Nickel-Catalyzed Electrochemical Reductive Relay Cross-Coupling of Alkyl Halides to Aryl Halides

Article abstract of DOI:10.1002/anie.201912753

A highly regioselective Ni-catalyzed electrochemical reductive relay cross-coupling between an aryl halide and an alkyl halide has been developed in an undivided cell. Various functional groups are tolerated under these mild reaction conditions, which pro

Full text of DOI:10.1002/anie.201912753

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Accepted Article
Title: Nickel-Catalyzed Electrochemical Reductive Relay Cross-
Coupling of Alkyl Halides to Aryl Halides
Authors: Ke-Jin Jiao, Dong Liu, Hong-Xing Ma, Hui Qiu, Ping Fang,
and Tian-Sheng Mei
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912753
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Nickel-Catalyzed Electrochemical Reductive Relay Cross-
Coupling of Alkyl Halides to Aryl Halides
Ke-Jin Jiao,[a] Dong Liu,[a] Hong-Xing Ma,[a],[b] Hui Qiu,[a] Ping Fang,[a] and Tian-Sheng Mei*[a]
coupling of alkyl bromides and aryl bromides could take place by
Abstract:
A Highly regioselective Ni-catalyzed electrochemical
taking advantage of “chain-walking” of an alkyl-nickel species.[16–
reductive relay cross-coupling between an aryl halide and an alkyl
halide has been developed in an undivided cell. Various functional
groups are tolerated under this mild reaction conditions, which
provides an alternative approach for the synthesis of 1,1-
diarylalkanes.
19]
Herein, we report the first such example of Ni-catalyzed
electrochemical relay cross-coupling of aryl halides and alkyl
bromides, affording 1,1-diarylalkanes with good to excellent
selectivity and yield (Scheme 1b). This envisioned
transformation is challenging as a result of a multitude of
undesired side reactions, including those depicted in path a, b,
and c (Scheme 1c).
Nickel-catalyzed cross-coupling reactions of organometallic
reagents and organic electrophiles have emerged as powerful
synthetic tools for forging C(sp2)–C(sp3) bonds.[1] Recently,
substantial effort has also been spent on the development of
nickel-catalyzed reductive cross-coupling reactions between aryl
electrophiles and alkyl electrophiles, wherein organometallic
reagents is avoided.[2] For instance, in 2010 Weix and co-
workers reported efficient Ni-catalyzed cross-couplings of aryl
halides with unactivated alkyl halides using Mn as the reductant
(Scheme 1a).[3] Inspired by this seminal work, many Ni-catalyzed
reductive cross-couplings between aryl halides and alkyl halides
have been developed, including asymmetric variants.[4,5]
However, these reactions require a metal reductant (typically Mn
or Zn) to regenerate the Ni catalyst. The use of stoichiometric
metal additives has some drawbacks: 1) the metal reductant
(typically a powder) often requires surface activation; 2) the
reactivity could vary depending on the source of the metal
powder; 3) some functional groups react readily with Zn or Mn.
To circumvent such issues, the use of organic or inorganic
reductants[6] and photoredox catalysis have emerged as popular
strategies.[7] Alternatively, Ni-catalyzed electrochemical reductive
coupling could provide an attractive solution, whereby electric
current is used to turn over the Ni catalysis.[8,9] However,
electrocatalysis aside, reductive cross-coupling of aryl halides
and unactivated alkyl halides is inherently challenging due to the
difficulty of obtaining selectivity for the cross-coupled product
over homo-coupled products.[10,11] Recently, Hansen and co-
workers reported Ni-catalyzed electrochemical cross-coupling of
aryl bromides and unactivated alkyl bromides using 4-4’-
dimethoxy-2-2’-bipyridine (dmbpy) or amidine-based ligands with
Zn as a sacrificial anode.[12] However, to the best our knowledge,
Ni-catalyzed electrochemical reductive relay cross-coupling of
Scheme 1. Reductive Cross-Coupling Reactions
Initially, we probed various reaction conditions using 4-
bromoanisole (1a) and (2-bromoethyl)benzene (2a) as reaction
partners. To our delight, using Ni(ClO4)2•6H2O as precatalyst,
2,9-dimethyl-1,10-phenanthroline (Ligand 1) as the ligand, n-
Bu4NBr as the electrolyte, and N,N-dimethylacetamide (DMA) as
the solvent in an undivided cell with iron and Ni foam as
electrodes under 6 mA current for 10 hours at room temperature,
the relay cross-coupling product was obtained in a good isolated
yield of 80% (Table 1, entry 1). Using NiI2 as catalyst resulted in
a slightly lower yield (entry 2). When using reticulated vitreous
carbon (RVC) instead of Ni foam as the cathode, the yield
decreased to 74% (entry 3). In addition, when we replaced iron
with magnesium as the sacrificial anode, the efficiency of the
reaction decreased precipitously (entry 4). Increasing or
decreasing the amount of 2a gave lower yields (entries 5 and 6).
Similar outcomes were also obtained when changing the electric
current to 4 mA or 8 mA (entries 7 and 8). It is worth noting that
the methyl groups on the ligand L1 and L2 (entry 9) are crucial
for the reaction (see Table S1 in the Supporting Information for
details). A control experiment revealed that no coupling product
was produced in the absence of the catalyst or ligand (entry 10).
With the optimized reaction conditions in hand, we
investigated the generality of this electrochemical reductive
coupling reaction. As shown in Scheme 2, the catalytic system
exhibited good functional group tolerance. Arenes substituted
aryl bromides and alkyl bromides is unknown. Such
a
transformation would be valuable for the construction of 1,1-
diarylalkanes, which are common structural motifs in many
natural products and biologically active compounds.[13]
As part of our ongoing interest in metal-catalyzed
electrochemistry[14] and 1,1-diarylalkane synthesis,[15] we
questioned whether electrochemical reductive relay cross-
[a]
[b]
K.-J. Jiao, D. Liu, Dr. H.-X. Ma, H. Qiu, P. Fang, Prof. Dr. T.-S. Mei
State Key Laboratory of Organometallic Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese
Academy of Science
345 Lingling Road, Shanghai 200032, China
E-mail: mei7900@sioc.ac.cn
Dr. H.-X. Ma
School of Chemistry and Chemical Engineering, Yancheng Institute
of Technology, Yancheng 224051, China
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Table 1. Reaction Optimization with Substrate 1a[a]
catalyst is more easily reduced to a lower valency (Figure S2).
When the ligand is present, the complex exhibits two quasi-
reversible reductive peaks at −1.29 V and −1.82 V versus
Ag/AgNO3 in dimethylacetamide (curve d, Figure 1), which may
be attributed to the reductive potential of Ni(II)/Ni(I) and
Ni(I)/Ni(0), respectively. Indeed, the controlled potential
electrolysis (E = −1.5 V) does not afford the desired product,
whereas the product is obtained in 10% yield at lower potential
(E = −1.9 V). In addition, the yield can be increased to 50%
when five times the amount of electricity is passed (Scheme 4).
These results indicate that the Ni(0) complex is generated at the
cathode and acts as the active catalyst. In addition, in the
absence of electricity, the stoichiometric reaction with Ni(cod)2
as catalyst can afford the desired product in 25% yield (Scheme
5).
[a] Standard conditions: 1a (0.3 mmol), 2a (1.5 equiv),
Ni(ClO4)2·6H2O (10 mol%), Ligand (12 mol%), n-Bu4NBr (1.0
equiv), and DMA (4 mL), in an undivided cell with iron (1.5 × 0.5
cm2) and Ni foam (2.5 × 1.5 cm2) as electrodes, rt, 6.0 mA, 10 h.
1
[b] The yield was determined by H NMR using CH2Br2 as an
internal standard. [c] Isolated yield in parentheses.
with a variety of functional groups such as alkyl, ether,
trifluoromethyl, and alkenyl groups were well tolerated affording
good to excellent yields (3a–3e, 3p). For those substrates
bearing more reactive groups such as hydroxyl, amino or
protected amino groups (3f–3l), the electrochemical reductive
relay cross-coupling reactions can proceed smoothly, with good
yields. A morpholine group substituted on the aromatic ring is
tolerated as well (3m). In addition, for di- or tri-substituted
arenes, the reaction can also deliver acceptable yields (3n–3r).
Encouragingly, when we investigated the corresponding aryl
chlorides, the reductive relay cross-coupling reaction can
proceed well with good to excellent yields. Acetyl, ester, nitrile,
and sulfonyl groups on said substrates can be well tolerated,
affording good to excellent yields (3s–3w, 3y). In addition,
quinoline is also well tolerated in this electrochemical method
(3x). Commercially available pharmaceuticals like fenofibrate, a
medicine used to treat or prevent cardiovascular disease
participated smoothly in the electrochemical reductive coupling,
affording the indicated product (3z) in excellent yield at both 0.3
mmol and 3.0 mmol scale, thus demonstrating the synthetic
potential of this protocol. Unfortunately, electron-rich aryl
chlorides are not effective (e.g. chloroanisole).
Next we moved to examine the scope of the alkyl bromide. As
shown in Scheme 3, alkyl bromides substituted with a variety of
functional groups such as chloro, fluoro, ether, and hydroxyl
were well tolerated under the standard reaction conditions,
affording the relay products in good yields (4a−4g). To our
delight, this relay process can matriculate along three or four
carbon-length chains with only slightly diminished yield (4h and
4i). In addition, even a secondary alkyl bromide is a suitable
partner under the standard conditions, affording the
corresponding product in satisfactory yield (4h).
Scheme 2. Evaluation of Arene Scope
We then sought to understand which substrates the catalyst
prefers to react with. To our delight, catalytic currents were
observed when either of the two substrates were added into the
mixture of nickel catalyst and ligand. In addition, when an
activated aryl bromide was added, the current was significantly
increased (Figure S3–S5). When the alkyl bromide (2a) was
added first, the catalytic current was slightly increased whereas
the catalytic current was significantly increased (about six fold)
To gain insight into the reaction mechanism, we conducted a
series of cyclic voltammetric analyses (Figure 1, 2, and S2–S8,
Supporting Information). Compared to the substrates, the nickel
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10.1002/anie.201912753
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after the addition of aryl bromide 1a (Figure 2). Furthermore,
when the aryl bromide (1) was added first, the catalytic current is
significantly increased whereas the catalytic current was slightly
increased (only one-seventh) following the subsequent addition
of alkyl bromide 2a (Figure S6). This phenomenon was much
more obvious when an activated aryl bromide was used (Figure
S7–S8). Based on the above cyclic voltammetric (CV) studies,
the putative Ni(0) complex reacts more readily with an aryl
bromide.
Scheme 5. Stoichiometric Reaction Without Electric Current
a) blank
b) Ni catlyst/Ligand (1/1)
60
57.2 μA
55.5 μA
c) Ni/L + 2a
d) Ni/L + 2a + 1a
55.2 μA
d
c
b
40
20
0
a
-20
-40
0.0
-0.5
-1.0
-1.5
-2.0
E vs Ag/AgNO3/V
Figure 2. Cyclic voltammograms recorded on a glassy carbon
electrode at 100 mVs-1. (A): (a) DMA containing 0.1 M of n-
Bu4NBr; (b) solution (a) with 7.5 mM of Ni(ClO4)2•6H2O and
Ligand 1 added; (c) solution (b) with 10 mM of 2a added; (d)
solution (c) with 10 mM of 1a added.
PMP = 4-methoxylphenyl.
Based on literature reports[20] and our mechanistic studies
(see Supporting Information for more details), a plausible
mechanism is presented for the Ni-catalyzed electrochemical
reductive couplings (Scheme 6). First, the Ni(II) catalyst is
reduced to Ni(0) (A) via cathodic reduction. Then, after oxidative
addition of an aryl bromide to Ni(0), aryl Ni(II) species (B) is
formed, which can react with an alkyl radical to generate a Ni(III)
species (C). Direct reductive elimination from C can generate a
linear by-product, C can also be converted into species E, a
more thermodynamically stable benzylic Ni(III) intermediate via
multiple β-hydride elimination/reinsertion steps. Upon reductive
elimination, the desired cross-coupling product and a Ni(I)
species (F) are formed. By single electron transfer and cathodic
reduction, the active Ni(0) is then regenerated.
Scheme 3. Evaluation of Alkyl Halides
a) blank
b) Ni(ClO4)2·6H2O
100
80
60
40
20
0
c) Ligand 1
d) Ni catlyst/Ligand (1/1)
b
-1.82V
-1.29V
c
d
a
-20
-40
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
E vs Ag/AgNO3/V
Figure 1. Cyclic voltammograms recorded on a glassy carbon
electrode at 100 mVs-1. (a) DMA containing 0.1 M of n-Bu4NBr;
(b) solution (a) with 5 mM of Ni(ClO4)2•6H2O added; c) solution
(a) with 5 mM of 2,9-Dimethyl-1,10-phenanthroline added. d)
solution (a) with 7.5 mM of Ni(ClO4)2•6H2O and 2,9-Dimethyl-
1,10-phenanthroline (Ni/L = 1/1) added.
Scheme 6. Plausible Catalytic Cycle
Scheme 4. Controlled Potential Electrolysis
In summary, we have demonstrated the first example of a Ni-
catalyzed electrochemical reductive relay cross-coupling of aryl
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affording
1,1-diarylalkanes
with
good
yields
and
regioselectivities. The protocol is operationally simple and
robust. Further research to explore the mechanism and to
develop more transition metal-catalyzed electrochemical
reductive relay cross-couplings is currently underway in our
laboratory.
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This work was financially supported by the Strategic Priority
Research Program of the Chinese Academy of Sciences (Grant
XDB20000000), NSF of China (Grants 21821002 and
21772222), and S&TCSM of Shanghai (Grants 17JC1401200,
and 18JC1415600, and 19YF1458500).
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Keywords: Organic electrochemistry • reductive relay cross-
coupling • nickel • 1,1-diarylalkanes
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10.1002/anie.201912753
Angewandte Chemie International Edition
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Ke-Jin Jiao, Dong Liu, Hong-Xing Ma,
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Nickel-Catalyzed Electrochemical
Reductive Relay Cross-Coupling of
Alkyl Halides to Aryl Halides
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