Direct C(sp3)-H Cross Coupling Enabled by Catalytic Generation of Chlorine Radicals

Article abstract of DOI:10.1021/jacs.6b08397

Here we report the development of a C(sp³)-H cross-coupling platform enabled by the catalytic generation of chlorine radicals by nickel and photoredox catalysis. Aryl chlorides serve as both cross-coupling partners and the chlorine radical source for the α-oxy C(sp³)-H arylation of cyclic and acyclic ethers. Mechanistic studies suggest that photolysis of a Ni(III) aryl chloride intermediate, generated by photoredox-mediated single-electron oxidation, leads to elimination of a chlorine radical in what amounts to the sequential capture of two photons. Arylations of a benzylic C(sp³)-H bond of toluene and a completely unactivated C(sp³)-H bond of cyclohexane demonstrate the broad implications of this manifold for accomplishing numerous C(sp³)-H bond functionalizations under exceptionally mild conditions.

Full text of DOI:10.1021/jacs.6b08397

Communication
pubs.acs.org/JACS
Direct C(sp3)−H Cross Coupling Enabled by Catalytic Generation of
Chlorine Radicals
Benjamin J. Shields and Abigail G. Doyle*
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
ABSTRACT: Here we report the development of a
C(sp3)−H cross-coupling platform enabled by the catalytic
generation of chlorine radicals by nickel and photoredox
catalysis. Aryl chlorides serve as both cross-coupling
partners and the chlorine radical source for the α-oxy
C(sp3)−H arylation of cyclic and acyclic ethers. Mecha-
nistic studies suggest that photolysis of a Ni(III) aryl
chloride intermediate, generated by photoredox-mediated
single-electron oxidation, leads to elimination of a chlorine
radical in what amounts to the sequential capture of two
photons. Arylations of a benzylic C(sp3)−H bond of
toluene and a completely unactivated C(sp3)−H bond of
cyclohexane demonstrate the broad implications of this
manifold for accomplishing numerous C(sp3)−H bond
Figure 1. (A) Interfacing chlorine radical C(sp3)−H bond activation
and cross coupling. (B) Chlorine radical generation via photolysis of
high-valent nickel chloride complexes.
functionalizations under exceptionally mild conditions.
ree-radical halogenation of alkanes is one of the oldest and
1,2 Though
Fmost well-studied reactions in organic chemistry.
radical halogenation, these characteristic challenges would
impede the development of a general C(sp3)−H, C−X cross-
alkanes are notoriously unreactive compounds, halogen radicals,
particularly chlorine radicals, can activate virtually any C(sp3)−H
coupling platform.
We recognized that it should be possible to address these
challenges by using the Ni cross-coupling catalyst to generate
bond at room temperature by hydrogen atom abstraction.2
Interfacing the capability of chlorine atoms to activate C(sp3)−H
bonds with catalytic functionalization reactions of the resulting
alkyl radicals could allow for the development of a wide range of
elusive bond constructions, enabling the functionalization of
both complex molecules and feedstock hydrocarbons.
chlorine radicals from chemically inert chloride precursors. It has
been shown that visible light excitation of high oxidation state
transition metal halides can lead to halogen radical formation via
dissociation from a charge-transfer excited state.8 Specifically, the
Nocera laboratory recently reported the reversible, visible-light-
promoted elimination of chlorine atoms from Ni(III) trichloride
complexes (Figure 1B).9,10 We reasoned by analogy that
photolysis of a Ni(III) aryl chloride species, generated by
single-electron oxidation of a typical Ni(II) intermediate in cross
coupling, might allow for the catalytic generation of chlorine
atoms. Taken together with the ability of Ni(II) to accept alkyl
radicals, it was hypothesized that photocatalytically generated
chlorine atoms could participate in C−H abstraction to generate
a substrate-derived alkyl radical poised to rebound to the Ni
center in a manner compatible with Ni-catalyzed cross coupling.
A photoredox catalyst was envisioned to promote the necessary
single-electron oxidation and reduction of the Ni catalyst to
facilitate the overall redox-neutral process. Importantly, whereas
most photoredox catalysts do not have sufficient energy to
oxidize chloride anion (E° = 2.03 V vs SCE in MeCN),11 this
strategy offers a visible-light-driven mechanism for halogen
Over the past decade, nickel catalysis has emerged as a
powerful platform for C(sp3)−C bond formation.3,4 Recently, it
has been shown that Ni catalysts can intercept and functionalize
alkyl radicals generated by distinct pathways, and that this
approach can enable the development of C(sp3)−C bond-
forming reactions utilizing starting materials otherwise unlikely
to engage in cross coupling.3,5−7 In this context, we questioned
whether hydrogen atom abstraction by chlorine radicals could be
integrated with Ni-catalyzed alkyl cross coupling. Such a
manifold would offer the possibility of achieving directing
group-free C−H, C−X cross coupling with even the strongest
C(sp3)−H bonds (Figure 1A).
Successful realization of this goal, however, would require the
identification of a mechanism for the catalytic generation of
chlorine radicals under mild conditions from a stable precursor.
Chlorine radicals are usually derived from highly reactive
reagents such as chlorine gas or N-chlorosuccinimide that can
competitively oxidize a Ni catalyst, chlorinate alkyl radical
intermediates, and react with desirable functional groups present
in organic substrates. Despite the positive attributes of free
Received: August 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b08397
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Journal of the American Chemical Society
Communication
a
radical formation enabled by the sequential capture of two
photons.
Table 1. Scope Studies
As a model coupling reaction, we examined the direct C−H
functionalization of ethers to generate benzylic ethers,12
a
valuable pharmacophore in drug development. We recently
reported Ni/photoredox-catalyzed functionalization of anilines
via a photoredox-driven oxidation/α-C−H deprotonation
sequence.6 Ethers, however, are not susceptible to this activation
mechanism, given their high oxidation potential (tetrahydrofuran
(THF) solvent oxidation onset potential E = 1.75 V vs SCE).13
We envisioned instead that oxidative addition of Ni(0) (1) into
an aryl chloride would produce Ni(II) aryl chloride intermediate
2 (Figure 2). Concurrently, irradiation of iridium(III) photo-
a
Yields are isolated yields. Reaction times varied between 36 and 75 h;
b
see SI for individual substrates. Mixture of regioisomers.
product is formed. Furthermore, the reaction takes place in the
absence of base, albeit with reduced reaction efficiency (Table
S1). Notably, this transformation employs abundant, low cost
aryl chlorides, which have seen little use in the emerging field of
metallaphotoredox catalysis. A variety of electron-neutral (10−
13), -rich (14), and -poor (15−17) chloroarenes as well as
substrates bearing steric encumbrance (12, 18, 19) underwent
efficient coupling to give the corresponding α-arylated products.
Gratifyingly, aryl chlorides with diverse functionality including
nitrile 15, ketones (16, 17), aldehyde 19, amides (22, 24), and
alkene 24 were well tolerated, a showcase of the mild reaction
conditions. Finally, medicinally relevant heteroaryl chlorides
derived from pyridine (21), indole (22), and quinoline (23) and
the complex aryl chloride loratadine (24) performed well in the
reaction, demonstrating the potential applicability of this system
to late-stage coupling.
We next evaluated ether coupling partners in the C−H
functionalization reaction. We were pleased to find that, along
with THF, other cyclic and acyclic ethers performed well under
identical conditions, delivering both secondary (25, 26, 27) and
primary (27, 28) C−H functionalization products. Interestingly,
the reaction efficiency with different ether substrates trends with
radical nucleophilicity, suggesting that polar effects may play an
important role in these reactions. In addition, functionalization of
1,2-dimethoxyethane occurred at both primary and secondary
carbons, giving the branched product preferentially (1.35:1
branched:linear) in a combined 91% yield, indicating moderate
selectivity for the weaker C−H bond. Notably, this method
produces benzylic ethers under extraordinarily mild conditions, a
technology that could be of great utility for modulating small
molecule hydrophobicity, an important consideration in drug
design.15
Figure 2. Proposed catalytic cycle. 3 = Ir[dF(CF3)ppy]2(dtbbpy)PF6;
dF(CF3)ppy = 2 (2,4-difluorophenyl)-5-(trifluoromethyl)pyridine;
dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine.
catalyst 3 would produce a highly oxidizing long-lived triplet
excited *Ir(III) state (τ0 = 2.3 μs, *E1/2 = 1.21 V vs SCE in
MeCN) (4) which would be capable of oxidizing 2 (EP = 0.85 V
vs SCE in THF, Figure S33) to produce fleeting Ni(III)
intermediate 5.14 Photolysis of 5 would result in the generation of
a chlorine atom and Ni(II) species 6, and the resulting chlorine
radical would rapidly abstract a hydrogen atom from THF (H−
Cl BDE = 102 kcal mol−1, THF BDE = 92 kcal mol−1). Rebound
of the resulting carbon-centered radical to 6 would produce
Ni(III) species 7. Subsequent reductive elimination would forge
the desired C(sp3)−H cross-coupling product. Finally, single-
electron-transfer (SET) reduction of the resulting Ni(I)
intermediate 8 (EP = −1.17 V vs SCE in THF, Figure S32) by
highly reducing Ir(II) species 9 (E1/2 = −1.37 V vs SCE in
MeCN) would regenerate both the Ni(0) and Ir(III) catalysts.14
With this mechanistic hypothesis in hand, we examined the
proposed α-oxy functionalization with aryl chlorides and THF as
solvent. We were pleased to find that the combination of
Ni(cod)2 (cod = 1,5-cyclooctadiene), dtbbpy, and Ir[dF(CF3)-
ppy]2 (dtbbpy)PF6 (3) with 2 equiv of potassium phosphate
under irradiation with blue LEDs enabled the cross coupling of
numerous aryl chlorides with THF in good to excellent yields at
room temperature (Table 1). Optimization studies revealed that
in the absence of Ni catalyst, light, or photoredox catalyst, no
We next turned our attention to mechanistic experiments
designed to interrogate the halogen photoelimination and
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Journal of the American Chemical Society
Communication
hydrogen atom abstraction hypothesis, beginning with an
evaluation of the role of chloride. For the proposed mechanism,
we anticipated that aryl iodides would not be competent coupling
partners because the weak H−I bond (BDE = 71 kcal mol−1)
renders an iodine radical incapable of abstracting a hydrogen
atom from THF. Indeed, the yield of the coupling reaction
showed a strong dependence on the halide identity: aryl iodide
29-I performed poorly, giving only trace THF product (10)
(Figure 3A, entries 1−3). Nevertheless, the generation of even
consistent with chlorine radical generation in reactions of aryl
chlorides.
It was hypothesized that the addition of chloride salts might
resurrect the reaction of aryl iodides by halide exchange on Ni.
Indeed, the reaction of 29-I containing 1 equiv of TBACl (TBA =
tetrabutylammonium) showed a dramatic improvement in
reaction efficiency, demonstrating the critical role of chloride
(Figure 3A, entries 4−6). This observation indicates the
potential to utilize a broad range of electrophiles that do not
contain chloride such as aryl triflates (see Table S6). Monitoring
the reaction of 29-I with TBACl over time it was observed that
the generation of approximately equimolar aryl chloride (29-Cl)
accompanied product formation (see Figures S3−S5). A Ni-
catalyzed halogen exchange mechanism, through either a
common catalytic intermediate or generation and subsequent
consumption of aryl chloride, readily accommodates this
observation.18 To our knowledge, no previously reported
halogen exchange occurs under such mild conditions.19,20
Intriguingly, the reaction of 29-I with TBACl is complete after
only 3 h, significantly faster than the reaction of 29-Cl. The
improved reaction rate offers one pathway for further
optimization (see Supporting Information (SI), section VII, for
a discussion of mechanistic implications).
We next sought to gain insight into the role of photoredox
catalyst 3. According to our mechanistic hypothesis, the excited
photocatalyst serves as an oxidant to generate a transient Ni(III)
complex from Ni(II) oxidative adduct 2. To test this, we
synthesized Ni(II) complex 33 (Ar = 2-methylphenyl) (Figure
4A). Complex 33 was stoichiometrically competent in the
presence of light and photocatalyst, and its first oxidation
potential (EP = 0.85 V vs SCE in THF), as measured by cyclic
voltammetry, indicates that *Ir(III) 4 should be a suitable
oxidant. Indeed, Stern−Volmer quenching studies indicate that
33 is not only capable of quenching *Ir(III) 4 competitively, it is
likely the species responsible for quenching in the reaction
mixture (see SI for additional data, controls, and statistics).
In a stoichiometric sense, it should therefore be possible to use
a non-photoredox oxidant to generate transient Ni(III) in order
to separate the two roles of light in the oxidation and halogen
elimination. Indeed, reaction of 34 (Ar = 4-methylphenyl) with 1
equiv of the single-electron oxidant [TBPA]SbCl6 (tris(4-
bromophenyl)ammoniumyl hexachloroantimonate, E°′ = 1.16
V vs SCE in dichloromethane) under irradiation with 34 W blue
LEDs gave 10 in 28% yield (Figure 4B; see Table S13 for
additional data and controls).21 Importantly, in the absence of
light or oxidant, 10 was not observed. These data demonstrate
that, from the isolable Ni(II) aryl chloride complex, oxidant, and
light are necessary. The mass balance of this key experiment can
be accounted for by competitive reaction pathways such as
Figure 3. (A) Halide additive studies. See Table S6 for additional
experiments. (B) Deuterium labeling experiments. Ar = 2-(4-
a
1
halophenyl)-6-methyl-pyridine. Yields determined by GC-FID or H
NMR using 1-fluoronaphthalene as an external standard. bYields
determined by 2H NMR using DMF-d7 as an external standard.
trace product 10 with 29-I suggests that an alternative
mechanism could be operative. In seminal studies by Kochi
and co-workers, it was shown that oxidative addition of aryl
halides to Ni(0) proceeds via SET to generate an aryl radical
anion intermediate that can collapse to generate a Ni(II) aryl
halide or fragment toward a Ni(I) halide and aryl radical.16 To
account for product formation with aryl iodide, we hypothesized
that the aryl radical resulting from cage escape could abstract a
hydrogen atom from THF (k = 4.8 × 106 M−1 s−1).17 If the THF
radical intercepted a Ni(II) aryl halide complex, a false positive
could in principle be observed in up to 50% yield. To test this, we
evaluated reactions with aryl halides (30-Cl, -Br, and -I) and
THF-d8 for deuterodehalogenated arene (31), a requisite
product of the aryl radical abstraction pathway (Figure 3B).
Notably, aryl iodide (30-I) delivered 66% yield of deuterodeha-
logenated 31 while ≤3% yield of 31 was observed with 30-Cl and
30-Br. This result indicates that hydrogen atom abstraction by
aryl radicals is significant only with aryl iodides and is fully
Figure 4. (A) Emission quenching of *Ir(III) 4. Ni complex 33 (Ar = 2-methylphenyl) gives a similar quenching rate to the reaction mixture consisting
of Ni(dtbbpy)(cod) and 2-chlorotoluene. Additional data, controls, and statistics may be found in the SI. (B) Stoichiometric studies with Ni(II) complex
34 (Ar = 4-methylphenyl). See Table S13 for additional experiments. adtbbpy (1 equiv), K3PO4 (2 equiv), 2 mM THF. bYields determined by GC-FID
using 1-fluoronaphthalene as an external standard. c1 mM THF.
C
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Journal of the American Chemical Society
Communication
formation of aryl chloride 29-Cl, likely the result of reductive
elimination from 35 and consistent with halogen exchange
experiments.22
AUTHOR INFORMATION
Corresponding Author
*agdoyle@princeton.edu
■
We recognize this system operates in a distinct ligand field
from the recently reported Ni(III) trihalide complexes.9,10
Though the structure of the proposed Ni(III) intermediate is
unknown, preliminary DFT studies suggest that photoelimina-
tion even from a distorted square planar Ni(III) complex is
feasible (see SI for computational studies). The calculated
absorption spectrum for four coordinate [Ni(dtbbpy)(Ph)Cl]+
shows high-energy features (∼400−500 nm) that arise from Ni−
Cl σ→σ* charge-transfer transitions (Figures S38 and S39).
Taken together with the computed Ni−Cl bond dissociation free
energy of 47 kcal mol−1, these states are expected to be
dissociative.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by NIGMS (R01 GM100985).
We thank Kevin Wu, Marherita Maiuri, Daniel Oblinsky, Andrew
Proppe, Hilary Shi, and Robert Knowles for helpful discussions.
́ ́
We thank Mate Bezdek of the Chirik laboratory for the kind
donation of FcBArF4 and Eric Webb for the preparation of 30-I.
The authors thank G. Molander and co-workers for graciously
offering to concurrently publish a related study.
Overall, these preliminary studies are consistent with a
mechanism in which photolysis of a Ni(III) aryl chloride
intermediate, generated by single-electron oxidation, leads to
elimination of a chlorine radical capable of activating C(sp3)−H
bonds by abstraction. Chlorine radicals are known to form
stabilized adducts with aromatic functional groups.9,10 Therefore,
we reasoned that if benzene were utilized as a solvent, we could
promote the desired photoelimination and simultaneously
prevent competitive solvent C(sp3)−H abstraction. We
recognized that the ability to use an inert solvent and limiting
C−H coupling partner would be highly desirable, facilitating the
application of this manifold to a broad range of C−H coupling
partners under general reaction conditions. Gratifyingly, with
benzene as a solvent, the α-arylation reaction could be carried out
with only 10 equiv of THF to give 16 in 71% yield, a 30-fold
reduction in THF (Figure 5; see Table S3 for experiments with 1
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b08397.
■
S
Procedures, experimental data, emission quenching data
and statistics, computational data, and spectroscopic data,
including Tables S1−S18 and Figures S1−S39 (PDF)
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