Nickel-Catalyzed Chain-Walking Cross-Electrophile Coupling of Alkyl and Aryl Halides and Olefin Hydroarylation Enabled by Electrochemical Reduction

Article abstract of DOI:10.1002/anie.201915418

The first electrochemical approach for nickel-catalyzed cross-electrophile coupling was developed. This method provides a novel route to 1,1-diarylalkane derivatives from simple and readily available alkyl and aryl halides in good yields and excellent regioselectivity under mild conditions. The procedure shows good tolerance for a broad variety of functional groups and both primary and secondary alkyl halides can be used. Furthermore, the reaction was successfully scaled up to the multigram scale, thus indicating potential for industrial application. Mechanistic investigation suggested the formation of a nickel hydride in the electroreductive chain-walking arylation, which led to the development of a new nickel-catalyzed hydroarylation of styrenes to provide a series of 1,1-diaryl alkanes in good yields under mild reaction conditions.

Full text of DOI:10.1002/anie.201915418

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Nickel catalyzed chain walking cross-ele ctrophile coupling
of alkyl and aryl halides and olefin hydroarylation enabled by
electrochemical reduction
Authors: Sathish Kumar Gadde, Anatoly Peshkov, Aleksandra
Brzozowska, Pavlo Nikolaienko, Chen Zhu, and Magnus
Rueping
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915418
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10.1002/anie.201915418
Angewandte Chemie International Edition
RESEARCH ARTICLE
Nickel catalyzed chain walking cross-electrophile coupling of
alkyl and aryl halides and olefin hydroarylation enabled by
electrochemical reduction
Gadde Sathish Kumar,§ Anatoly Peshkov,§ Aleksandra Brzozowska, Pavlo Nikolaienko, Chen Zhu and
Magnus Rueping*
Abstract: The first electrochemical approach for the nickel-catalyzed
cross-electrophile coupling was developed. This method provides a
novel route to afford 1,1-diarylalkane derivatives from simple and
readily available alkyl and aryl halides in good yields and excellent
regioselectivities under mild conditions. The procedure shows good
tolerance for a broad variety of functional groups and both primary
and secondary alkyl halides can be used. Furthermore, the reaction
was successfully scaled up to the multigram scale proving the
potential for the industrial application. Mechanistic investigations
suggested the formation of a nickel hydride in the electroreductive
chain walking arylation which led to the development of a new nickel
catalyzed hydroarylation of styrenes providing a series of 1,1-diaryl
alkanes in good yields under mild reaction conditions.
the cross-coupling of benzylic and aryl halides.[8] As an
alternative reductive nickel catalyzed ligand-controlled relay
cross-coupling were reported.[9-10] Organic electrosynthesis[11]
serves as a reliable alternative to the conventional methods and
may be used to replace hazardous or/and toxic reductants and
oxidants by electric current.
Introduction
Transition metal-catalyzed cross-coupling reactions have been
extensively used as powerful, selective and high-yielding
methods for the carbon-carbon bond formation.[1] In this regard,
reductive cross-electrophile coupling reactions have recently
gained interest. Given that the preparation and handling of
sometimes hazardous organometallics can be circumvented by
the direct usage of readily available electrophile precursors[2] in
combination with cheap metal catalysts, reductive cross
couplings are a promising tool for atom and step economic
syntheses.[3] Alkyl halides are reactive, stable and easily
accessible compounds and thus a starting material for C(sp3)-C
bond formation reactions. However, due to the unproductive β-
hydride elimination their application in transition metal-catalyzed
coupling reactions may be limited. At the same time, this
undesired feature can be utilized for selective C-H
functionalizations through iterative migratory insertion/β-
hydrogen elimination sequences.[4] These chain walking
processes combined with cross-coupling strategies provide thus
an attractive possibility for remote functionalization of non-
activated C(sp3)-H bonds.[5,6]
Figure 1. Selected examples of biologically active 1,1-diarylalkanes.
Besides better control, electrosynthetic reactions typically
proceed under milder reaction conditions and feature new or
complementary reactivity and mechanistic pathways. Reinforced
by the utilization of the renewable energy sources (e.g. solar
energy) organic electrosynthesis aims to meet sustainability
requirements by decreasing waste formation and cost reduction.
Electrochemically driven metal-catalyzed cross-couplings are
therefore of considerable interest.[12] Regeneration of the active
catalyst in such processes is typically controlled by the electrode
material as well as by applied potential/current density. Here, we
report for the first time an electrochemical and nickel-catalyzed
approach for the cross-electrophile coupling involving a ligand-
induced chain walking process as well as an extension to the
electroreductive hydroarylation of olefins (Scheme 1).
The 1,1-diarylalkane motif is present in many biologically
active natural products and relevant pharmaceuticals[7] (Figure
1). As a result, efforts have been devoted to develop new
methods for the synthesis of these important scaffolds, including
[*]
Dr. G. S. Kumar, Dr. A. Peshkov, Dr. P. Nikolaienko, Ms.C.
Aleksandra Brzozowska, Dr Chen Zhu and Prof. Dr. M. Rueping
KAUST Catalysis Center (KCC), Department
Scheme 1. Benzylic C-H arylation through Nickel catalyzed electroreductive
cross-coupling of aryl and alky halides and electroreductive hydroarylation.
King Abdullah University of Science and Technology (KAUST)
Thuwal 23955-6900, Saudi Arabia
E-mail: Magnus.rueping@kaust.edu.sa
In order to develop a convenient and straightforward process we
decided to use a non-divided electrochemical cell equipped with
a cathode and anode. This simple set-up was chosen as the
separation of the chambers by a membrane would be more cost
[§]
These authors contributed equally to this work
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201915418
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RESEARCH ARTICLE
intensive and less convenient. Additionally, the only side-product
would be a carbon-free metal salt which acts as supporting
electrolyte during the reaction; thus, decreasing the amount of
consumed energy due to increased solution conductivity. We
started the development of the new method by optimizing the
reaction parameters including variation of electrodes (cathodes
and anodes), electrolytes, current densities, solvents,
concentrations and nickel complexes for the reductive cross
coupling of phenylethyl bromide 1a with bromoanisole 2a
(Scheme 2, SI: tables; entries 1-50).
entries 39-41). Use of nickel acetylacetonate or nickel iodide as
catalyst did not improve the reaction and desired product was
obtained in 41 and 57% yield, respectively (SI entries 42-43).
Applying neocuproine and bathocuproine as ligand resulted in
lower yields as compared to dimethyl bipyridine (see SI, entries
44-45) and with nickel phthalocyanine no product formation was
observed (SI entry 46). Importantly, increasing the concentration
had positive effect and the desired 1,1-diarylalkane was
obtained in 80% yield (see SI, entries 47 – 48). Finally, with the
change of reactant ratio the isolated yield of the desired product
was increased up to 91%. With use of the optimized conditions
the scope of the new electro-reductive cross coupling using
various bromoalkyl-aryl and bromo(het)aryl substrates was
examined (Figure 2). Variation of the electronic properties of the
phenyl-alkyl bromides did not affect the reaction rate. Thus, 1,1-
diphenylethanes possessing methoxy-, halide- or trifluoromethyl-
group (3b – 3f) as well as bulkier 1-naphthalenyl residue were
obtained in good to excellent yields. Notably, all of these
substrates besides ortho-chloro substituted 3d were formed with
exceptional regioselectivity, and in many cases the linear
product was not detectable in the crude 1H-NMR spectra.
Encouraged by these results, we turned our attention to the alkyl
halide and examined the effect of longer chain halides on the
reaction yield and selectivity. Gratefully, chain elongation from
ethyl to propyl and butyl (3h – 3j) only slightly diminished the
yield (83, 81 and 75% respectively) while the regioselectivity
was not affected. Additionally, secondary alkyl bromide and
indolyl-3-ethyl bromide were also successfully transformed to
1,1-diarylalkanes 3k and 3l, respectively. Next, we tested the
variation of the aryl bromide substituents. Ortho substitution did
not have an impact on the yield and the corresponding products
3m and 3d were obtained in good yield. This observation also
indicates that the transmetallation step (vide infra) proceeds
when the chain walking ends at the stabilized benzylic position.
The electronic properties of the aryl counter-parts have no
significant influence, and use of both, electron-rich (4-
dimethylamino) and electron-poor (4-fluoro) aryl bromides
provided the products 3n and 3o in good yield. Despite the
electrochemical conditions more sensitive methyl carboxylate
and acetyl substituents are tolerated and corresponding
products 3p and 3q we isolated in moderate yield with high
regioselectivity. Furthermore, even the free hydroxy- and amino
groups are tolerated as well. Thus, 3-bromophenol and 3-
bromoaniline were converted to the corresponding 1,1-
diarylethanes 3r and 3s. To further enhance the synthetic
applicability of this electrochemical reductive coupling, boronate-
(3t) and triflate- (3u) derivatives were used allowing further
functionalization. Use of the bulky 9-bromo anthracene, which is
widely used in organic electronics[13] resulted in the desired
products in lower yields (3v, 3w). In order to widen the substrate
scope heteroaryl bromides, including 2-methyl-7-bromo
quinoline, unprotected bromo indoles and bromo benzofurane
were successfully applied to give the desired products (3x, 3y,
3z, 3aa, 3ab) in good yield. In summary the newly developed
electroreductive cross electrophile coupling is rather general and
allows the C-H benzylation to occur with high chemoselectivity
under mild reaction conditions.
Scheme 2. Reaction optimization of the reductive cross coupling of alkyl and
aryl halides using a combined nickel and electrochemical approach.
Results and Discussion
The initial cross coupling reaction was carried out using DMA as
a solvent, an iron nail as anode, an iron sheet as cathode, (6,6′-
dimethyl-2,2′-dipyridyl)NiBr2 5 as catalyst and tetrabutylammo-
nium tetrafluoroborate as a supporting electrolyte. Under these
conditions the desired product was observed in 25% yield.
Despite full consumption of both starting materials, significant
amounts of homo-coupling products were obtained. Replacing
iron anodes to magnesium, zinc or aluminum provided cross-
coupling product only in trace amount (see SI, entries 2-4)
Application of different cathode materials such as brass, copper,
titanium, tantalum, platinum, tin, nickel, RVC and stainless steel
showed similar results (see SI, entries 5-13). In order to keep
the overall costs of the reaction as low as possible, which is
particularly important for scale-up, we decided to use only iron or
stainless-steel electrodes. Further tests revealed a strong
current density effect (see SI, entries 14-17). High current
density led to a complete decomposition of starting materials,
while a decrease resulted in the desired product in 45% yield.
Variation of the reagent ratio improved the yield (see SI, entries
18-21). Interestingly, the use of different supporting electrolytes
had no considerable effect (see SI, entries 22-38). Due to the
low price and high availability we decided to use potassium
bromide for further experiments. Among the different solvents
tested DMA was found to be the best reaction medium (see SI,
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10.1002/anie.201915418
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RESEARCH ARTICLE
Figure 2. Scope of the electro-reductive cross-coupling reaction of alkyl and aryl bromides. [a] Reaction conditions: 10 mol% of [Ni], 0.075 M KBr, 0.15 M aryl
bromide (either 0.6 mmol or 2.1 mmol), 0.30 M alkyl bromide, stainless steel anode and cathode, J = 1.5 mA/cm2, Q = 4.5 F/mol, isolated yields; [b] PMP – p-
methoxyphenyl ; [c] the ratio between regio-isomers (branched+linear) is noted in brackets, otherwise is not observed.
To get insight into the mechanism of the reductive process,
cyclic voltammetry (CV) measurements were performed.
Platinum, nickel and iron were used as working electrodes,
along with a canonical platinum wire counter electrode, and
Ag/AgNO3 (0.01 M in 0.1 M Bu4NPF6 in acetonitrile) as a
reference. The redox potentials of direct concerted reduction of
both phenethyl bromide 1a and bromoanisole 2a were found to
be lower than ERed = − 3.0 V under the conditions and were
difficult to detect due to the solvent's (acetonitrile)
electrochemical window. In contrast, Ni2+ to Ni0 electrochemical
reduction proceeds at higher potential (ERed > − 2.0 V).[14] The
cyclic voltammogram of the nickel catalyst 5 in acetonitrile
These results attest to the generation of a Ni0-species essential
for start and to continuation of the catalytic cycle. Further
investigation of the nickel complex 5 were conducted. CV
studies in DMA as a solvent and KBr as a supporting electrolyte
showed
a
more complex behavior (see supporting
information).[15] Thus, DFT calculations for the oxidative addition
step at Ni0 were conducted (Figure 3a; computational methods,
see SI). The Ni0 was stabilized by the ligand (6,6′-dimethyl-bpy)
and one DMA molecule at triplet state (B triplet) since the singlet
state (B singlet) is higher in energy. Starting from this Ni0-
species, the two different oxidative addition pathways to aryl and
alkyl bromide were explored. Replacement of the DMA molecule
and coordination of Ni0 to the arene results in an increase by 4.3
kcal/mol and the electronic state switches to the singlet state (C).
The conventional two-electron oxidative addition of aryl bromide
to the Ni0 occurs with three-membered ring transition state (C-
TS). The overall energy barrier is 13.5 kcal/mol. Alternatively,
the alkyl bromide coordinates to the Ni0 complex B and the
energy is elevated by 9.0 kcal/mol (E). Complex E undergoes
the SET-oxidative addition via C(alkyl)-Br bond dissociation (E-
TS) to give the NiI-Br intermediate F and alkyl radical (A3) with
an overall energy barrier of 19.3 kcal/mol. Thus, the oxidative
addition of Ni0 to aryl bromide is favored, if compared to the
oxidative addition of the alkyl bromide.
showed two reversible peaks at E1/2
= − 1.0 V and − 1.4 V,
Red
which can be attributed to formation of the Ni1+ and Ni0-species,
respectively (see SI). In order to reveal the oxidation state (Ni1+
or Ni0) after the initial reduction of the Ni-catalyst 5, preparative
electrolysis with controlled potentials − 1.1 V and − 1.5 V vs
Ag/Ag+ were conducted. The change of cell current was
recorded over time and the reaction was conducted until
4.5 F/mol of charge was passed. As expected, with a set-
potential of E = −1.1 V vs Ag/Ag+ low conversion and yield of 3a
was observed due to the low current density (0.1 – 0.3 mA/cm2).
In contrast, the applied potential of E = – 1.5 V vs Ag/Ag+
caused the overall increase of the cell current up to 3 mA/cm2
and, thus, the desired cross-coupling product was obtained.
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10.1002/anie.201915418
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RESEARCH ARTICLE
a
b
E-TS (triplet)
19.3
13.5
DMA
11.4
C-TS(singlet)
B (singlet)
E (triplet)
9.0
A2
(alkyl bromide)
4.3
C (singlet)
time
DMA
0.0
A1
B (triplet)
(aryl bromide)
45 min
90 min
2%
1%
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
4%
5%
7%
F (doublet) +A3
-16.7
135 min
180 min
300 min
720 min
1440 min
11%
18%
32%
64%
80%
ΔΔG‡
19.3
6%
-22.2
D (singlet)
7%
13.5
12%
13%
2.54
1.86
2.24
2.14
2.40
2.55
d
C-TS(singlet)
E-TS (triplet)
c
e
Figure 3. [a] DFT-computed energy profiles for the oxidative addition step at Ni0. Free energies in solution (in kcal·mol-1) at the SMD(DMA)-M06/Def2-
TZVPP//PBE/Def2-TZVP(Ni)/Def2-SVP (other atoms) level are displayed. Selected DFT geometries are listed. Bond lengths are in Å. [b] Reaction process
monitoring the formation of the β-methyl styrene and the product versus the reaction time. [c] Proposed mechanism for the remote C-H functionalization. [d]
Hydroarylation proving the formation of a NiII-hydride species. [e] The use of solar energy for the reductive cross coupling.
To understand the chain walking pathway, the reaction mixture
was analyzed after several intervals (Figure 3b). Formation of
allyl benzene was not observed, which shows that the chain
walking pathway is fast and proceeds until the more stable
benzylic position is reached. The accumulation of internal olefin
(β-methyl styrene) indicates that the reductive elimination is the
rate determining step. Based on these observations, we propose
a mechanistic pathway for the migratory Ni-catalyzed electro-
reductive cross-coupling reaction (Figure 3c). The reaction is
initiated by the reductive generation of the Ni0 species I at the
cathode surface. The oxidative addition of Ni0 to aryl bromide by
two-electron-transfer pathway followed by a one electron
reduction results in the formation of intermediate III. The latter
undergoes SET oxidative addition with alkyl bromide to generate
the alkyl radical and intermediate IV. Subsequent one electron
cathodic reduction will lead to intermediate V. The following alkyl
radical addition to the NiI-Ar intermediate leads to the NiII-
intermediate VI, from which Ni will undergo the chain walking
process involving a β-hydride elimination to give NiII hydride VII
and reinsertion to provide VIII. These steps are occurring until
the thermodynamically more stable benzylic-nickel complex IX is
formed. Subsequent, reductive elimination provides the desired
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10.1002/anie.201915418
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1,1-diarylalkane cross-coupling product 3 and the active Ni0
species. The formation of the minor linear product can be
explained for cases in which the aryl moiety of the alkyl bromide
is bulky (e.g. 3d, 3g, 3w or 3x) and the chain walking is slowed
down.
In order to prove the proposed reaction pathway of migratory
insertion, we also reacted the Ni0-complex with n-propyl bromide
in the presence of the aryl bromide and allyl benzene (Figure 3d).
Following initially the same pathway as in the cross electrophile
coupling, the propyl bromide (Figure 3, R=H) would react with
Ni-complex III via a SET oxidative addition to Ni(II) species VI.
Upon β-hydride elimination the Ar-NiII-H species VII’ is formed
(Figure 3c, green pathway). The in-situ formed NiII hydride
species VII’ subsequently undergoes an olefin exchange
reaction with the allylbenzene to give VII along with volatile
propylene. Migratory insertion provides intermediate VIII. The
following isomerization to IX and reductive elimination from NiII
gives the desired chain-walking hydroarylation product 3 (or 7 in
the case of styrenes, Figure 4).
Based on this observation we decided evaluate the Ni-
catalyzed electroreductive hydroarylation[16] by applying a series
of styrene derivatives 7a-h and aryl bromides. In general, the
electronic properties of aromatic ring did to not significantly
influence on the reactivity. Electron-donating substituents at
various positions of benzene ring were tolerated, leading to the
corresponding products in very good yields (products 7a-c),
Figure 4). Styrene, as well as 2-vinylnaphthalene both reacted
smoothly providing the 1,1-diarylalkanes in the yields of 67%
and 70%, respectively (7d-e). Furthermore, functional groups
including p-CO2Me, OAc or the carbazole moiety were tolerated
and the corresponding products 7f-h were obtained in
acceptable yields. In addition to varying the olefin we also
applied different aryl bromides which again resulted in the
desired diarylmethanes (7i-n) in good yields.
Figure 4. Scope of the electro-reductive hydroarylation of styrenes. Reaction
conditions:[a] 10 mol% of [Ni], 0.05 M KBr, 0.1 M styrene (0.4 mmol), 0.8 M
aryl bromide, stainless steel anode and cathode, J = 3.33 mA/cm2, Q = 7.5
F/mol, isolated yields; [b] PMP: p-methoxyphenyl, PFP: p-fluorophenyl.
Following the successful development of the nickel catalyzed
electroreductive hydroarylation as well as the electroreductive
cross electrophile coupling we decided to extend the utility of our
electrochemical approach. Thus, as model reaction the cross
coupling was conducted using photovoltaic panels as an
alternative source of electricity (Figure 3e).[17] The reaction
pattern remained the same and desired product 3a was isolated
in good yield. In order to prove practicability, a multigram scale
reaction was also performed (see SI). The cell was constructed
from a coaxial positioned stainless-steel rod and plate. The
product was isolated in comparable yield at 75 mmol scale. For
larger scale processes the price of the ligand 4 (6,6′-dimethyl-
2,2′-dipyridyl) may become expensive. Thus, we decided to
prepare the ligand from the much cheaper 2-bromo-6-
methylpyridine and nickel bromide in situ (Scheme 3).[18] The
resulting solution was directly used without the catalyst isolation
to afford desired 1,1-diarylalkane 3a in 72% (11.6 g) isolated
yield. After the completed reaction the cell was easily cleaned,
whereas the solvent was recovered by distillation. Thus, the
system can be reused multiple times.
Scheme 3. Cross-coupling reaction catalyzed by nickel complex generated in
situ.
Conclusion
In summary, we have developed a sustainable Ni-catalyzed
electroreductive cross-coupling of non-activated alkyl and aryl
bromides and a hydroarylation of styrenes and allyl benzene.
The new protocols enable the synthesis of pharmaceutically
relevant 1,1-diarylalkanes with good functional group
compatibility and excellent regioselectivity. The described
protocols have several advantages as they address limitations of
traditional cross-electrophile couplings by avoiding the use of
pyrophoric metal powders and over-stoichiometric amounts of
sensitive organic reductants. The mechanistic studies provide
insight into the reaction mechanisms and confirm that the
catalytic cycles involve the generation of Ni0 species.
Furthermore, in both electroreductive reactions, the cross-
electrophile coupling as well as in the hydroarylation a Ni-
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10.1002/anie.201915418
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proceed and to provide the desired diarylalkanes. Furthermore,
the established concept could be effectively applied on
multigram scale and is, therefore, readily applicable for the
development of further electroreductive coupling reactions.
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Acknowledgements
G.S.K., A.P., A.B., P.N., C.Z and MR acknowledges King
Abdullah University of Science and Technology (KAUST) for
support and C.Z. acknowledges the KAUST Supercomputing
Laboratory for providing computational resources of the
supercomputer Shaheen II.
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Keywords: electrosynthesis • migratory cross-coupling • 1,1-
diarylalkanes • nickel • β-hydride elimination
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This article is protected by copyright. All rights reserved.

10.1002/anie.201915418
Angewandte Chemie International Edition
RESEARCH ARTICLE
Yu. M. Kargin, A. V. Il’yasov, Yu. N. Vyakhireva, O. G. Sinyashin, Russ.
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[19] Please also see an excellent article describing work which was done in
parallel to ours: J. Jiao, D. Liu, H.-X. Ma, H. Qiu, P. Fang, T.-S. Mei,
Angew. Chem. Int. Ed. 2020, DOI. 10.1002/anie.201912753.
This article is protected by copyright. All rights reserved.

10.1002/anie.201915418
Angewandte Chemie International Edition
RESEARCH ARTICLE
Sathish Kumar Gadde, Anatoly
Peshkov, Pavlo Nikolaienko, Magnus
Rueping*
Page No. – Page No.
Nickel catalyzed chain walking cross-
electrophile coupling of alkyl and aryl
halides and olefin hydroarylation
enabled by electrochemical reduction
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