SYNTHESIS0039-78 1 437-210X

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2020, 52, A–N
short review A
en

Syn thesis Y. Ping, W. Kong Short Review

Ni-Catalyzed Reductive Difunctionalization of Alkenes

Yuanyuan Ping
Wangqing Kong* 0-0326-097 R1 X
Ni catalyst R1
+ R2 X
reductant R2
The Center for Precision Synthesis (CPS), Institute for Advanced
Studies (IAS), Wuhan University, Wuhan 430072, P. R. of China
wqkong@whu.edu.cn
no preformed organometallic reagents regioselectivity
high functional group tolerance enantioselectivity

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Received: 16.12.2019
Accepted after revision: 09.01.2020
Published online: 19.02.2020
DOI: 10.1055/s-0039-1690807; Art ID: ss-2019-m0683-sr

Abstract Alkene difunctionalization represents one of the most effi-

cient methods to synthesize highly functionalized molecules from sim-
ple and readily available starting materials. In contrast to the well-estab-
lished redox-neutral alkene difunctionalization reactions, reductive
alkene difunctionalization, which simultaneously introduces two elec-
trophiles on both sides of the double bond, has been much less devel-
oped, especially in enantioselective manner. This review summarizes re-
cent advances in the nickel-catalyzed reductive difunctionalization of
alkenes and highlights the enantioselective transformations. Yuanyuan Ping received her M.S. degree from Jiangxi Normal Universi-
1 Introduction ty. In 2017, she joined Prof. Kong’s group at Wuhan University as a
2 Nickel-Catalyzed Racemic Reductive Difunctionalization of Ph.D. student. Her work focuses on Ni-catalyzed asymmetric difunc-
Alkenes tionalization of alkenes.
3 Nickel-Catalyzed Enantioselective Reductive Difunctionalization
of Alkenes Wangqing Kong received his Ph.D. in chemistry (2011) under the guid-
3.1 Diarylation of Alkenes ance of Prof. Shengming Ma at Zhejiang University. After postdoctoral
3.2 Aryl-alkenylation of Alkenes research with Prof. Cristina Nevado at the University of Zurich and Prof.
3.3 Aryl-monofluoroalkenylation of Alkenes Jieping Zhu at École Polytechnique Fédérale de Lausanne (EPFL), he
3.4 Reductive Cyclization/Coupling with Alkynyl Bromides or Asym- joined the faculty of the Institute for Advanced Studies, Wuhan Univer-
metric Internal Alkynes sity in 2017. His group is interested in the development of Ni-catalyzed
3.5 Aryl-alkylation of Alkenes enantioselective Heck reactions for the construction of quaternary ste-
3.6 Aryl-amination of Alkenes reocenters.
4 Summary and Outlook

Key words nickel catalysis, alkene difunctionalization, reductive
cross-coupling, enantioselectivity, Heck cyclization
1 Introduction
Alkenes are excellent starting materials in organic syn-
thesis due to the versatile reactivity of the C=C bond and
the ready availability of many unfunctionalized alkenes.
Alkene difunctionalization by simultaneous addition of two
different functional groups across the double bond in a sin-
gle operation, allowing rapid access to complex molecules,
has enormous potential for industrial applications, and
thus has attracted the attention of researchers for extensive
development over the past few decades. In this context,
transition-metal-catalyzed redox-neutral alkene difunc-
tionalization involving the introduction of an electrophile
and a nucleophile on each side of the double bond has been
well developed (Scheme 1A).1 However, the carbon nucleo-
philes are often organometallic reagents, such as Grignard
reagents or organolithium, organozinc, organozirconium,
and organoboron reagents. The requirement for these high-
ly reactive organometallic reagents can often lead to func-
tional group compatibility issues, which may limit their
broad use in organic synthesis. In addition, the synthesis of

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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany
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Syn thesis Y. Ping, W. Kong Short Review

these organometallic reagents requires the use of numer- donating groups (SMe, OMe) as well as electron-withdraw-
ous stoichiometric transformations and generates substan- ing groups (F, CO2Et). Heterocyclic aromatic iodides such as
tial amounts of byproducts upon reaction. 4-iodo-1-methyl-1H-indole and 5-iodo-1-methyl-1H-in-
dole were also compatible. All of the products, which con-
(A) Redox-Neutral Difunctionalization of Alkenes
tained a linear-fused perhydrofuro[2,3-b]furan or -pyran
R2 X skeleton were formed in moderate yields with excellent
pre-activation
endo diastereoselectivity (Scheme 2). This reaction was
subsequently extended to a range of alkenyloxy sub-
R1 X
+ R2 M
transition-metal catalyst R1 strates.3b–g
R2
O
(B) Ni-Catalyzed Reductive Difunctionalization of Alkenes
Me O Me
EC (90 mol%) Ar
R1 X ( )n Br H
nickel catalyst NiCl2 (30 mol%)
R1 ( )n H
+ R2 X + ArI
reductant R2 O O Zn (3 equiv)
H O
Pyridine/MeCN = 1:2 O
50 °C H
no preformed organometallic reagents

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R H
high functional group tolerance R
R = H, 60% H
commercially available starting materials H R = SMe, 63% R = F, 58%
H O
R = COOEt, 51% O R = OMe, 60%
R = BPin, 54% H R = COOEt, 53%
O
Scheme 1 Transition-metal-catalyzed difunctionalization of alkenes O
H
OMe N Me
H
On the other hand, nickel-catalyzed reductive cross- H H N Me
H H
H
coupling reactions, initiated by the Weix and Gong groups, O
O
O
O H
have gained extensive attention over the past decade2 as H
O
56% H
O 54% 49%
they represent a powerful tool for the construction of di-
Scheme 2 Ni-mediated reductive alkyl-arylation of alkenes
verse C–C bonds and allow reactions to proceed under mild
conditions with high functional group tolerance, without
any additional prepreparation of sensitive organometallics, Subsequently in 2018, the Peng group further applied
in comparison to classical redox-neutral regimes. In addi- the nickel-catalyzed fully intramolecular reductive coupling
tion, nickel is a low-cost, nontoxic, abundant, and sustain- method for the sequential construction of C–C bonds in tet-
able element, and it undergoes facile oxidative addition on rahydronaphtho[2,3-c]furan core scaffolds of antineoplastic
account of its smaller size, allowing for the use of much less aryltetralin lactone lignans. In particular, this tandem cy-
reactive electrophiles. Despite tremendous advances, this clization provided expeditious syntheses of several closely
field of expertise remains essentially confined to the forma- related podophyllum members, including naturally occur-
tion of a single C–C bond. Due to the challenges of con- ring podophyllotoxin (Scheme 3).4
trolling regio- and enantioselectivity in the carbon–carbon On the basis of the early work of the Peng group, the
bond forming events, reductive alkene difunctionalization Diao group reported a related reductive dicarbofunctional-
reactions remain unexploited. Only recently, some break- ization of alkenes in the presence of 10 mol% of NiBr2(dme)
throughs in the nickel-catalyzed reductive difunctionaliza- and 12 mol% of 1,10-phenanthroline as the catalyst
tion of alkenes have been made (Scheme 1B). In this review, (Scheme 4).5 This reaction is compatible with a large variety
we will summarize the recent advances in the nickel- of functional groups, such as trifluoromethyl, chloro, ke-
catalyzed reductive difunctionalization of alkenes and high- tone, and aldehyde groups, and exhibits a broad scope with
light the enantioselective transformations. both aryl and alkyl electrophiles, allowing efficient access
to cyclopentane, tetrahydrofuran, and pyrrolidine deriva-
tives in good yields.
2 Nickel-Catalyzed Racemic Reductive Di- Mechanistically, two different reaction pathways ‘radi-
functionalization of Alkenes cal chain’ and ‘sequential reduction’ were considered
(Scheme 5). In the ‘radical chain’ mechanism (cycle A and
In 2012, the Peng group reported the first example of cycle B), alkyl halides were activated by Ni(I)Br to form a
the Ni-mediated reductive alkyl-arylation of alkenes by us- radical. In cycle A, the radicals combine with the reduced
ing [Ni0·2EC·Py] as the catalyst, which can be readily pre- Ni(0) followed by oxidative addition to ArBr; in cycle B, oxi-
pared in situ from a mixture of Zn/NiCl2/pyridine/ethyl cro- dative addition of ArBr to Ni(0) takes place prior to radical
tonate (EC).3a The 5-exo-trig cyclization of the alkyl bro- combination with Ni(II). The alternative ‘sequential reduc-
mide precedes the intermolecular reductive cross-coupling tion’ mechanism, cycle C, reverses the sequence of electro-
with various aromatic iodides that bear both electron- phile activation in the ‘radical chain’ mechanism. Oxidative

© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

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Syn thesis Y. Ping, W. Kong Short Review

O H H
O Br O O
Br Me O Me O O
O O EC (90 mol%) O O
NiCl2(DME) (30 mol%) H OMe H OMe
OMe +
Zn (1.5 equiv)
Pyridine, DMA, rt, 4 h MeO OMe MeO OMe
MeO OMe
OMe OMe OMe
41% 35%

HCl then PCC 68% HCl then PCC 62%

H H H
O O O
O O O
O O O
LDA, THF, –78 °C H O H O
H O
then HOAc
93%
MeO OMe MeO OMe MeO OMe
OMe OMe OMe
(–)-Deoxypopodophyllotoxin (+)-Deoxypicropodophyllin (+)-Isodeoxypodophyllotoxin

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NBS, hν, dioxane
then silica gel
81%
OH O OH
H H H
O O O
O O O
O PDC L-Selectride O
O
H O H O THF, –78 °C H O
DCM
90% 87%
MeO OMe MeO OMe MeO OMe
OMe OMe OMe
(–)-Epipodophyllotoxin (–)-Podophyllotoxone (–)-Podophyllotoxin

Scheme 3 Divergent syntheses of podophyllotoxin and related family members via Ni-mediated reductive alkyl-arylation of alkenes

addition of Ni(0) to ArBr affords Ni(II)(Ar)(Br), followed by
the reduction of Ni(II) to form Ni(I)-Ar. Activation of the al-
kyl bromide by Ni(I)-Ar generates a radical, which com-
bines with Ni(II) to form a Ni(III) intermediate.
The Diao group performed extensive mechanistic stud-
ies on this reductive alkene alkyl-arylation reaction and a
revised mechanism was proposed (Scheme 6).6 In this new
mechanism, (phen)Ni(I)-Br first reacts with ArBr to form
(phen)Ni(II)Br2 and (phen)Ni(II)(Ph)(Br) via bimolecular ox-
idative addition, followed by subsequent reduction to give a
Ni(I)-Ar species; (phen)NiBr2 and (phen)Ni(II)(Ph)(Br) both
exist as the catalyst resting state. Then (phen)Ni(I)-Ar reacts
with the alkyl bromide to form a radical that rapidly cycliz-
es and coordinates to Ni(II)(Br)(Ar) to afford a Ni(III) inter-
mediate prior to reductive elimination. Zn is only sufficient
to reduce (phen)Ni(II) to (phen)Ni(I), and Ni(0) is not pres-
ent in the reaction. Oxidation addition of ArBr with
(phen)Ni(I)-Br precedes the activation of alkyl bromides by
Ni(I)-Ar via single-electron activation to give radicals. This
sequence illustrates the selectivity observed in cross-
electrophile coupling reactions.
Ni-catalyzed directed intermolecular reductive alkyl-
arylation reaction of alkenes was carried out by the Nevado
group (Scheme 7).7 The three-component reaction using
tertiary alkyl iodides and aryl iodides in the presence of
tetrakis(dimethylamino)ethylene (TDAE) as stoichiometric
Radical Chain Sequential Reduction

Br
Z Z
NiBr2(dme) (10 mol%) Ar LnNiI-Ar
Br Phenanthroline (12 mol%) Z NiIII
Z + R-X Z R Ar
Zn (2.0 equiv) Ar Br (B) Ar
LnNiII
Z = C, N, O DMA, 50 °C ArBr LnNiII
Z Br
NiILn Z Br
R = CF3, 95% Me
R = Cl, 80% MeOOC Z ArBr (C)
MeOOC R R = Ph, 99% LnNiI-Br
MeOOC N Ar
MeOOC R = COPh, 74% Z
R = CHO, 85% (A) LnNi0 NiIII
Me Z
99% Br
Br Br
MeOOC Ph Ph
TsN Ph Ts N
Z LnNiII LnNiI-Br Ar
MeOOC Br
Ph O Me Z
45% 82% 64%, 1:4.9 97%, 1.1:1
Scheme 5 Proposed mechanism for the reductive alkyl-arylation reac-
Scheme 4 Ni-catalyzed reductive dicarbofunctionalization of alkenes tion

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Syn thesis Y. Ping, W. Kong Short Review

ZnII Br Michael acceptors (methyl acrylate and acrylonitrile) were

(phen)NiI-Ar Z successfully transformed under the optimal conditions to
Zn
furnish the corresponding products in good yields. In addi-
Ar
tion, electron-rich alkenes such as enol esters were also ca-
Br Ar (phen)NiII
(phen)NiII (phen)NiII
Z Br pable of guiding the desired transformations. However, the
Br
resting state
Br alkenes were limited to electronically biased alkenes as well
Ar as allylic systems bearing weak coordinating groups.
Z
NiIII
ArBr Br Chu and co-workers described an analogous three-com-
ponent carboacylation of alkenes with acyl chlorides and
(phen)NiI-Br Ar
fluoroalkyl iodides, providing facile access to -(fluoro-
Z
alkyl)-substituted ketones (Scheme 8).8 Alkenes tethered
Scheme 6 Revised mechanism for Ni-catalyzed reductive alkyl-aryla- with different chelating groups, including esters, carbon-
tion reaction
ates, carbamates, sulfonates, and phosphates, were compat-
ible with this reductive coupling and gave the correspond-
organic reductant enables the direct formation of Csp3–Csp3 ing products in moderate to excellent yields.
and Csp3–Csp2 bonds across a C=C bond in a regio- and ste- Lin and co-workers reported a nickel-catalyzed reduc-

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reoselective fashion. Allylic alcohols, phosphonates, ani- tive 1,2-dialkynylation of alkenes using 8-aminoquinoline
lines, and amides were amenable substrates producing the as the directing group. This reaction provided an efficient
corresponding products in synthetically useful yields. method to access diverse synthetically flexible 1,5-diynes
(Scheme 9).9
In 2019, the Nevado group modified their previous pro-
NiCl2(Py)4 (10 mol%)
R1 dtbbpy (10 mol%) Ar R1 cedure and further developed an intermolecular nondirect-
R + Ar-I + I R2
R3 TDAE (2.15 equiv), THF R R3
R2 ed reductive dicarbofunctionalization of alkenes (Scheme
electronically biased with coordinating group
O
EWG X (X = OH, OCOR, NHR)
O R R
tBu
R3 R1 = R3
= H, R2
= OMe, 78% O Br O
NiI2 (10 mol%)
R2 R1 = R3 = H, R2 = F, 64% R1 + R1
tBu N ( )n N ( )n
R1 = R3 = CF3, R2 = H, 46% H Mn (3 equiv)
N H
R1 = OMe, R2 = Br, R3 = H, 69% R DMF or MeCN, rt N
R1 tBu
R
R1 = Cl, R2 = H, R3 = COOMe, 65% R = OH, 54%
AcO R2 = R3 = H, R1 = OMe, 71% R = PO(OEt)2, 52% R
R2 = R3 = H, R1 = CF3, 62% R = NHPh, 43% O O O
R = NHAc, 51%
tBu
tBu AQ AQ AQ OPh
tBu tBu TIPS Ph
R Me tBu
Me Me OCOtBu
AcO TIPS Ph
R = CN, 85% PhO
R = CO2Me, 90% 62% 81% 93% 61% 48%

Scheme 7 Ni-catalyzed directed reductive alkyl-arylation of alkenes Scheme 9 Ni-catalyzed reductive 1,2-dialkynylation of alkenes

NiCl2(dme) (10 mol%)

dtbbpy (20 mol%)
O Mn (3.0 equiv) RF Ar
R + I-RF +
Cl Ar MeCN, 25 °C R O
42–94% yield

R = C6H13, 93% O O O O
O O
R = Ph, 89% P O S
R O Ar EtO O Ph
R = Me, 85% OEt tBu
R = tBu, 71% C4F9 tBu C4F9
C4F9
R = OMe, 94% 54%
Ar = 4-tert-butylphenyl 42%

C4F9 O Me
O O H Me O
O C4F9
N O H H
O tBu
H
O C4F9 tBu
O O
tBu
49% 63% 67%

Scheme 8 Ni-catalyzed directed carboacylation of alkenes

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Syn thesis Y. Ping, W. Kong Short Review

NiBr2⋅dme (5 mol%) process tolerated a wide variety of sensitive functional

R1 dtbbpy (6 mol%) Ar R1 groups, such as free N–H or O–H groups. Heterocyclic aro-
R + Ar-I + I R2 2
R3 TDAE (3 equiv), dioxane 3R
R R matic iodides containing indole and pyridine moieties were
Ph Ph Ph successfully applied in this protocol. However, such a trans-
formation is still limited to the use of tertiary alkyl iodides.
Me Me Me Computational studies revealed the feasibility of a radi-
Me Me MeO Me Me Me Me
cal-based mechanism, which favors the Ni(I), Ni(II), and
F 74%
H2N
62%
HO
70% Ni(III) species compared to the original proposal invoking a
Ph Ph
Ph Ni(0) intermediate at the outset of the reaction. The role of
Ph O
Me
the reductant has also been investigated, demonstrating
Me
Me Me that TDAE-mediated one-electron reduction to form a Ni(I)
Me Me N Me Me
MeO2C Cl species is a highly favorable process. Further, the preferen-
Cl
N
H 66% 61% 61%
tial activation of alkyl vs aryl halide by the ArNi(I) complex
as well as the high affinity of ArNi(II) for secondary over
Scheme 10 Ni-catalyzed nondirected reductive alkyl-arylation of
alkenes tertiary C-centered radicals explains the lack of undesired
homo- and direct coupling products (Ar-Ar, Ar-Alk) in this

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transformation (Scheme 11).
Ar
Alk
Our group discovered a Ni-catalyzed three-component
R Ar-I
NiI-I
reductive alkene arylacylation reaction for the synthesis of
a variety of 3,3-disubstituted oxindoles having an all-
Ni(III)-Ar carbon quaternary stereocenter containing a ketone group
Alk
Ni(III)-Ar (Scheme 12).11 Unlike previously reported carbonylation re-
R
actions that generally use highly toxic CO as the carbonyl
Alk
R TDAE source, hence a specially designed high-pressure reaction
device is generally required, the advantage of this protocol
R
is that liquid isobutyl chloroformate was used as the CO
Ni(II)-Ar Alk
Ni(I)-Ar surrogate, which is very safe and easy to handle. Remark-
ably, various primary and secondary alkyl iodides contain-
ing phenyl, cyano, and ester groups were all compatible. Al-
Alk-I
kyl chlorides survived under the standard conditions. Inter-
Scheme 11 Proposed mechanism for reductive alkyl-arylation of estingly, benzyl chlorides were found to be reactive in this
alkenes
system when Zn was used as the reducing agent at 60 °C.
Unlike previously reported carbonylative couplings, the
10).10 This protocol allows the simultaneous addition of al- nickel carbonyl species is generated by oxidative addition of
kyl and aryl groups across nonelectronically biased C=C ClCO2iBu to the Ni(0) center followed by decarbonylation.12
bonds devoid of any directing or coordinating group. The However, our transformation was initiated by the oxidative

Me Me

(20 mol%) Alkyl

X N N R2
O O
Ar NiBr2(dme) (10 mol%)
+ Alkyl-X + Ar O
N Cl OiBu TMSCl (0.5 equiv) O
R1 R2 N
Mn (4 equiv), 40 °C
DMA/THF = 1:1 R1

R1 = R2 = H, 63% Cy
Me
R2 Cy R1 = H, R2 = Me, 60% Me Me Cy
Me
R1 = H, R2 = OMe, 67% O
O R1 = H, R2 = CF3, 58% O O
R1 N N
O N O
N R1 = H, R2 = F, 60%
Me
Me R1 = Me, R2 = H, 66%
R1 = OMe, R2 = H, 69% 49% 70%
R1 = Cl, R2 = H, 58%
O
Me Me O
R = Ph, 50% R = H, 69%
R = CN, 42% R = CF3,
O
N R = COOMe, 60% N O R 56%
Me R R = Cl, 57% R = F, 62%
Me
R = Cl, 68%

Scheme 12 Ni-catalyzed reductive aryl-acylation of alkenes

© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

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Syn thesis Y. Ping, W. Kong Short Review

tBu termediate, followed by further oxidative addition with

Me Cy ClCO2iBu to produce the nickel carbonyl species. The addi-
Me N O Mn, TMSCl
+ CyI + tion of an alkyl radical to the carbonyl species furnishes the
Ni Cl OiBu DMA/THF = 1:1 O
O
O Br N 40 °C N acyl-Ni(III)-alkyl intermediate, which undergoes reductive
N tBu Me
Me elimination to produce the desired ketone product (Scheme
36%
13).
Br
O
Mn(II)
Mn0 R2
LnNi0 N
R2 R RX NiII-Ln R1 3 Nickel-Catalyzed Enantioselective Reduc-
O NiI-Ln
tive Difunctionalization of Alkenes
N O R2
NiIILn
R1
R O 3.1 Diarylation of Alkenes
R2 N
NiIIILnX
R1

N OO Mn0 Asymmetric reductive alkene difunctionalization reac-

R
R1 tions had not been explored by virtue of the difficulties in
MnII
controlling regio- and enantioselectivity. The first ever en-

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R2 R2 antioselective reductive diarylation reaction of two struc-
NiIILnX NiILn
O
turally distinguishable aryl bromides by using a catalytic
O N O
N amount of a nickel catalyst was reported by our group
R1 R2 CO2iBu R1
(Scheme 14).13
NiIIILn O
MnII Mn0 Our initiated investigation focused on the coupling of
N O Cl ClCOiBu
alkene-tethered aryl bromides with arylboronic acids
R1
through domino Heck cyclization and Suzuki coupling.14
Scheme 13 Proposed mechanism for the reductive aryl-acylation of
However, attempts to render this transformation asymmet-
alkenes
ric failed. One possible explanation is that the transmetala-
tion event seems to require high reaction temperatures. Re-
addition of Ni(0) to the aryl halide. Clear evidence is that ductive cross-coupling reactions can be performed under
the target product was obtained in 36% yield when the - very mild conditions due to the ability of Ni catalysts for
alkyl-Ni(II) complex was submitted to the reaction with CyI facile oxidative addition and ready access to multiple oxida-
and ClCO2iBu. We therefore speculated the in situ generated tion states. We therefore carried out the reductive diaryla-
-alkyl-Ni(II) species is reduced to form a -alkyl-Ni(I) in- tion of alkenes under reducing conditions. To our delight, a

Br Ni(COD)2 (10 mol%) R3 R2 O iPr

Br Ar
O (S,Sp)-iPr-Phosferrox N
R3
R2 + Ar
Z N Zn, B2Pin2, K3PO4 Z O PPh2
N
R1 KI, NMP, 40 °C Fe
R1
>30 examples
90–99% ee (S,Sp)-iPr-Phosferrox

R = H, 68%, 97% ee
Me R = OMe, 60%, 90% ee Me Me
R Bpin O
R = CN, 30%, 95% ee
R = NMe2, 63%, 95% ee
N O R = F, 50%, 90% ee O O
N N
Me Me Me
60%, 90% ee 60%, 95% ee

Me X Me Me N
N O
N Et
O N O O
N N
Me Me Me

X = O, 61%, 99% ee
X = S, 50%, 95% ee 40%, 95% ee 50%, 95% ee

OMe
Me Ph Me Ph Bn OMe
Me
OMe
Cl O O
N N N O
N O OMe
N
Me Me Me
Me
51%, 96% ee 51%, 94% ee 62%, 97% ee 60%, 97% ee

Scheme 14 Ni-catalyzed enantioselective reductive diarylation of alkenes

© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

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Syn thesis Y. Ping, W. Kong Short Review

range of bis-heterocycles bearing an all-carbon quaternary to the optimized reaction conditions the desired product
center was obtained in synthetically useful yields (up to was not produced. Interestingly, the desired product was
81%) and excellent enantioselectivity (90–99% ee) by using formed when organic reducing agent TDAE was used in-
(S,Sp)-iPr-Phosferrox as ligand and Zn/B2Pin2 as the reduc- stead of zinc powder. These results confirm that the reac-
tants. The reaction occurs under very mild conditions (40 °C) tion mechanism is different from the previously reported
and is tolerant of a variety of functional groups (alkoxy, redox-neutral alkene diarylation reactions involving an
amino, chloro, fluoro, ketal, and boronate) and heterocycles aryl-zinc intermediate.
(benzodioxan, pyridine, dibenzofuran, dibenzothiophene, To further clarify the mechanism of the reaction, we
indole, and benzofuran). Remarkably, the reaction was suc- prepared some possible organometallic complexes (Scheme
cessfully applied to the synthesis of an azaoxindole, (R)-3- 15). A 2-Tolyl-Ni(II) complex was synthesized and submit-
benzyl-1,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin- ted to the reaction with PhBr, giving biphenyl in 68% yield
2-one, in 51% yield and 94% ee, which is of particular inter- together with the reductive elimination product 1-bromo-
est since previous reports indicated that Pd-catalyzed reac- 2-methylbenzene in 37% yield. This result indicates that the
tion conditions generally were unsuccessful. oxidative addition of Ni(0) with aryl halide is reversible.
A series of control experiments were designed to ex- Treatment of a -alkyl-Ni(II) complex with PhBr afforded
plore the reaction mechanism (Scheme 15). The reaction the desired product in 35% yield, confirming that the alkyl-

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without nickel does not consume the starting material, sug- Ni(II) complex is the key intermediate of this transforma-
gesting that the direct insertion of zinc into aryl bromide is tion. The corresponding product was also isolated in 25%
not possible. When PhZnBr, prepared in situ, was subjected yield when a 2-tolyl-Ni(II) complex and a -alkyl-Ni(II)

tBu tBu

DMA Br
N N +
+ PhBr Ph Ph
Ni
Br Me
37% 68%
Me
tBu
Me
Me N Zn, B2Pin2, K3PO4
+ PhBr
Ni DMA, 100 °C N O
N O Br N Me
tBu
Me 35%
tBu tBu tBu
Me
N Me
Me
+ N N DMA
Ni
Ni 100 °C O
N O Br N Br N
tBu Me
Me Me 25%

ArNi(II)Br Z O
R2 tBu tBu
ArBr N
X R1
Zn(II) L
* Ni(0) N N
Zn L Ni
Ni(II)L* COD
L Zn(II) O
* Ni(I) O
L Zn Z N
R2 NiBr2 Me THF
R1 R2 N rt, 2 h
Ar Br Me
+
Z O R2
N tBu
Ni(II)L*
R1 Ar
Z O R2
R2 N pathway Ni(II)L* Me N
Ni(III)L* R1 B Ni
Z O
Z
N O Ar N
N O Br N
tBu
ArNi(II)Br R1
R1 pathway Me
A prepared as pink solid
R2
Ni(I)L*
Zn
ArBr
Z O Zn(II)
N
R1

Scheme 15 Mechanistic proposal diarylation of alkenes

© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

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Syn thesis Y. Ping, W. Kong Short Review

complex were mixed together, demonstrating that the
mechanism of transmetalation cannot be excluded.
Two possible pathways were proposed based on the
above results (Scheme 15). Oxidative addition of aryl bro-
mide to Ni(0) species followed by an intramolecular migra-
tory insertion into the double bond produces a -alkyl-
Ni(II) species, which is reduced by stoichiometric Zn0 pow-
der. A second oxidative addition of the resulting -alkyl-
Ni(I) intermediate with aryl bromide will form a -alkyl-
Ni(III)ArX species, which undergoes subsequent reductive
elimination to furnish the desired product while regenerat-
ing Ni(0) catalyst upon reduction (pathway A). Another
plausible Ni(0)/Ni(II) catalytical cycle involves transmetala-
tion between the -alkyl-Ni(II) species and aryl-Ni(II) com-
plex to form a -alkyl-Ni(II)ArX species, which generates
the product following reductive elimination (pathway B).
Control experiments showed that using a 1:1 ratio of
Ni/ABNO is critical for success, revealing that an auxiliary
N-oxyl serves as a ligand. However, such a transformation is
still limited to the use of styrenes as the alkene acceptors
and two identical aryl bromides.
3.2 Aryl-alkenylation of Alkenes
Our group further expected to extend the reductive di-
arylation to aryl-alkenylation reaction by using alkenyl bro-
mides as electrophiles. This transformation is more chal-
lenging since alkenyl bromides are more reactive than aryl
bromides and are prone to reductive self-coupling. An effi-
cient approach was developed using a chiral bisoxazoline li-
gand for the synthesis of alkenyl-functionalized 3,3-disub-
stituted oxindoles in good yields and enantioselectivities

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In 2019, the Diao group demonstrated a nickel-cata- (up to 95%) by the reductive cyclization/cross-coupling of
lyzed intermolecular asymmetric reductive diarylation of alkene-tethered aryl bromides with alkenyl bromides
styrenes, enabling the preparation of chiral ,,-triarylat- (Scheme 17).16 This transformation is quite useful, and it
ed ethanes with moderated to high enantioselectivities was applied to the synthesis of the biologically active alka-
(Scheme 16).15 Notably, the N-oxyl radical additive (ABNO) loid natural products (+)-physovenine and (+)-physostig-
exerted a significant effect on the enantioselectivity. mine.
In 2019, Shu and co-workers reported a similar reduc-
O O tive aryl-alkenylation reaction by the cross-coupling of aryl
(20 mol%)
iBu N N iBu
iodides with vinyl triflates (Scheme 18).17 This method pro-
Ar2 vided access to a number of biologically important chiral
Ar1 NiBr2(dme) (10 mol%) •O
+ Ar2Br Ar2 N
Zn (2 equiv) Ar1 molecules such as dihydrobenzofurans, indolines, and in-
(4 equiv) ABNO (8 mol%)
DMPU/THF = 1:1, 10 °C, 16 h 55~94% ee danes in good yield and high enantioselectivities (up to
ABNO
99%).
R Ph
R = F, 60%, 90% ee
R = Cl, 57%, 91% ee
Ph
3.3 Aryl-monofluoroalkenylation of Alkenes
R = CF3, 44%, 86% ee
R R = COOMe, 48%, 93% ee R
R = Bpin, 76%, 55% ee The monofluoroalkene moiety is of particular interest,
R = OMe, 70%, 89% ee R = NMe2, 78%, 91% ee
R = OMe, 82%, 82% ee since it has been recognized as a useful fluorinated synthon
AcO R = CF3, 73%, 79% ee
R = COOMe, 53%, 83% ee in organic chemistry and is valuable as a peptide bond
O isostere in medicinal chemistry and drug discovery. Howev-
O
Ph er, despite its importance, only limited methods are avail-
O Ph able for its synthesis. We further extended the alkenyl bro-
O N
mides to more reactive gem-difluoroalkenes. Therefore, a
Me nickel-catalyzed enantioselective reductive aryl-fluoroalke-
70%, 83% ee 72%, 88% ee 68%, 85% ee nylation reaction followed by a radical isomerization of the
Scheme 16 Ni-catalyzed reductive diarylation of styrenes

O
O Me
O O HN
Me N
Bn N N Bn R4 N
Br R3 (20 mol%) R2 H Me
O Me
Ar R5 Ni(COD)2 (10 mol%) R5 (+)-Physostigmine
+ Br Ar
Z N R3 O
R4 Zn, DMA, rt Z O O
N
R1 R2 Me
R1 HN
Me
up to 95% ee O
N
H
Me
(+)-Physovenine

Scheme 17 Ni-catalyzed enantioselective reductive aryl-alkenylation of alkenes

© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

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Syn thesis Y. Ping, W. Kong Short Review

NiI2 (10 mol%)

O
I F3C (14 mol%)
Ar R2 N N tBu R1 R2
+ TfO
X Ar
R1 Mn (4 equiv)
(1 equiv) X
X = O, C, N DMF/THF = 1:1, rt, 24 h
up to 99% ee

Me Me Me Me

Me O
O O O
Me
79%, 98% ee 72%, 99% ee 65%, 97% ee 42%, 97% ee

tBu Me
Me
Me Me
Me

O NTs Me NTs
O
75%, 97% ee 82%, 97% ee 46%, 89% ee
Me
R2 Me R1 = R2 = H, 46%, 83% ee

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R1 = Me, R2 = H, 75%, 83% ee O
R1 N
N R1 = H, R2 = Me, 72%, 85% ee O
Boc
Boc R1 = Cl, R2 = H, 58%, 96% ee
38%, 84% ee

Scheme 18 Ni-catalyzed enantioselective aryl-alkenylation of alkenes

resulting double bonds was developed, predominantly pro- plied to the late-stage monofluoroalkenylation of complex
viding various synthetically useful oxindoles containing a biologically active compounds (Scheme 19).
(Z)-monofluoroalkenyl substituent in good yields with 85– Treatment of -alkyl-Ni(II) complex with gem-difluoro-
95% ee.18 Notably, the synthetic method can be further ap- alkene under standard conditions produced the target

O
F3C (20 mol%)
N N tBu
X (1) NiBr2 (10 mol%) R2
O
Ar F MgCl2, Mn, DMSO, rt R
+ R Ar
N
F (2) p-thiocresol, AIBN N OF
R1 R2
toluene, 110 °C R1
up to 95% ee

Me Me Me

N OF R N O FNC N OF S

Me Me Me
R = CN, 55%, 90% ee 68%, 90% ee 75%, 95% ee
R = COOMe, 62%, 92% ee
R = SO2Me, 74%, 90% ee Me
Me Me
R = Bpin, 64%, 86% ee O
O O
F O Me
Me N O
O O Me
Me O
MeO Fructose
N OF (E) (26%, dr > 20:1)
Me Me (Z) (40%, dr > 20:1)
67%, 90% ee
F O
N O
H
Me O
Estrone Me
(E) (20%, dr > 20:1)
(Z) (37%, dr > 20:1) O
H
Me H

N OF O
Me Me Me
Me O
O Me
Me Me
(+)-δ-Tocopherol
(E) (20%, dr > 20:1); (Z) (27%, dr > 20:1)

Scheme 19 Ni-catalyzed enantioselective reductive aryl-fluoroalkenylation of alkenes

© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

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Syn thesis Y. Ping, W. Kong Short Review

product in 50% isolated yield. However, in the case where
Mn0 was not added, the desired product was not obtained.
These findings suggest that the -alkyl-Ni(II) complex
might be reduced to the more nucleophilic Ni(I) first, then
react with the gem-difluoroalkenes. The reaction of (E)-
monofluoroalkene under the standard conditions furnished
the desired product with high E selectivity (E/Z = 11:1).
However, the coupling reaction of (Z)-monofluoroalkene
provided the desired product as a 3:2 mixture of isomers.
These results imply that the reaction is not stereospecific
and the pathway involving C–F bond oxidative addition fol-
lowed by reductive elimination is unlikely. Based on the
above results, we speculated that the more nucleophilic -
alkyl-Ni(I) species is formed upon reduction of the cyclized
-alkyl-Ni(II) species by stoichiometric Mn0. Migratory in-
sertion or nucleophilic addition of the -alkyl-Ni(I) com-
3.4 Reductive Cyclization/Coupling with Alkynyl
Bromides or Asymmetric Internal Alkynes
In addition to aryl bromides and alkenyl bromides, we
believe the more reactive alkynyl bromides might also be
able to perform analogous reductive aryl-alkynylation reac-
tion. To our surprise, the reductive coupling of aryl bromide
tethered acrylamide with alkynyl bromide does not give the
expected aryl-alkynylation product, but generates the cor-
responding 2,3-fused cyclopentannulated indolines in good
yields with high regioselectivities (>20:1), which is widely
present as core structures in a large number of biologically
active natural products (Scheme 21).19
Preliminary mechanistic studies (Scheme 22) reveal
that a 1,3-diyne is the key intermediate, which is formed
from the homocoupling of alkynyl bromides. The stoichio-

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plex to the gem-difluoroalkene affords a ,-difluoro-sub-
stituted alkyl-Ni(I) intermediate, which undergoes -F
elimination to deliver the desired monofluoroalkene prod-
uct (Scheme 20).
metric experiments with -alkyl-Ni(II) complex are partic-
ularly illustrative; the target product was cleanly produced
in 74% yield in the presence of MnBr2. However, in the case
where MnBr2 was not added, only a trace of product was
observed. These results indicate that MnBr2 can act as a
Lewis acid to activate the amide group, thereby promoting
the nucleophilic cyclization process.

tBu

Me
Me N MgCl2
F
Ni +
F DMSO, rt N OF
N O Br N
tBu Me
Me
with Mn0 50% yield
without Mn0 0%
Me
O
Me Standard conditions
N +
F N O
Br Me
Me
10% yield (E/Z = 11:1)
Me
O
F Standard conditions
Me +
N O
Me N
Br
Me
18% yield (E/Z = 3:2)
L
Mn(II)
* Ni(0)
Mn0 L
Ni(II)L*
Br Ar O
Ar O
L N
* Ni(I)-F N R1 R2
L
R2 R1 R2
R
Ar R2
N OF Ar Ni(II)L*
β-F elimination
R1 N O
R1

Ni(I)L* Mn0
R2 H
Ar R Mn(II)
F R2
N OF F
Ni(I)L*
Ar
R1 F R O
N
R1
migratory insertion

Scheme 20 Proposed mechanism for aryl-fluoroalkenylation of alkenes

© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

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Syn thesis Y. Ping, W. Kong Short Review

MeOOC COOMe
R2
Br Br (20 mol%) R3
O N N Ar
Ar +
N NiCl2(dme) (10 mol%) N
OH
R1 R2 R3 Mn (4 equiv) R1
R3
THF, 60 °C, 24 h
>20:1 regioselectivity

Me F Me Me Me
Ph Ph Ph Ph
MeO Cl
N N N N
OH OH OH OH
Me Me Me Me
Ph Ph Ph
72% 73% Ph 70% 69%
OMe Me
Me Ph
Ph Ph Ph
Ph
N N N
N N OH OH
OH OH Me Bn
Me Me Ph
Ph Ph
60% 63% Ph 61% 69%

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Me Br Me
Me S

N N Cl N
OH OH OH
Me Me Cl Me

63% 45% 63%

S
Br

Scheme 21 Ni-catalyzed reductive cyclization/coupling with alkynyl bromides

A possible catalytic cycle for this tandem reaction is MeO2C CO2Me

proposed. Regioselective migratory insertion of 1,3-diyne
(20 mol%)
into the -alkyl-Ni(II) species generates the seven- N N
membered alkenylnickel intermediate. Intramolecular nucleo- Ph Br
NiCl2(dme) (10 mol%)
Ph Ph
Mn (4 equiv)
philic addition of the alkenylnickel species to MnBr2-acti- THF, 60 °C 70%
vated amide leads the nickel alkoxide intermediate, which
MeO2C CO2Me
can undergo protonolysis to release the desired 2,3-fused
cyclopentannulated indolines (Scheme 22). Ph (20 mol%)
Br N N R2
On the basis of the above mechanistic study where the O NiCl2(dme) (10 mol%) Ph
1,3-diyne is the key intermediate, we expect to further ex- Me +
N Mn (4 equiv) N
THF, 60 °C OH
tend the scope of our protocol to simple asymmetric Me
Ph Me
Ph
alkynes. Upon modification of the reaction protocol, a high- 71%

ly regio- and enantioselective reductive cyclization of acryl- Br

O
Ar
amides with internal alkynes was therefore developed.
N
Since 2-hydroxyindolines are less stable for silica gel col- R1 R2
R2 R2
umn chromatography, a reductive step was incorporated R3
Ar NiIIX
into the reaction sequence. This transformation takes place R3
O LnNi0 N
Br N
under mild conditions with high efficiency, providing a rap- R1
OH
homo-coupling R1 R3
id access to structurally diverse cyclopentannulated indo-
MII
lines in good yields with high regioselectivity (>20:1) and R3
R3 M0
enantioselectivity (27 examples, 82–96% ee) (Scheme 23).
R3 R2
R3 R3
R2
3.5 Aryl-alkylation of Alkenes Ar
Ar

NiIIX N
O II
N R1 ONi X R3
Zhou and co-workers reported the first example of a R1
MnBr2
nickel-catalyzed asymmetric reductive aryl-alkylation reac-
tion of 1-(2-chlorobenzoyl)indole and n-butyl bromide. Scheme 22 Proposed mechanism for cyclization/coupling with alkynyl
They employed Pfaltz’s semicorrin as the ligand to afford bromides

© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

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Syn thesis Y. Ping, W. Kong Short Review

(1) NiCl2(dme) (10 mol%)

L (20 mol%)
Br R3 Mn, MnBr2, Et3N R2
O THF, 60 °C, 12 h R3
Ar Ar O
R2 +
N
(2) NaBH3CN, 12 h N R4 N N
R1 R4 H
R1 L

F Me MeO Me Bn
Me Me
Me Me Me
Cl
N
N
H Ph N N
H Ph H Ph
H Ph Me Me
Me Me
61%, 90% ee 56%, 89% ee 57%, 90% ee 50%, 92% ee
Me Me Me
Me Me Me
Me Me Me

N N
N H Ph N Ph H H
H Me Me
Bn
OMe F
43%, 94% ee 62%, 90% ee 65%, 85% ee 61%, 90% ee
Me Me Me
Me Me Me
nPr Ph

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N N H N
H N nPr OH
Me Me H Me
Me Ph
N
O
58%, 88% ee 68%, 88% ee Me 40%, 90% ee 46%, 82% ee

Scheme 23 Ni-catalyzed enantioselective reductive cyclization/coupling with aryl bromides or asymmetric internal alkynes

the cyclized coupling fused indoline in 35% yield with 99% 3.6 Aryl-amination of Alkenes
ee, along with an uncyclized coupling product in 45% yield
(Scheme 24).20 Following the same concept, Zhu and co-workers re-
ported a nickel-catalyzed reductive aryl-amination of
CN alkenes (Scheme 26).23 A variety of -chiral amines with an
O O
enantioenriched aryl-substituted quaternary carbon center
N HN
were obtained in good yields and with excellent enantiose-
Me Ph Ph nBu

N ligand (12 mol%)

H
Me Me lectivities (88–99%) when NiI2 was used as the catalyst and
NiBr2(dme) (10 mol%) N
O + nBuBr +
(S)-Ad-Pyrox as the chiral ligand. The key to success is the
Mn, Na2CO3, H2O N O
DMF, 50 °C
use of O-benzoyl-hydroxylamine as the nitrogen source.
Cl
O Bun Both electron-rich and electron-deficient substituents on
35% yield, 99% ee 45% yield

Scheme 24 Ni-catalyzed enantioselective reductive aryl-alkylation of NiBr2(dme) (15 mol%) R2

alkenes O O R1
Br (15 mol%)
R1 N N
Ar + Bn Bn Ar
X Br R2 X
( )n ( )n
Zn (4 equiv)
Following this, Wang and co-workers demonstrated a X = C, N, O 51–75%
DMA, 40 °C 17–95% ee
nickel-catalyzed enantioselective reductive aryl-alkylation
of alkenes (Scheme 25).21 Under the catalysis of a Ni/BOX R = Me, 69%, 94% ee
Me OAc
R = Et, 67%, 94% ee
system, various aryl bromides, incorporating a pendant R OAc R = nPr, 62%, 93% ee
alkenyl unit, were successfully reacted with an array of pri- R = iPr, 50%, 91% ee N
Me
R = iBu, 59%, 88% ee
mary alkyl bromides in the presence of Zn as a reductant,
R = cHex, 55%, 89% ee
O
providing a series of benzene-fused five-member ring com- R = (CH2)6Cl, 63%, 93% ee 65%, 81% ee Me
pounds bearing a quaternary stereocenter in moderate to H
high enantioselectivities. However, one limitation of this OAc F H
H
method was observed in the use of secondary and tertiary
Me
bromides as coupling partners, which failed to deliver the Me
Me
O
Me
desired products. The same group further developed a nickel-
N O
catalyzed reductive aryl-alkylation of alkenes involving de-
73%, 44% ee 58%, dr = 97:3
carboxylative coupling using primary and secondary redox 61%, 17% ee

active NHP esters, high enantiomeric excess was achieved, Scheme 25 Ni-catalyzed enantioselective reductive aryl-alkylation of
albeit with low yield.22 alkenes

© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

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Syn thesis Y. Ping, W. Kong Short Review

the aryl ring were well tolerated, affording the cyclized am- The reductive difunctionalization of alkenes can pro-
ination products in good yields with high enantioselectivi- ceed under very mild conditions with high functional group
ty. This protocol is also efficient with alkene substrates con- tolerance, without any additional prepreparation of sensi-
taining a variety of functional groups, including a furan, tive organometallics. Therefore, we expect to see that this
ethers, and an olefin, although a more steric hindered alkyl reaction will become more general and will be able to be
group led to a slight lower yield and ee. applied in the asymmetric synthesis of a variety of natural
products.
NiI2 (10 mol%)
O
(12 mol%)
I
R3 O N N Ad
R1
R3 Funding Information
R1 + N N
X O Mes TMSCl (3 equiv)
R2 X R2 Grateful for financial support from the ‘1000-Youth Talents Plan’,
CoPc (10 mol%)
X = CH2, O
Zn (3 equiv), DMF 42–78% yield National Natural Science Foundation of China (No. 21702149), Funda-
88–99% ee
mental Research Funds for the Central Universities (2042018kf0012),
Me R Me
R1 NBn2 NBn2 NBn2 and Wuhan University.NationlNaturlScienFoundatiofChina(217049)FundamentlRsearchFundsfortheCntralUiverst,WuhanUiversty(20418kf02)

R2 O O R
References

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R1 = R2 = H, 78%, 96% ee nC
R = 5H11, 65%, 94% ee
R1 = Me, R2 = H, 67%, 96% ee R = Bn, 71%, 96% ee
R1 = F, R2 = H, 52%, 92% ee
R = iPr, 42%, 88% ee
R1 = iPr, R2 = Me, 70%, 96% ee
Me OMe
O Angew. Chem. Int. Ed. 2019, 58, 1562.
NBn2 NBn2
O O O O
60%, 94% ee 63%, 98% ee 55%, 96% ee
Scheme 26 Ni-catalyzed enantioselective reductive aryl-amination of
alkenes
4 Summary and Outlook
Many successful examples presented in this review con-
vincingly demonstrate the great potential of reductive di-
functionalization of alkenes in asymmetric synthesis. De-
spite the significant progress made in this fast-growing re-
search field over the past few years, many interesting
challenges and also opportunities remain to be addressed.
First, the enantioselective reductive difunctionalization
of alkenes is still limited to intramolecular forms. The fur-
ther extension to the fully intermolecular form (three-
component reaction) represents another important direc-
tion for future investigations, which would further expand
the reaction scope of the accessible compounds.
Second, even though high levels of enantioselectivities
have been achieved, the mechanism remains unclear in
many transformations. We expect future efforts to be di-
rected towards the details and mechanistic studies. Our
ability to design and develop new catalytic systems will
benefit from deeply understanding key organometallic in-
termediates.
Third, reductive cross-couplings are still limited to the
use of stoichiometric amounts of Zn or Mn powder as the
reducing agent, and further development of other catalyti-
cal systems, such as the use of electro- or photocatalytic
systems,24 represent other important directions for future
research.
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