Terminal C(sp3)–H alkylation of internal alkenes via Ni/H-catalyzed isomerization

Article abstract of DOI:10.1016/j.tetlet.2018.05.008

An efficient nickel-catalyzed reductive relay cross-coupling of internal alkenes with alkyl (or aryl) halides has been developed. This method has demonstrated broad substrate scope, mild reaction conditions and excellent terminal-selectivity. Moreover, th

Full text of DOI:10.1016/j.tetlet.2018.05.008

Accepted Manuscript
Terminal C(sp3)-H alkylation of internal alkenes via Ni/H-catalyzed isomeri-
zation
Zhen-Yu Wang, Jia-Hao Wan, Gao-Yin Wang, Rui Wang, Ruo-Xing Jin, Quan
Lan, Xi-Sheng Wang
PII:
S0040-4039(18)30589-6
https://doi.org/10.1016/j.tetlet.2018.05.008
TETL 49955
DOI:
Reference:
Tetrahedron Letters
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28 April 2018
3 May 2018
Please cite this article as: Wang, Z-Y., Wan, J-H., Wang, G-Y., Wang, R., Jin, R-X., Lan, Q., Wang, X-S., Terminal
C(sp3)-H alkylation of internal alkenes via Ni/H-catalyzed isomerization, Tetrahedron Letters (2018), doi: https://
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Zhen-Yu Wang, Jia-Hao Wan, Gao-Yin Wang, Rui Wang, Ruo-Xing Jin, Quan Lan and Xi-Sheng Wang*

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Terminal C(sp3)-H alkylation of internal alkenes via Ni/H-catalyzed isomerization
Zhen-Yu Wang, Jia-Hao Wan, Gao-Yin Wang, Rui Wang, Ruo-Xing Jin, Quan Lan, Xi-Sheng Wang∗
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, 96 Jinzhai
Road, Hefei, Anhui 230026, PR China
ARTICLE INFO
ABSTRACT
Article history:
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Received in revised form
Accepted
An efficient nickel-catalyzed reductive relay cross-coupling of internal alkenes with alkyl (or
aryl) halides has been developed. This method has demonstrated broad substrate scope, mild
reaction conditions and excellent terminal-selectivity. Moreover, this efficient strategy could be
applied to the terminal-selective alkylation of isomeric mixtures of internal alkenes.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
nickel-catalyzed
isomerization
alkylation
terminal-selectivity
internal alkenes
ins via so-called ‘chainwalking’.7-8 Starting from different kinds
of alkenes, two chainwalking paths have been demonstrated to
Introduction
Transition-metal-catalyzed cross-coupling has emerged as a
powerful strategy for effective syntheses of complex organic
compounds which are widely used in agricultural, pharmaceutical
chemistry and material science.1 During the past several decades,
the widely known cross-coupling between nucleophilic reagents,
normally alkyl or aryl organometallic reagents, and electrophilic
partners has been developed as an ideal method to forge C-C
bonds.2-3 Since alkyl metal species are always difficult to store,
inconvenient to operate and commonly prepared in situ, the
discovery of more stable and readily available nucleophiles to
avoid the use of organometallic reagents has been regarded as an
important issue in this area. As an important feedstock on large
scale from petrochemical industry, simple olefins have been used
directly as alkyl organometallics equivalents in transition-metal-
catalyzed cross-coupling reactions recently, in which silanes
were typically used as hydride sources.4
produce linear (Scheme 1a) or branched chain products (Scheme
1b), which can be explained by the lower barrier for reductive
elimination of terminal nickel species7 or the thermodynamical
stability of some specific alkylnickel intermediates.7b,8 However,
C(sp3)-C(sp3) bond forming reaction via such nickel-catalyzed
tandem isomerization/hydroalkylation of internal alkenes is rare
and remains as a challenge.9 As part of our continuous efforts to
develop novel methods on nickel-catalysis,10 we envisioned that
ligands would play an important role in the remote C(sp3)-H
As a result of β-hydride elimination and insertion of metal
hydride, double bond isomerization along the carbon skeleton
often occurs in metal-hydride-catalyzed alkenes functionalization
reactions and the isomerization will generate a selective remote
transformation of alkenes.5 However, there are still few reports
on the remote C(sp3)-H functionalization of alkenes with these
catalytic systems till date.5-9 As an abundant and low-cost
alternative to precious metal catalyst, nickel-hydride-catalyzed
reductive relay cross-coupling has recently been developed as a
powerful method to construct C(sp3)-C bonds from internal olef-
Scheme 1. Remote C(sp3)-H functionalization of alkenes via
Ni/H-catalyzed chainwalking.
———
∗ Corresponding author. e-mail: xswang77@ustc.edu.cn (X.-S. Wang).

2
alkylation of internal olefins. Herein, we report a nickel-
catalyzed reductive relay cross-coupling reaction between
internal alkenes and alkyl (or aryl) halides, in which excellent
terminal-selectivity, broad substrate scope and mild conditions
have been demonstrated (Scheme 1c). The key to success is the
use of bis(oxazoline) as the ligand to improve the reactivity of
both olefin isomerization and cross-coupling in this nickel-
catalyzed reaction.
Meanwhile, the examination of nickel source effects showed
that the use of other nickel catalysts failed to improve yields
(entries 12-15), and NiI2 was proved to be the best nickel sources.
In addition, control experiments demonstrated that nickel
catalyst, ligand and reduce agent were all crucial to the reductive
relay cross-coupling reaction (Table 1, entries 16-18).
With the optimized reaction conditions in hand, a range of
alkyl or aryl halides and internal olefins with different functional
groups could undergo the tandem isomerization and hydroalkyla-
tion to afford terminal selective products with modest to
excellent yields and good to excellent regioselectivity (Table 2).
Firstly, the scope of the electrophiles (R-I) were investigated with
2-octene (cis- and trans- mixture) 2a used as the alkene source.
Not surprisingly, increasing the side chain length of the
secondary alkyl iodides has almost no impact on the reactivity
(3b). To our delight, a variety of functional groups, including
ether (3c), fluoride (3d), amine (3e), ester (3f), sulfonamide (3g,
3h) and amide (3i) were well compatible with this terminal
alkylation reaction system. In addition, heterocycles such as
furan (3j) and thiophene (3k) could also be used as suitable
substrates in this transformation. Moreover, both alkyl bromide
(3gʹ) and aryl iodides (3l, 3m) offered the desired products
Results and discussion
Our initial study commenced with 2-iodo-4-phenylbutane 1a
and 2-octene (cis- and trans- mixture) 2a as the model substrate,
in the presence of a catalytic amount of NiI2 (10 mol%) and
(EtO)3SiH as hydrogen source in DMAc at 30 °C. As expected,
the desired product 3a was obtained successfully in 22% yield,
albeit with a relatively low regioselectivity (61:39 regioisomeric
ratio) when dtbbpy L7 was used as the ligand (Table 1, entry 1).
Considering the key role of ligand to improve the reactivity and
regioselectivity, different kinds of nitrogen ligands, including
bipyridine (L1-L3), phenanthroline (L4-L5), pyrox (L6), and
box (L7), were next examined. To our delight, the desired
product 3a was obtained with excellent regioselectivity (97:3
regioisomeric ratio) and higher yield (38%) using L7 as the
ligand (Table 1, entry 7). To improve the yield further, a careful
survey of bases was then performed, which indicated K3PO4 was
the best choice with 86% yield and 98:2 rr (Table 1, entry 9).
Table 2. Substrate scope.a
Table 1. Optimization of reaction conditions.a
Entry
1
Ni source
NiI2
Ligand
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
-
Base
Yieldb/%
rrc
61:39
-
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
K3PO4
KF
22
0
2
NiI2
3
NiI2
0
-
4
NiI2
14
0
93:7
-
5
NiI2
6
NiI2
0
-
7
NiI2
38
35
86d
76
0
97:3
96:4
98:2
96:4
-
8
NiI2
9
NiI2
10
11
12
13
14
15
16e
17
18
NiI2
NiI2
NaOAc
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
NiCl2
NiCl2·6H2O
NiBr2
Ni(OTf)2
NiI2
72
84
31
72
0
95:5
95:5
95:5
96:4
-
NiI2
0
-
-
L7
0
-
aReaction conditions: 1a (0.3 mmol, 1.5 eq.), 2a (0.2 mmol, 1.0 eq.), [Ni] (10
mol%), L (15 mol%), Base (2.0 eq.), (EtO)3SiH (2.5 eq.), DMAc (0.8 mL),
30︒C, 12 h, N2.
aReaction Conditions: 1 (0.3 mmol, 1.5 eq.), 2 (0.2 mmol, 1.0 eq.), NiI2 (10
mol%), L7 (15 mol%), K3PO4 (2.0 eq.), (EtO)3SiH (2.5 eq.), DMAc (0.8 mL),
30︒C, 12 h, N2; Isolated yield; Ratios in parentheses are regioisomeric ratios
determined by GC analysis, which represents the ratio of the linear product to
the sum of all other isomers.
bYield was determined by GC analysis using dodecane as an internal
standard.
cThe rr is regioisomeric ratio, represents the ratio of the linear product to the
sum of all other isomers as determined by GC analysis.
dIsolated yield.
balkyl bromide.
c24 h.
d1 (2.0 eq.), NiI2 (15 mol%), L7 (22.5 mol%).
eWithout (EtO)3SiH.

3
successfully, albeit with relatively lower yields. It was
noteworthy that primary alkyl iodide (3n) underwent the reaction
smoothly with modest yield and good regioselectivity (95:5 rr).
Importantly, this catalytic system worked pretty well for the
tandem isomerization-hydroalkylation of various internal
Conclusions
In conclusion, we have developed a novel and efficient
terminal-selective alkylation of internal alkenes via nickel-
catalyzed isomerization/hydroalkylation reaction. This method
demonstrated broad scope, mild conditions and excellent
regioselectivity. The key to success is the use of bis(oxazoline) as
the ligand to improve the reactivity of this nickel-catalyzed
tandem reaction. Further studies of the mechanistic details of this
transformation and the application of this method for the late-
stage modification of some complex bioactive molecules are still
ongoing in our laboratory.
ʹ
ʹʹ
alkenes. Both trans-3-octene (3a ) and trans-4-octene (3a )
could be selectively alkylated to give the terminal alkylation
products in good yields with excellent selectivities. To our
interest, trans-5-decene was also hydroalkylated smoothly in
moderate yield and high selectivity (3o), in which a long
chainwalking was required before the terminal alkylation.
Finally, internal alkenes with various functional groups, such as
ether (3p), ester (3q) and acetal (3r), could be well tolerated in
this transformation.
On the basis of the above results and previous reports,11
a
Acknowledgments
plausible mechanism involving a Ni(I)/Ni(III) catalytic cycle is
proposed as shown in Scheme 2. Firstly, the Ni-H species B
could be generated via transmetalation between the Ni(I) species
A with the silane under the activation of K3PO4. Subsequently,
the insertion of internal alkene into Ni-H species B generates
alkyl-nickel intermediate C, which undergoes β-hydride
elimination to afford the intermediate D. After readdition of Ni-H
species, a new primary alkyl-nickel(I) species E is formed. This
alkyl-nickel intermediate E thus reacts preferentially with the
alkyl halide (R-X) to generate Ni(III) species F.12 Finally, the
terminal selective coupling product 3 is obtained after the
reductive elimination from intermediate F, and Ni(I) catalyst A is
regenerated to complete the catalytic cycle.
We gratefully acknowledge the National Basic Research
Program of China (973 Program 2015CB856600), the National
Science Foundation of China (21772187, 21522208, 21372209)
for financial support.
References and notes
1.
For reviews or books on cross-coupling reactions, see (a) Liu, C.;
Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780; (b) Seechurn,
C. C. C. J.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem.
Int. Ed. 2012, 51, 5062; (c) Crawley, M. L.; Trost, B. M.; Shen, H. C.
Selected Applications of Transition Metal-Catalyzed Carbon-Carbon
Cross-Coupling Reactions in the Pharmaceutical Industry, Wiley-VCH,
Weinheim, 2012.
To demonstrate the application prospect of this method, our
newly developed catalytic system has been applied to the
isomerization-hydroalkylation of isomeric mixtures of aliphatic
olefins, which are usually obtained from petrochemical sources
and thus substantially cheaper and more easily accessible than
pure olefin isomers. As shown in Scheme 3, under the standard
conditions, a mixture of octenes with equimolar amounts of four
octene isomers afforded the terminal alkylated product with good
yield (82%) and excellent regioselectivity (97:3 rr). This result
suggested the great potential of this transformation in organic
synthesis.
2.
For selected reviews, see: (a) Miyaura, N. Metal-Catalyzed Cross-
Coupling Reactions, 2th ed., Wiley-VCH, Weinheim, 2008, pp. 41-123;
(b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633; (c)
Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.;
Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem. Int. Ed. 2003, 42,
4302; (d) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117; (e)
Haas, D.; Hammann, J. M.; Greiner, R.; Knochel, P. ACS Catal. 2016,
6, 1540; (f) Phapale, V. B.; Cárdenas, D. J. Chem. Soc. Rev. 2009, 38,
1598; (g) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111,
1417; (h) Geist, E., Kirschning, A.; Schmidt, T. Nat. Prod. Rep. 2014,
31, 441; (i) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 2001, 40, 4544; (j) Netherton, M. R.; Fu, G. C. Adv.
Synth. Catal. 2004, 346, 1525; (k) Hu, X. Chem. Sci. 2011, 2, 1867; (l)
Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299;
(m) Ananikov, V. P. ACS Catal. 2015, 5, 1964; (n) Choi, J.; Fu, G. C.
Science 2017, 356, 152.
3.
For selected examples, see: (a) Giannerini, M.; Fañanás-Mastral,
M.; Feringa, B. L. Nat. Chem. 2013, 5, 667; (b) Li, L.; Wang, C.-Y.;
Huang, R.; Biscoe, M. R. Nat. Chem. 2013, 5, 607; (c) Vechorkin, O.;
Hu, X. Angew. Chem. Int. Ed. 2009, 48, 2937; (d) Yu, X.; Yang, T.;
Wang, S.; Xu, H.; Gong, H. Org. Lett. 2011, 13, 2138; (e) Johnston, C.
P.; Smith, R. T.; Allmendinger, S.; MacMillan, D. W. C. Nature 2016,
536, 322; (f) Le, C.; Liang, Y.; Evans, R. W.; Li, X.; MacMillan, D. W.
C. Nature 2017, 547, 79; (g) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.;
Edwards, J. T.; Kawamura, S. B.; Maxwell, D.; Eastgate, M. D.; Baran,
P. S. Science 2016, 352, 801; (h) Schmidt, J.; Choi, J.; Liu, A. T.;
Slusarczyk, M.; Fu, G. C. Science 2016, 354, 1265.
4. For selected examples on unactivated olefins used as alkyl
organometallics equivalents, see: (a) Yang, Y.; Shi, S.-L.; Niu, D.; Liu,
P.; Buchwald, S. L. Science 2015, 349, 62; (b) Gui, J.; Pan, C.-M.; Jin,
Y.; et al. Science 2015, 348, 886; (c) Sakae, R.; Hirano, K.; Miura, M.
J. Am. Chem. Soc. 2015, 137, 6460; (d) Xi, Y.; Butcher, T. W.; Zhang,
J.; Hartwig, J. F. Angew. Chem. Int. Ed. 2016, 55, 776; (e) Waser, J.;
Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 5676; (f) Gaspar, B.;
Carreira, E. M. Angew. Chem. Int. Ed. 2007, 46, 4519; (g) Su, W.;
Gong, T.-J.; Lu, X.; Xu, M.-Y.; Yu, C.-G.; Xu, Z.-Y.; Yu, H.-Z.; Xiao,
B.; Fu, Y. Angew. Chem. Int. Ed. 2015, 54, 12957; (h) Lo J. C.; Yabe,
Y.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 1304; (i) Miki, Y.;
Hirano, K.; Satoh, T.; Miura, M. Angew. Chem. Int. Ed. 2013,
52, 10830; (j) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2014, 16, 1498; (k) Waser, J.; Carreira, E. M. Angew. Chem. Int. Ed.
2004, 43, 4099; (l) Lo, J. C.; Gui, J.; Yabe, Y.; Pan, C. M.; Baran, P. S.
Nature 2014, 516, 343; (m) Wang, Y.-M.; Bruno, N. C.; Placeres, Á. L.;
Zhu, S.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 10524; (n) Lu,
X.; Xiao, B.; Zhang, Z.; Gong, T.; Su, W.; Yi, J.; Fu, Y.; Liu, L. Nat.
Commun. 2016, 7, 11129.
Scheme 2. Proposed mechanism.
Scheme 3. Terminal-selective alkylation of mixture of alkene
isomers.
5.
For books or reviews on remote functionalization through alkene isome-

4
rization, see: (a) Hermann, W. A. & Prinz, M. in Applied Homogeneous
Catalysis with Organometallic Compounds 2nd, ed., Wiley-VCH, 2002,
pp. 1119–1124; (b) Larionov, E.; Li H.; Mazet, C. Chem. Commun. 2014,
50, 9816; (c) Vasseur, A.; Bruffaerts, J.; Marek, I. Nat. Chem. 2016, 8,
209; (d) Sommer, H.; Juliá-Hernández, F.; Martin, R.; Marek, I. ACS
Cent. Sci. 2018, 4, 153.
6.
For recent examples on transition-metal-catalyzed remote C(sp3)-H
functionalization of alkenes, see: (a) Lata, C. J.; Crudden, C. M. J. Am.
Chem. Soc. 2010, 132, 131; (b) Yotphan, S.; Bergman, R. G.; Ellman, J.
A. Org. Lett. 2010, 12, 2978; (c) Martínez, J. I.; Smith, J. J.; Hepburn,
H. B.; Lam, H. W. Angew. Chem. Int. Ed. 2016, 55, 1108; (d) Dupuy,
S.; Zhang, K.-F.; Goutierre, A.-S.; Baudoin, O. Angew. Chem. Int. Ed.
2016, 55, 14793; (e) Singh, S.; Bruffaerts, J.; Vasseur, A.; Marek, I.
Nat. Commun. 2017, 8, 14200; (f) Obligacion, J. V.; Chirik, P. J. J. Am.
Chem. Soc. 2013, 135, 19107; (g) Chirik, P. J.; et al. J. Am. Chem. Soc.
2014, 136, 12108; (h) Scheuermann, M. L.; Johnson, E. J.; Chirik, P. J.
Org. Lett. 2015, 17, 2716; (i) Palmer, W. N.; Diao, T.; Pappas, I.;
Chirik, P. J. ACS Catal. 2015, 5, 622; (j) Yamakawa, T.; Yoshikai, N.
Chem. Asian J. 2014, 9, 1242; (k) Jia, X.; Zhang, L.; Qin, C.; Leng, X.;
Huang, Z. Chem. Commun. 2014, 50, 11056; (l) Jia, X.; Huang, Z. Nat.
Chem. 2016, 8, 157; (m) Bart, S. C.; Lobkovsky, E.; Chirik, P. J. J. Am.
Chem. Soc. 2004, 126, 13794; (n) Masarwa, A.; Didier, D.; Zabrodski,
T.; Schinkel, M.; Ackermann, L.; Marek, I. Nature 2014, 505, 199; (o)
Buslov, I.; Becouse, J.; Mazza, S.; Montandon-Clerc, M.; Hu, X.
Angew. Chem. Int. Ed. 2015, 54, 14523; (p) Buslov, I.; Song, F.; Hu, X.
Angew. Chem. Int. Ed. 2016, 55, 12295.
7.
8.
Ni-catalyzed chainwalking to produce linear products, see: (a) Bair, J.
S.; Schramm, Y.; Sergeev, A. G.; Clot, E.; Eisenstein, O.; Hartwig, J. F.
J. Am. Chem. Soc. 2014, 136, 13098; (b) JuliáHernández, F.; Moragas,
T.; Cornella, J.; Martin, R. Nature 2017, 545, 84; (c) Gaydou, M.;
Moragas, T.; Juliá-Hernández, F.; Martin, R. J. Am. Chem. Soc. 2017,
139, 12161.
Ni-catalyzed chainwalking to produce branched products, see: (a) Lee,
W.-C.; Wang, C.-H.; Lin, Y.-H.; Shih, W.-C.; Ong, T.-G. Org. Lett.
2013, 15, 5358; (b) He, Y.; Cai, Y.; Zhu S. J. Am. Chem. Soc. 2017,
139, 1061; (c) Chen, F.; Chen, K.; Zhang, Y.; He, Y.; Wang, Y.-M.;
Zhu, S. J. Am. Chem. Soc. 2017, 139, 13929; (d) Peng, L.; Li, Y.; Li,
Y.; Wang, W.; Pang, H.; Yin, G. ACS Catal. 2018, 8, 310; (e) Peng, L.;
Li, Z.; Yin, G. Org. Lett. 2018, 20, 1880.
9.
During the preparation of this manuscript, a remote C(sp3) -H alkylation
of alkenes was published online, see: Zhou, F.; Zhu, J.; Zhang, Y.; Zhu,
S. Angew. Chem. Int. Ed. 2018, 57, 4058.
10. (a) Su, Y.-M.; Feng, G.-S.; Wang, Z.-Y.; Lan, Q.; Wang, X.-S. Angew.
Chem. Int. Ed. 2015, 54, 6003; (b) Li, G.; Wang, T.; Fei, F.; Su, Y.-M.;
Li, Y.; Lan, Q.; Wang, X.-S. Angew. Chem. Int. Ed. 2016, 55, 3491; (c)
Wu, Y.; Zhang, H.-R.; Cao, Y.-X.; Lan, Q.; Wang, X.-S. Org. Lett.
2016, 18, 5564; (d) Wu, Y.; Zhang, H.-R.; Jin, R.-X.; Lan, Q.; Wang,
X.-S. Adv. Synth. Catal. 2016, 358, 3528; (e) Sheng, J.; Ni, H.-Q.; Liu,
G.; Li, Y.; Wang, X.-S. Org. Lett. 2017, 19, 4480; (f) Sheng, J.; Ni, H.-
Q.; Bian, K.-J.; Li, Y.; Wang, Y.-N.; Wang, X.-S. Org. Chem. Front.
2018, 5, 606; (g) Wang, Z.-Y.; Wan, J.-H.; Wang, G.-Y.; Jin, R.-X.;
Lan, Q.; Wang, X.-S. Chem. Asian J. 2018, 13, 261.
11. (a) Pappas, I.; Treacy, S.; Chirik, P. J. ACS Catal. 2016, 6, 4105; (b)
Kuang, Y.; Anthony, D.; Katigbak, J.; Marrucci, F.; Humagain, S.;
Diao, T. Chem 2017, 3, 268; ref. 7-9.
12. A TEMPO-quench experiment in mechanism studies indicated that the
catalytic cycle might proceed via a radical pathway. For details, see the
SI.

5
Research highlights
1. An efficient nickel-catalyzed reductive relay
cross-coupling of internal alkenes with
alkyl/aryl halides has been developed;
2. This method has demonstrated broad substrate
scope, mild reaction conditions and excellent
terminal-selectivity;
3. The efficient strategy can be applied to the
terminal-selective alkylation of isomeric
mixtures of internal alkenes.