Remote migratory cross-electrophile coupling and olefin hydroarylation reactions enabled by in situ generation of nih

Article abstract of DOI:10.1021/jacs.7b08064

A highly efficient strategy for remote reductive cross-electrophile coupling has been developed through the ligand-controlled nickel migration/arylation. This general protocol allows the use of abundant and bench-stable alkyl bromides and aryl bromides for the synthesis of a wide range of structurally diverse 1, 1-diarylalkanes in excellent yields and high regioselectivities under mild conditions. We also demonstrated that alkyl bromide could be replaced by the proposed olefin intermediate while using n-propyl bromide/Mn0 as a potential hydride source.

Full text of DOI:10.1021/jacs.7b08064

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Article
Remote Migratory Cross-Electrophile Coupling and Olefin
Hydroarylation Reactions Enabled by in situ Generation of NiH
Fenglin Chen, Ke Chen, Yao Zhang, Yuli He, Yi-Ming Wang, and Shaolin Zhu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08064 • Publication Date (Web): 07 Sep 2017
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Remote Migratory Cross-Electrophile Coupling and Olefin Hydroary-
lation Reactions Enabled by in situ Generation of NiH
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Fenglin Chen,1 Ke Chen,1 Yao Zhang,1 Yuli He,1 Yi-Ming Wang,*,2 and Shaolin Zhu*,1
1State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing Univer-
sity, Nanjing, 210093, China
2Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States
Supporting Information Placeholder
the presence of an external reductant, circumvents the syn-
thesis of organometallic reagents of limited stability and
commercial availability and is amenable to parallel synthesis.
ABSTRACT: A highly efficient strategy for remote reductive
cross-electrophile coupling has been developed through the
ligand-controlled nickel migration/arylation. This general
protocol allows the use of abundant and bench-stable alkyl
bromides and aryl bromides for the synthesis of a wide range
of structurally diverse 1,1-diarylalkanes in excellent yields and
high regioselectivities under mild conditions. We also
demonstrated that alkyl bromide could be replaced by the
proposed olefin intermediate while using n-propyl bro-
mide/Mn0 as a potential hydride source.
2
As a consequence, the construction of Csp3–Csp bonds from
the corresponding halides has received considerable atten-
tion in the recent years.6 In recent years, encouraging pro-
gress for reductive cross coupling has been made by using
both nickel and palladium catalysis.7 As a variation of this
process, a migratory cross-electrophile coupling of aryl and
alkyl halides with benzylic selectivity should be of considera-
ble synthetic utility. However, such a process poses a signifi-
cant challenge and remains unreported. In related work,
Baudoin has reported
a palladium-catalyzed terminal-
selective reductive coupling of moderate regioselectivity us-
ing aryl triflates and alkyl bromides as starting materials.2d
We recently reported a NiH-catalyzed remote reductive C–H
arylation reaction by using hydrosilane as the exogenous
reducing agent (Figure 1a).2v Significant drawbacks of this
protocol, however, are the requirements for aryl iodides as
coupling partners and CsF as the base for regeneration of the
nickel hydride (NiH) species, both of which reduce the prac-
ticality of the protocol. To address these shortcomings, we
sought to develop a procedure for the coupling of alkyl and
aryl bromides under mild and base-free conditions.
In order to achieve high yields such a process, conditions
for the preferential oxidative addition of a low-valent nickel
species to an alkyl bromide in the presence of an aryl bro-
mide needed to be uncovered. As first demonstrated by
Weix and co-workers,6b,d Ni(0) complexes will generally react
preferentially with an aryl bromide before engaging an unac-
tivated alkyl bromide to produce the direct coupling product
(Figure 1b, left). The complementary selective oxidative addi-
tion of an unactivated alkyl bromide in preference to an aryl
bromide is currently unknown.8 If this inversion of selective
could be achieved, a NiH species and olefin could be gener-
ated in situ from subsequent β-hydrogen elimination of an
abundant and bench-stable alkyl bromide.4,11d The in situ-
generated NiH would trigger an iterative elimina-
tion/reinsertion process to potentially allow for functionali-
zation at remote sites of an alkyl chain. In particular, we pos-
tulated that functionalization at a benzylic site could occur
with high regioselectivity, allowing for a subsequent nickel-
catalyzed cross-coupling reaction to generate 1,1-
INTRODUCTION
Cross-coupling chemistry is a powerful technology for the
construction of carbon-carbon bonds. In classical cross-
coupling reactions, C–C bond formation occurs at the site of
reactive functional groups pre-installed on two coupling
partners. Complementary strategies that allow the new C–C
bond formation at remote, unfunctionalized sites would en-
able new strategies for complex molecule synthesis to be
employed and allow access to structures that would other-
wise be difficult to prepare.1 An iterative migratory inser-
tion/β-hydrogen elimination process mediated by metal hy-
dride intermediates represents a profitable strategy for the
activation of remote unfunctionalized sites.2 The combined
application of cross-coupling and metal-hydride chemistry3
in remote C–H functionalization, however, is reported in
only a few contexts.2m-w,4 As an important class of com-
pounds, alkyl halides are reactive, yet bench-stable and
readily available starting materials for synthesis. Although
transition metal-catalyzed reactions involving alkyl halides
often suffer from isomerization mediated by β-hydrogen
elimination, we felt that this often undesired side reaction
might be leveraged for use in a migratory and reductive
cross-coupling process.
Over the past decade, catalysis utilizing earth-abundant
nickel has emerged as a practical tool for carbon-carbon
bond formation, most notably through the Negishi, Suzuki-
Miyaura, Kumada, Stille, and Hiyama cross coupling reac-
tions.5 As an alternative approach, reductive cross-
electrophile coupling,6 a strategy wherein two shelf-stable
electrophiles (typically alkyl or aryl halides) are coupled in
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Page 2 of 8
diarylalkanes (Figure 1b, right side), a privileged class of
L1 were found to be critical to the success of the reaction.11
compounds in medicinal chemistry and materials science.9 In
this article, we report the successful implementation of this
strategy using a nickel catalyst supported by 6,6’-dimethyl-
2,2’-bipyridyl as the ligand. The mild (room temperature and
base free), regioselective, and efficient conditions reported
herein were applicable to a wide range of both simple and
functionalized alkyl and aryl bromide substrates, potentially
serving as a useful and complementary addition to previous
methods for the synthesis of 1,1-diarylalkanes. In addition,
some insights gleaned from a preliminary mechanistic study
Use of the parent bpy (L2) or the 6,6’-dimethoxy derivative
(L3) resulted in only the linear coupling product 3A (entries
10, 11, see SI for details). In line with our expectations, for-
mation of the desired product was not observed in control
experiments in which Ni, ligand, or Mn0 were omitted. Final-
ly, using NiI2·xH2O lead to diminished yield for the current
combination of substrates, but was beneficial in the case of
electron-poor aryl bromides (entry 12).
1
2
3
4
5
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7
8
Scheme 1. Variation of Reaction Parameters.a,b
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are also presented.
(a) NiH-catalyzed remote hydroarylation through alkene isomerization (prior work)
(Het)Ar
Ni/L
proposed via
NiH-catalyzed alkene isomerization
+
(Het)Ar–I
Ph
R3SiH
Ph
Me
alkene
aryl iodide
remote sp3 C–H arylation
(b) New approach: Ni-catalyzed migratory reductive cross-electrophile coupling
(Het)Ar
Ph
Ni/L
Ni/L'
(Het)Ar
Br
+
(Het)Ar–Br
Ph
Ph
alkyl bromide
Mn
known
Mn
this work
Me
aryl bromide
traditional
crossꢀelectrophile coupling
migratory
ligandꢀcontrolled selective OA
crossꢀelectrophile coupling
Ar–Br
Ni
H
Ph
migratory
insertion
Ar–Br
alkyl–Br
reduction
(Het)Ar NiII Br
Ph
Ni(II)ꢀaryl OA complex
NiH generated in situ
ꢀ Ligandꢀcontrolled selective oxidative addition
ꢀ NiH generated in situ and induced migration
ꢀ Abundant and shelfꢀstable alkyl/aryl bromide
ꢀ Room temperature, base free, broad scope
Figure 1. Design plan: Migratory cross-electrophile coupling.
RESULTS
Based on our previously reported coupling of olefins with
aryl iodides, we initially investigated the use of 1-iodo-4-
phenylbutane and 4-iodoanisole as substrates. As shown in
Scheme 1a, we were pleased to find that the desired migrato-
ry coupling product 3a could indeed be formed in moderate
isolated yield (47%) with good regioselectivity [r.r. (1,1-
diarylalkane: all other isomers) = 17:1] under our previous
remote hydroarylation reaction conditions2v. Based on this
preliminary result, we next turned our attention to the cou-
pling of the less reactive bromide substrates 1-bromo-4-
phenylbutane (1a) and 4-bromoanisole (2a). Although these
previously reported conditions were almost completely inef-
fective in the case of bromide substrates (entry 2, Scheme 1b),
a thorough optimization of the nickel source, solvent, re-
ductant, and a range of other parameters afforded a mild
protocol for efficient and selective coupling: under optimized
conditions, 3a was obtained in good isolated yield (81%) and
with excellent regioselectivity [r.r. = 38:1] (entry 1). Interest-
ingly, it was found that an inorganic base was not required
for catalytic turnover in this system.
Postulating that it would act as an additional hydride
source, we incorporated n-PrBr (0.5 equiv) into the reaction
mixture as an additive. Indeed, improved yields were ob-
served (entry 1 vs. 3).4,9d Notably, arylation of n-PrBr itself
was not observed, demonstrating the excellent chemoselec-
tivity of this cross-coupling system. Zinc as a reducing agent
gave poor results compared to manganese (entry 4), while
replacement of DMA with other polar aprotic solvents (en-
tries 5, 6), raising the reaction temperature (entry 7), or re-
ducing the number of equivalents of aryl bromide (entry 8)
all led to somewhat lower yields. Moreover, use of the more
reactive 4-iodoanisole in place of the 4-bromoanisole led to
poor yields with almost complete loss of regioselectivity; the
homocoupled biaryl was observed to be the major side prod-
uct (entry 9). It is worth pointing out that methyl groups of
aYields were determined by GC using dodecane as the internal
standard, the yield in parentheses was isolated yield of purified
product and is an average of two runs (0.2 mmol scale). brr refers
to regioisomeric ratio, represents the ratio of the major (1,1-
diarylalkane) product to the sum of all other isomers as deter-
mined by GC analysis (See SI for details). PMHS, polymethylhy-
drosiloxane;
DMA,
N,N-dimethylacetamide;
PMP,
4-
methoxyphenyl.
We next turned our attention to the substrate scope of the
transformation. Evaluation of a wide range of starting mate-
rials revealed the broad applicability of this protocol. In
terms of electronic properties, both electron-rich and elec-
tron-withdrawing aryl bromides could undergo the desired
migratory coupling with excellent regioselectivity (3a and 3w,
Table 1). For the alkyl bromide substrate, a wide variety of
substituents on the remote aryl ring were also well tolerated,
including those that were electron withdrawing (3o–q) or
electron donating (3s, 3t). Since the optimized protocol
avoided the addition of exogenous acids or bases as addi-
tives, a broad range of sensitive functional groups were ex-
pected to be compatible. Indeed, under these exceptionally
mild reaction conditions, a tertiary amine (3b), esters (3c,
3w, and 3y), a nitrile (3h), a Boc carbamate (3j), a silane (3s),
and a ketone (3z), an aryl chloride (3o), a phosphate ester
(3e), a boronic acid pinacol ester (3x), and an aldehyde (3a’)
were all left intact. Notably, various basic and acidic func-
tional groups, including a primary aniline (3d), a secondary
amine (3k), a primary alcohol (3g), and a phenol (3r), were
also compatible with the current protocol, thereby eliminat-
ing the need for efficiency-reducing protection / deprotec-
tion sequences often required by traditional cross-coupling
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reactions using stoichiometric organometallic reagents. Ad-
walking process after every turn of the catalytic cycle.4,11d As
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ditionally, heterocycles frequently found in medicinally ac-
tive agents, such as an indole (3i, 3j), a benzofuran (3l), a
furan (3u), and pyridines (3b’, 3c’), were also competent cou-
pling partners. Importantly, both primary and secondary
alkyl bromides were suitable partners under our standard
conditions (Table 1b), and high selectivity for migra-
tion/arylation at the benzylic position was observed, regard-
less of the starting position of the C–Br bond (3a, 3m, 3n, 3r,
3v, 3f’). Finally, we found that 3a could be prepared on a 10-
mmol scale with only a slightly diminished yield and un-
changed regioselectivity, demonstrating the robustness and
practicality of the procedure.
illustrated in Table 2, this turned out to be a viable strategy.
As before, migratory arylation of n-PrBr was not observed,
again demonstrating the excellent chemoselectivity for this
coupling process. We were pleased to find that a wide array
of alkenes and aryl bromides can be efficiently coupled.12
A
range of alkenes, including terminal olefins (6a
vated internal olefins (6g j), both E and Z olefins, as well as
E/Z mixtures (6g i) were suitable partners, regardless of the
starting position of the C=C bond. Electron donating (6b, 6f)
and electron withdrawing substituents (6c e) on the remote
–f), unacti-
–
–
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–
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aryl ring were all well-tolerated. Encouraged by these results,
further interrogation of the reaction scope also demonstrated
the broad scope of aryl bromide partner. Of particular note, a
triflate (6k), ketones (6n, 6q), and an acetal (6r) could be
used. Moreover, heteroaromatic bromides, such as those
containing a pyridine (6s) and a pyrimidine (6t) in place of
the aryl group were competent substrates for the current
protocol.
In light of these results and our proposed reaction pathway
(Figure 1b), we questioned whether readily available olefins,
which are proposed intermediates in the above process,2v,4
could be used directly through the addition of a stoichio-
metric quantity of n-propyl bromide to regenerate the NiH
species (via β-H elimination) needed to initiate the chain-
Table 1. Cross-electrophile Coupling: Scope of the Alkyl Bromide/Aryl Bromide Coupling.a,b
aIsolated yields on 0.20 mmol scale (average of two runs). brr refers to regioisomeric ratio, represents the ratio of the major (1,1-
diarylalkane) product to the sum of all other isomers as determined by GC analysis, ratios reported as >20:1 were determined by
crude 1H NMR analysis. cNiI2·xH2O used. d1.5 equiv aryl bromide used. See supplementary information for experimental details.
Table 2. Remote Hydroarylation: Scope of the Olefin/Aryl Bromide Coupling.
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b
aNiI2·xH2O used. 0.10 mmol 4b used. Yield and r.r. are as defined in Table 1. See supplementary information for experimental de-
tails.
(a) Alkyl bromides with internal substitution on the alkyl chain
Interestingly, an alkyl bromide with internal branching (a
tertiary sp3 carbon atom) along the alkyl chain (1g’, Figure 2a)
could also undergo migratory cross-coupling under the cur-
rent conditions. Coupling product 3g’ was obtained with
high regioselectivity. Yield and overall conversion, however,
were modest in this case. Furthermore, branched and func-
tionalized olefins could also be employed (Figure 2b), includ-
ing a 1,1-disubstituted alkene (4u) and a free allylic alcohol
(4w). Notably, even a trisubstituted internal alkene (4v), a
challenging substrate for transition metal catalysis in gen-
eral, could also undergo remote hydroarylation, although
under the current conditions, the desired process only pro-
gressed to about 30% conversion. Surprisingly, excellent
benzylic selectivity was still observed when methyl cin-
namate (4x), an α,β-unsaturated ester, was employed.2v
We could also extend this chemistry to heteroatom-
substituted cyclic olefins. In preliminary studies, the use of
2,5-dihydrofuran and a N-phenyl-3-pyrroline led to for-
mation of the migratory arylation product with excellent
selectivity for arylation at the carbon α to the heteroatom,
producing α-arylether 8 and α-arylamine 10, respectively
(Figure 2c). Finally, since they may serve as inexpensive
chemical feedstocks, regioisomeric mixtures of alkyl halides
are of considerable interest as starting materials for the mi-
gratory cross-coupling reaction. To demonstrate the poten-
tial applicability of our protocol to mixtures of alkyl halides,
an equimolar mixture of 1- and 2-bromo-4-phenylbutane was
treated with aryl bromide 2y under catalytic conditions. This
process retained much of its chemical efficiency and regiose-
lectivity (Figure 2d), as compared to the same transformation
using regioisomerically pure alkyl halide as starting material
(Table 1).
5 mol% Ni(ClO4)2—6H2O
Me
Br
PMP Me
6 mol% L1
+
Ph
Br
Me
0.5 equiv nꢀPrBr
2.0 equiv Mn
DMA (0.2 M), 25 °C, 24 h
Ph
MeO
(2.0 equiv)
1g' (±)
(1.0 equiv)
2a
3g'
35% yield, 17:1 rr
1:1 dr
(b) Branched and functionalized olefins
Me
Ph
Me
O
Ph
Ph
OH
OH
Ph
Me
Ph
OMe
OMe
4u
4v
PMP
4w
4x
PMP Me
PMP
PMP O
Me
Ph
Ph
Me
Ph
Me
6u
59% yield, >99:1 rr
6v
26% yield, >99:1 rr
6w
6x
59% yield, >99:1 rr
44% yield, >99:1 rr
(c) Expanding the alkenes scope
5 mol% NiI2—xH2O
6 mol% L1
Br
+
PMP
O
2.5 equiv nꢀPrBr
2.5 equiv Mn
DMA (0.2 M), 25 °C, 24 h
O
MeO
2a (2.0 equiv)
7
8 50% yield, >99:1 rr
5 mol% NiBr2—3H2O
Br
6 mol% L1
+
PMP
N
N
2.5 equiv nꢀPrBr
2.5 equiv Mn
DMA (0.2 M), 25 °C, 24 h
MeO
2a (2.0 equiv)
Ph
9
Ph
10 76% yield, 51:1 rr
(d) Regioconvergent cross-electrophile coupling
CO2Me
5 mol% NiI2—xH2O
Br
MeO2C
Br
6 mol% L1
Ph
+
(1:1)
0.5 equiv nꢀPrBr
2.0 equiv Mn
Br
Ph
nꢀPr
DMA (0.2 M), 25 °C, 24 h
Ph
Me
2y
(1.5 equiv)
3y 75% yield
21:1 rr
Figure 2. Expanded substrate scope and regioconvergent
experiment.
DISCUSSION
A working model of the catalytic cycle for our migratory
cross-electrophile coupling reaction is depicted in Figure 3.
In contrast to the majority of previously developed nickel-
catalyzed reductive coupling reactions,6b,6d the process is
initiated by selective oxidative addition of ligand-bound
Ni(0) complex I to the unactivated alkyl bromide, rather
than the aryl bromide, to form an alkylnickel(II) intermedi-
ate (II). Reduction of II by Mn0 and β-hydrogen elimination
of the resultant Ni(I)-alkyl (III) forms key the nickel(I) hy-
dride species, IV.8c-d A series of iterative insertion and elimi-
nation reactions ultimately provides access to benzylnickel(I)
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intermediate VI. Selective reaction of VI with aryl bromide 2,
(at least in the case of aryl bromides) follows chainwalking
followed by reductive elimination of nickel(III) adduct VII10,13
then delivers the migratory arylation product 3 and nickel(I)
bromide VIII, the reduction of which regenerates I to com-
plete the catalytic cycle. Using alkenes in place of alkyl bro-
mides as starting materials (Table 2), a stoichiometric
amount of n-PrBr is necessary, in order to generate IV via a
nickel(I) hydride intermediate. Oxidative addition of propyl
bromide to LNi0 (I) followed by β-hydrogen elimination af-
fords the propene adduct of a NiH species. Alkene exchange
of this complex with the olefin substrate (4), presumably by a
dissociative mechanism, then provides IV to initiate the
chainwalking process (Figure 3a).
1
2
3
4
5
6
7
8
and serves as a regiodetermining step.
In the presence of a large excess of manganese metal,
Ni(II) complexes are known to be reduced to the correspond-
ing Ni(I) species.15a Moreover, Ni(I) hydride and alkyl species
have previously been proposed as intermediates in nickel-
catalyzed olefin isomerization reactions.8c,15b We therefore
tentatively propose that chainwalking occurs via iterative
migratory insertion/β-hydrogen elimination of Ni(I)-hydride
and -alkyl intermediates. However, at the moment, we can-
not rule out the involvement of Ni(II) species in this pro-
cess.15c
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(Het)Ar
3
1
1/2Mn0
1/2MnBr2
Br
H
Ph
Ph
alkyl bromide
migratory coupling
reduction
LNi0
LNiIBr
Figure 4. Olefin isomerization in the absence of aryl bro-
mide.
VIII
reductive
elimination
I
oxidative
addition
Br
Ar(Het)
NiIII
To examine the hypothesis that olefin isomerization oc-
curs through rapid and reversible β-hydrogen elimina-
tion/reinsertion steps, we investigated alkyl bromide and
alkene substrates bearing an oxygen atom (1h’) or an iso-
propylidene (4y) spacer in the chain between the aryl group
(and its neighboring benzylic position) and the bromide sub-
stituent or the double bond. Since the spacer groups lack a β-
hydrogen, the chainwalking that leads to the putative ben-
zylnickel intermediates is blocked. Indeed, in accord with the
proposed mechanism for chainwalking, neither of the cou-
pling products that could arise from these intermediates was
observed under the optimized protocols (eq 1 and 2).
To gain more insight into the chainwalking process, deu-
terium-labeling experiments were performed for the olefin
coupling protocol using perdeuterated propyl bromide. The
standard protocol was followed for the preparation of 6a
from 4a and 5a, using n-C3D7Br as the alkyl bromide additive.
Consistent with its proposed role, deuterium transfer from
the alkyl bromide to the coupling product was observed,
with incorporation of deuterium into all positions along the
hydrocarbon chain of 6a (eq 3).8c,16 Notably, only small
amount deuterium incorporation at the benzylic position in
6a-D was observed, suggesting that β-migratory insertion
with the styrenic intermediate to form the benzylnickel spe-
cies occurs with high regioselectivity.
Moreover, we sought to determine whether NiH remains
ligated on the substrate throughout the chainwalking process.
Thus, a mixture of an alkyl bromide and a sterically and elec-
tronically similar alkene were subjected to the coupling con-
ditions. When a mixture of alkyl bromide 1i’ and alkene 4a
were subjected to Ni salt, ligand, and manganese metal, both
coupling products 3i’ and 6a could be detected in roughly
equal amounts during all stages of the coupling process (eq
4). If the initially formed alkylnickel species (II in Figure 3)
underwent chainwalking without dissociation of NiH, then
the coupling product 3i’ derived from 1i’ should form exclu-
sively in the initial stages of the reaction. The observed for-
mation of both 3i’ and 6a in comparable amounts, even at
the start of the reaction, supports a mechanism in which
chainwalking occur with rapid dissociation and reassociation
of free NiH, allowing for rapid formation of alkylnickel spe-
cies derived from both alkyl halide and olefin starting mate-
rials. Interestingly, in this case, as well as when olefin and
aryl bromide alone were used as the starting materials (see
Scheme 2b below), an induction period was observed, with
NiII
H
VII
II Ph
Br
Ph
1/2Mn0
oxidative
addition
reduction
Nickel
2
1/2MnBr2
NiI
(Het)Ar–Br
aryl bromide
NiI
H
H
VI
III
Ph
Ph
migratory
insertion
β-hydride
elimination
fast
fast
NiI H
NiI
V
IV
H
Ph
Ph
hydrometallation
fast
(a) Role of nꢀPrBr: poviding extra NiH in the present of Mn0
Me
Ph
Ni
LNi0
Ni
H
Br
H
Ni
Me
Ph
(b) Ligandꢀcontrolled arylation reactivity: benzylnickel(I) >> other alkyl nickel(I)
Me
Me
Mn
IV
4
NiI
NiI
NiI
>>
R1
R2
R
,
Ph
Me
Figure 3. Proposed pathway of migratory cross-electrophile
coupling.
With these preliminary proposals as a starting point, a se-
ries of mechanistic experiments were conducted to gain a
more accurate and detailed understanding of the migratory
cross coupling reactions. To gain some insight into the na-
ture of the species involved in the chainwalking olefin isom-
erization, olefin 4a was subjected to the usual reaction condi-
tions in the absence of aryl bromide. A mixture of olefins
arising from olefin isomerization, as well as a small amount
of homocoupling product, was observed to form within sev-
eral hours (Figure 4).14
These results indicate that olefin isomerization does not
depend on the presence of the aryl bromide to occur, and
suggest that chainwalking precedes oxidative addition by the
aryl bromide. As further evidence against an alternative sce-
nario in which chainwalking occurs after oxidative addition
of the aryl bromide, we note that regioselectivity increases
dramatically from 1:1 to 38:1 rr upon switching from aryl io-
dide to aryl bromide as the coupling partner (Scheme 1b,
entry 1 vs. 9). If chainwalking were to occur after oxidative
addition of aryl halide for both aryl bromide and iodide sub-
strates, we would expect only a small difference, if any, in the
regioselectivities obtained for these reactions. On the other
hand, the large difference in regioselectivity is consistent
with a mechanism wherein oxidative addition of aryl halide
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Deuterium-labeling experiments were also carried out to
no reaction or olefin isomerization occurring in the first
hour, while no induction period was observed when alkyl
1
2
3
4
5
6
7
8
probe the stereochemical course of the reaction and gain
insight into the C–C bond forming process. Interestingly,
when indene and 5a were used as the substrates, with C3D7Br
as the additive, a 1:1 diastereomeric mixture of deuterated 6z
was produced. The D incorporation into the 2-position of the
indene was nearly complete (96% overall). We attribute this
result to homolysis of the L(Ar)(2-indanyl)Ni(III)Br interme-
diate, so that the Ni(III) species exists in rapid equilibrium
with the Ni(II) complex and the benzylic radical, resulting in
a diastereomeric mixture of isotopically-labeled products.10b,c
Despite this evidence for a radical intermediate,17,18 the addi-
tion of radical inhibitors like BHT (2,6-di-tert-butyl-4-
methylphenol) or DHA (9,10-dihydroanthracene) to the reac-
tion system had a negligible effect on the result, suggesting
that homolysis and radical recombination are likely rapid
and occurs in-cage (Figure 5b). Additional studies to fully
elucidate the reaction pathway are underway.
bromide and aryl bromide alone were used.
5 mol% Ni(ClO4)2—6H2O
6 mol% L1
PMP
OEt
Br
+
PMP–Br
(1)
Ph
O
Ph
2.0 equiv Mn
DMA (0.2 M), 25 °C, 24 h
1h'
2a (2.0 equiv)
3h' (not observed)
5 mol% Ni(ClO4)2—6H2O
PMP
6 mol% L1
+
+
PMP–Br
Ph
(2)
(3)
Ph
Me
2.5 equiv nꢀPrBr
2.5 equiv Mn
DMA (0.2 M), 25 °C, 24 h
Me Me
Me Me
4y
5a (2.0 equiv)
6y (not observed)
9
5 mol% NiBr2—DME
6 mol% L1
(0.03 D)
PMP
(0.08 D)
(0.54 D)
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
PMP–Br
Ph
Tol
2.5 equiv nꢀPrBrꢀd7
2.5 equiv Mn
Ph
Me
(0.30 D)
DMA (0.2 M), 25 °C, 24 h
4a
1i'
5a (2.0 equiv)
6a-D 66% yield, >99:1 rr
Br
5 mol% Ni(ClO4)2—6H2O
PMP
nꢀPr
PMP
Ph nꢀPr
6 mol% L1
(1.0 equiv)
+
+
PMP–Br
(4)
2.0 equiv Mn
DMA (0.2 M), 25 °C, 24 h
Tol
Ph
4a
2a
3i'
6a
(1.0 equiv)
(2.0 equiv)
3i' (%)a
6a (%)a
entry
time
1 h
2 h
1
2
3
4
5
6
0
9
0
7
15
22
23
31
4 h
22
35
39
53
aYields were determined by GC using
dodecane as the internal standard, and is
an average of two runs (0.2 mmol scale).
8 h
12 h
24 h
To further understand the behavior of NiH, we moni-
tored the material balance over time for both the standard
migratory cross-electrophile coupling and olefin remote hy-
droarylation reactions (Scheme 2). As depicted in Scheme 2a
and 2b, during partial conversion, small amount of both posi-
tional isomers of the olefin (4a’ and 4a’’) were observed,
providing additional evidence of the dissociation of the NiH
species from the olefin during chainwalking. In addition, the
data in Scheme 2b suggests that olefin isomerization is rapid
compared to the subsequent coupling process. As observed
for the process depicted in eq 4, there was an induction peri-
od for this process, with no isomerization of the olefin or
coupling with the aryl bromide observed during the first
hour (also see Scheme S5 in SI for details). The origin of this
induction period is still under investigation.
Figure 5. Mechanistic study.
CONCLUSION
Scheme 2. Tracing Experiments.
In conclusion, we have developed a mild and highly ro-
bust nickel-catalyzed migratory remote cross-electrophile
coupling reaction via the formation of NiH in situ from alkyl
halides. Excellent regio- and chemoselectivity were observed,
in terms of both alkyl bromides and alkenes precursors. This
versatile protocol provides a versatile and synthetically valu-
able addition to the current processes for reductive cross-
coupling. Mechanistic studies are consistent with a mecha-
nism in which a nickel(I) hydride species effects the rapid
isomerization of olefin isomers, with the ultimate regiochem-
ical outcome likely determined by the subsequent oxidative
addition of the aryl halide. Developing an asymmetric ver-
sion of the current transformation is under investigation in
our laboratory, and progress in this area will be reported in
due course.
ASSOCIATED CONTENT
Table S1, Scheme S1–7, experimental procedures, characteri-
zation data for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
aYields were determined by GC using dodecane as the internal
standard, and is an average of two runs (0.2 mmol scale).
AUTHOR INFORMATION
Corresponding Author
shaolinzhu@nju.edu.cn
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Journal of the American Chemical Society
were disclosed for remote carboxylation: Juliá-Hernández, F.;
ym.wang@pitt.edu
1
2
3
4
5
6
7
8
Moragas, T.; Cornella, J.; Martin, R. Nature 2017, 545, 84.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Research reported in this publication was supported by the
“1000-Youth Talents Plan”, NSFC (21602101, 21772087), NSF of
Jiangsu Province (BK20160642). Y.-M.W. thanks the Univer-
sity of Pittsburgh for the generous provision of startup funds.
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(18) To test whether alkyl radical species come into play, we
carried out an experiment of (6-bromohex-1-en-1-yl)benzene
under our standard conditions (see: Scheme S6 in Supporting
Information). The ratio of acyclic and 5-exo-trig cyclization
products increased at higer Ni/L1 loadings. It indicates that a
radical-type intermediate is possible.
9
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(14) Use of our previously reported conditions, in which a hy-
drosilane was used as the reductant, afforded similar results
when an olefin was used as starting material (see Scheme S4 in
SI for details).
For Table of Contents Only (TOC)
remote sp3 C–H arylation via migratory crossꢀelectrophile coupling
()n
cat. NiII/L, Mn
(Het)Ar
Ar
Ar
R
Br
alkyl bromide
()n
R
(Het)Ar–Br
migratory coupling
N
N
aryl bromide
(remote C–H arylation)
Me
Me
L
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