Stereospecific Synthesis of E-Alkenes through Anti-Markovnikov Hydroalkylation of Terminal Alkynes

Article abstract of DOI:10.1021/jacs.9b04800

We have developed a method for stereospecific synthesis of E-alkenes from terminal alkynes and alkyl iodides. The hydroalkylation reaction is enabled by a cooperative action of copper and nickel catalysts and proceeds with excellent anti-Markovnikov selectivity. We demonstrate the broad scope of the reaction, which can be accomplished in the presence of esters, nitriles, aryl bromides, ethers, alkyl chlorides, anilines, and a wide range of nitrogen-containing heteroaromatic compounds. Mechanistic studies provide evidence that the copper catalyst activates the alkyne by hydrocupration, which controls both the regio- and diastereoselectivity of the overall reaction. The nickel catalyst activates the alkyl iodide and promotes cross coupling with the alkenyl copper intermediate.

Full text of DOI:10.1021/jacs.9b04800

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Stereospecific Synthesis of E‑Alkenes through Anti-Markovnikov
Hydroalkylation of Terminal Alkynes
Avijit Hazra, Jason Chen, and Gojko Lalic*
University of Washington, Seattle, Washington 98103, United States
S
* Supporting Information
Scheme 1. Hydroalkylation of Alkynes
ABSTRACT: We have developed a method for stereo-
specific synthesis of E-alkenes from terminal alkynes and
alkyl iodides. The hydroalkylation reaction is enabled by a
cooperative action of copper and nickel catalysts and
proceeds with excellent anti-Markovnikov selectivity. We
demonstrate the broad scope of the reaction, which can be
accomplished in the presence of esters, nitriles, aryl
bromides, ethers, alkyl chlorides, anilines, and a wide
range of nitrogen-containing heteroaromatic compounds.
Mechanistic studies provide evidence that the copper
catalyst activates the alkyne by hydrocupration, which
controls both the regio- and diastereoselectivity of the
overall reaction. The nickel catalyst activates the alkyl
iodide and promotes cross coupling with the alkenyl
copper intermediate.
lkenes are ubiquitous in organic chemistry. They are used
Aas versatile synthetic intermediates and are common
among complex organic molecules with important applications.
The importance of alkenes in organic chemistry has fueled
persistent efforts aimed at developing new methods for their
synthesis. As a result of these efforts, the hydroalkylation of
alkynes has recently emerged as a powerful new approach to
alkene synthesis. The main benefit of this approach is the use
of simple and readily available alkynes as precursors to a variety
of alkenes.
Current methods for the hydroalkylation of alkynes provide
access to several classes of alkenes (Scheme 1). Z-Substituted
aryl alkenes can be prepared using a radical hydroalkylation of
aryl alkynes that was reported in 2015 by Hu et al. (Scheme
1a).1 More recently, Fu et al. developed a selective synthesis of
1,1-disubstituted alkenes through a nickel-catalyzed hydro-
alkylation of terminal alkynes (Scheme 1b).2 A similar
transformation of terminal alkynes into 1,1-disubstituted
alkenes was subsequently accomplished by MacMillan et al.
using a cooperative photoredox/nickel catalysis (Scheme
1b).3,4 This approach has also allowed the transformation of
sterically differentiated internal alkynes into trisubstituted
alkenes with moderate regioselectivity.3
Surprisingly, there are few hydroalkylation methods that
effectively target disubstituted E-alkenes. In 2015, our group
reported the copper-catalyzed hydroalkylation of terminal
alkynes using alkyl triflates as electrophiles (Scheme 1c).5,6
This transformation demonstrates key benefits of hydro-
alkylation as an approach to the synthesis of E-alkenes. The
reaction increases both the structural and the stereochemical
complexity of the starting materials. A new C−C bond is
formed, and, in the process, the stereochemistry of the new
alkene is established. The excellent regioselectivity and
diastereospecificity of the reaction allow the exclusive
formation of a single E-alkene.
Nevertheless, our original hydroalkylation reaction has some
significant limitations. The reaction is highly sensitive to steric
properties of the electrophile and only linear primary alkyl
triflates with no α-branching were viable substrates.
Additionally, both alkyl triflates and reagents used in their
preparation are highly reactive, further limiting the reaction
scope and introducing practical problems related to the
preparation, purification, and stability of the starting electro-
philes.
In this Communication, we report the development of a new
method for the hydroalkylation of terminal alkynes that
Received: May 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b04800
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
addresses the key shortcomings of our original hydroalkylation
reaction, while retaining its major benefits. We demonstrate
that a dual Cu/Ni catalyst system allows the use of both
primary and secondary alkyl iodides as coupling partners and
enables the stereospecific synthesis of a wide range E-alkenes
from terminal alkynes.
Scheme 3. Preliminary Results
The hydroalkylation of alkynes that we reported in 2015
involves hydrocupration of an alkyne followed by electrophilic
functionalization of alkenyl copper intermediate 3 (Scheme
2a).7,8 The key hydrocupration step is highly regioselective and
Scheme 2
Contrary to our expectations, the Markovnikov hydro-
alkylation product was not a significant byproduct in these
reactions. Instead, the major problem was the formation of a
mixture of higher molecular weight products. We reasoned that
these products are likely formed through Reppe’s trimeriza-
tion18 and related tetramerization19 of alkynes promoted by
nickel(0) complexes.20−24 A mechanistically distinct trimeriza-
tion of alkynes is also promoted by nickel hydride complexes.25
Established mechanisms of these major side reactions
suggested that the desired reactivity of the nickel catalyst
may be achieved using tridentate ligands. Considering the
mechanism of Reppe’s trimerization, tridentate ligands should
suppress this side reaction by preventing simultaneous
coordination of two alkyne molecules.26 Additionally, the less
common trimerization promoted by nickel hydride complexes
requires a tricoordinate nickel hydride intermediates.27 Again,
strongly coordinating tridentate ligands should prevent
formation of such an intermediate. We also found precedent
indicating that the formation of the nickel hydride complexes is
suppressed by tricoordinate nitrogen-based ligands.28 This
observation is consistent with Fu’s recent finding that
tridentate nitrogen-based ligands completely suppress the
Markovnikov hydroalkylation of alkynes,2 although no
explanation for this effect was offered. Finally, the documented
use of tridentate ligands in nickel-catalyzed cross coupling
reactions of alkyl halides29 indicates that these ligands should
allow the desired cross coupling of alkenyl copper intermediate
with alkyl iodides.
Indeed, the use of tridentate ligands was the key
modification that allowed us to develop the hydroalkylation
reaction shown in Table 1. The best results in a reaction of
terminal alkyne 12 and cyclohexyl iodide were obtained using
IPrCuCl catalyst and a nickel(I) co-catalyst supported by
tridentate tpy′ ligand (Table 1). Additionally, Ph3SiH was used
as a hydride source and LiOi-Pr as a turnover reagent for the
copper catalyst (for the role of LiOi-Pr, see Scheme 4).
During the development of the reaction, we made several
observations about reaction parameters (Table 1). Alkyl
iodides were superior substrates, while alkyl bromides provided
dramatically lower yields (entry 2). As in most other copper-
catalyzed hydrofunctionalization reactions of alkynes, catalysts
supported by IPr and the closely related SIPr ligands were the
only competent catalysts (entry 3). Even IMesCuCl catalyst
provided only 5% of the product (entry 4). The identity of the
nickel catalyst was also key for the success of the reaction. The
catalyst prepared in situ from NiI2 performed nearly as well as
the optimal catalyst, while the catalyst prepared from NiCl2
syn-stereospecific, ultimately resulting in excellent regio- and
diastereoselectivity of the overall reaction. Unfortunately, the
low reactivity of alkenyl copper complexes makes their
alkylation difficult. The stoichiometric reaction of alkenyl
copper complex 5 with alkyl triflate 6 provides the desired
product, while the less reactive alkyl iodide 7 does not react
and under more forcing conditions leads to the decomposition
of the starting materials (Scheme 2b).5 Mankad et al. have
made similar observations about the reactivity of alkenyl
copper complexes with alkyl halides.9
Inspired by the pioneering work of Nakao10,11 and
Brown,12−14 our plan was to use a nickel co-catalyst to
facilitate the cross coupling of the organocopper intermediate
with alkyl iodides (Scheme 2c). The main challenge in
implementing this cooperative catalysis15−17 approach to
hydroalkylation of alkynes was a clear overlap in the reactivity
of the nickel and the copper catalyst systems. The nickel-
catalyzed Markovnikov hydroalkylation2 (Scheme 1b) is
performed under conditions that are very similar to those
required for copper hydride formation. Both reactions require
a combination of a silane and a base additive. In principle, the
nickel co-catalyst in the hydroalkylation reaction may promote
not only the desired alkylation of the alkenyl copper
intermediate, it could also promote a Markovnikov hydro-
alkylation and compromise the regioselectivity of the overall
transformation.
In our initial experiments we found that the common cross
coupling catalyst (dtbpy)NiCl2 promotes efficient cross
coupling of the isolated alkenyl copper intermediate 5 and
cyclohexyl iodide (Scheme 3a). However, in a catalytic
hydroalkylation reaction, the same nickel catalyst provides
desired E-alkene in only 23% yield (Scheme 3b). Equally
unsuccessful, were reactions with a variety of mono and
bidentate phosphine and nitrogen-based ligands.
B
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Journal of the American Chemical Society
Communication
tolerated. The reaction is compatible with a wide range of
functional groups and can be accomplished in the presence of
nitriles (19), esters (20), aryl ethers (15), silyl ethers (13, 17,
21, and 27), alkenes (15), alkyl chlorides (26), sulfonamides
(31), dialkyl anilines (25), and aryl bromides (18). The
synthesis of compound 16 on a 5 mmol scale demonstrates
that the reaction can be used as a preparative method.30
One of the limitations of our original hydroalkylation
method was that nitrogen-based heteroarenes were not
compatible with the reaction. The new reaction tolerates a
wide range of heteroarenes including furans (23), 2-
chloropyridines (24), pyridazines (30), thiazoles (28),
pyrimidines (29), tetrazoles (33), and benzoxazoles (34). In
general, heteroarenes less basic than pyridine are tolerated,
while pyridine and more basic heterocycles are not.
We also explored the reaction with a range of secondary
alkyl iodides. Cyclic substrates, such as 5- through 7-membered
cyclic alkyl iodides, generally perform well (36, 40, 41).
Acyclic alkyl iodides are also viable substrates, although yields
tend to be lower.
Our initial attempts at using primary alkyl iodides as
coupling partners were unsuccessful. Under the reaction
conditions used for coupling secondary alkyl iodides, product
8 was formed in only 32% yield. The major side reactions in
this case were the reduction of the alkyl iodide31 and the semi-
reduction of the alkyne to an alkene. Eventually, we found that
with subtle changes to the reaction conditions we can obtain
alkene 8 in 90% yield (eq 1).
Table 1. Reaction Development
a
entry
change from standard conditions
yield (%)
1
2
none
CyBr instead of Cyl
88
2
3
4
SIPrCuCl instead of IPrCuCl
IMesCuCl instead of IPrCuCl
87
5
5
6
7
8
9
tpy′ + Nil2 instead of (tpy′)Nil
(tpy′)NiCl2 instead of (tpy′)Nil
(tpy)Nil instead of (tpy′)Nil
(dtbpy)NiCl2 instead of (tpy′)Nil
NiCl2(DME) + i-PrPybox instead of (tpy′)Nil
82
71
48
8
0
10
11
LiOt-Bu instead of LiOi-Pr
NaOi-Pr instead of LiOi-Pr
3
34
12
THF instead of DME
78
13
14
15
Ph2MeSiH instead of Ph3SiH
PMHS instead of Ph3SiH
Ph2SiH2 instead of Ph3SiH
51
8
12
a
Determined by GC using internal standard.
To achieve these results, we changed the catalyst from
IPrCuCl to SIPrCuCl, changed the solvent from DME to
DME/isooctane (1:1), adjusted the stoichiometry of the
turnover reagent (from 1.5 to 2.0 equiv), and lowered the
loading of the nickel catalyst (from 5 to 3 mol%).32
The conditions developed for the synthesis of 8 proved
general for a range of primary alkyl halides (Table 2). In
departure from the original hydroalkylation with alkyl triflates,
we could achieve hydroalkylation using α-branched (46, 49,
50, and 51) and even neopentyl-like alkyl iodide (45) in
relatively high yield. Similarly, electrophiles with heteroatoms
in the α position (46), which are incompatible with the
previous hydroalkylation, are also tolerated.
We also noted a few limitations of the hydroalkylation
reaction. Protic functional groups, such as hydroxyl and amino,
are not tolerated. Reducible functional groups, such as
aldehydes and activated alkene are also not compatible with
reactions conditions. Finally, tertiary alkyl iodides, aryl-
substituted alkynes, and disubstituted alkynes did not
participate in the hydroalkylation reaction.
gave a lower yield (entries 5 and 6). Nickel complexes
supported by other closely related ligands were inferior (entries
7−9). With LiOt-Bu in place for LiOi-Pr we observed a small
amount of Sonogashira product and complete recovery of the
starting silane (entry 10). These results suggest that IPrCuOt-
Bu does not readily react with Ph3SiH to form IPrCuH and
instead leads to the formation of copper-acetylide and
Sonogashira product. Similarly, changing the alkoxide counter-
ion from lithium to sodium led to lower yield of the product
(entry 11).
Among common ethereal solvents, THF was the only
solvent other than DME that afforded the desired product in a
significant yield (entry 12). Finally, PMHS and silanes closely
related to Ph3SiH were all significantly inferior to Ph3SiH
(entries 13−15).
Using the standard conditions shown in Table 1 (entry 1),
we explored the scope of the reaction and found that a wide
range of E-alkenes can be prepared (Table 2). It is important
to note that all products shown in Table 2 are obtained as a
single regioisomer and a single diastereoisomer. Even severe
steric hindrance in the propargylic position does not impede
the formation of the product (17) and substitution at the
propargylic (13) and homopropargylic position (27) is
Considering the generally established mechanisms of
copper-catalyzed hydrofunctionalization of alkynes8 and
nickel-catalyzed cross coupling reactions,33 we propose that
the hydroalkylation reaction proceeds according to the
mechanism shown in Scheme 4. Initial hydrocupration of the
alkyne (V → VI) is followed by transmetalation to nickel (VI
→ VIII). The alkyl iodide is activated by the newly formed
alkenyl nickel complex (VIII). Reductive elimination results in
C
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a
Table 2. Reaction Scope
a
b
Yields of isolated products are reported. Reactions performed on 0.5 mmol scale. Conditions A: see Table 1, entry 1. Conditions B: see eq 1.
c
d
e
The product was isolated as a free alcohol after TBS deprotection. SIPrCuCl was used as a catalyst. See SI for details.
the formation of the desired product and the regeneration of
the nickel(I) catalyst (VII). The copper hydride intermediate
(V) is regenerated in sequential reactions of the copper catalyst
with the alkoxide and the silane.
D
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Communication
Scheme 4. Proposed Mechanism
Experimental procedure and product characterization
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*lalic@chem.washington.edu
ORCID
Avijit Hazra: 0000-0002-1102-8581
Gojko Lalic: 0000-0003-3615-3423
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge Professor Forrest Michael for stimulating
discussions. We thank NIH for funding (1R01GM125791-
01A1).
REFERENCES
■
(1) Cheung, C. W.; Zhurkin, F. E.; Hu, X. Z-Selective Olefin
Synthesis via Iron-Catalyzed Reductive Coupling of Alkyl Halides
with Terminal Arylalkynes. J. Am. Chem. Soc. 2015, 137, 4932.
(2) Lu, X.-Y.; Liu, J.-H.; Lu, X.; Zhang, Z.-Q.; Gong, T.-J.; Xiao, B.;
Fu, Y. 1,1-Disubstituted Olefin Synthesis via Ni-Catalyzed Markovni-
kov Hydroalkylation of Alkynes with Alkyl Halides. Chem. Commun.
2016, 52, 5324.
In preliminary experiments, we probed the proposed
interaction of the two established catalytic cycles. In a nickel-
catalyzed cross coupling of the presumed alkenyl copper
intermediate with a secondary alkyl iodide we obtained the
expected E-alkene in 92% yield (Scheme 5a). In the absence of
Scheme 5
(3) Till, N. A.; Smith, R. T.; MacMillan, D. W. C. Decarboxylative
Hydroalkylation of Alkynes. J. Am. Chem. Soc. 2018, 140, 5701.
(4) Wang, Z.; Yin, H.; Fu, G. C. Catalytic Enantioconvergent
Coupling of Secondary and Tertiary Electrophiles with Olefins.
Nature 2018, 563, 379.
(5) Uehling, M. R.; Suess, A. M.; Lalic, G. Copper-Catalyzed
Hydroalkylation of Terminal Alkynes. J. Am. Chem. Soc. 2015, 137,
1424.
(6) Suess, A. M.; Uehling, M. R.; Kaminsky, W.; Lalic, G.
Mechanism of Copper-Catalyzed Hydroalkylation of Alkynes: An
Unexpected Role of Dinuclear Copper Complexes. J. Am. Chem. Soc.
2015, 137, 7747.
(7) Suess, A. M.; Lalic, G. Copper-Catalyzed Hydrofunctionalization
of Alkynes. Synlett 2016, 27, 1165.
(8) Jordan, A. J.; Lalic, G.; Sadighi, J. P. Coinage Metal Hydrides:
Synthesis, Characterization, and Reactivity. Chem. Rev. 2016, 116,
8318.
(9) Cheng, L.-J.; Mankad, N. P. Cu-Catalyzed Hydrocarbonylative
C−C Coupling of Terminal Alkynes with Alkyl Iodides. J. Am. Chem.
Soc. 2017, 139, 10200.
(10) Semba, K.; Ariyama, K.; Zheng, H.; Kameyama, R.; Sakaki, S.;
Nakao, Y. Reductive Cross-Coupling of Conjugated Arylalkenes and
Aryl Bromides with Hydrosilanes by Cooperative Palladium/Copper
Catalysis. Angew. Chem., Int. Ed. 2016, 55, 6275.
(11) Semba, K.; Nakao, Y. Arylboration of Alkenes by Cooperative
Palladium/Copper Catalysis. J. Am. Chem. Soc. 2014, 136, 7567.
(12) Logan, K. M.; Smith, K. B.; Brown, M. K. Copper/Palladium
Synergistic Catalysis for the syn- and anti-Selective Carboboration of
Alkenes. Angew. Chem., Int. Ed. 2015, 54, 5228.
(13) Logan, K. M.; Brown, M. K. Catalytic Enantioselective
Arylboration of Alkenylarenes. Angew. Chem., Int. Ed. 2017, 56, 851.
(14) Smith, K. B.; Brown, M. K. Regioselective Arylboration of
Isoprene and Its Derivatives by Pd/Cu Cooperative Catalysis. J. Am.
Chem. Soc. 2017, 139, 7721.
the nickel catalyst we did not detect the formation of the E-
alkene. These experiments demonstrate the feasibility of the
proposed nickel-catalyzed cross coupling of the alkenyl copper
intermediate and an alkyl iodide and establish the need for the
nickel catalyst.
Next, we probed the relationship between transmetalation
and alkyl halide activation. We propose that the activation of
the alkyl iodide happens only after the transmetalation and the
formation of the alkenyl nickel intermediate VIII. In some
nickel-catalyzed cross coupling reactions the activation of the
alkyl halide occurs prior to transmetalation.34,35
To probe this alternative mechanism, we exposed cyclohexyl
iodide to our nickel(I) catalyst ((tpy′)NiI). After 1 h at room
temperature, the starting alkyl iodide was fully recovered
(Scheme 5b). This result suggests that, in our reaction,
transmetalation (VI → VIII) likely precedes the activation of
the alkyl iodide (VIII → IX). Further studies of the reaction
mechanism are underway in our laboratory.
(15) Allen, A. E.; MacMillan, D. W. C. Synergistic Catalysis: A
Powerful Synthetic Strategy for New Reaction Development. Chem.
Sci. 2012, 3, 633.
(16) Fogg, D. E.; dos Santos, E. N. Tandem Catalysis: A Taxonomy
and Illustrative review. Coord. Chem. Rev. 2004, 248, 2365.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b04800.
■
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(17) Patil, N. T.; Shinde, V. S.; Gajula, B. A One-Pot Catalysis: The
Strategic Classification with Some Recent Examples. Org. Biomol.
Chem. 2012, 10, 211.
(18) Reppe, W.; Schlichting, O.; Klager, K.; Toepel, T. Cyclisierende
̈
Polymerisation von Acetylen I Uber Cyclooctatetraen. Justus Liebigs
Ann. Chem. 1948, 560, 1.
(19) Diercks, R.; Stamp, L.; Kopf, J.; tom Dieck, H. Elementary
Steps in Catalytic 1-Alkyne Coupling to Substituted Cyclooctate-
traenes. Angew. Chem., Int. Ed. Engl. 1984, 23, 893.
(20) Chini, P.; Santambrogio, A.; Palladino, N. Cyclisation of 2-
Methylbut-3-yn-2-ol. Part I. Cyclisation to Aromatic Compounds. J.
Chem. Soc. C 1967, 830.
(21) Mori, N.; Ikeda, S.-i.; Odashima, K. Chemo- and Regioselective
Cyclotrimerization of Monoynes Catalyzed by a Nickel(0) and
Zinc(II) Phenoxide System. Chem. Commun. 2001, 181.
(22) Rodrigo, S. K.; Powell, I. V.; Coleman, M. G.; Krause, J. A.;
Guan, H. Efficient and Regioselective Nickel-Catalyzed [2 + 2 + 2]
Cyclotrimerization of Ynoates and Related Alkynes. Org. Biomol.
Chem. 2013, 11, 7653.
(23) Xi, C.; Sun, Z.; Liu, Y. Cyclotrimerization of Terminal Alkynes
Catalyzed by the System of NiCl2/Zn and (Benzimidazolyl)-6-(1-
(arylimino)ethyl)pyridines. Dalton Trans. 2013, 42, 13327.
(24) Pal, S.; Uyeda, C. Evaluating the Effect of Catalyst Nuclearity in
Ni-Catalyzed Alkyne Cyclotrimerizations. J. Am. Chem. Soc. 2015,
137, 8042.
(25) Inoue, Y.; Itoh, Y.; Hashimoto, H. Novel Cyclodimerization
and Cyclotrimerization of 3-Hexyne by Cationic Nickel Hydride
Complex. Chem. Lett. 1978, 7, 911.
́
(26) Orsino, A. F.; Gutierrez del Campo, M.; Lutz, M.; Moret, M.-E.
Enhanced Catalytic Activity of Nickel Complexes of an Adaptive
Diphosphine−Benzophenone Ligand in Alkyne Cyclotrimerization.
ACS Catal. 2019, 9, 2458.
(27) Fan, L.; Krzywicki, A.; Somogyvari, A.; Ziegler, T. Theoretical
Study of Ethylene Oligomerization by an Organometallic Nickel
Catalyst. Inorg. Chem. 1996, 35, 4003.
(28) Buslov, I.; Becouse, J.; Mazza, S.; Montandon-Clerc, M.; Hu, X.
Chemoselective Alkene Hydrosilylation Catalyzed by Nickel Pincer
Complexes. Angew. Chem., Int. Ed. 2015, 54, 14523.
(29) Zhou, J.; Fu, G. C. Cross-Couplings of Unactivated Secondary
Alkyl Halides: Room-Temperature Nickel-Catalyzed Negishi Reac-
tions of Alkyl Bromides and Iodides. J. Am. Chem. Soc. 2003, 125,
14726.
(30) We found that the active nickel catalyst can be prepared in situ
from air-stable precursors, which allows the reaction to be executed
without the use of a glovebox (see SI for details).
(31) Dang, H.; Cox, N.; Lalic, G. Copper-Catalyzed Reduction of
Alkyl Triflates and Iodides: An Efficient Method for the
Deoxygenation of Primary and Secondary Alcohols. Angew. Chem.,
Int. Ed. 2014, 53, 752.
(32) For details on how each variable affects the yield of a reaction
with primary alkyl iodides, see SI.
(33) Hu, X. Nickel-Catalyzed Cross Coupling of Non-Activated
Alkyl Halides: A Mechanistic Perspective. Chem. Sci. 2011, 2, 1867.
(34) Schley, N. D.; Fu, G. C. Nickel-Catalyzed Negishi Arylations of
Propargylic Bromides: A Mechanistic Investigation. J. Am. Chem. Soc.
2014, 136, 16588.
(35) 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.
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