R
R
CF3
L2B
R'
CnFm
L2B
R'
or
Ar
cat: Pd/Ni, L*
cat: Cu/L*
cat: Cu/(RO)*2PO2H
Nu = Indoles
R' = Alk, Ar
M = Li, Mg, Zn
E = Ar-X, Alk-X
X = Br, I
Nu = TMSCN, ArB(OH)2
C. This work: Asymmetric Radical Relayed Reductive Coupling
L*
L = (+)-secButyl-
bisoxazoline
Csp2
*
Ni,
Organic Reductant
Csp3
E1 (Csp3)
E2 (Csp2)
> 30 examples
up to 96 ee%
+
+
THF, 25º C
O
II
L
Csp2
[
*Ni ]-
Csp3-I
Ar-I
III
*Ni ] Csp2
II
N
R
L
[
-
H
Alk-I
L*Ni
Red
Csp3
HetAr-I
Vinyl-Br
BPin
O
Alk = 3ary
Csp2-I
P
III
OEt
OEt
Csp3·
I
Single L*, high ee
Devoid of sensitive organometallic species
Broad functional group tolerance
Operationally simple
Applicable to multiple type of olefins
3º Alkyl groups
Scheme 1. Strategies towards metal-catalyzed asymmetric
intermolecular dicarbofunctionalization of alkenes.
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Further, many of these protocols rely on highly reactive and
the substituents in α-position to the nitrogen atom seemed to
play a major role in the reaction outcome.
1
thus sensitive organometallic species such as organo-lithium, -
zinc or -magnesium reagents. In this context, the ability to
promote asymmetric intermolecular dicarbofunctionalizations
for a variety of olefins that would rely on neutral precursors
would be highly desirable. Readily available, both Csp2- and
Csp3-halides would be ideal reaction partners, as they would
prevent the use of stoichiometric, highly reactive,
organometallic reagents thus improving the operational
simplicity, functional group compatibility and cost-efficiency
of these transformations. Multiple obstacles including the
inherent low reactivity of these electrophiles an their potential
side reactions (i.e. homocoupling, β-hydride elimination, direct
cross-coupling etc.) would need to be overcome in order to
ensure a successful outcome.11 Inspired by the advantages of
reductive cross-coupling approaches,12,13 several nickel-
catalyzed intermolecular alkene dicarbofunctionalizations have
been recently disclosed.14 Here, we have devised a highly
efficient asymmetric example of this type of transformations
(Scheme 1c). Mechanistically, our design relies on the
activation of an alkyl iodide with nickel15 to produce an alkyl
radical I under the reductive conditions.16 Further, Csp2-X
precursors (Csp2 = Ar, vinyl; X = Br, I) are activated via
oxidative addition producing Csp2-nickel intermediates of type
II. Instead of the direct coupling between these two species,17
alkyl radical I is trapped by different olefins so that, in a relay
process, a new alkyl-Ni(III) complex is formed (III). The
combination of complexes II and III enable the second C-C
bond forming reaction via reductive elimination. A novel (L)-
(+)-Isoleucine-based chiral bisoxazoline ligand has been
identified to control the stereochemical outcome in this
process.18 Two distinct readily available electrophiles, namely
Csp2- and Csp3- halides are thus simultaneously added across
multiple, readily available olefins including vinyl amides, vinyl
2
3
4
5
6
7
8
9
NiBr2 DME (5 mol%)
Ligand (6 mol%)
TDAE (2 equiv)
H
H
N
I
N
Ph
Ph
+
+
tBuI
O
O
THF, 25 ºC
tBu
1
O
N
O
N
R1 R1
O
N
O
O
N
R
R
R
N
N
R2
R2
L5
R = Bn, 26% (39% ee)
R = tBu, trace
R = iPr, 64% (88% ee)
L6
L7
L8
L1
, R1 = Et, R2 = iPr, trace
, R1 = -(CH2)4-, R2 = Bn, trace
L3
L4
R = iPr: 13% (46% ee)
R = CH2OTBS: 94% (18% ee)
L2
R = (S)-sec-Bu, 69% (91% ee)
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NiBr2 DME (7.5 mol%), L8 (9 mol%), 95% (94% ee)
Optimized conditions:
Figure 1. Ligand optimization. For preliminary experiments to find
optimal conditions, see Supporting Information.19 Standard
protocol uses vinyl amide (0.1 mmol), tBuI (0.3 mmol), PhI (0.15
mmol), TDAE (2 equiv.) NiBr2·glyme (5 mol%), Ligand (6 mol%),
in 1 mL of THF at 25 ºC for 13 hours. Yield determined by H
NMR using mesitylene as internal standard. The ee value was
determined by HPLC with a chiral stationary phase.
1
Thus, whereas the use of a more bulky tert-butyl derivative
L6 resulted in decreased reactivity, iso-propyl-derivative L7
delivered compound 1 in good yields with high level of
stereocontrol. Interestingly, a rather unexplored sec-butyl
bisoxazoline ligand L8,20 readily synthesized from (L)-(+)-
Isoleucine, delivered the corresponding dicarbofunctionalized
amide in 69% yield and 91% ee. Finally, the combination of L8
(9 mol%) with NiBr2·DME catalyst (7.5 mol%) furnished the
chiral amide 1 in almost quantitative yield (95%) with excellent
stereocontrol (94% ee).
With the optimized reaction conditions in hand, the substrate
scope of this transformation was examined next (Scheme 2). A
broad range of electronic and sterically differentiated
substituted iodoarenes (Ar-I with Ar = Ph, Tol, p-OMeC6H4, p-
tBuC6H4, m-CF3-C6H4, p-F-C6H4, 2,3- and 3,5-(CH3)2-C6H3, p-
COMe-C6H4) delivered the corresponding products 1-9 in good
to excellent yields (40 to 97%) with high enantioselectivities
(90 to 94% ee). Hetereocycles such as pyridine and indoles,
which are also challenging partners for reported processes using
vinyl boron-ate species,9 were well-tolerated in this mild three-
component reaction as shown by the efficient formation of
products 10-12. Interestingly, vinyl bromides could also be
successfully incorporated in these transformations by
increasing the Ni-catalyst load to 10 mol% so that the
corresponding chiral allyl amides 13 and 14 could be isolated in
62 and 73% yield with 81 and 92% ee, respectively. In all
abovementioned cases, excellent regio- and enantioselectivities
were observed across the panel of utilized iodoarenes (Scheme
2a). The absolute configuration of the relayed cross-coupling
products was unambiguously confirmed as by X-ray diffraction
analysis of p-fluoro substituted amide (R)-6.
boranes, vinyl phosphates in
a completely regio- and
stereoselective manner. This process, termed “Asymmetric
Radical Relayed Reductive Coupling” (ARRRC), is thus devoid
of sensitive of organometallic reagents and proceeds at room
temperature. Further, and in the case of the chiral amides
obtained in these transformations, subsequent derivatization
showcased the potential of this new methodology for the
straightforward assembly of chiral building blocks such as
primary and secondary amines, oxazolines, etc.
Results and Discussion
N-vinylbenzamide, iodobenzene and tert-butyl iodide were
chosen as reaction partners to find the optimal conditions for
this transformation. After a screening including different nickel
sources, solvents, reductants and additives (see Supporting
Information for further details)19, different chiral ligands
including mono- and bisoxazoline templates were evaluated
(Figure 1). Commercially available L1 and L2 ligands, which
have been successfully applied in nickel catalyzed
enantioselective reductive coupling reactions,18 failed to
produce the desired product. In contrast, the reaction with
PYBOX ligands L3 and L4 produced compound 1 in 13% and
94% yields, respectively with promising levels of stereocontrol
in both cases. These results highlight the importance of rigidity
and the bite angle of the N^N ligand for a successful reaction
outcome. Next, we turned our attention to C2-symmetric
bisoxazoline ligands. Interestingly, while L5 furnished
moderate levels of stereocontrol, the steric demand imposed by
As shown in Scheme 2b, the reaction could be successfully
extended to different tertiary halides. Both acyclic and cyclic,
alkyl iodides were incorporated into the corresponding amides
delivering the desired products with excellent level of enantio-
control (15-18, 74-85% yield, 93-94% ee).
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R3
Z
NiBr2 DME (7.5 mol%)
L8
O
N
O
N
H
Ligand
(9 mol%)
X
1
2
3
4
N
R2
H
TDAE (2 equiv)
R3
N
R2
+
+
*
R1-I
O
Z
THF (0.1 M), 25 ºC, 13 h
O
R1
L8
X = I, Br
1-24
5
(a) Aryl iodide and vinyl bromide coupling partners
6
7
8
9
Me
MeO
tBu
H
H
N
H
N
H
N
H
N
N
F3C
O
O
O
O
O
tBu
tBu
tBu
tBu
tBu
5
1
2
3
4
10
11
12
13
14
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90%
94% ee
95%
93% ee
91%
93% ee
95%
93% ee
40%
92% ee
Me
Me
Me
O
F
Me
H
N
H
N
H
N
H
N
Me
O
O
O
O
tBu
tBu
tBu
tBu
6
7
8
9
95%
92% ee
75%
94% ee
91%
90% ee
97%
93% ee
NH
Me
MeO
F3C
H
N
H
N
Me
H
N
H
N
Me
H
N
N
N
O
O
tBu
tBu
O
O
O
tBu
tBu
tBu
10
11
12
13
14
*
*
35%
62%
81% ee
85%
96% ee
91%
73%
92% ee
95% ee
96% ee
(b) Alkyl iodide coupling partners
H
N
H
H
H
N
N
N
O
O
O
Ph
O
Et
Ph
Me
Me
Me
Me
Me
Me
Me
15
16
17
18
85%
94% ee
85%
94% ee
74%
93% ee
83%
93% ee
(c) N-vinyl amide acceptors
Br
Me
Br
R
H
N
Me
H
N
H
N
H
N
H
N
Me
O
tBu
O
O
O
O
tBu
tBu
tBu
tBu
24*
23
19
22
20
,
, R = OMe 88%, 94% ee
21**
60%
,
, R = CF3 77%, 94% ee
72%
85% ee
90%
93% ee
96%
94% ee
93% ee
Scheme 2. (a) Substrate scope of Csp2 partners (Ar-I and and vinyl-Br). (b) Substrate scope of Alkyl-I partners (c) Scope on vinyl-
amides. All yields are isolated yields of pure products obtained after purification of the reaction mixtures via column
chromatography on silica gel. *Reaction was conducted using 10 mol% catalyst loading at -5 ºC for 13 h. ** Reaction was
conducted using 15 mol% NiBr2 DME and 18 mol% L8. Absolute configuration of products was assigned by analogy to that
determined by X-Ray diffraction analysis for compound 6.
.
(Scheme 2c). Interestingly, both electron-donating as well as
The ability to incorporate tertiary alkyl groups represent an
attractive feature as highly sterically hindered electrophiles are
typically difficult to engage in these transformations.10
Unfortunately, perfluoroalkyl iodides could not be successfully
incorporated under these conditions.21 The methodology is also
amenable to the utilization of different of vinyl amide acceptors
electron-withdrawing substituents on the aryl group bound to
nitrogen were well tolerated, although higher catalyst loading
was required to accomplish the transformation with electron-
deficient derivative 21. Naphthalene carboxamide as well as
acetamides were also nicely compatible with the optimized
reaction conditions. Orthogonal functionalities, such as Csp2-Br
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Page 4 of 8
bonds, remained intact under the standard protocol, opening the
acceptors such as N-Boc or N-Ts protected vinyl amides or
vinylsilanes. For an overview of the unsuccessful substrates,
please see Section 2 in the SI.19
1
2
3
4
5
6
7
8
possibility of subsequent functionalizations via classical Pd-
cross coupling reactions (23 and 24). Next, we sought to further
expand the scope with respect to the olefinic acceptor in these
transformations. To our delight, vinyl boronic esters, which are
useful intermediates22 in a wide range of transformations,
proved to be amenable to this asymmetric radical relayed
reductive cross-coupling upon minor modifications of the
previously optimized conditions. To this end, nickel complex
Cat1 was prepared by stirring of NiBr2·glyme with L8.19 The
use of 10 mol% of Cat1 in the presence of one equivalent of
LiBF4 resulted in clean formation of the desired secondary alkyl
boronic ester derivatives. For convenience, the resulting
products were oxidized in situ into the corresponding secondary
alcohols using NaBO3·4H2O in aqueous THF. As illustrated in
Scheme 3, a diverse range of aryl and vinyl halides as well as
tertiary alkyl iodides were incorporated across the vinyl boron
moiety with consistent yields and excellent regio- and absolute
stereocontrol. Substrates resembling steroid natural products as
well as amino acid derivatives were also amenable to the
asymmetric dicarbonfunctionalization protocol, providing the
corresponding products 31 and 32 with high levels of
diastereocontrol. Further, we also demonstrate that vinyl
phosphates can be transformed into the corresponding enan-
tioenriched adducts under our standard conditions, thus
highlighting the broad application potential of this mild
enantioselective three component coupling strategy (33).
Despite its broad applicability, our protocol could not be
successfully applied to secondary alkyl iodides nor to olefins
To further illustrate the synthetic utility of our protocol,
several transformations of the chiral amides initially obtained in
Scheme 2 were carried out (Scheme 4a). Palladium-catalyzed
hydrogenation of 14 furnished the corresponding chiral
secondary amine 34 with high levels of stereofidelity. It is
important to note that, enantioselective catalytic access to such
amines has proven elusive due to minimally differentiated steric
and electronic properties of the two aliphatic substituents. The
olefin group in 14 could be cleaved via oxidation by
RuCl3/NaIO4 to give α amino ketone 35 in 91% yield and 91%
ee. An enantio-enriched trisubstituted epoxide (36) containing
three contiguous chiral centers, could be assembled by
straightforward one-pot diastereoselective epoxidation reaction
in the presence of m-CPBA. A subsequent Lewis-acid catalyzed
ring opening reaction furnished a chiral mono-oxazoline 37 in
a 5:1 d.r. and 62% yield, thus showcasing the potential of our
method towards novel routes for ligand discovery. Finally,
deprotection of the benzamide moiety in the presence of
Schwartz reagent resulted in the clean formation of primary
amine 38 in almost quantitative yield almost perfect
stereocontrol (Scheme 4b).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
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32
33
34
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58
59
60
Cat 1
10 mol%
O
N
O
N
TDAE (2 equiv)
LiBF4 (1 equiv)
R2
I
X
X
-
R1
I
+
R2
+
Ni
THF, 25 ºC, 13h
Br
Br
Cat 1
R1
(X= BPin, then NaBO3 4H2O)
X = BPin
MeO
tBu
OH
OH
OH
OH
OH
Me
tBu
tBu
25
tBu
27
tBu
28
26
29
82%
85% ee
OH
tBu
58%
82% ee
82%
94% ee
85%
90% ee
65%
89% ee
Me
Me
Me
Me
X = PO(OEt)2
3
O
OH
Me
O
H
O
O
Boc
Cl
P
H
H
OEt
OEt
N
O
O
Me
Me
H
Me
t-Bu
32
O
tBu
30
31
50%
82 : 18 dr
HO
63%
single isomer
33
50%
87% ee
65%
82% ee
Scheme 3. Extension of the asymmetric reductive dicarbofunctionalization to vinyl boronic esters and vinyl phosphonates as olefin
acceptors.
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OH
Conclusion
O
Ph
Me
Me
O
1
2
Me
O
BF3 OEt3
Me
NH
tBu
Ph
0 oC, 4 h
N
In summary, we present here a highly efficient asymmetric
intermolecular reductive dicarbofunctionalization of alkenes. A
variety of readily available Csp2- and Csp3-halides are added
simultaneously across alkenes at room temperature in a highly
regio- and enantioselective manner. The reaction is devoid of
sensitive of organometallic reagents as it relies on an organic
reductant. The reaction proceeds through a chiral alkyl Ni(III)-
intermediate based on a (L)-(+)-isoleucine chiral bisoxazoline
ligand. DFT calculations confirm that in the transition state,
coordinating sites present on the alkene stabilize the Ni center
contributing to a stereodefined outcome in the Csp3-Csp2 bond
forming reaction. This transformation, termed “Asymmetric
Radical Relayed Reductive Coupling” (ARRRC) is able to
engage a variety of olefins (vinyl amides, vinyl boranes, vinyl
phosphates) under extremely mild reaction conditions. Further,
multiple transformations of the chiral amides obtained in this
process showcase the synthetic potential of our methodology
towards the straightforward assembly of chiral building blocks
such as primary and secondary amines, oxazolines, etc.
3
4
5
6
7
8
9
36
37
tBu
85%
> 20 : 1 dr
62%
5 : 1 dr
mCPBA,
CH2Cl2
R1 = Me
O
Ph
NH
tBu
O
Ph
NH
tBu
O
Ph
NH
tBu
O
R1
R1 = H
R1 = Me
10
11
12
13
14
15
16
17
18
19
20
21
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Me
Me
Pd/C, H2
EtOH
RuCl3 H2O, NaIO4
H2O/CH3CN
34
35
91%
91% ee
93%
81% ee
NH2
Schwartz reagent (2 eq.)
THF, 25 ºC. 30 min.
H
N
O
1
tBu
tBu
38
94% ee
91 %
93% ee
ASSOCIATED CONTENT
Supporting Information. Supplementary information including
compound synthesis, characterization, additional experiments and
DFT calculations. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 4. Derivatization of chiral dicarbofunctionalized
amides.
To shed light on the stereochemical outcome of this process,
DFT calculations were carried out for the reaction producing
amide 1.19 The transition state preceding the formation of
intermediate III for the observed (R) configured product (TSR)
showcases the interaction of the carbonyl group of the amide
with the Ni center (dNi-O= 2.093 Å). Although weak, this
interaction enables the partial decoordination of one of the
nitrogen atoms of L8 (dNi-N1= 2.098 and dNi-N2= 4.280 Å) which
results in a minimized steric contact between the incoming aryl
moiety and the sec-butyl chain of the bisoxazoline ligand, thus
explaining the R-configuration of the final product. The
transition state yielding the minor enantiomer (TSS) is
energetically disfavored (ΔΔG‡ = 2.1 kcal/mol) as a result of a
more congested environment around the metal center since no
significant interaction between the carbonyl group of the amide
and the metal center is observed (dNi-O= 2.203 Å) and, although
to a different extent, the two nitrogen atoms of the ligand remain
coordinated to Ni (dNi-N1= 2.630 and dNi-N2= 2.107 Å) (Scheme
5).19,23
AUTHOR INFORMATION
Corresponding Author
Cristina Nevado* (cristina.nevado@chem.uzh.ch)
Notes
The authors declare no competing financial interests.
Present Addresses
† Department of Organic and Inorganic Chemistry, Chemical
Research Institute Andrés M. del Río (IQAR), University of
Alcalá, 28805-Alcalá de Henares (Madrid), Spain.
ACKNOWLEDGMENT
We thank the European Research Council (ERC Starting grant
agreement no. 307948) and the Swiss National Science Foundation
(SNF 200020_146853) for financial support. We also thank Prof.
Anthony Linden for the X-ray diffraction analysis of 6 (CCDC
1981825).
REFERENCES
1. (a) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Catalytic
Markovnikov and anti-Markovnikov Functionalization of Alkenes and
Alkynes: Recent Developments and Trends. Angew. Chem., Int. Ed.
2004, 43, 3368–3398. (b) Zhang, J.‐S.; Liu, L.; Chen, T.; Han, L.‐B.
Transition-Metal-Catalyzed Three-Component Difunctionalizations of
Alkenes. Chem. Asian J. 2018, 13, 2277 –2291. (c) Giri, R.; Shekhar,
K. C. Strategies toward Dicarbofunctionalization of Unactivated
Olefins by Combined Heck Carbometalation and Cross-Coupling. J.
Org. Chem. 2018, 83, 3013-3022.
2. (a) Ouyang, X.-H.; Song, R.-J.; Hu, M.; Yang, Y.; Li, J.-H.
Silver‐Mediated Intermolecular 1,2‐Alkylarylation of Styrenes with
α‐Carbonyl Alkyl Bromides and Indoles. Angew. Chem., Int. Ed. 2016,
55, 3187–3191. (b) Wang, F.; Wang, D.; Mu, X.; Chen, P.; Liu, G.
Copper-Catalyzed Intermolecular Trifluoromethylarylation of
Alkenes: Mutual Activation of Arylboronic Acid and CF3+ Reagent. J.
Am. Chem. Soc. 2014, 136, 10202–10205. (c) Klauck, F. J. R.; Yoon,
H.; James, M. J.; Lautens, M.; Glorius. F. Visible-Light-Mediated
Scheme 5. Stereochemical model supported by DFT
calculations. Reaction free energies and activation energies
(kcal/mol) calculated at UB3LYP/6-31G(d) (C,H,N),
LANL2DZ (Ni, I) level.19
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
Deaminative Three-Component Dicarbofunctionalization of Styrenes
(l) 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, 904-909. (m) García-
Domínguez A.; Mondal, R.; Nevado, C. Dual Photoredox/Nickel-
Catalyzed Three-Component Carbofunctionalization of Alkenes.
Angew. Chem. Int. Ed. 2019, 58, 12286-12290. (n) Mega, R. S.; Duong,
V. K.; Noble, A.; Aggarwal, V. K. Decarboxylative Conjuctive Cross-
coupling of Vinyl Boronic Esters using Metallaphotoredox catalysis.
Angew. Chem. Int. Ed. 2020, 59, 4375-4379. (o) Campbell, M. W.;
Compton, J. S.; Kelly, C. B.; Molander, G. A. Three-component Olefin
Dicarbofunctionalization Enabled by Nickel/Photoredox Dual
Catalysis. J. Am. Chem. Soc. 2019, 141, 20069-20078.
5. For intramolecular examples, see: (a) You, W.; Brown, M. K.
Catalytic Enantioselective Diarylation of Alkenes. J. Am. Chem. Soc.
2014, 137, 14578-14581. (b) Cong, H., Fu, G. C. Catalytic
Enantioselective Cyclization/Cross-coupling with Alkyl Electrophiles.
J. Am. Chem. Soc. 2014, 136, 3788–3791. (c) K. Wang, Z. Ding, Z.
Zhou, W. Kong. Ni-Catalyzed Enantioselective Reductive Diarylation
of Activated Alkenes by Domino Cyclization/Cross-Coupling. J. Am.
Chem. Soc., 2018, 140, 12364-12368; (d) T. Ma, Y. Chen, Y. Li, Y.
Ping, W. Kong Nickel-Catalyzed Enantioselective Reductive Aryl
Fluoroalkenylation of Alkenes. ACS Catal., 2019, 9, 9127-9133. (e)
Jin, Y.; Wang, C.; Nickel-catalyzed Asymmetric Reductive
Arylalkylation of unactivated Alkenes. Angew. Chem. Int. Ed. 2019,
58, 6722-6726. (f) Zhang, Z.-M.; Xu, B.; Wu, L.; Wu, Y.; Qian, Y.;
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, 14653-14659. (g)
Z.-X. Tian, J.-B. Qiao, G.-L. Xu, X. Pang, L. Qi, W.-Y. Ma, Z.-Z. Zhao,
J. Duan, Y.-F. Du, P. Su, X.-Y. Liu, X.-Z. Shu, Highly Enantioselective
Cross-Electrophile Aryl-Alkenylation of Unactivated Alkenes J. Am.
Chem. Soc., 2019, 141, 7637–7643. (h) Lan, Y., Wang, C. Nickel-
Catalyzed Enantioselec-tive Reductive Carboacylation of Alkenes.
Commun. Chem. 2020, 3, 45.
with Benzylic Radicals. ACS Catal. 2019, 9, 236–241. (d) Li. M.;
Yang, J.; Ouyang, X.-H.; Yang, Y.; Hu, M.; Song, R -J.; Li, J.-H. 1,2-
Alkylarylation of Styrenes with α-Carbonyl Alkyl Bromides and
Indoles Using Visible-Light Catalysis. J. Org. Chem. 2016, 81, 7148–
7154. (e) Yong, X.; Han, Y.-F.; Li, Y.; Song, R.-J.; Li, J.-H.
Alkylarylation of Styrenes via Direct C(sp3)–Br/C(sp2)–H
Functionalization Mediated by Photoredox and Copper Cooperative
Catalysis. Chem. Commun. 2018, 54, 12816-12819. (f) Lv, X.-L.;
Wang, C.; Wang, Q.-L.; Shu, W. Rapid Synthesis of γ-Arylated
Carbonyls Enabled by the Merge of Copper- and Photocatalytic
Radical Relay Alkylarylation of Alkenes. Org. Lett. 2019, 21, 56–59.
3. (a) Yin, G.; Mu, X.; Liu, G. Palladium(II)-Catalyzed Oxidative
Difunctionalization of Alkenes: Bond Forming at a High-Valent
Palladium Center. Acc. Chem. Res. 2016, 49, 2413–2423. 4. (b) Liao,
L.; Jana, R.; Urkalan, K. B.; Sigman, M. S. A Palladium-Catalyzed
Three-Component Cross-Coupling of Conjugated Dienes or Terminal
Alkenes with Vinyl Triflates and Boronic Acids. J. Am. Chem. Soc.
2011, 133, 5784–5787. (c) Wu, X.; Lin, H.-C.; Li, M.-L.; Li, L.-L.;
Han, Z.-Y.; Gong, L.-Z. Enantioselective 1,2-Difunctionalization of
Dienes Enabled by Chiral Palladium Complex-Catalyzed Cascade
Arylation/Allylic Alkylation Reaction. J. Am. Chem. Soc. 2015, 137,
13476–13479. (d) Urkalan, K. B.; Sigman, M. S. Palladium‐Catalyzed
Oxidative Intermolecular Difunctionalization of Terminal Alkenes
with Organostannanes and Molecular Oxygen. Angew. Chem., Int. Ed.
2009, 48, 3146–3149. (e) Liu, Z.; Zeng, T.; Yang, K. S.; Engle, K. M.
β,γ-Vicinal Dicarbofunctionalization of Alkenyl Carbonyl Compounds
via Directed Nucleopalladation. J. Am. Chem. Soc. 2016, 138, 15122–
15125.
4. (a) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.;
Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. A General
Alkyl-Alkyl Cross-Coupling Enabled by Redox-active Esters and
Alkylzinc Reagents. Science 2016, 352, 801–805. (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,
12270–12274. (c) Derosa, J.; Tran, V. T.; Boulous, M. N.; Chen, J. S.;
Engle, K. M. Nickel-Catalyzed β,γ-Dicarbofunctionalization of
Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling. J. Am.
Chem. Soc. 2017, 139, 10657–10660. (d) Shrestha, B.; Basnet, P.;
Dhungana, R. K.; Shekhar, K.C.; Thapa, S.; Sears, J. M.; Giri, R. Ni-
Catalyzed Regioselective 1,2-Dicarbofunctionalization of Olefins by
Intercepting Heck Intermediates as Imine-Stabilized Transient
Metallacycles. J. Am. Chem. Soc. 2017, 139, 10653–10656. (e)
Iwasaki, T.; Fukuoka, A.; Yokoyama, W.; Min, X.; Hisaki, I.; Yang,
T.; Ehara, M.; Kuniyasu, H.; Kambe, N. Nickel-catalyzed Coupling
Reaction of Alkyl Halides with Aryl Grignard Reagents in the Presence
of 1,3-Butadiene: Mechanistic Studies of Four-component Coupling
and Competing Cross-coupling Reactions. Chem. Sci. 2018, 9, 2195-
2211. (f) Basnet, P.; Dhungana, R. K.; Thapa, S.; Shrestha, B.; KC, S.;
Sears, J. M.; Giri, R. Ni-Catalyzed Regioselective β,δ-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, 7782–7786. (g) KC, S.,
Dhungana, R. K.; Shrestha, B.; Thapa, S.; Khanal, N.; Basnet, P.;
Lebrun, R. W.; Giri, R. 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, 9801–9805. (h) Li,
W.; Boon, J. K.; Zhao, Y. Nickel-catalyzed Difunctionalization of Allyl
Moieties Using Organoboronic Acids and Halides with Divergent
Regioselectivities. Chem. Sci. 2018, 9, 600-607. (i) Derosa, J.; van der
Puyl, V. A.; Tran, V. T.; Liu, M.; Engle, K. M. Directed Nickel-
catalyzed 1,2-Dialkylation of Alkenyl Carbonyl Compounds. Chem.
Sci. 2018, 9, 5278-5283. For Ni-catalyzed diarylation reactions in this
context, see: (j) Derosa, J.; 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, 17878-17883. (k) Basnet, P.; KC, S.; Dhungana, R. K.;
Shrestha, B.; Boyle, T. J.; Giri, R. Synergistic Bimetallic Ni/Ag and
Ni/Cu Catalysis for Regioselective γ,δ-Diarylation of Alkenyl
Ketimines: Addressing β-H Elimination by in Situ Generation of
Cationic Ni(II) Catalysts. J. Am. Chem. Soc., 2018, 140, 15586–15590.
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
6. (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, 15547-15550. (b) Wu, L.; Wang, F.; Wan, X.; Wang,
D.; Chen, P.; Liu, G. Asymmetric Cu-Catalyzed Intermolecular
Trifluoromethylarylation of Styrenes: Enantioselective Arylation of
Benzylic Radicals. J. Am. Chem. Soc. 2017, 139, 2904-2907. (c) Wu,
L; Wang, F.; Chen, P.; Liu, G. Enantioselective Construction of
Quaternary All-Carbon Centers via Copper-Catalyzed Arylation of
Tertiary Carbon-Centered Radicals. J. Am. Chem. Soc. 2019, 141,
1887-1892.
7. 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-Component Radical-Initiated 1,2-
Dicarbofunctionalization of Alkenes. J. Am. Chem. Soc. 2019, 141,
1074–1083.
8. Zheng, D.; Studer, A. Asymmetric Synthesis of Heterocyclic γ-
Amino-Acid and Diamine Derivatives by Three-Component Radical
Cascade Reactions. Angew. Chem. Int. Ed. 2019, 58, 15803-15807.
9. (a) Kischkewitz, M.; Okamoto, K.; Mück-Lichtenfeld, C.; Studer, A.
Radical-Polar Crossover Reactions of Vinylboron Ate Complexes
Science. 2017, 355, 936-938. (b) Silvi, M.; Sanford, C.; Aggarwal, V.
K. Merging Photoredox with 1,2-Metallate Rearrangements: The
Photochemical Alkylation of Vinyl Boronate Complexes. J. Am. Chem.
Soc. 2017, 139, 5736-5739.
10. (a) Zhang, L.; Lovinger, G. J.; Edelstein, E. K.; Szymaniak, A. A.;
Chierchia, M. P.; Morken, J. P. Catalytic Conjuctive Cross-Coupling
enabled by metal-induced metallate rearrangement. Science, 2016, 351,
70-74. (b) Lovinger, G. J.; Aparece, M. D.; Morken, J. P. Pd-catalyzed
Conjuctive Cross-Coupling between Grignard-Derived Boron “Ate”
Complexes and C(sp2) Halides or Triflates: NaOTf as a Grignard
Activator and Halide Scavenger. J. Am. Chem. Soc. 2017, 139, 3153-
3160. (c) Edelstein, E. K.; Namirembe, S.; Morken, J. P.
Enantioselective Conjunctive Cross-Coupling of Bis(alkenyl)borates:
A General Synthesis of Chiral Allylboron Reagents. J. Am. Chem. Soc.
2017, 139, 5027-5030. (d) Lovinger, G. J.; Morken, J. P. Ni-Catalyzed
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
Enantioselective Conjunctive Coupling with C(sp3) Electrophiles: A
(d) For a recent example combining photoredox and Ni catalysis, see:
Sun, S. Z.; Duan, Y.; Mega, R. S.; Somerville, R. J.; Martin, R. Site-
Selective 1,2-Dicarbofunctionalization of Vinyl Boronates through
Dual Catalysis. Angew. Chem. Int. Ed. 2020, 59, 4370-4373.
Radical-Ionic Mechanistic Dichotomy. J. Am. Chem. Soc. 2017, 139,
17293-17296. (e) Chierchia, M.; Law, C.; Morken, J. P. Nickel-
Catalyzed Enantioselective Conjunctive Cross-Coupling of 9-BBN
Borates. Angew. Chem. Int. Ed. 2017, 56, 11870-11874. (f) Chierchia,
Xu, P.; Lovinger, G. J.; Morken, J. P. Enantioselective Radical
Addition/Cross-Coupling of Organozinc Reagents, Alkyl Iodides, and
Alkenyl Boron Reagents. Angew. Chem. Int. Ed. 2019, 58, 14245-
14249.
11. (a) Bew, S. P. in Comprehensive Organic Functional Group
Transformations II (Katritzky, A. R.; Taylor, R. J. K. Eds.) Elsevier,
Oxford, 2005, pp 199. (b) Dicks, A. P.; Hent, A. Green Chemistry
Metrics, Springer Briefs in Green Chemistry for Sustainability, 2015,
VIII, 90.
12. For reviews, see: (a) Moragas, T.; Correa, A.; Martin, R.
Metal‐Catalyzed Reductive Coupling Reactions of Organic Halides
with Carbonyl‐Type Compounds. Chem. Eur. J. 2014, 20, 8242–8258.
(b) Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.;
von Wangelin, J. Reductive Cross‐Coupling Reactions between Two
Electrophiles. Chem. Eur. J. 2014, 20, 6828–6842. (c) Gu, J.; Wang,
X.; Xue, W.; Gong, H. Nickel-catalyzed Reductive Coupling of Alkyl
Halides with Other Electrophiles: Concept and Mechanistic
Considerations. Org. Chem. Front. 2015, 2, 1411–1421. (d) Weix, D.
J. Methods and Mechanisms for Cross-Electrophile Coupling of Csp2
Halides with Alkyl Electrophiles. Acc. Chem. Res. 2015, 48, 1767–
1775.
13. For selected examples, see: (a) Yu, X.; Yang, T.; Wang, S.; Xu, H.;
Gong, H. Nickel-Catalyzed Reductive Cross-Coupling of Unactivated
Alkyl Halides. Org. Lett. 2011, 13, 2138–2141. (b) Everson, D. A.;
Jones, B. A.; Weix, D. J. Replacing Conventional Carbon Nucleophiles
with Electrophiles: Nickel-Catalyzed Reductive Alkylation of Aryl
Bromides and Chlorides. J. Am. Chem. Soc. 2012, 134, 6146–6159. (c)
Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Nickel-catalyzed
1
2
3
4
5
6
7
8
15. (a) 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, 14490-14497; (b) Diccianni, J. B.; Katigbak, J.; Hu, C.; Diao, T.
Mechanistic Characterization of (Xantphos)Ni(I)-Mediated Alkyl
Bromide Activation: Oxidative Addition, Electron Transfer, or
Halogen-Atom Abstraction. J. Am. Chem. Soc. 2019, 141, 1788-1796.
(c) Kehoe, R.; Mahadevan, M.; Manzoor, A.; McMurray, G.;
Wienefeld, P.; Baird, M. C. Reactions of the Ni(0) Compound
Ni(PPh3)4 with Unactivated Alkyl Halides: Oxidative Addition
Reactions Involving Radical Processes and Nickel(I) Intermediates.
Organometallics, 2018, 37 , 2450–2467.
16. For examples of reductive cross-coupling using TDAE as reductant,
see (a) Broggi, J.; Terme, T.; Vanelle, P. Organic Electron Donors as
Powerful Single‐Electron Reducing Agents in Organic Synthesis.
Angew. Chem., Int. Ed. 2014, 53, 384–413. (b) 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, 11564–
11567. (c) Suzuki, N.; Hofstra, J. L.; Poremba, K. E.; Reisman, S. E.
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
Nickel-Catalyzed
Enantioselective
Cross-Coupling
of
N-
Hydroxyphthalimide Esters with Vinyl Bromides. Org. Lett. 2017, 19,
2150–2153.
17 (a) Colon, I. Kelsey, D. R. Coupling of aryl chlorides by nickel and
reducing metals. J. Org. Chem. 1986, 51, 2627-2637. (b) 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, 16192–16197.
18. (a) Cherney, A. H.; Kadunce, N. T.; Reisman, S. Catalytic
Asymmetric Reductive Acyl Cross-Coupling: Synthesis of
Enantioenriched Acyclic α,α-Disubstituted Ketones. J. Am. Chem. Soc.
2013, 135, 7442-7445. (b) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.;
Cherney, A. H.; Reisman, S. Nickel-Catalyzed Asymmetric Reductive
Cross-Coupling To Access 1,1-Diarylalkanes. J. Am. Chem. Soc. 2017,
139, 5684-5687. (c) Hofstra, J. L.; Cherney, A. H. ; Ordner, C. M.;
Reisman, S. Synthesis of Enantioenriched Allylic Silanes via Nickel-
Catalyzed Reductive Cross-Coupling. J. Am. Chem. Soc. 2018, 140,
139-142.
19. For further details, please check the Supporting Information.
20. D. Huang, D. Olivieri, Y. Sun, P. Zhang, T. R. Newhouse Nickel-
Catalyzed Difunctionalization of Unactivated Alkenes Initiated by
Unstabilized Enolates, J. Am. Chem. Soc. 2020, 142, 9604−9611.
21. During the preparation of this manuscript, an asymmetric
fluoroalkylarylation of unactivated oefins was independently reported:
H.-Y. Tu, F. Wang, L. Huo, Y. Li, S. Zhu, X. Zhao, H. Li, F.-L. Qing,
and L. Chu, J. Am. Chem. Soc. 2020, doi: 10.1021/jacs.0c03708.
22. (a) Lenori, D.; Aggarwal, V. K. Lithiation–Borylation
Methodology and Its Application in Synthesis. Acc. Chem. Res. 2014,
47, 3174-3183. (b) Diner, C.; Szabó, K. J. Recent Advances in the
Preparation and Application of Allylboron Species in Organic
Synthesis. J. Am. Chem. Soc. 2017, 139, 2-14. (c) Sandford, C.;
Cross-coupling
of
Unactivated
Alkyl
Halides
Using
Bis(pinacolato)diboron as Reductant. Chem. Sci. 2013, 4, 4022–4029.
(d) Kadunce, N.; Reisman, S. E. Nickel-Catalyzed Asymmetric
Reductive Cross-Coupling between Heteroaryl Iodides and α-
Chloronitriles. J. Am. Chem. Soc. 2015, 137, 10480–10483. (e) Arendt,
K. M.; Doyle, A. G. Dialkyl Ether Formation by Nickel‐Catalyzed
Cross‐Coupling of Acetals and Aryl Iodides. Angew. Chem., Int. Ed.
2015, 54, 9876–9880. (f) Huihui, K. M. M.; Caputo, J. A.; Melchor, Z.;
Olivares, A. M.; Spiewak, A. M.; Johnson, K. A.; DiBenedetto, T. A.;
Kim, S.; Ackerman, L. K. G.; Weix, D. J. Decarboxylative Cross-
Electrophile Coupling of N-Hydroxyphthalimide Esters with Aryl
Iodides. J. Am. Chem. Soc. 2016, 138, 5016–5019. (g) Konev, M. O.;
Hanna, L. E.; Jarvo, E. R. Intra‐ and Intermolecular Nickel‐Catalyzed
Reductive Cross‐Electrophile Coupling Reactions of Benzylic Esters
with Aryl Halides. Angew. Chem., Int. Ed. 2016, 55, 6730–6733. (h)
Wang, X.; Wang, S.; Xue, W.; Gong, H. Nickel-Catalyzed Reductive
Coupling of Aryl Bromides with Tertiary Alkyl Halides. J. Am. Chem.
Soc. 2015, 137, 11562–11565.
14. (a) García-Domínguez, A.; Li, Z.; Nevado, C. Nickel-Catalyzed
Reductive Dicarbofunctionalization of Alkenes. J. Am. Chem. Soc.
2017, 139, 6835–6838. (b) Shu, W.; García-Domínguez, A.; Quirós,
M. T.; Mondal, R.; Cárdenas, D. J.; Nevado, C. Ni-Catalyzed
Reductive Dicarbofunctionalization of Nonactivated Alkenes: Scope
and Mechanistic Insights. J. Am. Chem. Soc. 2019, 141, 13812-13821.
For a reductive carboacylation of alkenes bearing a coordinating group,
see: (c) 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. Nature Commun. 2018, 9, 3488.
Aggarwal,
V.
K.
Stereospecific
Functionalizations
and
Transformations of Secondary and Tertiary Boronic Esters. Chem
Commun. 2017, 53, 5481-5494.
23. Reductive elimination from intermediate III proceeds with retention
of configuration. See also ref. 14b.
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