Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications

Article abstract of DOI:10.1021/jacs.9b01886

C-N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.

Full text of DOI:10.1021/jacs.9b01886

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Article
Electrochemically Driven, Ni-Catalyzed Aryl
Amination: Scope, Mechanism, and Applications
Yu Kawamata, Julien Christian Vantourout, David P. Hickey, Peng Bai, Longrui Chen, Qinglong Hou,
Wenhua Qiao, Koushik Barman, Martin A. Edwards, Alberto F. Garrido-Castro, Justine N. deGruyter, Hugh
Nakamura, Kyle W. Knouse, Chuanguang Qin, Khalyd J. Clay, Denghui Bao, Chao Li, Jeremy T. Starr,
Carmen Garcia-Irizarry, Neal Sach, Henry S. White, Matthew Neurock, Shelley D. Minteer, and Phil S. Baran
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Mar 2019
Downloaded from http://pubs.acs.org on March 24, 2019
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Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope,
Mechanism, and Applications
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Yu Kawamata,1,7 Julien C. Vantourout,1 David P. Hickey,2,7 Peng Bai,3,7
Longrui Chen,4 Qinglong Hou,4 Wenhua Qiao,4 Koushik Barman,2,7 Martin A.
Edwards,2,7 Alberto F. Garrido-Castro,1 Justine N. deGruyter,1 Hugh
Nakamura,1 Kyle Knouse,1 Chuanguang Qin,1 Khalyd J. Clay,1 Denghui Bao,4
Chao Li,1 Jeremy T. Starr,5 Carmen Garcia-Irizarry,5 Neal Sach,6 Henry
S. White,2,7 Matthew Neurock,*3,7 Shelley D. Minteer,*2,7 Phil S. Baran*1,7
1
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California
92037, United States.
2
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States.
3
Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455,
United States.
4
Asymchem Life Science (Tianjin), Tianjin Economic-Technological Development Zone, Tianjin 300457, China.
5
Discovery Sciences, Medicine Design, Pfizer Global Research and Development, 445 Eastern Point Road, Groton,
Connecticut 06340, United States.
6
Department of Chemistry, La Jolla Laboratories, Pfizer, 10770 Science Center Drive, San Diego, CA 92121,
United States.
7
NSF Center for Synthetic Organic Electrochemistry
ABSTRACT: C–N cross-coupling is one of the most valuable and widespread transformations in organic synthesis.
Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both
academia and industry. The current study presents the development and mechanistic understanding of an
electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series
of electrochemical, computational, kinetic, and empirical experiments the key mechanistic features of this reaction have
been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and
amine nucleophiles, including complex examples on oligopeptides, medicinally-relevant heterocycles, natural products,
and sugars. Full disclosure of the current limitations as well as procedures for both batch and flow scale-ups (100 gram)
are also described.
Introduction
halides remain particularly challenging substrates for C–
N cross-coupling. As an example, the coupling of
secondary alkyl amines and oligopeptides proceeds in low
yields even under the most modern sets of conditions.3
Given the ubiquitous nature of the aniline motif in drugs
and natural products, there is a constant need for the
development of methods for mild and selective C(sp2)–N
bond formation.1 Currently, the stalwart methods to
achieve cross-coupling of aryl halides and amines employ
Pd- (Buchwald-Hartwig) and Cu-based (Ullmann)
catalysts, which rank among one of the most employed
Synthetic organic electrochemistry enables precise redox
control to achieve either known transformations with less
waste
or
to
accomplish
otherwise-intractable
transformations.4 Examples from our own lab range from
the anodic generation of alkyl radicals from sulfinate
salts5 to the C–H oxidation of allylic6 and unactivated
sites.7 Interactions with industrial collaborators in both
process and medicinal chemistry inspired us to evaluate
an electrochemical approach to C–N cross coupling. In
2017, we reported a Ni-catalyzed aryl amination—coined
transformations
in
modern
pharmaceutical
development.2 Indeed, there exists a myriad of reports
investigating the classic limitations of these reactions
such as the use of strong base and elevated temperature.1
Despite these reports, there is still documented and
anecdotal evidence that several classes of amines or aryl
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as e-amination—that exhibited a wide substrate scope for
Page 2 of 14
and Stewart 17 independently addressed the air sensitivity
issue of Ni0 catalysts by developing innovative air stable
Ni precatalysts. In 2010, Nicasio et al. reported the first
room temperature amination reaction of heteroaromatic
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the coupling of aryl halides and triflates with amines,
alcohols, and amides.8 The reaction uses commercial
reticulated vitreous carbon (RVC) and Ni-foam electrodes
in concert with an inexpensive and abundant Ni catalyst
at room temperature. We speculated the success of this
transformation relies on the curious co-existence of
multiple different Ni-oxidation states in the same reaction
vessel, a task perfectly suited to electrochemistry. Critical
assessment of the original conditions revealed that aryl
halide coupling partners were largely limited to electron-
poor derivatives and attempts with historically
chlorides using
heterocyclic carbene complex as
a
bulky allylnickel chloride/N-
well-defined
a
precatalyst 1.18 Despite all these advances, the scope of the
Ni-catalyzed amination of aryl halides has been limited to
the coupling of secondary alkylamines and arylamines,
while primary alkylamines, one of the most significant
classes of amines for such cross coupling, have been
shown to couple only with activated aryl chlorides. As a
breakthrough for this problem, Stradiotto and Hartwig et
al. independently reported the Ni-catalyzed amination for
a broad range of unactivated aryl/heteroaryl chlorides
and bromides with primary aliphatic amines.19 However,
secondary aliphatic amines have proven to be poor
coupling partners under their developed conditions,
despite the use of a sophisticated ligand 2 or air-sensitive
catalysts 3. These pioneering developments highlight the
difficulty in finding an efficient, general and practical set
of conditions for the Ni-catalyzed amination of aryl
halides.
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challenging
heteroaryl
halides
were
deemed
unsatisfactory. Additionally, the choice of amine was
restricted to primary and secondary alkyl substrates;
functionalized amines, including amino acids and
oligopeptides, did not perform well.
The limitations in scope were attributed to a lack of
understanding in the catalytic system. For instance, it was
not clear what oxidation state of Ni was engaging in
oxidative addition, the identity of the rate-determining
step, or even the effect of simple experimental parameters
such as ligand, electrolyte, or solvent. Thus,
a
comprehensive understanding of the reaction mechanism
was needed in order to improve the previous set of
conditions, with particular interest in identifying the rate-
determining step, along with the ligation and oxidation
states of catalytically active species. In this Article, a
detailed reaction profile for e-amination is delineated,
enabled by the strategic union of nuanced electrochemical
analysis, DFT calculations, and empirical optimization.
This collaborative endeavor facilitated the development of
a robust, well-defined, catalytic system resulting in a
greatly expanded substrate scope.
As a totally different approach to improve Ni-catalyzed
amination, Hillhouse and co-workers demonstrated
dramatic acceleration of C–N reductive elimination by
using an oxidant in the context of aliphatic systems
(Figure 1C).20 In 2012, Nakamura and co-workers
suggested that facile C–N bond formation could be
achieved under similar oxidative conditions for aryl
systems as well.21 Therefore, the reductive elimination
event can be promoted by the intermediacy of a high-
valent Ni species accessible via oxidation. These results
point to a critical challenge to achieve Ni-catalyzed
amination of aryl halides; namely, the coexistence of a
low-valent Ni catalyst to favor oxidative addition with a
high-valent Ni catalyst to facilitate reductive elimination.
In 2016, Buchwald, MacMillan and co-workers elegantly
employed photoinduced electron transfer to allow mild
generation of active Ni0 species and oxidatively-induced
reductive elimination in the same pot using an Ir
photosensitizer (Figure 1D).22 Subsequently, our group
reported an electrochemical approach to Ni-catalyzed
amination (e-amination) that proceeds smoothly at room
temperature or below without the aid of a strong
inorganic base or co-catalyst, together with a promising
substrate scope (Figure 1E).8
Background and Historical Context
Figure 1 graphically outlines the history of Ni-catalyzed
C–N cross coupling.9 In 1950, Hughes and co-workers
reported the first example of Ni mediated C–N cross-
coupling between chlorobenzene and methylamine using
NiCl2 at 200 °C (Figure 1A).10 Several decades later,
Cramer11 and Cristau12 conducted comprehensive studies
on the C–N bond formation between chlorobenzene and
different amine coupling partners in the presence of a Ni0
catalyst at elevated temperatures (100 °C to 230 °C). The
limited substrate scope did not favor the uptake of this
potentially valuable transformation. It was not until 1997,
when Buchwald and co-workers explored Ni0-catalyzed
amination in a synthetic context, that significant interest
in Ni-catalyzed C–N cross coupling emerged.13 As
recognized, Ni-based amination reactions might be more
practical than related Pd-systems on large scale due to
cost considerations. Moreover, owing to its high reactivity
towards less reactive electrophiles such as aryl chlorides,
Ni-catalysis provides an alternative approach to
palladium and copper catalysis. However, the
requirements of air-sensitive Ni0 catalysts, high
temperatures, and strong alkoxide bases remained
important unsolved drawbacks that significantly curtailed
the adoption of such systems.
Mechanistic Studies of e-Amination
As alluded to above, e-amination likely involves
accessing disparate Ni-oxidation states; the initial low-
valent Ni (Ni0 or NiI) for oxidative addition and the
intermediate high-valent state (NiIII) required for efficient
reductive elimination must harmoniously coexist in the
same vessel. Realization of such contradictory redox
events in a simultaneous manner is challenging under
conventional chemical conditions but ideally suited to an
electrochemical setup. In this section a careful study to
demystify the underlying steps of the catalytic cycle is
presented.
Through the years, several groups tackled the challenges
and limitations associated with the Ni-catalyzed C–N
bond formation (Figure 1B). Nolan,14 Buchwald,15 Doyle,16
Extensive mechanistic studies involving detailed
electrochemical analysis and DFT calculation have led to
elucidation of the mechanistic underpinnings of the e-
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amination, which is now presented in Figure 2A. First, the
absorption coefficients.23 Interestingly, the data
ligation state of the NiII precatalyst was determined by
UV-Vis spectroscopy (Figure 2B [A]). Concentration
profiles for each NiLnBr2 ligation state (L = Mebpy) were
constructed using reported λmax values and molar
suggested a mixed and dynamic NiII ligation states, and
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4
predominant species varies depending on the ligand/NiII
ratio. Importantly, the ligation profile suggests
substantial portion of NiII
a
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Figure 1. (A) Discovery of Ni-catalyzed amination; (B) Improvement of catalytic systems; (C) Accelerated reductive
elimination via NiIII intermediate; (D) Ni-catalyzed amination with photo-induced electron transfer catalysis; (E)
Electrochemical, Ni-catalyzed amination (e-amination).
remains unligated when the ligand is present in only one
equivalent relative to NiII. The presence of unligated NiII
species is postulated to be undesirable because
overreduction of such species could lead to excessive Ni0
aggregation which would manifest as Ni-black deposition
on the cathode. Consequently, the UV-Vis study suggested
the possibility of more efficient catalysis with higher
ligand loading.
indicate facile ligand association/dissociation is
thermodynamically feasible. In reality the situation is
likely competitive binding between the ligand, DMF, and
amine nucleophile. Hence, the population of various NiII
complexes is dependent on the molar fractions of all
solution phase compounds, which creates a dynamic and
complex ligation situation.
To shed light on the electrochemical reduction of
NiII(Mebpy)nBr2, DMF solution of NiBr2•3H2O with
various concentrations of Mebpy was analyzed by square
wave voltammetry (SWV, Figure 2B [B]). There are two
distinct sets of redox features grouped in the range of -0.8
to -1.2 V and -1.5 to -1.8 V (all potentials are reported vs
Ag/AgNO3). Computational analysis of various
NiII(Mebpy)nBr2 oxidation states (See SI for details)
suggests that these experimentally observed redox
potentials are similar to the calculated values for the
Ni(II/I) and Ni(I/0) redox transitions. The large
difference between the two redox couples suggest that the
NiI species is likely formed predominantly under constant
current conditions to initiate oxidative addition.
In parallel to these experiments, we performed density-
functional theory (DFT) calculations were performed
using the M06-L exchange-correlation functional, 6-
31+G** basis set, and Stuttgart/Dresden effective core
potentials, which took into account solvation effects with
the SMD model using DMF as the implicit solvent to gain
more insight about this equilibrium. The binding of the
first Mebpy ligand (NiIIBr2 → NiIILBr2) is substantially
exothermic with the calculated energy difference between
unligated and mono-ligated species ΔE = -323 kJ/mol
(See SI for details). Although much smaller energy gains
are observed for the binding of the second and third
ligands due to steric constraints, the energy differences
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Electrochemical analysis of NiII(Mebpy)nBr2 reduction To experimentally verify the oxidation of NiII to NiIII,
intermediate NiII(tBubpy)(4-MeOC6H4)Br 12 was
synthesized independently and cyclic voltammetry of 12
was studied in the presence or absence of hexyl amine.
Neither 12 nor hexyl amine showed electrochemical
oxidation within the electrochemical solvent/electrolyte
window (Figure 2B [E][F] middle). However, the addition
of a large excess of hexyl amine into the DMF solution of
12 (100 equivalents with respect to Ni) results in the
formation of a complex that is oxidized irreversibly at
~0.8 V, which again indicates slow amine
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using a microelectrode suggests that the nature of this
step is complicated and the involvement of Ni0 cannot be
completely ruled out (See SI for details). However, the
combination of computational evidence, SWV analysis,
and the variety of known comproportionation pathways
resulting in the rapid formation of NiI lead us to the
conclusion that NiI is most likely the active species toward
oxidative addition.24
Cyclic voltammograms (CVs) of NiII(Mebpy)Br2 in the
absence and presence of 4-bromoanisole as an
electrophile indicated the ability of NiI to undergo
oxidative addition under the reaction conditions (Figure
2B [C][D]). A loss of electrochemical reversibility of the
Ni(II/I) redox couple upon addition of 4-bromoanisole
suggests oxidative addition is occurring rapidly relative to
the time scale of the CV (100 mV/s), indicating this step
is unlikely to be the rate-determining step. Reaction
energy profiles determined by DFT (Figure 2B [C][D],
bottom) further corroborate this conclusion; after
endothermic ligand dissociation at ∆E = 99 kJ/mol,
oxidative addition occurs with relatively low activation
9
NiIIL(Ar)Br
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coordination/deprotonation
on
the
intermediate 7.
Taken together, our results are consistent with the
mechanism illustrated in Figure 2A involving [A] the
dynamic ligation state of NiII precatalyst, [B] the
electrochemical reduction of NiII to a NiI species 4 at the
cathode, [C] the rapid oxidative addition of NiI to an aryl
halide generating a transient NiIII species 5, [D] a second
electrochemical reduction at the cathode resulting in a
stable NiII aryl intermediate 7, [E] the coordination of the
amine and rate-limiting deprotonation to the
intermediate 8, [F] the electrochemical oxidation at the
anode to generate a high-energy NiIII complex 6, followed
by rapid reductive elimination to produce the arylamine
product while regenerating 4 as the active catalyst. Basic
kinetic analysis is in good agreement with this
mechanistic picture (See SI for detail).
‡
energy ∆E = 73 kJ/mol. As indicated, this oxidative
addition is quite exothermic (∆E = -162 kJ/mol). This
means that all NiII(Mebpy)nBr2 (n = 1-3) could undergo
rapid oxidative addition upon reduction due to the
relatively small activation barrier and large energy gain,
even considering the unfavorable ligand dissociation to
create open coordination sites. DFT results also suggest
that the generated NiIII(Mebpy)(Ar)Br2 5a (Ar = 4-
CF3C6H4) can be readily reduced to NiII(Mebpy)(Ar)Br 7a
(Ered ~ -0.5 V vs Ag/AgNO3), which is experimentally
supported by the observed increase in reductive current
of the Ni(II/I) redox couple in the presence of aryl halide
substrate.
It should be noted the current mechanistic evidence does
permit the possibility of a self-sustaining NiI/NiIII cycle
(Figure 2A, step [G]) in which NiIIIL(Ar)Br2 5 is not
immediately reduced at the cathode, but undergoes amine
coordination/deprotonation to generate the intermediate
6. A similar NiI/NiIII cycle is also proposed by Miyake and
co-workers in their photochemical amination work
recently investigated.25 The feasibility of this NiI/NiIII
pathway was tested by performing the reaction with a
catalytic amount of electricity (Figure 2B [G]). While 5%
yield of 10 was obtained after 15 minutes electrolysis/3
hours stirring, the current efficiency was merely 27%,
which clearly suggests that continuous electrolysis is
necessary in order to achieve appreciable yields. This
apparent inefficiency of NiI/NiIII cycle could be explained
by the comproportionation of 4 and 5 to generate stable
NiII intermediate 7, considering redox potential of
Ni(II/I) obtained by SWV (~ -1 V) and calculated
reduction potential of 5a (-0.5 V). Therefore, the role of
electricity is constant regeneration of the key catalytic
species such as 4 and 6 throughout the duration of the
reaction.
The evidence for rapid oxidative addition suggests that
either amine coordination/deprotonation or reductive
elimination is rate-determining in the overall catalytic
cycle. Experimentally, the reaction with a sterically
demanding t-butyl amine became sluggish, indicating
that slow coordination/deprotonation of the amine
nucleophile is potentially rate-determining (Figure 2B
[E][F], top). To further determine the energetic
requirements
of
amine
coordination
versus
deprotonation, we examined the coupling of morpholine
with 4-trifluoromethylbromobenzene. The DFT results
showed that in the absence of steric constraints, the dative
amine coordination should be relatively facile, with
energy release around ∆E = -46 kJ/mol for this step, while
the subsequent deprotonation from the basic amine
causes a large energy increase (∆E = 193 kJ/mol) and
similarly large values for the ensuing reductive
elimination (∆E ~ 204 kJ/mol, black line). However,
when excess free amine molecules exist in solution, their
action as a base in the deprotonation of the coordinated
amine compensates for the large positive ∆E for this step
(similarly accomplished by the addition of an exogenous
base such as DBU). In addition, ∆E for reductive
elimination drastically decreases if the NiII complex is
oxidized to NiIII one. Overall, combination of additional
base and oxidation of NiII to NiIII afford an energetically
feasible reaction pathway.
Collectively, the mechanistic results suggest the
ligand/NiII ratio should be optimized to afford enhanced
reactivity by avoiding deleterious Ni0 deposit.
Furthermore, the addition of appropriate amount of
external base would appear to facilitate the rate-limiting
deprotonation. With these mechanistic nuances in mind,
we began our forays on expanding the scope of e-
amination.
Optimization
Minimal arylation of glutamic acid di-tert-butyl ester
(14) was observed under our previously reported e-
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amination conditions (Table 1A, conditions A, 0.1 mmol 1/1 to 2/1 was found to be far superior with a greater than
1
2
3
4
5
6
scale), and therefore it was selected as a model reaction to
validate the insights obtained from the above mechanistic
study. A slight improvement was observed by changing
the electrolyte from LiBr to tetra-n-butylammonium
bromide (conditions B). As suggested by the UV-Vis
spectroscopic study, increasing the ligand/NiII ratio from
four-fold increase in yield obtained (conditions C).
Although increasing the ligand loading further
(ligand/NiII = 3/1, conditions D) seemed to have no effect
on the yield, deposition of nickel black on the cathode was
observed in some cases when 20 mol% ligand was
employed; this
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A. Proposed mechanism (Boxed red letters indicate the presence of supporting evidence)
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4
5
6
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8
Comproportionation with 4
A
ArBr
N
N
Ar
Br
II
Ni
N
N
Ar
Br
Basic kinetic analysis:
III
Ni
NiII
Upper limit of the overall rate is dependent on the current.
Cathodic reduction
Br
5
7
C
B
At sufficient current, decreasing amine loading slows
down the reaction.
D
Stable intermediate
Cathodic reduction
Ligand reorganization
NiIIL
The reaction is sluggish with decreased loading of base.
HNR1R2
+ base
HNR1R2
N
N
I
Ni Br
4
G
E
Key detail:
Comproportionation with 5
NiIIL2
minor pathway
H-base
+ Br-
RDS
NiI/NiIII cycle is self-sustaining, but inefficient due to
comproportionation of 4 and 5.
9
NiIIL3
Electricity is beneficial for the regeneration of crucial
intermediates 4 and 6.
N
N
Ar
II
Ni
Anodic oxidation
N
Ar
III
Ni
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Displacement of bromide with amine nucleophile is
the rate-detemining step (RDS).
NR1R2
NR1R2
NR1R2
N
F
Ar
8
Br
6
B. Evidence supporting the mechanistic proposal
Electrochemical reduction of NiII
A
Dynamic equilibrium of Ni-bpy complex
NiII NiIIL
Concentrations of each Ni species were deconvoluted based on UV absorption. (L = Mebpy)
B
Square wave voltammetry
DFT calculation
NiIIL2
NiIIL3
Ligand reduction
NiII/NiI
NiI/Ni0
Substantial portion of Ni remains unligated at Ni/L = 1/1.
UV-Vis spectroscopy
Concentration of:
(---) Ni/L = 1/0
(▬) Ni/L = 1/1
(▬) Ni/L = 1/2
(▬) Ni/L = 1/3
NiL0
NiL
NiL2
NiL3
NiIIL2Br2
Calc. Ered (NiII/NiI) ~ – 0.43 V
Ni/L = (▬):1/0, (▬): 1/1, (▬): 1/2, (▬): 1/3
NiIL2Br2
Calc. Ered (NiI/Ni0) ~ – 2.0 V
NiI is generated under constant current conditions
C
D
Oxidative addition and following rapid reduction
E
F
Amine coordination/deprotonation and following reductive elimination
NiBr2•glyme (10 mol%)
Cyclic voltammetry
1 mM NiBr2•3H2O with 1 mM Mebpy in DMF
tBubpy (10 mol%)
NHR
Br
LiBr (0.2 M), DMA
H2N
R
+
–
–
1:1:0 Ni/L/4-bromoanisole
1:1:2 Ni/L/4-bromoanisole
4 mA, 4.5 h, rt
(+)RVC/(−)Ni, undivided cell
F3C
a: Peak from Ni(II/I) redox couple
c
F3C
3.0 equiv.
R = Cy: 72% (10)
R = tBu: <5% (11)
b: Disappearence of the peak with
4-bromoanisole
Rapid oxidative addition at NiI.
Amine coordination/deprotonation could be R.D.S.
Cyclic voltammetry
c: Increase of reduction current
1 mM NiII(4-MeOC6H4)(Mebpy)Br 12 in DMF
b
scan
→
Indication for the further
reduction of NiIII intermediate
(Supported by calculated
reduction potential of 5a)
a
Reductive
elimination TS
–
–
12
12 + 100x hexylamine
1
Oxidative addition TS
DFT calculation
+204
Oxidation of NiIIL(Ar)(amine)
(Values in kJ/mol)
N
= Mebpy
+40
+40
N
N
N
I
– 102
Ni Br
4a
+73
Formation of NiIIL(Ar)(amine) is observable with large
excess of amine, indicating sluggish substitution.
+180
+
4-CF3C6H4Br
DFT calculation
– 162
N
N
Ar
+193
(Values in kJ/mol)
III
Ni
Amine coordination TS
Calc. Ered = -0.5 V
– 102
N
Br
6a
HN
O
N
Ar
III
+99
N
N
N
N
I
Ni
O
Ni
+
N
Br
Br
5a
+116
N
N
Ar
Br
II
Ni
Br
9
Br
NiII
Ligand dissociation
NiII oxidation state
NiIII oxidation state
Oxidative addition
N
N
Ar
7a
19
H
N
NiIII oxidation state + 1 eq. morpholine
G
Inefficiency of non-electrochemical pathway
– 65
NiBr2•glyme (10 mol%)
O
13
tBubpy (10 mol%)
NHCy
NH2
Deprotonation
RDS
Reductive elimination
Amine coordination
Br
LiBr (0.2 M), DMA, rt
+
F3C
(+)RVC/(−)Ni, undivided cell
4mA/15min; then
no electrolysis/3 h
Reductive elimination proceeds at NiIII oxidation state.
F3C
10: 5%
Current efficiency 27%
Additional base facilitates deprotonation.
Figure 2. (A) Proposed mechanism; (B) Experimental and computational evidence to support the proposed mechanism;
subpanels [A]-[G] represent evidence for each elementary step.
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1
Journal of the American Chemical Society
phenomenon was almost completely suppressed at 30
6-7), as these solvents have ideal characteristics for
2
mol%. Therefore, conditions D were chosen as the
standard conditions for additional optimization with the
impact of several reaction parameters summarized in
Table 1B. As generally observed in transition-metal
catalyzed coupling reactions, the choice of ligand was
found to be crucial for the success of this reaction. After
extensive screening of different ligand architectures (see
SI for the complete list), the best result was obtained with
simple, unsubstituted bipyridine (bpy, entry 1). This is
fortuitous considering that the ligand is the most
expensive component of this amination system. Similar
results were also obtained with Mebpy (entry 2), whereas
more sterically demanding 6,6’-Mebpy completely shut
down the reaction (entry 3), indicating that this reaction
is rather sensitive to the steric environment around the Ni
catalyst. Pyridine-oxazoline ligands were found to be
similarly effective for the of 14 (entry 4), but later were
found not to be generally applicable. Reduced quantities
of DBU were found to be deleterious to the reaction (entry
5), in good agreement with DFT calculations that the rate-
determining step—displacement of the bromide on the
intermediate 7 with the amine nucleophile—is facilitated
by an external base (vide supra). Highly polar and aprotic
solvents were found to be suitable for this reaction
(entries
electrochemical synthesis: good solubility of the
electrolyte and the Ni-catalyst, high dielectric constant
required for efficient conductivity, and an appropriate
electrochemical window.26 With regard to the counterion
of the electrolyte, perchlorate and chloride were slightly
3
4
5
6
7
8
9
less efficient than bromide (entries
8
and 9).
Concentration of the electrolyte did not have a major
impact on the reaction despite the apparent voltage
difference (entry 10, terminal potential 3-4 V for 0.2 M vs
4-6 V for 0.05 M). Finally, it was found that Ni(bpy)3Br2
(17),27 a bench-stable and free-flowing solid with no
apparent hygroscopicity, was an ideal precatalyst, which
improves operational simplicity of this reaction by
removing the need for the preparing stock solutions of
hygroscopic NiBr2•3H2O (entry 11). The preparation of
this known precatalyst is exceedingly simple as illustrated
in Table 1C and is currently being commercialized (Sigma-
Aldrich ALD00608).
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
Scope and Applications of e-Amination
Encouraged by the successful arylation of glutamic acid
ester 14, the generality of the revised electrochemical C–
N bond formation on various amino acid esters was
explored (Table 2A). Using readily-available amino acid
hydrochloride salts as starting materials, various amino
acid esters (including non-canonical amino acids) were
arylated efficiently with 4-trifluoromethylbromobenzene.
Reactions (0.1 mmol scale) were conveniently carried out
in an undivided cell with a readily-available RVC anode
and a nickel foam cathode. Yields under the previous
conditions are shown in parentheses, which highlight the
drastic improvement afforded under the revised
conditions. Although there have been multiple precedents
for the arylation of amino acid esters employing
palladium28, and copper catalysis,29 this is the first
example of successful C–N bond formation on amino acid
esters by Ni-catalysis. Of note, the sulfide in 24 and the
indole ring in 26—both of which are commonly
considered to be labile under oxidative conditions—were
found to be compatible.
A. Initial re-optimization
4-CF3C6H4Br (2.0 equiv.)
O
NiBr2•3H2O (10 mol%)
tBubpy (xx mol%)
electrolyte
tBuO2C
O
OtBu
tBuO2C
OtBu
3 Cl
NH
DBU (3.0 equiv.)
DMA, rt, 4 mA, 3 h
(+)RVC/(– )Ni, undivided cell
NH
14
15
F3C
(0.1 mmol, 1.0 equiv.)
Conditions
Electrolyte
ligand loading
Yield
A
B
LiBr (0.2 M)
10 mol%
10 mol%
<5%
9%
nBu4N•Br (0.05 M)
C
D
nBu4N•Br (0.05 M)
nBu4N•Br (0.05 M)
20 mol%
30 mol%
38%
38%
B. Impact of various reaction parameters
R
R
Entry
Yield
Change from conditions D
52%
40%
<5%
40%
5%
1
2
Ligand = bpy
Ligand = Mebpy
Ligand = 6,6’-Mebpy
Ligand = 16
N
N
As an extension of this scope, N-acetyl-4-bromoindole
29 was chosen (Table 2B) as an emblematic substrate for
challenging C–N coupling.30 Similar systems were
reported to require large amount of copper salt for
traditional Ullmann coupling conditions,31 and
applications of Buchwald-Hartwig coupling was found to
be challenging.32 Not surprisingly, our first-generation
conditions for e-amination failed to deliver the desired
coupling product 31 (entry 1). The optimized conditions
documented herein did in fact afforded 31 in 16% yield
(entry 2), and ultimately a small screening of electrolyte,
amount of base, ligands, nickel source (entries 3-7) was
required to arrive at a workable solution (entry 7, 32%).
Based on the conditions in entry 7, scale-up of the reaction
was attempted with a slight change of substrate and
electrolyte concentration. Fortunately, e-amination
performed on a larger scale delivered superior yield,
presumably due to the higher concentration of the
substrate and more appropriate current density (entry 8,
51%). This small study demonstrates that like other C–N
cross couplings, re-adjustment of reaction parameters
R = H : bpy
R = tBu : tBubpy
R = Me : Mebpy
3
4
5
1.0 equiv. DBU
6
42%
27%
45%
42%
54%
63%a
Solvent = NMP
Solvent = DMF
N
N
7
Me
Me
6,6’-Mebpy
Et4N•ClO4 (0.05 M)
8
Et4N•Cl (0.05 M)
nBu4N•Br (0.20 M)
10 mol% Ni(bpy)3Br2, nBu4N•Br (0.20 M), 4 h
9
O
10
11
N
N
16
a 66% ee was determined by chiral HPLC analysis.
C. Synthesis of Ni precatalyst
bpy (3.0 equiv.)
NiBr2•3H2O
Ni(bpy)3Br2
17
MeOH, rt, 10 min
87% yield
Free-flowing, non-hygroscopic
Sigma-Aldrich cat # = ALD00608
~80 g scale preparation
X-Ray structure
Table 1. (A) Initial re-optimization of amino acid arylation.;
(B) Effect of various reaction parameters. These entries were
performed in 0.1 mmol scale; (C) Simple preparation of the
precatalyst Ni(bpy)3Br2 17.
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such as precatalyst, ligand, and concentration of the
substrate may be necessary for the success of certain
substrate classes.
Page 8 of 14
heterocycles included in this table are privileged scaffolds
in pharmaceuticals.33 The high functional group tolerance
of this reaction deserves further comment. For instance,
the
1
2
3
4
5
6
7
A. Scope of Amino acid esters
O
O
Ni(bpy)3Br2 (10 mol%)
DBU (3.0 equiv.)
Br
R1
OR2
R1
OR2
3 Cl
(0.1 mmol)
+
nBu4N•Br (0.2 M)
DMA, rt, 4 mA, 3 h
(+)RVC/(– )Ni, undivided cell
NH
F3C
Ar
NH
Ar = 4-CF3-C6H4
(0.2 mmol)
8
9
CO2Me
NH
Me
CO2Me
Ph
CO2Me
NH
Me NH
Ar
Ar
Ar
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
18: 54% (<5%)a
19: 70% (24%)a
86% ee
20: 53% (<5%)a
85% ee
Me
tBuO
CO2Me
NH
CO2tBu
tBuO
Me
CO2Me
NH
NH
O
Ar
Ar
Ar
21: 47% (<5%)a
22: 49% (<5%)a
82% ee
23: 69% (<5%)a
64% ee
dr > 10:1
CO2tBu
NH
CO2tBu
NH
CO2Me
NH
NHBoc
MeS
N
Ar
Ar
Ar
Boc
24: 59% (<5%)a
78% ee
25: 54% (<5%)a
62% ee
26: 57% (47%)a
78% ee
Non-canonical amino acids
CO2tBu
BocHN
CO2tBu
NH
Ar
NH
27: 70% (<5%)a
99% ee
Ar
(±)-28: 51% (5%)a
B. Application to total synthesis - Optimization
Br
Me
HN
Me
Ni(bpy)3Br2 (10 mol%)
nBu4N•Br (0.2 M)
DBU (3.0 equiv.)
Me
O
CO2Me
+
Me
OMe
3 Cl
30 (1.7 equiv.)
DMA (0.05 M), rt, 4 mA, 4 h
(+)RVC/(– )Ni, undivided cell
NH
N
Table 3. Amination of heteroaryl halides with N-Boc-
piperazine in 0.2 mmol scale. () indicates yield under
previous conditions (conditions A)
Ac
N
Ac
a
29
31
(0.1 mmol, 1.0 equiv.)
Me
N
Entry
Change from standard conditions
Yield
free anilinic amine in 39 remained untouched. Sulfur-
containing heterocycles afforded the desired coupling
products 40-43, despite the fact that sulfur is commonly
considered to be poisonous to transition-metal catalysts
with the C–S bond being particularly labile in Ni-
catalysis.34
First generation conditions (conditions A)
None
N
1
2
0%
N
32
16%
Indolactam V
LiBr (0.2 M)
3
4
5
6
11%
20%
6%
Me
Me
Me
NiBr2•3H2O (10 mol%), Ligand = bpy (30 mol%)
NiBr2•3H2O (10 mol%), Ligand = 16 (30 mol%)
NiBr2•3H2O (10 mol%), Ligand = 32 (30 mol%)
OH
H
N
N
10%
O
NiBr2•glyme (19 mol%), Ligand = 32 (75
32%
7
8
mol%), LiBr (0.2 M)
To further explore the capability of electrochemical C–N
bond formation, the reaction was applied to more
challenging substrates. Table 4A illustrates C–N bond
formation on nucleoside analogs in 0.05-0.1 mmol scale.
TBS-protected 1-(4-bromophenyl)ribose was successfully
coupled with both primary and secondary amines. This
method enables rapid access to various substituted 1-
arylribose, which is potentially useful for the study of
artificial base-pairs to expand the genetic alphabet.35
Likewise, arylation of 3-amino thymidine was also
successful without protection on thymine. More
interestingly, the powerful electrochemical C–N bond
formation furnished a unique dinucleoside analog 5oa
linked by an aniline moiety, which is a highly intriguing
linker due to its non-hydrolyzable nature.
3.0 mmol scale with NiBr2•glyme (19 mol%)
51%a
(88% ee)
and 32 (75 mol%)
N
H
a LiBr (0.89 M), DMA (0.1 M), 100 mA, 7 h.
Table 2. (A) Arylation of amino acid esters in 0.1 mmol
() indicates yield under previous conditions
(conditions A). (B) Optimization for the coupling of N-
a
scale.
acetyl-4-bromoindole 29 with valine methyl ester 30.
In our initial report, a limited substrate scope of
heteroaryl amination was documented.8 Considering that
heteroaryl amines are essential in medicinal chemistry, a
more complete survey of this class of molecules was
undertaken. N-Boc-piperazine was chosen as the amine
coupling partner, since: (1) this motif frequently appears
in pharmaceuticals, and (2) secondary amines are
sometimes troublesome coupling partners even with
state-of-the-art palladium catalysis at room temperature.3
As shown in Table 3, a wide range of heteroaryl halides
deriving from quinoline (33, 34), indole (31, 35),
benzofuran (36), pyridines (37-39), thiophene (40, 41),
thiazole (42), pyrimidine (43) and azaindazole (44) were
successfully coupled with N-Boc-piperazine in 0.2 mmol
scale under essentially identical conditions optimized for
amino acid esters. Both aryl bromides and chlorides were
found to be competent in this reaction. Most of the
Another interesting application of this method was
found in oligopeptide modification (Table 4B). Slight
modification to the established conditions were made to
achieve synthetically useful efficiency in 0.05 mmol-scale
reactions. Thus, the use of a LiBr electrolyte was found to
give higher yield than tetra-n-butylammonium bromide,
and DBU was omitted by using an excess amine coupling
partner to avoid undesired racemization. With these
modifications,
e-amination
on
pendant
4-
bromophenylalanine residues proceeded surprisingly
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Journal of the American Chemical Society
well with only a catalytic amount of Ni precatalyst in Previously, 58 was prepared by four steps from
salicylaldehyde in 26% overall yield,38 though a more
straightforward synthesis is possible by using Pd-
catalyzed amination to form the C–N bond between
benzofuran fragment and piperidine.39 As an alternative
approach, e-amination of 59 with N-Boc-piperidine was
evaluated to prepare a closely-related compound 36.
After a brief investigation, it was found that tetra-n-
butylammonium bromide could be replaced with
inexpensive sodium bromide to further reduce the cost of
the production. Moreover, the RVC electrode was found
to be replaceable with an even simpler carbon felt
electrode. A 100 g scale reaction was successfully carried
out by employing a flow system with only a small drop in
yield (64% in 100 g vs 79% in 0.2 mmol). Notably, the
multi-frame
1
2
3
4
5
6
7
8
several cases. Various functional groups in canonical
amino acids were tolerated in protected form, as
demonstrated in the products 51-55. More strikingly, the
unprotected nona-peptide afforded the desired amination
product 56 in appreciable yield. To the best of our
knowledge, this is the first example of Ni-catalyzed C–N
bond formation on oligopeptides, which holds promise for
further application of such chemistry to biomolecule
modifications. This work is a complementary addition to
the growing area of transition-metal mediated
oligopeptide functionalization.36
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As we previously demonstrated in a batch decagram
scale reaction (Table 4C, top), the e-amination is easily
scalable. Compound 58 is an important intermediate for
the synthesis of vilazodone, a drug recently approved by
FDA for the treatment of major depressive disorder.37
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Page 10 of 14
O
N
A: C– N bond formation on nucleosidesa
O
R
1
2
3
4
5
6
N
Boc
N
O
N
O
O
Me
Me
NH
NH
O
NH
N
Me
N
TBSO
NH
TBSO
O
N
O
O
O
TBSO
TBSO
TBSO
TBSO
O
O
NH
TBSO
NH
O
O
7
8
9
R = H (50a)
R = CH2NMeAc (50b)
TBSO
OTBS
F3C
TBSO
OTBS
45: 50%
TBSO
OTBS
40% (a:b = 1:2.6)
46: 71%
47: 34%
48: 56%
49: 62%
TBSO
OTBS
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
B: C– N bond formation on oligopeptides
NHTrt
O
O
H
N
O
BocHN
O
OtBu
N
H
PGHN
CO2R
PGHN
CO2R
R1
AcHN
Amine (3.0 equiv.)
N
O
Me
O
N
H
Ni(bpy)3Br2 (30 mol%)
O
OMe
LiBr (4.0 equiv.)
DMA (0.025 M)
4 mA, 6 h, rt
O
N
N
Br
N
51: 51%
(+)RVC/(– )Ni, undivided cell
0.05 mmol
R2
O
52: 57%
HO
NH
O
56: 11% with 60 equiv amine and 100 mol% [Ni]
OtBu
O
N
Me
Me
NH2
NBoc
OR
H
NHAc
OtBu
Me
O
Me
N
N
O
O
NH
O
O
O
H
N
H
H
N
O
AcHN
N
OMe
N
H
N
H
NH
AcHN
N
N
O
N
O
O
H
H
O
N
H
H
H
O
O
O
tBuO
N
N
N
NH2
NH
N
N
N
H
H
H
S
O
O
O
O
PbfHN
N
Me
NH2
53: R = H 23%
54: R = Me 32% (45% with 100 mol% [Ni])
H
55: 39%
O
O
OH
C: Large scale amination
Batch scale-up8
Glass chamber in an argon bag
RVC plates
NiBr2•glyme (10 mol%), tBubpy (10 mol%)
LiBr (4 equiv.), DMA (0.1 M)
NBoc
Br
N
HN
NBoc
+
F3C
(+)RVC/(– )Ni, undivided cell
constant current, rt, 7 h
F3C
22.5 g
Ni foam plates
57: 66%
[22.5 gram scale]
(100 mmol)
300 mmol
Previous synthesis 36
Electrochemical flow setup
O
Reduction of
nitro group
Nitration
O
O
OH
CO2Et
•HCl
N
Piperazine
formation
NH2
N
Furan formation
CHO
HN
CN
58: 26% overall yield
N
100 g e-amination (Flow)
O
N-Boc-piperidine (1.5 equiv.)
NiBr2(10 mol%), bpy (50 mol%)
O
CO2Et
CO2Et
NH
NaBr (0.2 M), DBU (2.0 equiv.)
N
Br
DMA (0.1 M), r.t., (+)C felt/(– )C felt
59
Vilazodone
36: 64%
N
Peristaltic pump
Approved antidepressant
commercially available
Multi-frame cell
External reservoir
(79% in 0.2 mmol scale)
Boc
a
n
Table 4. (A) C–N bond formation on nucleosides. Reaction conditions: 10 mol% Ni(bpy)3Br2, Bu4N•Br (0.2 M), DBU (2.0
equiv.), DMA (0.025-0.05 M), (+)RVC/(−)Ni, 4 mA, r.t. in undivided cell. (B) C–N bond formation on oligopeptides. (C)
Synthesis of arylomycin analogs. (D) Scale-up synthesis of compound 36.
similar or slightly higher yields under the modified
conditions. With regard to the applicability of other types of
nitrogen nucleophiles, a lactam and ammonia were both
found to be competent (70, 71). However, e-amination with
aniline and sulfonamide were not successful due to low
nucleophilicity of these coupling partners (69, 72). Coupling
with oxygen-based nucleophile was also found to be feasible
as exemplified in the formation of 73-75. Phenol was not a
suitable nucleophile likely due to its susceptibility toward
oxidation (76). In contrast to relatively predictable reactivity
of nucleophiles, the reactivity of the aryl bromides seems to
be rather difficult to interpret. Some heteroaryl bromides
gave complex mixtures, whereas others were unreactive. It
implies that multiple mechanistic scenarios could exist in e-
cell set up used in this scale-up study accommodates
various reaction scales simply by changing the number of
frames (See SI for details). This scale-up example clearly
illustrates the simplicity and low-cost of scaling up e-
amination.
Applicability
of
other
nucleophiles
and
limitations of the e-amination
Finally, the efficiency of the modified conditions (higher
ligand loading together with the use of DBU as an external
base) over the first-generation conditions (Conditions A) as
well as limitations of e-amination in a preparative scale are
illustrated in Table 5. In the case of substrates previously
described,8 the desired products 60-68 were obtained in
amination,
depending
on
the
substrate
used.
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Journal of the American Chemical Society
relevant to drug discovery. It is anticipated that the
1
2
3
current work will be an important step in accelerating the
adoption of this useful means of controlling redox states
in organic synthesis.
4
5
6
7
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
8
9
Experimental procedures, additional electrochemical
analysis data, the detail of DFT calculation and compound
characterization data. (PDF)
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
X-ray crystallographic data for compound 17 (CIF)
AUTHOR INFORMATION
Corresponding Author
*mneurock@umn.edu
*minteer@chem.utah.edu
*pbaran@scripps.edu
Present Addresses
†Peng Bai: Department of Chemical Engineering, University
of Massachusetts, Amherst, MA, 01003, United States.
†Alberto F. Garrido-Castro: Department of Organic
Chemistry, Universidad Autónoma de Madrid, Madrid,
28049, Spain.
† Chuanguang Qin: Department of Applied Chemistry,
School of Natural and Applied Sciences, Northwestern
Polytechnical University, 127 Youyixilu, Xi'an, 710072,
Shaanxi, P. R. China.
Table 5. Comparison to previously-successful substrates and
a
limitations of e-amination in preparative scale.
obtained from ref 8. 10 equiv. of nucleophile used. 20
equiv. of water used.
Data
b
c
† Chao Li: National Institute of Biological Sciences, Beijing, 7
Science Park Road ZGC Life Science Park, Beijing, China.
Oxidative
addition,
rather
than
amine
coordination/deprtonation might be the possible rate-
determining step in some of these cases. It also needs to
be pointed out that electron-rich aryl halides are prone to
give lower yields due to slow oxidative addition or
oxidative degradation of the products, although e-
amination smoothly took place on indole (35),
benzofuran (36), thiophene (40) and electron-neutral
substrates such as nucleoside analogs and oligopeptides.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
Funding Sources
Financial support for this work was provided by NIH (GM-
118176), CCI NSF Synthetic Organic Electrosynthesis Center
(#1740656), George E. Hewitt foundation for postdoctoral
fellowship (Y.K.), Universidad Autónoma de Madrid (A.F.G.-
C.), NSF GRFP for graduate support (D.S.P. and J.N.D.) and
JSPS for postdoctoral fellowship (H. N.).
Conclusion
The present study commenced with a deep interrogation
of the mechanism of e-amination in order to demystify the
nature of the catalytic cycle and aid in the elucidation of
more general and robust conditions. By applying a range
of techniques, from empirical optimizations to DFT
calculations and kinetic studies, a second-generation set
of conditions was invented using a simple Ni-precatalyst.
The scope of e-amination was significantly expanded and
supplemented with multiple applications. The use of e-
amination is not limited to small scale applications and
simple setups for both batch and flow scale up are
delineated. Finally, this unique method for C–N bond
formation has been field tested in multiple programs
within the labs of our industrial collaborators. The
mainstream adoption of electrochemistry in areas like
medicinal chemistry has been stymied by a lack of
standardized equipment and reaction classes that are
ACKNOWLEDGMENT
We thank Prof. Donna Blackmond for assistance in
interpreting the kinetics data. We also thank Dr. D.-H.
Huang and Dr. L. Pasternack for NMR spectroscopic
assistance, Prof. A. L. Rheingold, Dr. C. E. Moore and Dr.
Milan Gembicky for X- ray crystallographic analysis, Dr.
Jason Chen and Brittany Sanchez (Scripps Automated
Synthesis Facility) for assistance with HPLC, HRMS and
LCMS. We gratefully acknowledge Dr. Jinshan Chen for
helpful discussions during the early stage of this work. We
also greatly appreciate insightful discussion with Dr. Martin
D. Eastgate, Dr. Amy C. Hart and Dr. Jennifer X. Qiao.
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