Electrochemically Enabled, Nickel-Catalyzed Amination

Article abstract of DOI:10.1002/anie.201707906

Along with amide bond formation, Suzuki cross-coupling, and reductive amination, the Buchwald–Hartwig–Ullmann-type amination of aryl halides stands as one of the most employed reactions in modern medicinal chemistry. The work herein demonstrates the potential of utilizing electrochemistry to provide a complementary avenue to access such critical bonds using an inexpensive nickel catalyst under mild reaction conditions. Of note is the scalability, functional-group tolerance, rapid rate, and the ability to employ a variety of aryl donors (Ar?Cl, Ar?Br, Ar?I, Ar?OTf), amine types (primary and secondary), and even alternative X?H donors (alcohols and amides).

Full text of DOI:10.1002/anie.201707906

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Electrochemically Enabled, Ni-Catalyzed Amination
Authors: Chao Li, Yu Kawamata, Hugh Nakamura, Julien C.
Vantourout, Zhiqing Liu, Qinglong Hou, Denghui Bao, Jeremy
T. Starr, Jinshan Chen, Ming Yan, and Phil S. Baran
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707906
Angew. Chem. 10.1002/ange.201707906
Link to VoR: http://dx.doi.org/10.1002/anie.201707906
http://dx.doi.org/10.1002/ange.201707906

10.1002/anie.201707906
Angewandte Chemie International Edition
COMMUNICATION
Electrochemically Enabled, Ni-Catalyzed Amination
Chao Li,†,[a] Yu Kawamata,†,[a] Hugh Nakamura,[a] Julien C. Vantourout,[a] Zhiqing Liu,[b] Qinglong Hou,[b]
Denghui Bao,[b] Jeremy T. Starr,[c] Jinshan Chen,[c] Ming Yan,[a] and Phil S. Baran*[a]
A. Context: Nickel-catalyzed amination of aryl halides.
Abstract: Along with amide bond formation, Suzuki cross-coupling,
[Ni]/[Ir]/PET (425 nm)
and reductive amination, the Buchwald-Hartwig-Ullmann type
HNR1R2
amination of aryl halides stands as one of the most employed
ArX
[Buchwald/
MacMillan]
X= Br
[Ni]
reactions in modern medicinal chemistry. This Communication
demonstrates the potential of utilizing electrochemistry to provide a
complementary avenue to access such critical bonds using an
inexpensive nickel catalyst under mild conditions. Of note is the
scalability, functional group tolerance, rapid rate, and the ability to
employ a variety of aryl donors (Ar–Cl, Ar–Br, Ar–I, Ar–OTf), amine
types (primary and secondary), and even alternative X-H donors
(alcohols and amides).
ligand/base/heat
HNR1R2
R1
R2
• hν setup
Ar
N
ArX
X = Cl, Br, or OR
Ni(II)/di-tBubpy, rt.
• Early precedents:
[Hughes, Cramer, Cristau]
HNR1R2
ArX
• Seminal contributions:
[Buchwald,
Hartwig, Garg, Knochel, Yang,
Fort and others]
electrochemistry
[This work]
X = Br, Cl, I, and OTf
• room
temperature
• scalable
• heat (generally ≥ 70 °C)
• sensitive cat.
• alkoxide base
Despite its short history of merely several decades, palladium
catalyzed amination of aryl halides has emerged rapidly as one of
the most widely utilized reactions in modern organic chemistry.1
In fact, a recent study ranks the venerable Buchwald-Hartwig
amination amongst one of the 20 most frequently used reactions
in medicinal chemistry in 2014.2 Similarly, the copper catalyzed
Ullmann coupling has also been a regular tool in medicinal
chemists’ armamentorium.3 Unequivocally, the formation of aryl
C–N bonds is of paramount importance in drug discovery. The
first example of nickel mediated C–N coupling dates back to the
1950s using NiCl2 at 200 °C;4,5 subsequent efforts by Cramer6(a)
and Cristau6(b) broadened the scope of similar reactions—
nevertheless, the harsh conditions still precluded broad adoption
(Figure 1A). It was not until 1997 when Buchwald’s seminal efforts
spawned strong interests in utilizing nickel (0) ligand complexes
to catalyze the cross-coupling reactions between aryl halides and
amines.7 Over the years, efficient protocols have been developed
by the groups of Buchwald,8(a) Hartwig,8(b) Garg,8(c) Knochel,8(d)
Yang,8(e) Fort,8(f) and others.8(g)-(j) Nickel’s inexpensive nature and
its high reactivity toward less reactive electrophiles such as aryl
chlorides offers an alternative approach to palladium and copper
catalysis. Nevertheless, these efforts are plagued by several
drawbacks, including the use of air-sensitive Ni(0) catalysts, the
need for high temperatures, and the necessity of alkoxide bases.
While elegant Ni(II) pre-catalysts and in situ methods of catalyst
generation have been devised to address the first problem,8 the
other issues remain largely unresolved. In 2016, Buchwald,
MacMillan, and co-workers reported a photochemically assisted
C–N cross-coupling via nickel catalysis wherein the photoinduced
electron transfer between an iridium sensitizer and nickel
catalysts allows readily available Ni(II) salts to serve as catalysts
under milder conditions.9
B. Reaction development and optimization.a
10 mol% NiBr2•glyme
10 mol% di-tBubpy, rt
H
N
Br
LiBr (4 equiv.), DMA (0.1 M)
(+)RVC/(–)Ni
F3C
F3C
undivided cell
I = 4 mA, 4.5 h
NH2
2 (3 equiv.)
3, 76%b (72%)c
1
Deviation from above
Yield%b
17–34
entry
1
2
Graphite, Al, or steel cathode
Zn sacrificial anode instead of RVC
8 mA, 2 h
7d
22
32
0
3
4
2 mA, 8 h
5
No electricity
6
15 min. electrolysis
No ligand
5
7
0
8
No Ni cat.
0
9
35
75
LiCl instead of LiBr
Pyridine (2.0 eq) as an additve
10
11
12
DABCO (2.0 eq) as an additive
Reaction under air
48
42
a 0.2 mmol. b Yield determined by gas chromatography (GC). c Isolated yield in
"()". d Complete consumption of starting material; formation of biaryl.
Figure 1. (A) Background and historical context of Ni-based aryl amination
methods. (B) Invention and optimization of Ni-catalyzed amination.
Abbreviations: RVC = reticulated vitreous carbon; di-tBubpy = 4,4’-di-tert-
butyl-2,2’-bipyridine; DMA = N, N’-dimethylacetamide.
These studies spanning two decades point to two critical
challenges to achieve nickel-catalyzed amination of aryl halides,
namely the generation of a reactive low valent nickel catalyst
and the C–N bond-forming process via reductive elimination.
The former often entails the reduction of a Ni(II) species10 while
the latter may be promoted by the intermediacy of a high valent
nickel species accessible via oxidation11,12—the ability to
access Ni complexes of various oxidation states in the same
pot is thus crucial. Electrochemistry represents the most direct
and controllable means of redox manipulation—each
electrochemical process seamlessly combines concurrent
anodic oxidations with cathodic reductions.13 As such, it was
surmised that various oxidation states of nickel complexes
could co-exist in harmony under electrolytic conditions. This
realization, coupled with the innate scalability, sustainability,
and tunability of electrochemistry,14 prompted the investigation
of electrochemically promoted cross-coupling reactions under
nickel catalysis.15
[a]
Dr. C. Li, Dr. Y. Kawamata, Dr. H. Nakamura, J. C. Vantourout, M. Yan,
and Prof. Dr. P. S. Baran.
The Scripps Research Institute (TSRI)
North Torrey Pines Road, La Jolla, California, 92037, United States
E-mail: pbaran@scripps.edu
[b]
[c]
Dr. Z. Liu, Q. Hou, Dr. D. Bao
Asymchem Laboratories, (Tianjin) Co., Ltd.,TEDA
Tianjin, 300457, P. R. China
Dr. J. T. Starr, Dr. J. Chen
Discovery Sciences, Medicine Design, Pfizer Global Research and
Development, 445 Eastern Point Road, Groton, Connecticut 06340,
United States
In this Communication, an electrochemical method to achieve
the cross-coupling between aryl halides and alkyl amines at
[†]
These authors contributed equally.
This article is protected by copyright. All rights reserved.

10.1002/anie.201707906
Angewandte Chemie International Edition
COMMUNICATION
room temperature and in the absence of an external base is
presented. The scope of this electrolytic protocol encompasses
aryl bromides, chlorides, triflates, and iodides. Additionally,
alcohols and amides can also serve as nucleophiles.
electrochemical coupling of aryl halides utilize sacrificial anodes
to prevent the competitive oxidation of low-valent nickel catalysts
and to avoid the need for a divided cell.15 Thus, the intermediacy
of high valent nickel species appears to be essential.16,17 As
mentioned above, such concurrent oxidation/reduction cycles are
ideally suited for electrochemistry. A current of 4 mA was optimal
on 0.2 mmol scales. Adjusting the current (while maintaining the
total amount of electron passage constant) lowered the yields of
coupling products (entries 3 and 4). Unsurprisingly, no coupling
products were observed in the absence of an electric current
(entry 5). Reducing the duration of electrolysis (the overall
reaction time is still 4.5 h), too, had detrimental effects (entry 6)—
thus, electricity does not merely initiate a chain reaction.
Figure 1B provides the optimal conditions alongside an
abbreviated picture of reaction optimization on the coupling of aryl
bromide 1 with cyclohexylamine (2). The use of expensive
electrode materials was avoided at the outset of the study—the
highest yield was obtained with an RVC anode and a nickel foam
cathode. Coupling products were still observed with alternative
cathode materials such as graphite, aluminum, and stainless steel,
albeit in diminished yields (entry 1, Figure 1B). The use of a zinc
sacrificial anode exerted deleterious effects on the reaction (entry
2)—homocoupling of the aryl halide ensued instead. This result
has mechanistic significance as most nickel catalyzed
[(hetero)aryl bromide]
[amine]
[amination]a
5–10 mol% NiBr2•glyme
5–10 mol% di-tBubpy, rt
• > 25 examples
• 1° and 2° amines
• chemoselective
• mild, scalable
• external base-free
• room temperature
• comparison w/ [PET],b
[Pd],c [Cu]c, [Ni]c
R1
R2
R1
R2
R
R
H
N
DMA
Br
Het
N
Het
or
or
Br
N
R1
R2
LiBr (4 equiv.)
(+)RVC/(–)Ni
undivided cell
I = 4 mA
(3 equiv.)
amine coupling partners
NBoc
OH
O
N
N
N
N
N
F3C
F3C
F3C
F3C
F3C
5, 73%, 4.5 h
6, 79%, 4.5 h; 71%,e 4.5 h
4, 86%, 3 h; 87%,e 3 h
7, 72%, 4.5 h; 70%,e 4.5 h
[Pd]18c 75%, 22 °C, 72 h
[Cu]18d 64%, rt, 6.5 d
8, 80%, 4.5 h
[Pd]18e 59%, 120 °C, 1 h
[0 °C] 55%, 4.5 h
[PET] 91%, rt, 8 h
[Pd]18b 95%, 60 °C, 0.5 h
[PET] 96%, rt, 4 h
[PET] 74%, 55 °C, 24 h
[Pd]18a 93%, 90 °C, 1 h
N
CN
CO2Et
N
N
N
N
N
N
Me
Me
F3C
F3C
F3C
F3C
F3C
11, 76%, 4.5 h
[Pd]18f 66%, 105 °C, 24 h
12, 53%, 3 h; 49%,e 3 h
13, 68%, 4.5 h
[PET] unsuccessful
9, 65%, 4.5 h
10, 78%, 4.5 h
[PET] 60%, 55 °C, 24 h
HO
H
N
H
N
H
N
H
N
O
OH
NBu2
(
)
6
F3C
F3C
3, 72%, 4.5 h; 60%,e 4.5 h
[under air] 42%, 4.5 h
F3C
F3C
F3C
14, 69%, 4.5 h
[PET] unsuccessful
[Cu]18d 30%, rt, 6.5 d
15, 41% , 4.5 h
[PET] 76%, rt, 16 h
16,d 33%, 5 h
17, 61%, 9 h; 56%,e 9 h
[PET] 78%, 55 °C, 24 h
[Pd]18g 37%, 100 °C, 3 h
(hetero)aryl bromide coupling partners
H
N
H
N
O
S
H
N
F3C
H
N
O
nHex
nHex
NH
nHex
nHex
nHex
N
MeHN
MeO2C
CN
CF3
O
O
18, 72%, 4.5 h
[PET] 70%, rt, 19 h
19, 69%, 4.5 h; 71%,e 4 h
[Pd]18h 72%, 21 h, 100 °C
20, 71%,f 8 h; 64%,e,f 4h
21, 79%, 4.5 h
22, 60%,f 8 h; 56%,e,f 4 h
[PET] 81%, 55 °C, 19.5 h
[PET] 83%, 55 °C, 24 h
[PET] 93%, 55 °C, 19 h
H
N
H
N
H
N
H
N
nHex
nHex
N
nHex
nHex
NH
nHex
N
NC
N
N
N
Me
23,f 46%, 8 h
24, 54%, 4.5 h; 51%,e 4.5 h
[PET] 71%, 55 °C, 16 h
[Pd]18l 89%, 110 °C, 15 min
[Cu]18m 70%, 80 °C, 24 h
26, 62%,f 9 h; 43%,e,f 4 h
[PET] 78%, rt, 15 h
[Pd]18n 96%, 110 °C, 24 h
[PET] 76%, 55 °C, 19 h
[Pd]18i 76%, 160 °C, 10 min
[Cu]18j 65%, 80 °C, 24 h
[Ni]18k 69%, 80 °C, 20 h
25, 76%, 5 h
[PET] 80%, 55 °C, 7 h
27, 57%,f 8 h;
49%,e,f 6 h
Scheme 1. Scope of the electrochemically enabled Ni-catalyzed amination of aryl bromides. a) Standard reaction conditions: aryl bromide (1.0 equiv.), amine (3.0
equiv.), NiBr2•glyme (10 mol%), di-tBubpy (10 mol%), DMA (0.1 M), LiBr (4 equiv.), RVC anode, Ni cathode, constant current (I = 4 mA for 0.2 mmol scale), rt. b)
Based on results reported in reference 9(a). c) Based on specified references for each substrate (footnote 18). d) I = 8 mA for 0.2 mmol scale. e) Using NiBr2•glyme
(5 mol%), di-tBubpy (5 mol%). f) I = 2 mA for 0.2 mmol scale.
This article is protected by copyright. All rights reserved.

10.1002/anie.201707906
Angewandte Chemie International Edition
COMMUNICATION
The inexpensive combination of NiBr2•glyme and a bipyridyl
ligand provides the most effective catalyst system for the
transformation—on substrate 1, the omission of either component
led to no product formation (entries 7 and 8). The choice of
electrolyte has a significant impact on the reaction outcome as
well—the use of LiCl instead of LiBr led to a significant drop in
yield (entry 9). The addition of external bases is unnecessary. In
fact, the presence of pyridine had little influence on the yield (entry
Electrochemical amination can facilitate many applications in
organic synthesis (Scheme 2). For instance, this reaction may be
utilized to derivatize amine motifs in bioactive molecules.
Electrochemcial N-arylation has been achieved on amoxapine
and paroxetine, affording 28 and 29 respectively (Scheme 2A). In
each case, the amine was used as the limiting reagent (3–5 equiv.
of aryl bromide; 2 equiv. of DBU was added), highlighting the
applicability of this method to complex and possibly precious
10), whereas the use of DABCO had deleterious effects (entry 11). amine starting materials. It is also noteworthy that the aryl chloride
Although optimal results are obtained when the reaction was set
up under protective atmosphere of argon, rigorous
motif in amoxapine was left unscathed after the coupling.
The scalability of this reaction has also been demonstrated
through the cross-coupling of 1 and N-Boc-piperazine on a 23-
gram scale (Scheme 2B). Aniline product 5 was afforded in 66%
yield. Moreover, this large-scale electrolysis was complete within
7 h, attesting to the high reaction rate and practicality.
a
deoxygenation is unnecessary. The coupling product was
afforded in 42% yield even under air (entry 12). Overall, C–N
coupling is accomplished under galvanostatic (constant current)
conditions in a simple undivided cell at room temperature
generally within five hours.
Aside from aryl bromides, other aryl (pseudo)halides can also
serve as coupling partners under electrochemical conditions. For
example, cross-coupling of aryl chlorides have been successfully
achieved under room temperature, affording 4–6 in good yields
with no changes to the standard reaction conditions in Scheme 1.
Additionally, the coupling using aryl triflates and aryl iodides is
also possible under the standard conditions, as shown by the
preparations of 4 and 30 respectively (Scheme 2C).
With the optimized conditions in hand, the scope of the reaction
was probed next. Medicinally privileged cyclic secondary amines
such as pyrrolidine, piperazine derivatives, morpholine, and
piperidine have all proven to be viable substrates, affording 4–7
in good yields. Amines containing hydroxyl, pyridinyl, cyano, and
ester substituents (see 8–11) have also been successfully
coupled with 1, underscoring the functional group compatibility of
the reaction. Cyclic amines bearing an additional a-substituent
(e.g., 2-methyl-pyrrolidine and 2-methyl-piperidine) can be used
in the reaction as well, as is evidenced through the formation of
12 and 13. Notably, the attempted coupling of 2-methyl-piperidine
(to furnish 13) under PET was unsuccessful. Additionally, cross-
couplings using acyclic secondary amines have been
demonstrated. Although dibutylamine is not a competent coupling
partner under PET, it was found to react via this electrolytic
system, affording 14 in 69% yield. Aside from cyclohexylamine
(see 3), other primary amines can also be coupled with aryl
bromides—these include ethylene-glycol derived 2-(2-
aminoethoxy)ethanol (see 16). It is of note that the ability to
rapidly incorporate poly-PEG motifs into small molecule
pharmaceuticals has recently gained importance due to exploding
interest in PROTACs, where a poly-PEG chain often links a target
binding motif with an E3 ligase recognition motif.19
This versatile system may be adapted for the coupling between
aryl halides and other nucleophilic species (Scheme 2D). For
example, the coupling of an aryl bromide with a primary alcohol
has been demonstrated; 31 was afforded in a moderate yield with
the addition of a base (DBU). Inclusion of an external base also
allowed pyrrolidinone to serve as the nucleophile in this
electrochemically facilitated cross-coupling, 32 was furnished in
55% yield.
From a practical vantage point, this robust reaction does not
require rigorous deoxygenation procedures (a simple air/argon
exchange usually suffices, see SI for details). Admittedly, as with
other electrochemical reactions under constant current conditions,
fluctuations in applied potential as a result of varying cell
resistance stemming from variabilities in setups may undermine
the yield of the coupling. This can be circumvented through the
use of additional electrolyte. As shown in Figure 1, the choice of
electrode materials also exerted a substantial impact on the
reaction. Nevertheless, preliminary results indicate that readily
available graphite plates and stainless steel rods can serve as
anode and cathode materials. With regards to substrate scope,
the current conditions are not compatible with anilines. Under the
present system, the use of 3 equiv. of amine is optimal when the
aryl halide is the limiting reagent (for the synthesis of 3, the use
1.5 equiv. of amine led to 41% GC yield instead of 76%, see SI).
To summarize, nickel catalyzed coupling between aryl
(pseudo)halides and aliphatic amines has been enabled at room
temperature, in the absence of an external base, through a simple
and inexpensive experimental setup (constant current, undivided
cell) using electrochemistry. The scalability and practicality of this
protocol, which utilizes inexpensive catalysts and electrode
materials, is not surprising as this is often the case in
electrochemistry.14(a) The utility of reaction has already been field-
tested in both process (Asymchem) and medicinal chemistry
(Pfizer) settings.
This reaction also showcased a broad scope with respect to the
aryl bromide electrophiles. Various electron-withdrawing
functional groups were tolerated, such as amide (18), ester (19),
nitrile (20, 25), and sulfonamide (21). Couplings with heteroaryl
bromides derived from pyridine, pyrimidine, and quinoline have
also been successful (see 24–27). In addition, unsubstituted
bromobenzene can be employed as a coupling partner (see 23).
Across a number of substrates, coupling products were afforded
in comparable yields to those obtained under photochemical,
palladium-catalyzed, copper-catalyzed, and nickel catalyzed
(thermal) conditions. The amount of the catalyst/ligand can be
reduced to 5 mol%—12 of the substrates were furnished in similar
yields under these conditions. In fact, 4 and 19 were afforded in
higher yields with lower catalyst loading. The use of
electrochemistry enables C–N coupling at ambient conditions. 5
could even be synthesized at 0 °C (55%, 4.5 h) with this
technology.
This article is protected by copyright. All rights reserved.

10.1002/anie.201707906
Angewandte Chemie International Edition
COMMUNICATION
A. Applications in drug
modifications.a
B. Electrochemical amination on decagram scale.
10 mol% NiBr2•DME
RVC plates
Glass
chamber
10 mol% di-tBubpy
LiBr (4 equiv.)
DMA (0.1 M), rt
Boc
N
NBoc
Br
O
Cl
N
F3C
(+)RVC/(–)Ni
undivided cell
constant current
rt, 7 h
N
H
N
N
F3C
Ni foam plates
1; 22.5 g
(100 mmol)
300 mmol
5, 66%
A side-view of the reaction setup
on decagram scale
N
[22.5 gram scale]
Ar
C. Electrochemical amination of aryl chlorides, aryl iodides, and aryl triflates under "standard conditions."b,c
Ar = 4-CF3C6H4:
28, from amoxapine
(1 equiv.): 86%
standard
conditions
R = CF3: 4
from ArCl: 73%, 3 h
R2
Y
R1
Y = NBoc: 5
from ArCl: 67%, 4.5 h
[Ni]8d 92%, 130 °C, 18 h
N
H
Ar Cl
[Pd]18o 71%, 100 °C, 24 h
[Ni]8d 95%, 130 °C, 18 h;
N
N
standard
conditions
R2
R2
R1
R1
R2
R1
Ar
N
N
H
N
Ar OTf
from ArI: 73%, 3h
[Cu]18p 94%, rt, 24–30 h;
Y = O: 6
Ar
from ArCl: 48%, 4.5 h
[Pd]18q 87%, rt, 4 h
[Ni]18r 91%, 100 °C, 4 h
standard
conditions
O
R = CO2Me: 30
from ArOTf: 68%, 8 h
N
H
Ar
I
O
R
CF3
O
D. Electrochemically enabled coupling between aryl bromides and alcohols or amides.b,c
standard conditions
with DBU (1.5 equiv.)
N
ROH
F3C
F
RO Ar
Ph
( )5
O
R1
O
Ar = 4-CF3C6H4:
29,
F3C
N
R1
O
32, 55%, 8 h
[Pd]18s 90%, 120 °C, 16 h
[Cu]18t 83%, 100 °C, 16 h
Ar Br
O
standard conditions
with DBU (3 equiv.)
from paroxetine hydrochloride
(1 equiv.): 62%
H
R2
N
31, 58%, 3 h
Ar
R2
Scheme 2. Applications and extensions of the electrochemically enabled amination reaction to achieve (A) drug modifications, (B) decagram scale C–N coupling,
(C) amination of aryl chlorides/triflates/iodides, (D) cross-coupling using alcohols and amides as nucleophiles. a) Reaction conditions: aryl bromide (3.0–5.0 equiv.),
amine (1.0 equiv.), NiBr2•glyme (10 mol%), di-tBubpy (10 mol%), DBU (2.0 equiv.), DMA (0.08 M), LiBr (4.8 equiv.), RVC anode, Ni cathode, constant current (I = 4
mA for 0.167 mmol scale), rt (See SI for experimental details). b) experimental procedures adapted from the standard conditions with modifications indicated. For
details, see SI. c) Comparisons based on specified references for each substrate (footnote 18 and reference 8d).
[1]
(a) P. Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016, 116, 12564; (b)
J. F. Hartwig, Angew. Chem. Int. Ed. 1998, 37, 2046; (c) For another
recent summary, see: Y. Ishihara, A. Montero, P.S. Baran, The Portable
Chemist’s Consultant, version 2.7.1, Apple Publishing Group: New York,
2016.
This work represents a rare example where anodic and cathodic
processes are reconciled to synergistically generate reactive
catalyst species in different oxidation states—a sacrificial
electrode is thus not involved.20 From a holistic standpoint, this
study is reminiscent of Moeller’s electrochemically assisted Heck
reaction using simple unmodified electrodes21—a pioneering
contribution that has largely been overlooked by the community.
Little’s work on electroreductive coupling provides another
instructive example where electrochemistry opens up new
dimensions in nickel catalysis.22 Taken together, electrochemical
strategies to facilitate challenging cross-coupling reactions in a
simple and sustainable fashion represent an exciting area whose
full potential is yet to be realized.23
[2]
[3]
Analysis based on representative publications in J. Med. Chem.: D. G.
Brown, J. Boström, J. Med. Chem. 2016, 59, 4443.
For a recent review on the Ullmann coupling, see: C. Sambiagio, S. P.
Marsden, A. J. Blacker, P. C. McGowan, Chem. Soc. Rev. 2014, 43,
3525.
[4]
[5]
E. C. Hughes, F. Veatch, V. Elersich, Ind. Eng. Chem. 1950, 42, 787.
For a review on nickel catalyzed amination of aryl halides, see: M. Marín,
R. J. Rama, M. C. Nicasio, Chem. Rec. 2016, 16, 1819.
[6]
(a) R. Cramer, D. R. Coulson, J. Org. Chem. 1975, 40, 2267; (b) H.-J.
Cristau, J.-R. Desmurs, Ind. Chem. Libr. 1995, 7, 240.
Acknowledgements
[7]
[8]
J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 6054.
Financial support for this work was provided by NIH (grant number
GM-118176), Pfizer, China Scholarship Council (CSC)
(postdoctoral fellowship to C.L.), Hewitt Foundation (postdoctoral
fellowship for Y.K.), JSPS (postdoctoral fellowship to H. N.), and
GlaxoSmithKline/University of Strathclyde (travel grant to J.C.V.).
We are grateful to D.-H. Huang and L. Pasternack (The Scripps
Research Institute) for assistance with nuclear magnetic
resonance spectroscopy. We acknowledge Dr. Evan Horn
(Celgene) for helpful discussions during the early stages of this
work.
For other selected examples of aryl C–N couplings using nickel catalysis,
see: (a) N. H. Park, G. Teverovskiy, S. L. Buchwald, Org. Lett. 2014, 16,
220; (b) S. Ge, R. A. Green, J. F. Hartwig, J. Am. Chem. Soc. 2014, 136,
1617; (c) N. F. Fine Nathel, J. Kim, L. Hie, X. Jiang, N. K. Garg, ACS
Catal. 2014, 4, 3289; (d) G. Manolikakes, A. Gavryushin, P. Knochel, J.
Org. Chem. 2008, 73, 1429; (e) C. Chen, L.-M. Yang, J. Org. Chem.
2007, 72, 6324. (f) E. Brenner and Y. Fort, Tetrahedron Lett. 1998, 39,
5359; (g) K. Matsubara, K. Ueno, Y. Koga, K. Hara, J. Org. Chem. 2007,
72, 5069; (h) T. Shimasaki, M. Tobisu, N. Chatani, Angew. Chem. Int.
Ed. 2010, 49, 2929; (i) M. J. Iglesias, A. Prieto, M. C. Nicasio, Adv. Synth.
Catal. 2010, 352, 1949; (j) C. M. Lavoie, P. M. MacQueen, N. L. Rotta-
Loria, R. S. Sawatzky, A. Borzenko, A. J. Chisholm, B. K. V. Hargreaves,
R. McDonald, M. J. Ferguson, M. Stradiotto Nature Comm. 2016, 7,
11073.
Keywords: nickel catalysis • electrochemistry • amination •
cross-coupling • arylation
This article is protected by copyright. All rights reserved.

10.1002/anie.201707906
Angewandte Chemie International Edition
COMMUNICATION
[9]
(a) E. B. Corcoran, M. T. Pirnot, S. Lin, S. D. Dreher, D. A. DiRocco, I.
W. Davies, S. L. Buchwald, D. W. C. MacMillan, Science 2016, 353, 279;
the PET facilitated amination can also be achieved using semiconductor
quantum dots: J. A. Caputo, L. C. Frenette, N. Zhao, K. L. Sowers, T. D.
Krauss, D. J. Weix, J. Am. Chem. Soc. 2017, 139, 4250.
Organometallics 2013, 32, 6148; (r) J. Magano, S. Monfette, ACS Catal.
2015, 5, 3120; (s) W. C. Shakespeare, Tetrahedron Lett. 1999, 40, 2035;
(t) L. Jiang, Molecules 2014, 19, 13448.
[19] (a) A. M. Gilbert, M. C. Noe, Med. Chem. Rev. 2016, 51, 347; (b) K.
Raina, C. M. Crews, Curr. Opinion Chem. Biol. 2017, 39, 46; (c) A. C.
Lai, C. M. Crews, Nat. Rev. Drug Discov. 2017, 16, 101; (d) M. S. Gadd,
A. Testa, X. Lucas, K.-H. Chan, W. Chen, D. J. Lamont, M. Zengerle, A.
Ciulli, Nat. Chem. Biol. 2017, 13, 514.
[10] (a) T. T. Tsou, J. K. Kochi, J. Am. Chem. Soc. 1979, 101, 6319; (b) D. G.
Morrell, J. K. Kochi, J. Am. Chem. Soc. 1975, 97, 7262.
[11] (a) K. Koo, G. L. Hillhouse, Organometallics 1995, 14, 4421; (b) K. Koo,
G. L. Hillhouse, Organometallics 1996, 15, 2669; (c) D. J. Mindiola, G. L.
Hillhouse, J. Am. Chem. Soc. 2001, 123, 4623; (d) B. L. Lin, C. R.
Clough, G. L. Hillhouse, J. Am. Chem. Soc. 2002, 124, 2890.
[20] Arene amination can also be achieved in an anodic process, see: (a) T.
Morofuji, A. Shimizu, J. I. Yoshida, J. Am. Chem. Soc. 2013, 135, 5000;
(b) S. R. Waldvogel, S. Möhle, Angew. Chem. Int. Ed. 2015, 54, 6398;
(c) S. Herold, S. Möhle, M. Zirbes, F. Richter, H. Nefzger, S. R.
Waldvogel, Eur. J. Org. Chem. 2016, 1274; (d) S. Möhle, S. Herold, F.
Richter, H. Nefzger, S. R. Waldvogel, ChemElectroChem 2017, early
view (DOI: 10.1002/celc.201700476); (e) L. J. Wesenberg, S. Herold, A.
Shimizu, J.-I. Yoshida, S. R. Waldvogel, Chem. Eur. J. 2017, early view
(DOI: 10.1002/chem.201701979); (f) T. Morofuji, A. Shimizu, J.-I.
Yoshida, Chem. Eur. J. 2015, 21, 3211; (g) T. Morofuji, A. Shimizu, J.-I.
Yoshida, J. Am. Chem. Soc. 2014, 136, 4496; (h) T. Morofuji, A. Shimizu,
J.-I. Yoshida, J. Am. Chem. Soc. 2015, 137, 9816.
[12] For
a review on reductive eliminations in C–Heteroatom coupling
reactions, see: J. F. Hartwig, Acc. Chem. Res. 1998, 31, 852.
[13] O. Hammerich, B. Speiser, Eds., Organic Electrochemistry, 5th ed.,
Revised and Expanded, CRC Press 2015
[14] For selected reviews on electrochemistry, see: (a) E. J. Horn, B. R.
Rosen, P. S. Baran, ACS Cent. Sci. 2016, 2, 302; (b) K. D. Moeller,
Tetrahedron 2000, 56, 9527; (c) J. B. Sperry, D. L. Wright, Chem. Soc.
Rev. 2006, 35, 605; (d) J.-I. Yoshida, K. Kataoka, R. Horcajada, A.
Nagaki, Chem. Rev. 2008, 108, 2265; (e) R. Francke, R. D. Little, Chem.
Soc. Rev. 2014, 43, 2492;
[21] J. Tian, K. D. Moeller, Org. Lett. 2005, 7, 5381.
[15] For early reports on the use of Ni-complexes in the electrochemical
coupling of ArX, see: (a) M. Mori, Y. Hashimoto, Y. Ban, Tetrahedron
Lett. 1980, 21, 631; (b) Y. Rollin, M. Troupel, D. G. Tuck, J. Perichon, J.
Organomet. Chem. 1986, 303, 131; (c) G. Schiavon, G. Bontempelli, B.
Corain, J. Chem. Soc. Dalton Trans. 1981, 0, 1074; (d) T. Yamamoto, N.
Saito, Macromol. Chem. Phys. 1996, 197, 165; For selected reviews on
metal-catalyzed electrochemical cross-couplings, see: (e) J.-Y. Nédélec,
J. Périchon, M. Troupel, Top. Curr. Chem. 1997, 185, 141; (f) E. Duñach,
D. Franco, S. Olivero, Eur. J. Org. Chem. 2003, 1605.
[22] J. A. Miranda, C. J. Wade, R. D. Little, J. Org. Chem. 2005, 70, 8017.
[23] For examples of electrochemical cross-coupling reactions, see reference
15; also see: (a) B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Francke, S.
Waldvogel, Angew. Chem. Int. Ed. 2014, 53, 5210; (b) T. Morofuji, A.
Shimizu, J.-I. Yoshida, Angew. Chem. Int. Ed. 2012, 51, 7259; (c) Q.-L.
Yang, Y.-Q. Li, C. Ma, P. Fang, X.-J. Zhang, T.-S. Mei, J. Am. Chem.
Soc. 2017, 139, 3293; (d) R. J. Perkins, D. J. Pedro, E. C. Hansen, Org.
Lett. 2017, 19, 3755; (e) S. Sengmany, A. Vitu-Thiebaud, E. Le Gall, S.
Condon, E. Léonel, C. Thobie-Gautier, M. Pipelier, J. Lebreton, D.
Dubreuil, J. Org. Chem. 2013, 78, 370.
[16] Nakamura and co-workers reported an example of oxidatively induced
reductive elimination in Ni-catalyzed amination of aryl-Grignard reagents
with a chemical oxidant: L. Ilies, T. Matsubara, E. Nakamura, Org. Lett.
2012, 14, 5570.
[17] During the electrochemical between 1 and 2, the potential at the cathode
was measured to be ca. –1.5 V vs Ag/AgCl which corresponds to the
reduction of Ni(II) bipyridine complexes. The anodic potential was ca. +
1 V vs Ag/AgCl.
[18] Yield, reaction temperature, and reaction times based on the reaction of
the same starting materials (for substrates with multiple reports, data
from the latest one was chosen): (a) M. Keenan, J. H. Chaplin, P. W.
Alexander, M. J. Abbott, W. M. Best, A. Khong, A. Botero, C. Perez, S.
Cornwell, R. A. Thompson, K. L. White, D. M. Shackleford, M. Koltun, F.
C. K. Chiu, J. Morizzi, E. Ryan, M. Campbell, T. W. von Geldern, I.
Scandale, E. Chatelain, S. A. Charman, J. Med. Chem. 2013, 56, 10158;
(b) A. Winkler, K. Brandhorst, M. Freytag, P. G. Jones, M. Tamm,
Organometallics 2016, 35, 1160; (c) I. C. Lerma, M. J. Cawley, F. G. N.
Cloke, K. Arentsen, J. S. Scott, S. E. Pearson, J. Hayler, S. Caddick, J.
Organomet. Chem. 2005, 690, 5841; (d) X. Ding, M. Huang, Z. Yi, D. Du,
X. Zhu, Y. Wan, J. Org. Chem. 2017, 82, 5416; (e) M. Masui, M. Adachi,
H. Mikamiyama, A. Matsumura, M. Tsuno, JP 2009067784 A, 2009; (f)
A. Bozzoli, C. L. Branch, H. Marshall, D. J. Nash, WO 2006002956,
2006; (g) L. E. Hagopian, A. N. Campbell, J. A. Golen, A. L. Rheingold,
C. Nataro, J. Organomet. Chem. 2006, 691, 4890; (h) J. P. Wolfe, S. L.
Buchwald, J. Org. Chem. 2000, 65, 1144; (i) C. Singh, J. Rathod, V. Jha,
A. Panossian, P. Kumar, F. R. Leroux, Eur. J. Org. Chem. 2015, 6515;
(j) C.-Z. Tao, W.-W. Liu, J.-Y. Sun, Z.-L. Cao, H. Li, Y.-F. Zhang,
Synthesis 2010, 8, 1280; (k) S. S. Kampmann, B. W. Skelton, D. A. Wild,
G. A. Koutsantonis, S. G. Stewart, Eur. J. Org. Chem. 2015, 5995; (l) J.
C. Yang, D. Niu, B. P. Karsten, F. Lima, S. L. Buchwald, Angew. Chem.
Int. Ed. 2016, 55, 2531; (m) H.-J. Xu, F.-Y. Zheng, Y.-F. Liang, Z.-Y. Cai,
Y.-S. Feng, D.-Q. Che, Tetrahedron Lett. 2010, 51, 669; (n) D. Maiti, B.
P. Fors, J. L. Henderson, Y. Nakamura, S. L. Buchwald, Chem. Sci.
2011, 2, 57; (o) W. Fang, J. Jiang, Y. Xu. J. Zhou, T. Tu, Tetrahedron
2013, 69, 673; (p) Y. Wang, J. Ling, Y. Zhang, A. Zhang, Q. Yao, Eur. J.
Org. Chem. 2015, 4153; (q) C. A. Wheaton, J.-P. J. Bow, M. Stradiotto,
This article is protected by copyright. All rights reserved.

10.1002/anie.201707906
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Chao Li, Yu Kawamata, Hugh
Nakamura, Julien C. Vantourout,
Zhiqing Liu, Qinglong Hou, Denghui
Bao, Jeremy T. Starr, Jinshan Chen,
Ming Yan, and Phil S. Baran
R1
R2
Amines
Alcohols
Amides
Het
X
Het
O
N
[> 30 examples]
[ambient
temperature]
[practical]
[scalable]
[Ni] cat.
[simple electrodes]
R1
R2
X = Br,
Cl, I, OTf
[versatile]
Ar
O
[undivided cell]
[constant
current]
Ar
N
R1
[sustainable]
Electrochemically Enabled, Ni-
Catalyzed Amination
Amination, electrified: Arguably one of the most important types of bonds, the
C–N bond can now be forged under Ni-catalysis with the aid of electrochemistry.
Broad scope, scalability, sustainability, mildness, and rapid reaction rates are
some highlights of this interesting new reaction.
This article is protected by copyright. All rights reserved.