General Paradigm in Photoredox Nickel-Catalyzed Cross-Coupling Allows for Light-Free Access to Reactivity

Article abstract of DOI:10.1002/anie.201916398

Self-sustained Ni^I/III cycles are established as a potentially general paradigm in photoredox Ni-catalyzed carbon–heteroatom cross-coupling reactions through a strategy that allows us to recapitulate photoredox-like reactivity in the absence of light across a wide range of substrates in the amination, etherification, and esterification of aryl bromides, the latter of which has remained, hitherto, elusive under thermal Ni catalysis. Moreover, the accessibility of esterification in the absence of light is especially notable because previous mechanistic studies on this transformation under photoredox conditions have unanimously invoked energy-transfer-mediated pathways.

Full text of DOI:10.1002/anie.201916398

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International Edition
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Accepted Article
Title: General Paradigm in Photoredox Ni-Catalyzed Cross-Coupling
Allows for Light-Free Access to Reactivity
Authors: Rui Sun, Yangzong Qin, and Daniel G. Nocera
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201916398
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10.1002/anie.201916398
Angewandte Chemie International Edition
RESEARCH ARTICLE
General Paradigm in Photoredox Ni-Catalyzed Cross-Coupling
Allows for Light-Free Access to Reactivity
Rui Sun, Yangzhong Qin and Daniel G. Nocera*
Abstract: We establish self-sustained Ni(I/III) cycles as a potentially
general paradigm in photoredox Ni-catalyzed carbon-heteroatom
cross-coupling reactions by presenting a strategy that allows us to
recapitulate photoredox-like reactivity in the absence of light across
a wide range of substrates in the amination, etherification, and
esterification of aryl bromides, the latter of which has remained,
hitherto, elusive under thermal Ni catalysis. Moreover, the
accessibility of esterification in the absence of light is especially
notable since previous mechanistic studies on this transformation
under photoredox conditions have unanimously invoked energy
transfer-mediated pathways.
30
28
Zn
Ni
58.69
65.38
Introduction
Transition metal catalyzed cross-coupling of aryl halides with
nucleophiles is a powerful strategy employed in the construction
of the sp2 carbon-heteroatom bonds that are ubiquitous in
pharmaceutical and natural products.[1] Although Pd-catalyzed
cross-coupling reactions constitute an established field, there
has been interest in developing Ni-catalyzed systems due to the
broader range of accessible electrophiles and innately more
sustainable qualities of Ni as an earth-abundant metal.[2]
Traditionally, the development of these methodologies
emphasizes the design of elaborate and specialized ligands
(Figure 1A) to make the stereoelectronic properties of the metal
center amenable towards the elementary steps that constitute a
cross-coupling cycle.[3] However, recent developments in
photoredox catalysis (Figure 1B) have demonstrated that these
transformations can be effected using simple commercially
available ligands under exceptionally mild conditions through the
synergistic action of a photocycle and a transition metal cross-
coupling cycle.[4] Several seminal studies in this field have
demonstrated that the amination, etherification, and
esterification of aryl bromides can be realized under Ni
photoredox catalysis using either no exogenous ligand
(amination) or simple bipyridyl ligands (etherification and
esterification), whereby an Ir(III) photocatalyst has been
proposed to generate Ni(II) excited state or Ni(III) intermediates
that are necessary for the kinetically challenging reductive
elimination of carbon-heteroatom bonds.[5] The interest ignited
by these discoveries has led to an immense and ever-growing
body of photochemical literature that report the recapitulation of
this Ni-catalyzed carbon-heteroatom cross-coupling reactivity
across a myriad of different photocatalyst combinations.[6]
Figure 1. Strategies for carbon-heteroatom cross-coupling: A traditional
thermal catalysis, ligand-controlled reactivity; B redox catalysis, oxidation
state-controlled reactivity; C this work, light-free access to photoredox-like
oxidation state-controlled reactivity.
methodologies has been comparatively underemphasized. In
particular, the energy cost of the photons employed (typically
blue, violet, or near-UV) in photoredox chemistry has often been
overlooked, despite the importance of Energy Intensity, defined
as energy consumption per unit mass of product, as a metric in
quantifying the sustainability of chemical processes.[7]
Furthermore, the majority of photocatalysts used are based on
precious metals such as iridium and ruthenium, and the reaction
mechanisms, an understanding of which is critical for rational
optimization towards more energy efficient and sustainable
methodologies, remain largely undefined. Previous work by our
group demonstrated that, in contrast to the closed photocycles
commonly proposed for photoredox cross-coupling reactions
(Scheme 1, A and B),[5, 6b-d, 8] a Ni(I/III) cycle (Scheme 1, C) may
be operative in the reaction between aryl bromides and alcohols
to form O-aryl ethers, where the photon serves to resuscitate the
cycle once the catalytically active Ni(I) or Ni(III) species are
depleted to form inactive Ni(II) complexes via a highly exergonic
comproportionation reaction, akin to what had been proposed for
the related electrochemical amination of aryl bromides.[9] Given
the various mechanistic possibilities proposed for photoredox Ni
cross-coupling,[8] it was unclear if similar dark cycles were
operative in other reactions. A productive dark cycle has
important ramifications for methodology development and
optimization, as it implies that the necessity of both continuous
energy input and precious metal photocatalysts can be entirely
obviated while preserving all the advantages of photoredox
cross-coupling systems (i.e. exceptionally mild conditions using
inexpensive and readily accessible ligands under Ni catalysis).
Despite numerous examples of Ni(I/III) cross-coupling cycles,[10]
the propensity of Ni to undergo one-electron redox processes
has made elucidation of reaction mechanisms challenging in
many cases,[11] and the factors that dictate whether a reaction
occurs through a Ni(0/II) or a Ni(I/III) cycle are not fully
Notwithstanding the high chemical efficiency achievable
under photoredox cross-coupling, the sustainability of these
R. Sun, Dr. Y. Qin, and Prof. Dr. D. G. Nocera
Department of Chemistry and Chemical Biology
Harvard University
12 Oxford St., Cambridge MA 02138, United States of America
E-mail: dnocera@fas.harvard.edu
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201916398
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RESEARCH ARTICLE
Scheme 1. Mechanisms invoked in photoredox Ni-catalyzed cross-coupling: A energy transfer-mediated catalysis; B oxidation state modulation; C thermally-
sustained Ni(I/III) cycle.
understood. Hence, a general strategy for selectively engaging
the Ni(I/III) redox couple under thermal catalysis has remained
largely elusive.
Table 1. Optimization of light-free amination.
Herein, we demonstrate that photoinitiated, thermally
sustained reactivity may constitute a general paradigm in
photoredox nickel cross-coupling by showing that the amination,
etherification, and esterification of aryl bromides are all
accessible under strictly thermal conditions. To this end, we
show that photoredox-like reactivity can be recapitulated in the
complete absence of a photon source by replacing the Ir
photocatalyst and light with a substoichiometric amount of an
earth-abundant heterogeneous reductant. Although the
combination of a mild heterogeneous reductant and NiX2
precatalysts has been previously utilized in reductive coupling
reactions and as a convenient substitute for sensitive Ni(0)
catalysts,[12] we demonstrate that the biphasic nature of the
reduction process can allow for selective access to a Ni(I/III)
cycle by ensuring that the active Ni(I) and Ni(III) intermediates
are maintained at sufficiently low concentrations to mitigate
Piperidine
Ar-NR2
Entry R group
Base (equiv)
T (°C)
equiv
Yield (%)
1
2
3
4
5
6
7
CF3
CF3
CF3
CF3
CF3
CH3
CH3
1.5
1.5
1.5
1.5
1.5
2.0
2.0
NEt3 (1.5)
DABCO (1.5)
RT
RT
RT
40
73[a]
91[a]
88[a]
72[a]
53[a]
27[b]
56[b]
DABCO (0.1) + NEt3 (1.5)
DABCO (0.1) + NEt3 (1.5)
DABCO (0.1) + NEt3 (1.5)
DABCO (1.8)
60
RT
RT
Quin. (1.8)
comproportionation. Using this approach,
a
variety of
[a] Yields determined by 19F NMR. [b] Yields determined by 1H NMR. DMA =
N,N-dimethylacetamide. DABCO
heteroatomic nucleophiles (amines, alcohols, and carboxylic
acids) can be successfully cross-coupled with aryl bromides in
the absence of light or precious metal photocatalysts under
conditions which otherwise bear resemblance to the parent
photoredox systems.
= 1,4-diazabicyclo[2.2.2]octane. Quin. =
quinuclidine.
ethane) furnished the expected aniline product in the cross-
coupling between 4-bromobenzotrifluoride and piperidine in the
presence of triethylamine at room temperature without
exogenous ligand (Entry 1), thereby recapitulating the reactivity
observed under photoredox conditions. Upon further
optimization, 1,4-diazabicyclo[2.2.2]octane (DABCO) was found
to be a more effective base (Entry 2) and elevated temperatures
were deleterious (Entries 3-5). For more electron rich arenes
(e.g. 4-bromotoluene), quinuclidine was found to be superior to
DABCO in furnishing cross-coupled product (Entries 6 and 7),
consistent with its higher basicity facilitating the requisite
deprotonation of amine.[13] It is noteworthy that the superior
performance of DABCO and quinuclidine under this light-free
protocol parallels their status as the most effective bases in
previously reported photoredox-mediated ligand-free amination
reactions, consistent with the existence of a common productive
dark cycle as we propose.
Results and Discussion
We began our investigation by studying the photoredox-
mediated ligand-free amination of aryl bromides, for which we
measured a quantum yield of Φ = 2.7 ± 0.1 (see Supporting
Information). This confirms the presence of a dark cycle, in
contrast to the closed Ni(0/II/III/I) cycle previously proposed for
this reaction.[5a] Thus, we hypothesized that Zn(0), a commonly
employed reductant in Ni cross-coupling catalysis, could replace
the combination of photocatalyst and light due to the
heterogeneity of the reduction process leading to the slow
formation
of
Ni(I)
equivalents,
thereby
disfavoring
comproportionation.
As shown in Table 1, a substoichiometric amount of Zn(0)
metal in combination with (dme)NiBr2 (dme = 1,2-dimethoxy-
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10.1002/anie.201916398
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RESEARCH ARTICLE
Table 2. Optimization of light-free etherification.
of halides required to stabilize in situ generated Ni(I) species.
For less active aryl bromides, the use of 7-methyl-1,5,7-
triazabicyclo[4.4.0]dec-5-ene (MTBD) in place of DBU resulted
in superior yields (Entries 4 and 5), whereas increasing the base
concentration had a deleterious effect (Entry 6), consistent with
the coordinative inhibition of catalytic intermediates by amine
bases previously observed for related Pd-catalyzed systems.[15]
We next targeted cross-coupling carboxylic acids with aryl
bromides to generate the respective O-aryl esters. As shown in
Entry 1 of Table 3, we observed the formation of the desired
ester in the reaction between 4´-bromoacetophenone and
benzoic acid in the presence of (dtbbpy)NiBr2 and Zn(0) metal.
Reaction optimization revealed HN(tBu)(iPr) to be the most
effective base (Entries 2 and 3) and, in contrast to amination and
etherification, a higher Zn(0) loading was found to be necessary
for efficient cross-coupling (Entry 4). Increasing the amount of
acid and base beyond two equivalents did not increase the yield
(Entry 5). The use of tetrabutylammonium benzoate in place of
benzoic acid and base gave a comparable yield (Entry 6),
suggesting that the active nucleophile engaging with the nickel
catalyst may be carboxylate rather than carboxylic acid.
Entry
R group
Base (equiv)
Solvent Ar-OR Yield (%)[a]
1
2
3
4
5
6
Ac
Ac
NEt3 (3.0)
DBU (1.1)
MeCN
THF
87
95
Ac
Quin. (0.1) + K3PO4 (3.0)
DBU (1.1)
THF
N.D.
14
CH3
CH3
CH3
THF
MTBD (1.1)
THF
37
MTBD (2.0)
THF
5
[a] Yields determined by 1H NMR. Ac
=
acetyl. DBU = 1,8-diazabi-
cyclo[5.4.0]undec-7-ene. MTBD = 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.
Table 3. Optimization of light-free esterification.
The success of aryl esterification is noteworthy given the
diminished nucleophilicity of carboxylates relative to other
heteroatomic cross-coupling substrates, as demonstrated by the
requirement for super-stoichiometric amounts of silver salts in a
reported Pd-catalyzed methodology for the esterification of aryl
iodides,[16] and a scarcity of examples for the direct cross-
coupling of carboxylic acids with aryl bromides under thermal
nickel catalysis. Moreover, reports of this transformation under
photochemical conditions unanimously invoke photosensitization
Entry
BzOH equiv
Base (equiv)
Quin. (2.0)
Zn0 equiv Ar-O2CR Yield (%)[a]
pathways that necessitate access to a Ni(II) excited state as a
1
2
3
4
5
6
2.0
0.1
0.1
0.1
0.5
0.5
0.5
46
54
64
82
61
75
6d, 6g, 6l]
precondition for reductive elimination,[5c,
whereas our
2.0
NEt3 (2.0)
reactions in the absence of light preclude any possibility of
excited state formation. These results suggest a Ni(I/III) pathway
as an alternative, and hitherto unexplored, mechanistic strategy
for achieving this transformation.
Next, we performed a series of control experiments to
assess our contention that the dominant productive pathways in
all three transformations involve a Ni(I/III) cycle. The necessity of
both nickel and Zn(0) was demonstrated by the absence of
product formation when either was excluded under the ‘A’
2.0
HN(tBu)(iPr) (2.0)
HN(tBu)(iPr) (2.0)
HN(tBu)(iPr) (3.0)
None
2.0
3.0
2.0 as [TBA][OBz]
[a] Yields determined by 1H NMR. TBA
benzoate
= tetrabutylammonium. OBz =
conditions in Figure
2
(see Supporting Information).
Furthermore, the yields were greatly diminished when the
combination of Ni(II) and Zn(0) was replaced with a Ni(0) source
under analogous conditions (Figure 2, B), suggesting that the
Ni(II) aryl species which form after oxidative addition of the aryl
bromide are incapable of undergoing the requisite carbon-
heteroatom reductive elimination. Control experiments wherein
COD was added to the reactions under the 'A' conditions of
Figure 2 showed that the difference in reactivity between the 'A'
and 'B' conditions of Figure 2 is not entirely attributable to the
presence of COD (see Supporting Information). This is
Given the similarity of conditions employed across Ni
photoredox cross-coupling methodologies,[5, 14] we hypothesized
that this strategy of using a heterogeneous reducing agent to
thermally access and sustain a Ni(I/III) cycle may be generalized
to other nucleophiles. As shown in Entry 1 of Table 2, we
obtained the expected cross-coupled product in the reaction
between methanol and 4´-bromoacetophenone using only 0.01
equivalents of Zn(0) and 1 mol% (dtbbpy)NiCl2 (dtbbpy = 4,4′-di-
tert-butyl-2,2′-dipyridyl) prepared in situ from (dme)NiCl2 and
dtbbpy. This result further lends credence to the productive
Ni(I/III) cycle invoked in our previous mechanistic study.[9a]
Upon further optimization, we discovered that switching to
THF in combination with the stronger amidine base, 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU), led to a higher yield (Entry 2).
Inorganic bases such as K3PO4 were ineffective (Entry 3),
possibly due to slow proton transfer kinetics or the precipitation
consistent with
a Ni(I/III) mechanism being the dominant
productive pathway as suggested by our previous mechanistic
study and literature precedent proposing the necessity of Ni(III)
8a, 8b, 9a, 10b, 17]
for reductive elimination.[6b,
The background
reactivity observed in these control experiments with Ni(0)
sources may be attributed to the generation of Ni(I) equivalents
during oxidative addition of aryl bromide to Ni(0) as previously
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10.1002/anie.201916398
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C-N coupling was observed in the presence of alcoholic
functionality (3). The yield was found to be highly sensitive
towards the coordinating abilities of the amine, with attempts to
couple linear primary alkyl amines and heterocyclic aryl
bromides being unsuccessful, consistent with their greater
binding affinity resulting in the formation of coordinatively
saturated Ni(I) species that are unable to dissociate a sufficient
number of ligands to undergo concerted oxidative addition.[20]
This supposition is supported by the observation that a sterically
hindered primary amine (cyclohexylamine) could be successfully
coupled (6). Given the evidence for mechanistic substrate
dependence in Ni cross-coupling reactions,[21] the inefficiency of
these recalcitrant coupling partners under our light-free
conditions may imply that the extent to which photochemical
resuscitation of inactive Ni(II) complexes contributes to the
overall observed reactivity could be similarly substrate
dependent. With respect to the aryl bromide, the highest yields
were obtained with those possessing electron deficient
substituents such as ketone (11), sulfone (12), nitrile (19), and
trifluoromethyl ether (20) functionality. Protic moieties such as
those found in amides were well-tolerated (16 and 17), and C–N
bond formation occurred preferentially at the bromide-
functionalized carbon with high fidelity when carbon-chlorine
bonds were present on the arene (13). Arenes without electron
withdrawing groups could also be cross-coupled, albeit in lower
yields (14 and 15). For etherification, sterically unencumbered
primary alcohols (21-23) were found to be the most active
substrates, consistent with the photoredox system. Notably,
weakly nucleophilic alcohols such as 2,2,2-trifluoroethanol could
be coupled in moderate yield (22). However, secondary alcohols
more sterically hindered than cyclobutanol (24) were ineffective
under our conditions. We discovered that cross-coupling with
water proceeds well under conditions analogous to those for
esterification (see Supporting Information), allowing us to obtain
25 in 75% yield. Electron deficient arenes were found to be the
most reactive with various polar groups being well-tolerated (26,
27, and 29). The inclusion of amide functionality significantly
diminishes the yield (30), possibly due to coordinative inhibition
of the nickel catalyst. Regarding esterification, Boc-protected
amino acids and benzoic acid were very efficiently coupled (31,
33–35), and sterically hindered pivalic acid gave product in
moderate yield (32). Aryl bromide reactivity was consistent with
that observed for etherification and amination, where electron
poor arenes proved to be efficient substrates (36–38). However,
in contrast to the two previous reactions, derivatives of
heterocyclic amines were also accessible (39 and 40). Taken
together, the breadth of products for which we could
successfully recapitulate photoredox-like reactivity in the
absence of light establishes the generality of a Ni(I/III) cycle as a
productive pathway in photoredox-mediated Ni cross-coupling
catalysis.
Amination
A: 5% (dme)NiBr2 + 0.10 equiv Zn0
B: 5% Ni(cod)2
C: 5% Ni(cod)2 + 0.10 equiv Zn0
Br
N
+
N
H
1.8 equiv DABCO
DMA, RT, 18 h
CF3
CF3
400 mM
2.0 equiv
A: 97%, B: 27%, C: 90%
Etherification
A: 1% (dtbbpy)NiCl2 + 0.02 equiv Zn0
B: 1% (dtbbpy)Ni(cod)
C: 1% (dtbbpy)Ni(cod) + 0.02 equiv Zn0
Br
OMe
+
MeOH
1.1 equiv DBU
THF, 40 oC, 24 h
O
O
250 mM
1.5 equiv
A: 95%, B: <5%, C: 25%
Esterification
A: 5% (dtbbpy)NiBr2 + 0.50 equiv Zn0
B: 5% (dtbbpy)Ni(cod)
C: 5% (dtbbpy)Ni(cod) + 0.50 equiv Zn0
O
Br
O
Ph
O
+
2.0 equiv HN(tBu)(iPr)
DMF, 40 oC, 24 h
HO Ph
O
O
200 mM
2.0 equiv
A: 88%, B: <5%, C: 69%
Figure 2. Effects of nickel source on yields for the three cross-coupling
reactions. Yields were determined by 19F NMR for amination and 1H NMR for
etherification and esterification. cod = 1,5-cyclooctadiene.
proposed.[18] We also discovered that Ni(0) in combination with
Zn(0) gave higher yields than Ni(0) alone (Figure 2, C),
suggesting that inactive Ni(II) aryl complexes may be reductively
resurrected to re-enter the Ni(I/III) cycle. This may indicate that
Zn(0) can further reduce Ni(II) aryl complexes to form Ni(I) aryl
species that undergo subsequent oxidative addition to give on-
cycle Ni(III) intermediates, in a manner analogous to what has
been proposed for Ni-catalyzed reductive coupling.[11]
We were able to establish further parallels between the
reactivity reported herein and that under the previously studied
photochemical conditions. For example, we observed the
formation of a previously characterized Ni(I)-Ni(II) dimer upon
treatment of a solution containing Ni(II) precatalyst with Zn(0)
(see Figure S1 in the Supporting Information),[9a] suggesting that
Zn(0) serves a role analogous to the Ir photocatalyst in the
related photoredox reaction by providing access to Ni(I)
equivalents necessary for catalysis. Furthermore, similar to the
photoredox reaction, there is evidence to suggest the existence
of deleterious bimetallic pathways leading to the formation of off-
cycle intermediates since we observed a decrease in reaction
yield with increasing nickel loading under certain conditions (see
Figure S2 in the Supporting Information for details).
In order to verify the generality of our conclusions across
multiple substrates, we investigated the scope to which
photoredox-like reactivity could be recapitulated without light, as
shown in Figure 3. For amination, anilines (8-10) and cyclic
secondary amines (1-5) such as piperidine, which is the most
ubiquitous
heterocyclic
moiety
in
FDA-approved
pharmaceuticals, can all be effectively cross-coupled.[19] Notably,
pyrrolidine was not required as an additive for the cross-coupling
of anilines, in contrast to the photoredox-mediated reaction
where it serves an indispensable role.[5a] More challenging
substrates such as cyclic primary amines (6) or acyclic
secondary amines (7) can be successfully cross-coupled using
quinuclidine as the base. Furthermore, high chemoselectivity for
Conclusion
We demonstrate that a thermally sustained Ni(I/III) cycle
may constitute a general productive mechanism in Ni-catalyzed
photoredox-mediated cross-coupling. Our results show that Ni-
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Amination
Br
5% (dme)NiBr2, 0.1 equiv Zn0
1.8 equiv Base
NR2
HNR2
2.0 equiv
+
DMA (400 mM)
RT, 18 h
R
R
OH
O
OMe
F
N
N
N
N
N
HN
N
HN
HN
HN
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
1
2
3
4
5
6
7
8
9
10
81%[a]
93%[a]
81%[a]
86%[a]
68%[a]
80%[a]
33%[b]
63%[c]
86%[a]
83%[a]
N
N
N
N
N
N
N
N
N
N
OCF3
O
S
O
Cl
CN
O
O
O
O
NH2
NHMe
OMe
11
95%[a]
12
86%[a]
13
58%[c]
14
47%[c]
15
53%[c]
16
84%[c]
17
81%[c]
18
51%[c]
19
94%[a]
20
78%[a]
Etherification/Hydroxylation
Esterification
O
O
1% (dtbbpy)NiCl2, 0.02 equiv Zn0
5% (dtbbpy)NiBr2, 0.5 equiv Zn0
2.0 equiv HN(tBu)(iPr)
Br
OR
Br
R
O
1.1 equiv Base
ROH
+
+
1.5 equiv
THF (250 mM)
40 oC, 24 h
HO
R
DMF (200 mM)
40 or 60 oC, 24 h
R
R
R
2.0 equiv
R
O
SMe
O
O
O
O
Ph
O
CF3
O
O
OH
O
Boc
N
O
Ph
O
tBu
O
O
O
NHBoc
NHBoc
O
O
O
O
O
O
O
O
O
O
21
61%[d]
22
65%[e]
23
51%[d]
24
60%[d]
25
75%[f]
31
32
33
75%[g]
35
76%[g]
O
34
82%[g]
77%[g]
43%[h]
O
O
O
O
OMe
OMe
OMe
OMe
OMe
O
Ph
O
Ph
O
Ph
O
Ph
O
Ph
N
tBu
tBu
O
N
CN
S
O
O
O
NH2
CF3
S
O
O
OMe
O
26
86%[d]
27
59%[d]
28
17%[e]
29
87%[d]
30
28%[e]
36
67%[h]
37
77%[g]
38
74%[g]
39
32%[g]
40
77%[g]
Figure 3. Demonstration of the generality of light-free reactivity. [a] DABCO used as the base. [b] Quinuclidine used as the base and DMSO used as the solvent.
[c] Quinuclidine used as the base. [d] DBU used as the base. [e] MTBD used as the base. [f] See Supporting Information for details. [g] Reaction performed at
40 °C. [h] Reaction performed at 60 °C. Boc = tert-butyloxycarbonyl.
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Arias-Rotondo, J. K. McCusker, D. W. C. MacMillan. Science 2017, 355,
380-385.
catalyzed amination, etherification, and esterification of aryl
bromides can all be realized across a wide range of
substrates without light under conditions which otherwise bear
resemblance to the parent photochemical methodologies. To
this end, one may wish to re-evaluate the growing body of
literature that invokes energy transfer as the mechanism for
catalysis.[5c, 6d, 6f, 6g, 6ℓ, 14, 21] As we show here, only a small amount
of Ni(I) can initiate self-sustained Ni(I)/Ni(III) thermal catalysis.
We suspect that in many of the cycles ascribing catalysis to
energy transfer there may well be the production of small
amounts of Ni(I) through photoreduction.
Whereas various methodologies exist for the amination and
etherification of aryl bromides, our esterification protocol
described herein is especially notable given the scarcity of direct
Ni-catalyzed cross-coupling between carboxylic acids and aryl
bromides under light-free conditions. Critical to this dark
reactivity is the ability to selectively engage and sustain a Ni(I/III)
catalytic cycle while attenuating deactivation of the catalyst to
inactive Ni(II) complexes through bimetallic pathways. This may
be achieved through the slow formation of Ni(I) equivalents from
NiX2 precursors with substoichiometric amounts of an earth-
abundant heterogeneous reducing agent, thereby allowing us to
access photoredox-like cross-coupling reactivity with its intrinsic
advantages while obviating the need for continuous irradiation
using high-energy photons or precious metal photocatalysts.
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Acknowledgements
This work was supported by the National Science Foundation
under grant CHE-1855531. We thank Drs. Qilei Zhu, Miguel
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Keywords: cross-coupling • green chemistry • photoredox
catalysis • sustainable chemistry • transition metals
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This article is protected by copyright. All rights reserved.

10.1002/anie.201916398
Angewandte Chemie International Edition
RESEARCH ARTICLE
R. Sun, Y. Qin, D. G. Nocera*
Page No. – Page No.
General Paradigm in Photoredox Ni-
Catalyzed Cross-Coupling Allows for
Light-Free Access to Reactivity
Self-sustained Ni(I/III) cycles are established as a potentially general paradigm in
photoredox cross-coupling reactions. We show that photoredox-like reactivity can
be recapitulated with high fidelity in the complete absence of light across multiple
substrates and transformations, thus obviating the need for high-energy photons
and precious metal photocatalysts.
This article is protected by copyright. All rights reserved.