Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Chlorides with Primary Alkyl Chlorides

Article abstract of DOI:10.1021/jacs.0c02673

Alkyl chlorides and aryl chlorides are among the most abundant and stable carbon electrophiles. Although their coupling with carbon nucleophiles is well developed, the cross-electrophile coupling of aryl chlorides with alkyl chlorides has remained a chall

Full text of DOI:10.1021/jacs.0c02673

Subscriber access provided by Uppsala universitetsbibliotek
Communication
Nickel-Catalyzed Cross-Electrophile Coupling
of Aryl Chlorides with Primary Alkyl Chlorides
Seoyoung Kim, Matthew J Goldfogel, Michael M. Gilbert, and Daniel J. Weix
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 15 May 2020
Downloaded from pubs.acs.org on May 15, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Chlorides with
Primary Alkyl Chlorides
Seoyoung Kim, Matthew J. Goldfogel†, Michael M. Gilbert, Daniel J. Weix*
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
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States
Supporting Information Placeholder
Based upon our proposed mechanism for the coupling of
ABSTRACT: Alkyl chlorides and aryl chlorides are among
the most abundant and stable carbon electrophiles. Although
their coupling with carbon nucleophiles is well developed,
the cross-electrophile coupling of aryl chlorides with alkyl
chlorides has remained a challenge. We report here the first
general approach to this transformation. The key to produc-
tive, selective cross-coupling is the use of a small amount of
iodide or bromide along with a recently reported ligand, pyr-
idine-2,6-bis(N-cyanocarboxamidine) (PyBCamCN). The
scope of the reaction is demonstrated with 35 examples (63%
16% ave yield) and we show that the Br– and I– additives act
as co-catalysts, generating a low, steady-state concentration of
more-reactive alkyl bromide/iodide.
-
17 19
aryl iodides with alkyl iodides, overcoming this dual reac-
tivity-selectivity challenge requires a catalyst that selectively
reacts with the Ar-Cl over the Alkyl-Cl, yet can slowly gener-
ate an alkyl radical from the Alkyl-Cl starting material. Here-
in we show that this can be accomplished through the use of
salt additives to maintain a very low, steady-state concentra-
tion of an alkyl bromide/iodide and a uniquely selective pyr-
,
idine-2,6-bis(N-cyanocarboxamidine) (PyBCamCN
ed nickel catalyst (Scheme 1).
)
ligat-
20 21
Scheme 1. Challenges in the Cross-Electrophile Coupling
Organic Chlorides.
Challenges: Improve Reactivity and Maintain Selectivity
[Ni]
Cl
Cl
Cl
Cl
Br/I
Br/I
+
Mn or Zn
rt to 80 °C
Cross-electrophile coupling has rapidly become an im-
portant approach to the synthesis of Csp -Csp bonds, but
engaging less reactive C-Cl bonds, outside of activated sys-
2
3
1
Csp2–Cl
18 examples
Csp3–Cl
8 examples
Challenge 1 C–Cl bonds are
unreactive functional groups
2
3
tems or intramolecular reactions, has proven challenging.
Indeed, unactivated C-Cl bonds are well-tolerated functional
NiCl2(dme)
Ligand
Cl
Cl
+
4
groups in cross-electrophile coupling methods (Scheme
1). The ability to cross-couple with organic chlorides is
valuable for several reasons – first, organic chlorides are more
LiCl, Zn, NMP, 80 °C
Me
Me
,
5 6
phen
4% product
Ar-Cl biaryl
tpy
10% product
Ar-Cl unreactive
Challenge 2
known catalysts
are unselective
7
abundant than organic bromides or organic iodides; second,
Alkyl-Cl unreactive Alkyl-Cl dimer + Alkyl-H
the low reactivity of the C-Cl bond allows it to be introduced
, ,
8 9 10
This Work: Cross-Selective Coupling With 1° Alkyl Chlorides
early in a synthesis and later diversified.
NiX2 (X = Br, I)
PyBCamCN
The central challenge presented by C-Cl bonds in cross-
electrophile coupling is the need for higher reactivity without
sacrificing selectivity (Scheme 1). While the homodimeriza-
Cl
Cl
+
LiCl, Zn, NMP, 80 °C
Me
Me
Key Advances
c
8
11
X–
Keq < 0.1
tion of alkyl chlorides and aryl chlorides has been report-
new ligand
&
halide exchange
(L)NiII(Ph)Cl
12
ed, no general cross-selective approach has yet been found.
Recently, Zhang reported couplings of a variety of aryl chlo-
rides, but only with an excess of ClCF2R reagents. Several
groups have reported on the coupling of aryl chlorides with
alkyl bromides or tertiary alkyl oxalate esters. However,
the coupling of chlorobenzene with a simple alkyl bromide
[Ni]
H2C
Br/I
13
fast
Me
Me
14
15
During reaction development, we observed a strong syner-
gistic effect between the catalyst and the presence of sub-
stoichiometric amounts (10-30 mol%) of bromide or iodide
(Table 1 and Supporting Information Figures S1, S3-S6).
While no catalysts were found that provided high yields of
product in the absence of bromide or iodide, high selectivity
a
14
provided less than 25% yield of cross-coupled product.
Switching to an alkyl chloride further diminishes selectivity
16
and yield using our standard conditions (Scheme 1).
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 8
could be achieved in reactions with PyBCamCN ligand and
alkyl halides, converted alkyl chloride to dimeric and hy-
drodehalogenated products without consuming aryl chlo-
ride. In contrast to tpy, reactions with 4,4´,4´´-tri-tert-butyl-
2,2´:6´,2´´-terpyridine (tpy´´´), which is useful in Negishi
23
1
2
3
4
5
6
7
8
NiBr2(dme) or NiI2•4H2O; and in reactions with PyBCam
ligand and NiBr2(dme) (Table 1, bold-faced entries). Reac-
tions with bipyridine (bpy) or pyridine 2-carboxamidine
(PyCam) ligands, which are optimal for the coupling of aryl
24
cross-coupling reactions of alkyl halides, consumed both
substrates but formed approximately 1:1:1 product/alkyl
dimer/aryl dimer. See also Chart S1 in the Supporting In-
,
20 22
bromides with alkyl bromides, favored formation of aryl
dimer products (bpy) or hydrodehalogenated arene
(PyCam) without consuming the alkyl chloride. Reactions
with terpyridine (tpy), which is useful for the dimerization of
25
formation.
9
Table 1. The Effect of Ligands and Additives on the Cross-Electrophile Coupling of Chlorobenzene with Chlorooctane.a
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
R
tpy, R = H
tpy´´´, R = tBu
R
NiX2
Ligand
Cl
Cl
R
bpy
+
N
N
N
N
Me
Me
12
LiCl
Zn
NMP, 80 °C
Me
Me
N
N
N
5
4
1a
2a
3a
R
R
PyBCam •2HCl, R = H
PyBCamCN, R = CN
1 equiv
1 equiv
HN
NH
NH
2 PyCam
Dimer Products
NH
NH
• HCl NH
Yield 3a
Yield 4
Yield 5
Yield 3a
Yield 4
Yield 5
Ligand
bpy
X
Ligand
PyCam
X
(%)b
(%)b
(%)b
(%)b
(%)b
(%)b
Cl
Br
I
2
9
48
43
39
0
1
Cl
Br
I
16
43
19
9
6
5
4
17
10
4
17
25
40
16
16
19
8
19
2
3
Cl
Br
I
Cl
11
0
0
tpy
2
PyBCam•2HCl Br
53
0
0
2
1
0
I
18
23
7
Cl
Br
I
38
22
4
28
26
33
Cl
46
1
tpy´´´
PyBCamCN
Br
I
65
0
0
9
87 (82)c
6
aReaction conditions: chlorobenzene (0.5 mmol), 1-chlorooctane (0.5 mmol), NiX2 = NiI2•4H2O/NiBr2(dme)/NiCl2(dme) (0.05
mmol), ligand (0.05 mmol), LiCl (0.5 mmol), Zn (1.0 mmol), and NMP (1 mL) were assembled in a N2 filled glovebox and heated for
24 h. Yields were determined by GC analysis calibrated against 1,3,5-trimethoxybenzene as an internal standard. Isolated yield after
column chromatography.
b
c
Routine optimization with PyBCam and PyBCamCN
demonstrated that PyBCamCN was superior, that reactions
were best conducted at 60-80 °C, and that a variety of iodide
bromides previously, under these conditions electron-poor
aryl chlorides could be coupled with alkyl chlorides for the
first time, with yields ranging from 53-73% yield (3c, 3h, 3i,
14
25
20
and bromide additives provide similar results. Reactions
3s, 3u, 3v). As expected with PyBCam ligands, a variety of
with bromide additive provided the highest yields when the
alkyl chloride was added slowly, either portionwise via sy-
ringe or dropwise through an addition funnel. Reactions with
iodide additive did not benefit from slow addition. The pri-
mary side products in both cases are the alkyl dimer and aryl
hydrodehalogenated product.
heterocycles could be coupled, including both electron-poor
quinoline (3s, 63%) and pyridine (3u, 66% and 3v, 73%);
and electron-rich indole (3r, 71%) and thiophene (3t, 33%).
A particular advantage of cross-electrophile coupling is toler-
ance for alkyl halides with b-leaving groups (3z-3ad). The
analogous organometallic reagents would be prone to elimi-
nation. Finally, secondary alkyl chlorides do couple under
these conditions, but in lower yield (3ai, 44%).
The optimized conditions were then applied to a variety of
primary alkyl chlorides and chloroarenes (Scheme 2). Elec-
tron-rich aryl chlorides, which were unreactive under our
previously published conditions, coupled in 69-72% yield
(3b, 3f, 3g, 3r). However, a more sterically hindered aryl
chloride, 2-chlorotoluene, coupled poorly (3e, 15% yield).
While we had coupled electron-poor aryl chlorides with alkyl
Despite the higher temperatures, functional group compat-
ibility remained broad. The low basicity of the conditions
allowed us to tolerate both aryl and alkyl pinacol boronic acid
esters (3o-3q, 49-73% yield), providing opportunities for
further elaboration of the products. Acidic N-H (3ag, 60%)
ACS Paragon Plus Environment

Page 3 of 8
Journal of the American Chemical Society
and O-H (3ae, 57%) groups are tolerated, which would be a
thyl and ethyl ester exchange). For this reason, we coupled
1
2
3
4
5
6
7
8
26
challenge for organomagnesium or organozinc reagents. As
chloroarenes bearing esters (3i, 3j) with 1-chlorooctane.
Other functional group highlights include a benzylic dieth-
ylphosphonate ester (3n, 51%) and a trimethoxysilane (3y,
32%). Despite the low yield, the cross-coupling to form tri-
methoxysilane product 3y is notable because it is a different
a testament to the low basicity of the conditions, a free thiol
was tolerated (3g, 70% yield), avoiding competing SN2 with
the alkyl electrophile and S-arylation (pKa of thiophenol in
27
DMSO is 10.3, which makes it more acidic than acetic ac-
,
28
29 30
id). On the other hand, despite the presence of Lewis acids
approach to forming functionalized silanes that could be
(ZnII salts, Li+ salts) at 60-80 °C, Boc groups on nitrogen
were still tolerated (3ag, 60%; 3ah, 71%). While esters were
tolerated, we did observe scrambling when two different es-
ters were present due to transesterification (for example, me-
useful in attaching molecules to glass or silica. As in our
31
previous studies on cross-electrophile coupling reactions
9
with less reactive substrates, this chemistry can be scaled up
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
32
using
standard
techniques
(3ac).
Scheme 2. Reaction Scope for the Nickel-Catalyzed Coupling of Aryl Chlorides with Alkyl Chlorides.
NiX2 (10 mol%)
CN
HN
CN
NH
Cl
Alkyl
PyBCamCN (10 mol%)
Alkyl
+
N
Cl
LiCl (1 equiv)
NH
NH
Zn (2 equiv), NMP, 80 °C
1
2
3
1 equiv
1 equiv
PyBCamCN
Aryl Scope
OEt
OEt
OEt
OEt
OEt
MeO
Me
O
O
O
O
O
Me2N
CF3
HS
3b, p; X = Br, 69%a
X = I, 41%
3d, p; X = Br, 61%
X = I, 48%
3e, o; X = Br, 15%
3f, X = Br, 72%
3g, X = Br, 70%
3h, X = Br, 59%
X = I, 26%
X = I, 54%
3c, m; X = Br, 87%a
X = I, 59%
O
MeO
OEt
O
OEt
O
O
MeO
Me
O
O
MeO
Me
3i, X = Br, 53%
3j, X = Br, 59%
3k, X = Br, 79%
3l, X = Br, 62%a
X = I, 69%
MeO
OEt
OEt
O
OEt
Ph
Bpin
O
Bpin
Ph
(EtO)2OP
O
F
3m, X = I, 67%
3n, X = I, 51%
3o, X = Br, 49%
3p, p; X = I, 73%
3q, m; X = Br, 65%
H
N
OEt
O
OEt
OEt
OEt
O
S
O
O
N
Me
N
MeO
N
3r, X = Br, 71%
3s, X = Br, 63%a
3t, X = I, 33%
3u, X = I, 66%
3v, X = I, 73%
Alkyl Scope
O
Ph
Si(OMe)3
MeO
O
O
MeO
Me
MeO
MeO
MeO
MeO
3w, X = Br, 73%
3x, X = Br, 84%a
3y, X = Br, 32%
3z, X = Br, 64%a
3aa, X = Br, 69%a 3ab, p; X = Br, 90%
3ac, m; X = Br, 63%a, b
O
Boc
N
Boc
O
N
H
O
Me
O
HO
MeO
MeO
Ph
MeO
MeO
3ad, X = Br, 54%
3ae, X = Br, 57%a
3af, X = Br, 52%a
3ag, X = I, 60%
3ah, X = Br, 71%
X = I, 57%
3ai, X = Br, 35%a
X = I, 44%
aReaction was conducted with 1.25 equiv of alkyl chloride (0.75 mmol) with either NiBr2(dme) or NiI2•4H2O as NiX2. Reaction
was run on a 7.0 mmol scale.
b
The distinctive feature of this reaction, when compared to
other cross-electrophile couplings of aryl halides with alkyl
halides, is the ability to engage two relatively unreactive sub-
strates in a selective manner (Scheme 1). There are three
keys to the success of this method.
First, LiCl was essential for efficient reduction of the nickel
catalyst by the zinc surface. We have recently noted that
ZnCl2 can have an inhibitory effect on reduction of nickel
catalysts and that lithium chloride is among the best agents
33
for overcoming inhibition, consistent with previous reports
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 8
34
on reduction of organic molecules. Here too, reactions con-
ducted without LiCl resulted in 3% formation of the cross-
coupled product and primarily returned both substrates
(Supporting Information Figure S2). We also verified that
neither organic chloride reacts directly with zinc to form an
organozinc reagent (Supporting Information Figure S2).
to mimic those present catalytic reactions, we found that the
amount of alkyl iodide increased as the concentration of
ZnCl2 increased, although the ratio of alkyl-Cl/alkyl-I re-
mained large in all cases (≥98:2, Figure S10 and S16). We
tentatively attribute this phenomenon to the favorable for-
mation of LiZnCl3 over LiZnCl2Br or LiZnCl2I, resulting in
sequestration of chloride as the concentration of Zn2+ in-
1
2
3
4
5
6
7
8
Second, halide exchange plays a key role by increasing the
reactivity of the alkyl chloride. We found that 10-30% of bro-
mide or iodide, regardless of how it was introduced, was essential
for reasonable reaction rates (Scheme 3 and Supporting In-
formation Figures S4-S7). Importantly, the low concentra-
tion of bromide was essential; reactions run without any
bromide (Scheme 3d) or with only alkyl bromide (Scheme
3e) provided lower yields than reactions with a catalytic
amount of bromide (Scheme 3a – Scheme 3c and Table 1).
35
creases at later reaction times. The halogen exchange is also
somewhat faster than reported for exchanges in amide sol-
vents with only sodium bromide, but this process could be
catalyzed by zinc: catalysis of alkyl halogen exchange by tita-
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
36
nium, zirconium, rhodium, and iron salts has been reported.
While iodide exchange to enhance the reactivity of alkyl
14
37
38
11
bromides, sulfonic acid esters, epoxides, and chlorides
in cross-coupling reactions is now well established, the use of
bromide is more rare. In cases where iodide co-catalysis isn’t
39
Scheme 3. Evidence for Bromide Co-Catalysis.a
practical, the use of bromide co-catalysis should be consid-
ered.
NiBr2(dme) (10 mol%)
PyBCam (15 mol%)
Cl
Cl
+
(a)
(b)
LiCl (1 equiv)
Zn (3 equiv)
Finally, studies with a variety of ligands revealed that Py-
BCam nickel catalysts are unique in being able to react with
both substrates at similar rates, even with activation by halide
exchange (Table 1 and Supporting Information Figure S1).
Compared to nickel complexes of tpy´´´, which could also
react with both substrates but formed both biaryl and bialkyl,
nickel PyBCam catalysts avoid biaryl formation entirely and
form only small amounts of alkyl dimer. The origin of these
differences in reactivity are not yet clear and are the subject
of ongoing studies, but it is clear that PyBCam and Py-
BCamCN are a distinctive, new class of tridentate ligands for
Me
Me
1a
2a
3a
NMP, 100 °C, 48 h
63% yield
1 equiv
1 equiv
NiCl2(dme) (10 mol%)
PyBCam (15 mol%)
Cl
Cl
Cl
+
LiCl (0.8 equiv)
LiBr (0.2 equiv)
Zn (3 equiv)
Me
Me
3a
1a
2a
NMP, 100 °C, 48 h
1 equiv
1 equiv
63% yield
Me
NiCl2(dme) (10 mol%)
PyBCam (15 mol%)
Cl
2a
+
(c)
0.8 equiv
LiCl (1 equiv)
Zn (3 equiv),
40
Me
nickel catalysis.
Br
1a
3a
NMP, 100 °C, 48 h
Me
64% yield
In conclusion, the first selective cross-electrophile cou-
pling reaction of aryl chlorides with primary alkyl chlorides
has been developed by the synergistic effect of three changes:
a new, selective ligand (PyBCamCN), LiCl to enhance catalyst
turnover, and bromide/iodide co-catalysis. The mechanism
by which PyBCamCN improves yields is under investigation
and will be reported in due course. We expect that the gener-
ally unreactive nature of alkyl and aryl chlorides should make
this new method to functionalize them a useful addition to
synthesis.
1 equiv
8
0.2 equiv
NiCl2(dme) (10 mol%)
PyBCam (15 mol%)
Cl
Cl
+
+
(d)
LiCl (1 equiv)
Zn (3 equiv)
NMP, 100 °C, 48 h
Me
Me
3a
1a
2a
1 equiv
1 equiv
33% yield
NiBr2(dme) (10 mol%)
PyBCam (15 mol%)
Cl
Br
Me
(e)b
LiCl (1 equiv)
Zn (3 equiv)
NMP, 100 °C, 48 h
Me
3a
1a
2a
1 equiv
1.5 equiv
42% yield
ASSOCIATED CONTENT
aReactions were run on a 0.5 mmol scale. Yields were deter-
mined by GC analysis calibrated against 1,3,5-
trimethoxybenzene as an internal standard. Reaction run with
Supporting Information. The Supporting Information is avail-
able free of charge on the ACS Publications website.
b
DIPEA (20 mol%). DIPEA had no effect on reaction outcome.
Additional tables of optimization data, mechanistic studies,
detailed experimental procedures, characterization of products,
copies of product NMR spectra (PDF)
Studies on halide exchange showed that it is fast compared
to the rate of reaction (reaching equilibrium in 1-2 h vs 24 h
for reaction time) and unfavorable (Supporting Information
Figure S8-S16). Significantly, the presence of zinc and lithi-
um salts altered the equilibrium to more strongly favor alkyl
iodide/bromide. This led to the counterintuitive outcome
that increasing total chloride concentration increased alkyl
iodide concentration. Under concentrations of salts chosen
AUTHOR INFORMATION
Corresponding Author
dweix@wisc.edu
Present Addresses
ACS Paragon Plus Environment

Page 5 of 8
Journal of the American Chemical Society
† Chemical and Synthetic Development, Bristol-Myers Squibb,
1 Squibb Drive, New Brunswick, New Jersey 08903.
lowing instrumentation in the PBCIC was supported by: Ther-
mo Q ExactiveTM Plus by NIH 1S10 OD020022; Shimadzu
GCMS-QP2010S by the Department of Chemistry; Bruker
Avance III 400 by NSF CHE-1048642; Bruker Avance III 500
by a generous gift from Paul J. and Margaret M. Bender.
1
2
3
4
5
6
7
8
ACKNOWLEDGMENT
Research reported in this publication was supported by the Na-
tional Institute of General Medical Sciences of the National
Institutes of Health under award number R01GM097243
(DJW) and F32GM122362 (MJG). Analytical data were ob-
tained from the CENTC Elemental Analysis Facility at the Uni-
versity of Rochester, funded by NSF CHE-0650456. The fol-
REFERENCES
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
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
1
2
3
TOC Graphic
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
(1) (a) Goldfogel, M. J.; Huang, L.; Weix, D. J.: Cross-Electrophile Coupling. In Nickel Catalysis in Organic Synthesis; Ogoshi, S., Ed.; Wiley-VCH: Wein-
heim, 2020; pp 183-222. (b) Wang, X.; Dai, Y.; Gong, H. Nickel-Catalyzed Reductive Couplings. Top. Curr. Chem. 2016, 374, 43. (c) Everson, D. A.; Weix, D.
J. Cross-Electrophile Coupling: Principles of Reactivity and Selectivity. J. Org. Chem. 2014, 79, 4793-4798. (d) Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Cor-
pet, M.; Gosmini, C.; Jacobi von Wangelin, A. Reductive Cross-Coupling Reactions between Two Electrophiles. Chem.–Eur. J. 2014, 20, 6828-6842.
(2) For example, benzylic chlorides, allylic chlorides, and a-chloroesters react rapidly under conditions that were effective with unactivated alkyl bromides.
See the following examples: (a) Durandetti, M.; Nédélec, J.-Y.; Périchon, J. Nickel-Catalyzed Direct Electrochemical Cross-Coupling between Aryl Halides
and Activated Alkyl Halides. J. Org. Chem. 1996, 61, 1748-1755. (b) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A. H.; Reisman, S. E., Nickel-
Catalyzed Asymmetric Reductive Cross-Coupling To Access 1,1-Diarylalkanes. J. Am. Chem. Soc. 2017, 139, 5684-5687.
(3) Erickson, L. W.; Lucas, E. L.; Tollefson, E. J.; Jarvo, E. R. Nickel-Catalyzed Cross-Electrophile Coupling of Alkyl Fluorides: Stereospecific Synthesis of
Vinylcyclopropanes. J. Am. Chem. Soc. 2016, 138, 14006-14011.
(4) A survey of the literature discussed in reference 1a had 18 examples of Csp2–Cl and 8 examples of Csp3–Cl bonds being tolerated as functional groups
in reactions to form Csp2–Csp3 bonds.
(5) The coupling of aryl C-Cl bonds and alkyl C-Cl bonds with CO2 and related π-electrophiles has been reported. See the following lead references: (a)
Fujihara, T.; Nogi, K.; Xu, T.; Terao, J.; Tsuji, Y. Nickel-Catalyzed Carboxylation of Aryl and Vinyl Chlorides Employing Carbon Dioxide. J. Am. Chem. Soc.
2012, 134, 9106-9109; (b) Börjesson, M.; Moragas, T.; Martin, R. Ni-Catalyzed Carboxylation of Unactivated Alkyl Chlorides with CO2. J. Am. Chem. Soc.
2016, 138, 7504-7507.
(6) See also a recent report on the coupling of Ar-Cl with C-H bonds via arylnickel(II) intermediates: Shields, B. J.; Doyle, A. G. Direct C(sp3)–H Cross
Coupling Enabled by Catalytic Generation of Chlorine Radicals. J. Am. Chem. Soc. 2016, 138, 12719-12722.
(7) About 1.8 million organic chlorides are commercially available compared to about 841,000 organic bromides. Organic iodides and organometal rea-
gents each have <100,000 examples. Notably, aryl chlorides represent about ½ of all commercially available aryl-X (X ≠ H).
(8) Aryl chlorides are relatively unreactive under conditions used for aryl bromides and usually require specialized conditions. See: (a) Grushin, V. V.;
Alper, H. Transformations of Chloroarenes, Catalyzed by Transition-Metal Complexes. Chem. Rev. 1994, 94, 1047-1062. (b) Littke, A. F.; Fu, G. C. Palladi-
um‐Catalyzed Coupling Reactions of Aryl Chlorides. Angew. Chem., Int. Ed. 2002, 41, 4176-4211. (c) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Aryl-Aryl Bond Formation One Century after the Discovery of the Ullmann Reaction. Chem. Rev. 2002, 102, 1359-1470.
(9) Alkyl chlorides often require different conditions than alkyl bromides for success. See: (a) Frisch, A. C.; Beller, M. Catalysts for Cross-Coupling Reac-
tions with Non-activated Alkyl Halides. Angew. Chem., Int. Ed. 2005, 44, 674-688. (b) Zhou, J.; Fu, G. C. Palladium-Catalyzed Negishi Cross-Coupling Reac-
tions of Unactivated Alkyl Iodides, Bromides, Chlorides, and Tosylates. J. Am. Chem. Soc. 2003, 125, 12527-12530.
(10) Substitution reactions of alkyl bromides vs alkyl chlorides have krel of about 20. For oxidative addition, krel can be as high as 103. See: (a) Richard, J. P.;
Jencks, W. P. Concerted bimolecular substitution reactions of 1-phenylethyl derivatives. J. Am. Chem. Soc. 1984, 106, 1383-1396. (b) Labinger, J. A. Tutorial
on Oxidative Addition. Organometallics 2015, 34, 4784-4795. (c) Labinger, J. A.; Osborn, J. A.; Coville, N. J. Mechanistic studies of oxidative addition to low-
valent metal complexes. Mechanisms for addition of alkyl halides to iridium(I). Inorg. Chem. 1980, 19, 3236-3243.
(11) Prinsell, M. R.; Everson, D. A.; Weix, D. J. Nickel-Catalyzed, Sodium Iodide-Promoted Reductive Dimerization of Alkyl Halides, Alkyl Pseudohalides,
and Allylic Acetates. Chem. Commun. 2010, 46, 5743-5745.
(12) Martin has reported on the coupling of unactivated alkyl chlorides with CO2, see reference 5b. In collaboration with Pfizer and Asymchem, we had
noted a selective coupling with an alkyl chloride for the first time, but it was not general, see reference 20b. Finally, couplings with activated alkyl chlorides are
well known, see reference 2.
(13) Xu, C.; Guo, W.-H.; He, X.; Guo, Y.-L.; Zhang, X.-Y.; Zhang, X. Difluoromethylation of (hetero)aryl chlorides with chlorodifluoromethane catalyzed
by nickel. Nat. Commun. 2018, 9, 1170. (b) Liu, J.; Zhang, J.; Li, X.; Wu, C.; Liu, H.; Liu, H.; Sun, F.; Li, Y.; Liu, Y.; Li, X. Nickel-Catalyzed 1,1-
Difluoroethylation of (Hetero)aryl Halides with 1,1-Difluoroethyl Chloride (CH3CF2Cl). Asian J. Org. Chem. 2020, 9, 391-394.
(14) (a) Czaplik, W. M.; Mayer, M.; Jacobi von Wangelin, A. Domino Iron Catalysis: Direct Aryl-Alkyl Cross-Coupling. Angew. Chem., Int. Ed. 2009, 48,
607-610. (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. (b) Yang, Y.; Luo, G.; Li, Y.; Tong, X.; He, M.; Zeng, H.; Jiang, Y.; Liu, Y.; Zheng, Y.
Nickel‐Catalyzed Reductive Coupling for Transforming Unactivated Aryl Electrophiles into β‐Fluoroethylarenes. Chem. – Asian J. 2020, 15, 156-162.
(15) Ye, Y.; Chen, H.; Sessler, J. L.; Gong, H. Zn-Mediated Fragmentation of Tertiary Alkyl Oxalates Enabling Formation of Alkylated and Arylated Qua-
ternary Carbon Centers. J. Am. Chem. Soc. 2019, 141, 820-824.
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
(16) In reference 14a Jacobi von Wangelin reported the coupling of chlorocyclohexane with 2-bromoanisole (63% yield) and bromobenzene (25% yield)
using iron catalysis and Mg as the terminal reductant.
(17) 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) For related studies, see: (a) Breitenfeld, J.; Ruiz, J.; Wodrich, M. D.; Hu, X. Bimetallic Oxidative Addition Involving Radical Intermediates in Nickel-
Catalyzed Alkyl-Alkyl Kumada Coupling Reactions. J. Am. Chem. Soc. 2013, 135, 12004–12012; (b) Schley, N. D.; Fu, G. C. Nickel-Catalyzed Negishi Aryla-
tions of Propargylic Bromides: A Mechanistic Investigation. J. Am. Chem. Soc. 2014, 136, 16588-16593; (c) Zhao, C.; Jia, X.; Wang, X.; Gong, H. Ni-Catalyzed
Reductive Coupling of Alkyl Acids with Unactivated Tertiary Alkyl and Glycosyl Halides. J. Am. Chem. Soc. 2014, 136, 17645-17651.
(19) For alternative mechanistic hypotheses for related reactions, see: (a) Lin, Q.; Diao, T. Mechanism of Ni-Catalyzed Reductive 1,2-
Dicarbofunctionalization of Alkenes. J. Am. Chem. Soc. 2019, 141, 17937-17948. (b) Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.; Kozlowski, M.
C. Nickel-Catalyzed Cross-Coupling of Photoredox-Generated Radicals: Uncovering a General Manifold for Stereoconvergence in Nickel-Catalyzed Cross-
Couplings. J. Am. Chem. Soc. 2015, 137, 4896-4899. (c) Mohadjer Beromi, M.; Brudvig, G. W.; Hazari, N.; Lant, H. M. C.; Mercado, B. Q. Synthesis and
Reactivity of Paramagnetic Nickel Polypyridyl Complexes Relevant to C(sp2)–C(sp3)Coupling Reactions. Angew. Chem., Int. Ed. 2019, 58, 6094-6098.
(20) (a) Hansen, E. C.; Pedro, D. J.; Wotal, A. C.; Gower, N. J.; Nelson, J. D.; Caron, S.; Weix, D. J. New ligands for nickel catalysis from diverse pharma-
ceutical heterocycle libraries. Nat. Chem. 2016, 8, 1126-1130; (b) Hansen, E. C.; Li, C.; Yang, S.; Pedro, D.; Weix, D. J. Coupling of Challenging Heteroaryl
Halides with Alkyl Halides via Nickel-Catalyzed Cross-Electrophile Coupling. J. Org. Chem. 2017, 82, 7085-7092.
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
(21) PyBCam (Order No. 902047) and PyBCamCN (Order No. 902063) are commercially available from Sigma-Aldrich.
(22) Johnson, K. A.; Biswas, S.; Weix, D. J. Cross-Electrophile Coupling of Vinyl Halides with Alkyl Halides. Chem.–Eur. J. 2016, 22, 7399–7402.
(23) Goldup, S. M.; Leigh, D. A.; McBurney, R. T.; McGonigal, P. R.; Plant, A. Ligand-assisted nickel-catalysed sp3–sp3 homocoupling of unactivated alkyl
bromides and its application to the active template synthesis of rotaxanes. Chem. Sci. 2010, 383-386.
(24) (a) Anderson, T. J.; Jones, G. D.; Vicic, D. A. Evidence for a NiI Active Species in the Catalytic Cross-Coupling of Alkyl Electrophiles. J. Am. Chem.
Soc. 2004, 126, 8100-8101. (b) Jones, G. D.; Martin, J.; McFarland, C.; Allen, O.; Hall, R.; Haley, A.; Brandon, R.; Konovalova, T.; Desrochers, P.; Pulay, P.;
Vicic, D. Ligand Redox Effects in the Synthesis, Electronic Structure, and Reactivity of an Alkyl–Alkyl Cross-Coupling Catalyst. J. Am. Chem. Soc. 2006, 128,
13175-13183.
(25) See the Supporting Information for extensive ligand reactivity and selectivity data (Figure S1) as well as additional optimization data (Figures S3, S4,
S6).
(26) While Csp3–Csp2 bond-forming Negishi reactions with aryl iodides and bromides have been shown to tolerate O-H and N-H bonds in many cases,
fewer examples exist for couplings with C-Cl bonds. (a) Leroux, M.; Vorherr, T.; Lewis, I.; Schaefer, M.; Koch, G.; Karaghiosoff, K.; Knochel, P. Late‐Stage
Functionalization of Peptides and Cyclopeptides Using Organozinc Reagents. Angew. Chem., Int. Ed. 2019, 58, 8231-8234. (b) Pompeo, M.; Froese, R. D. J.;
Hadei, N.; Organ, M. G. Pd‐PEPPSI‐IPentCl: A Highly Effective Catalyst for the Selective Cross‐Coupling of Secondary Organozinc Reagents. Angew. Chem.,
Int. Ed. 2012, 51, 11354-11357.
(27) Bordwell, F. G.; Hughes, D. L. Thiol acidities and thiolate ion reactivities toward butyl chloride in dimethyl sulfoxide solution. The question of curva-
ture in Brøensted plots. J. Org. Chem. 1982, 47, 3224-3232.
(28) Nickel is known to catalyze C-S bond formation of aryl thiols with aryl chlorides. Arylzinc reagents and zinc powder have been used as promoters. See:
(a) Jones, K. D.; Power, D. J.; Bierer, D.; Gericke, K. M.; Stewart, S. G. Nickel Phosphite/Phosphine-Catalyzed C–S Cross-Coupling of Aryl Chlorides and
Thiols. Org. Lett. 2018, 20, 208-211. (b) Gehrtz, P. H.; Geiger, V.; Schmidt, T.; Sršan, L.; Fleischer, I. Cross-Coupling of Chloro(hetero)arenes with Thiolates
Employing a Ni(0)-Precatalyst. Org. Lett. 2019, 21, 50-55. (c) Gogoi, P.; Hazarika, S.; Sarma, M. J.; Sarma, K.; Barman, P. Nickel–Schiff base complex cata-
lyzed C–S cross-coupling of thiols with organic chlorides. Tetrahedron 2014, 70, 7484-7489.
(29) Generally, these compounds are made by hydrosilylation of olefins (with HSiCl3 or HSi(OMe)3) or Grignard reactions (with tetrachlorosilane). Hy-
drosilylation to form trimethoxysilanes requires (MeO)3SiH, which can form pyrophoric SiH4. A workaround is to use HSiCl3, but this is also prone to rapid
decomposition. (a) Buslov, I.; Song, F.; Hu, X. An Easily Accessed Nickel Nanoparticle Catalyst for Alkene Hydrosilylation with Tertiary Silanes. Angew.
Chem., Int. Ed. 2016, 55, 12295-12299. (b) Katoh, K.; Ito, S.; Wada, Y.; Higashi, E.; Suzuki, Y.; Kubota, K.; Nakano, K.; Wada, Y. Investigation of thermal
hazard during the hydrosilylation of 1,6-divinyl(perfluorohexane) with trichlorosilane. J. Chem. Thermodyn. 2011, 43, 1229-1234.
(30) The Kumada coupling of trimethoxysilanes is reported to be impractical, but triethoxysilanes can be cross-coupled. See: Brondani, D. J.; Corriu, R. J.
P.; El Ayoubi, S.; Moreau, J. J. E.; Wong Chi Man, M. Polyfunctional carbosilanes and organosilicon compounds. Synthesis via grignard reactions. Tetrahedron
Lett. 1993, 34, 2111-2114.
(31) (a) Sagiv, J. Organized monolayers by adsorption. 1. Formation and structure of oleophobic mixed monolayers on solid surfaces. J. Am. Chem. Soc.
1980, 102, 92-98. (b) Wasserman, S. R.; Tao, Y. T.; Whitesides, G. M. Structure and reactivity of alkylsiloxane monolayers formed by reaction of alkyltri-
chlorosilanes on silicon substrates. Langmuir 1989, 5, 1074-1087. (c) Ulman, A. Formation and Structure of Self-Assembled Monolayers. Chem. Rev. 1996,
96, 1533-1554. (d) Haensch, C.; Hoeppener, S.; Schubert, U. S. Chemical modification of self-assembled silane based monolayers by surface reactions. Chem.
Soc. Rev. 2010, 39, 2323-2334.
(32) See Supporting Information for a detailed procedure. For a recent publication on scale-up of related chemistry in flow, see: Watanabe, E.; Chen, Y.;
May, O.; Ley, S. V. A Practical Method for Continuous Production of sp3-Rich Compounds from (Hetero)Aryl Halides and Redox-Active Esters. Chem.–Eur.
J. 2020, 26, 186-191.
(33) Huang, L.; Ackerman, L. K. G.; Kang, K.; Parsons, A. M.; Weix, D. J. LiCl-Accelerated Multimetallic Cross-Coupling of Aryl Chlorides with Aryl Tri-
flates. J. Am. Chem. Soc. 2019, 141, 10978-10983.
(34) (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Efficient Synthesis of Functionalized Organozinc Compounds by the Direct Insertion of
Zinc into Organic Iodides and Bromides. Angew. Chem., Int. Ed. 2006, 45, 6040−6044. (b) Koszinowski, K.; Böhrer, P. Formation of Organozincate Anions in
LiCl-Mediated Zinc Insertion Reactions. Organometallics 2009, 28, 771−779. (c) Feng, C.; Cunningham, D. W.; Easter, Q. T.; Blum, S. A. Role of LiCl in
Generating Soluble Organozinc Reagents. J. Am. Chem. Soc. 2016, 138, 11156−11159. (d) Jess, K.; Kitagawa, K.; Tagawa, T. K. S.; Blum, S. A. Microscopy
Reveals: Impact of Lithium Salts on Elementary Steps Predicts Organozinc Reagent Synthesis and Structure. J. Am. Chem. Soc. 2019, 141, 9879−9884.
(35) (a) Anderson, T. J.; Vicic, D. A. Direct Observation of Noninnocent Reactivity of ZnBr2 with Alkyl Halide Complexes of Nickel. Organometallics
2004, 23, 623-625. (b) Koszinowski, K.; Böhrer, P. Formation of Organozincate Anions in LiCl-Mediated Zinc Insertion Reactions. Organometallics 2009, 28,
771-779. (c) Achonduh, G. T.; Hadei, N.; Valente, C.; Avola, S.; O'Brien, C. J.; Organ, M. G. On the role of additives in alkyl-alkyl Negishi cross-couplings.
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 8
1
2
3
4
5
6
7
8
9
Chem. Commun. 2010, 46, 4109-4111. (d) Hunter, H. N.; Hadei, N.; Blagojevic, V.; Patschinski, P.; Achonduh, G. T.; Avola, S.; Bohme, D. K.; Organ, M. G.
Identification of a Higher-Order Organozincate Intermediate Involved in Negishi Cross-Coupling Reactions by Mass Spectrometry and NMR Spectroscopy.
Chem.–Eur. J. 2011, 17, 7845-7851. (e) McCann, L. C.; Hunter, H. N.; Clyburne, J. A. C.; Organ, M. G. Higher-Order Zincates as Transmetalators in Alkyl–
Alkyl Negishi Cross-Coupling. Angew. Chem., Int. Ed. 2012, 51, 7024-7027. (f) Charboneau, D. J.; Brudvig, G. W.; Hazari, N.; Lant, H. M. C.; Saydjari, A. K.
Development of an Improved System for the Carboxylation of Aryl Halides through Mechanistic Studies. ACS Catalysis 2019, 9, 3228-3241.
(36) (a) Yoon, K. B.; Kochi, J. K. Catalytic bromide and iodide exchange of alkyl chlorides with hydrogen bromide and hydrogen iodide. J. Org. Chem.
1989, 54, 3028-3036. (b) Willy, W. E.; McKean, D. R.; Garcia, B. A. Conversion of Alkyl Chlorides to Bromides, Selective Reactions of Mixed Bromochloro-
alkanes, and Halogen Exchange. Bull. Chem. Soc. Jpn. 1976, 49, 1989-1995. (c) Wang, J.; Tong, X.; Xie, X.; Zhang, Z. Rhodium-Catalyzed Activation of
C(sp3)−X (X = Cl, Br) Bond: An Intermolecular Halogen Exchange Case. Org. Lett. 2010, 12, 5370-5373. (d) Mizukami, Y.; Song, Z.; Takahashi, T. Halogen
Exchange Reaction of Aliphatic Fluorine Compounds with Organic Halides as Halogen Source. Org. Lett. 2015, 17, 5942-5945. (e) Petrone, D. A.; Ye, J.;
Lautens, M. Modern Transition-Metal-Catalyzed Carbon–Halogen Bond Formation. Chem. Rev. 2016, 116, 8003-8104.
(37) (a) Liang, Z.; Xue, W.; Lin, K.; Gong, H. Nickel-Catalyzed Reductive Methylation of Alkyl Halides and Acid Chlorides with Methyl p-Tosylate. Org.
Lett. 2014, 16, 5620-5623. (b) Molander, G. A.; Traister, K. M.; O’Neill, B. T. Engaging Nonaromatic, Heterocyclic Tosylates in Reductive Cross-Coupling
with Aryl and Heteroaryl Bromides. J. Org. Chem. 2015, 80, 2907-2911. (c) Do, H.-Q.; Chandrashekar, E. R. R.; Fu, G. C. Nickel/Bis(oxazoline)-Catalyzed
Asymmetric Negishi Arylations of Racemic Secondary Benzylic Electrophiles to Generate Enantioenriched 1,1-Diarylalkanes. J. Am. Chem. Soc. 2013, 135,
16288-16291.
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
(38) Zhao, Y.; Weix, D. J. Nickel-Catalyzed Regiodivergent Opening of Epoxides with Aryl Halides: Co-Catalysis Controls Regioselectivity. J. Am. Chem.
Soc. 2014, 136, 48-51.
(39) While several reports on the conversion of alkyl chlorides to bromides are known (reference 36), we could not find explicit examples of this strategy
for transition-metal catalysis. Given the frequent use of metal bromide salts as catalyst precursors, we suspect this phenomenon is common.
(40) Hughes, J. M. E.; Fier, P. S. Desulfonylative Arylation of Redox-Active Alkyl Sulfones with Aryl Bromides. Org. Lett. 2019, 21, 5650-5654.
8
ACS Paragon Plus Environment