Photochemical Nickel-Catalyzed C-H Arylation: Synthetic Scope and Mechanistic Investigations

Article abstract of DOI:10.1021/jacs.6b04789

An iridium photocatalyst and visible light facilitate a room temperature, nickel-catalyzed coupling of (hetero)aryl bromides with activated α-heterosubstituted or benzylic C(sp³)-H bonds. Mechanistic investigations on this unprecedented transformation have uncovered the possibility of an unexpected mechanism hypothesized to involve a Ni-Br homolysis event from an excited-state nickel complex. The resultant bromine radical is thought to abstract weak C(sp³)-H bonds to generate reactive alkyl radicals that can be engaged in Ni-catalyzed arylation. Evidence suggests that the iridium photocatalyst facilitates nickel excitation and bromine radical generation via triplet-triplet energy transfer.

Full text of DOI:10.1021/jacs.6b04789

Communication
pubs.acs.org/JACS
Photochemical Nickel-Catalyzed C−H Arylation: Synthetic Scope and
Mechanistic Investigations
Drew R. Heitz, John C. Tellis, and Gary A. Molander*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
S
* Supporting Information
Scheme 1. Visible Light-Mediated C(sp3)−C(sp2) Cross-
Coupling with Ni and Ir/Ru
ABSTRACT: An iridium photocatalyst and visible light
facilitate a room temperature, nickel-catalyzed coupling of
(hetero)aryl bromides with activated α-heterosubstituted
or benzylic C(sp3)−H bonds. Mechanistic investigations
on this unprecedented transformation have uncovered the
possibility of an unexpected mechanism hypothesized to
involve a Ni−Br homolysis event from an excited-state
nickel complex. The resultant bromine radical is thought
to abstract weak C(sp3)−H bonds to generate reactive
alkyl radicals that can be engaged in Ni-catalyzed arylation.
Evidence suggests that the iridium photocatalyst facilitates
nickel excitation and bromine radical generation via
triplet−triplet energy transfer.
cross-coupling reactions. However, two activated partners are
required for effective reactivity. In an effort to develop more
redox-, atom-, and step-economic processes, we sought to utilize
C(sp3)−H bonds as more practical and efficient radical
precursors, thereby eliminating the waste generated in the
process of oxidative fragmentation and in the synthesis of the
requisite redox active fragment.
ecent efforts in photocatalysis have demonstrated the
Rsynthetic utility of employing visible light to facilitate
organic reactions. Light-harvesting complexes have been used to
activate organic molecules and to evolve challenging inter-
mediates through either electron or energy transfer.1 Perhaps
more importantly, photocatalysis has been creatively deployed in
the development of organic reactions that operate through
mechanistically novel pathways. These mechanistic changes may
lower kinetic barriers to target products, providing milder
conditions and more selective reactivity than could be achieved
via thermal activation. The ability to harness visible light through
photocatalysis is particularly attractive for the development of
new modes of C−H functionalization, because traditional
approaches to catalytic C−H functionalization often require
precious metals in relatively high loading, directing groups,
stoichiometric additives or oxidants, and/or high temperatures.2
Furthermore, C−H functionalizaton with inexpensive Ni
catalysts currently require chelation control, extremely high
temperatures (often greater than 140 °C), and/or peroxide
reagents that can be hazardous for large scale applications.3
Photoredox dual catalysis has demonstrated the propensity of
Ni catalytic systems to facilitate the coupling of alkyl radicals with
aryl and alkenyl halides (Scheme 1). Although various alkyl
radical precursors, including alkyltrifluoroborates,4 carboxylates,5
and silicates,6 have been developed, the mechanistic consid-
erations are the same.7 Thus, the radical precursor is activated by
single electron oxidation to afford an alkyl radical, and the nickel
catalyst is subsequently reduced by the photocatalyst to turn over
the cycle. Application of this single-electron transfer-based
mechanism enables these cross-couplings to proceed under mild
conditions with minimal side products compared to traditional
Initially, we hypothesized that incorporation of a diaryl ketone
catalyst could generate an alkyl radical from an activated C−H
bond through a well-precedented H-atom-transfer (HAT)
process from the excited state of the diaryl ketone.8 We
anticipated that this radical could be engaged in cross-coupling
with an aryl bromide via nickel catalysis. Studies commenced
with the reaction of bromobenzonitrile with THF as substrate
and solvent (Table 1). Employing benzophenone (1 equiv) with
standard Ir/Ni loadings, 2 was detected by GC-MS, although
conversion was incomplete after 24 h. Addition of Brønsted bases
in an effort to neutralize the HBr formally generated as a
byproduct of the reaction improved conversion significantly. In
the presence of base, catalytic loadings of benzophenone were
tolerated. Further optimization identified 4,4′-dimethoxybenzo-
phenone (DMBP, 4, 25 mol %) as being superior to
benzophenone as a co-catalyst. Replacing air-sensitive Ni-
(COD)2 with bench stable Ni(NO3)2·6H2O provided a modest
improvement in yield. Control experiments demonstrated that
Ni, Ir, and light were necessary for C−H arylation. However, we
unexpectedly observed product formation in the absence of 4,
which we had assumed was responsible for the observed
hydrogen-atom abstraction. Although this observation has
Received: May 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b04789
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Communication
Table 1. Select Optimization Results and Control Studies
Table 3. Scope of Aryl and Heteroaryl Bromides in Ni/Ir
Cross-Coupling with THF
a
Reactions performed on 0.05 mmol scale. Determined by HPLC
analysis relative to 4,4-di-tert-butylbiphenyl as an internal standard.
b
No ligand.
Table 2. Scope of C(sp3)−H Partners in Ni/Ir Cross-
Coupling
a
Product was isolated with trace DMBP (14:DMBP = 11.5:1).
Product was inseparable from DMBP. Reaction was performed in
b
c
the absence of DMBP. All reactions were conducted at 0.35 mmol
scale.
secondary position. Tetrahydrothiophene provided an appreci-
able yield of the desired product 9. Furthermore, toluene
effectively coupled at the benzylic position to afford the desired
diarylmethane 11 (87%, 72 h).
Notably, cyclohexane was found to be unreactive, and
substrates bearing allylic C−H bonds, such as cyclohexene and
3,4-dihydro-2H-pyran, produced complex product mixtures.
Despite the relatively limited scope, the unprecedented, direct
coupling of saturated heterocycles with aryl halides provides a
complementary approach to C(sp3)−C(sp2) products that are
difficult to access through photoredox cross-coupling, because
methods to synthesize the corresponding C(sp3)-organometallic
partner are not well established.
a
b
NMR yield relative to DMBP. No product detected by GCMS
analysis. All reactions were performed on 0.35 mmol scale, r.r. = ratio
Further interrogation of the reaction scope demonstrated that
the conditions were tolerant of a variety of aryl- and heteroaryl
bromides (Table 3). Electron-deficient bromides afforded
products in moderate to good yield. Electron-rich bromides
also coupled, providing 18 and 19. Furthermore, a series of
pyridines (22, 23, and 24) coupled well. Notably, a number of
bromides that contained homolytically weak C−H bonds
(aldehydes 15 and 21 and ethers 18 and 19) were non-
problematic. Attempts to extend the reaction to alkenyl bromides
or aryl iodides, chlorides, and triflates were unsuccessful,
returning only unreacted starting material. The ability to couple
1-bromo-4-chlorobenzene selectively at the C−Br bond (17)
provides opportunities for further functionalization of reaction
products. Reactions were demonstrated to occur successfully in
the presence and absence of DMBP at benchtop scale (0.35
mmol). Although the additive is sometimes difficult to separate
from the products chromatographically, reactions were often
faster, higher yielding, and more reproducible than correspond-
ing reactions performed without the additive.
of regioisomers.
important mechanistic implications (vide infra), the addition of 4
as a substoichiometric additive was nonetheless effective in
improving reaction yields.
Next, we elected to explore the types of C(sp3)−H bonds
capable of undergoing photochemical Ni/Ir dual catalyzed
arylation (Table 2). Importantly, a variety of common solvents
were found to participate in the reaction. Most effective were
ethereal solvents, including THF (89%, 72 h), DME (6, 91%, 72
h), and Et2O (7, 56%, 72 h). Other ethers, such as 1,4-dioxane
and MTBE, afforded cross-coupled products but required
extended reaction times with low yields. We attribute this
diminished reactivity to higher C−H bond dissociation energies
(BDEs) in these substrates, owing to inductive effects in the case
of dioxane9 and the reduced stability of the primary alkoxymethyl
radical for MTBE. Surprisingly, no cross-coupled product was
observed when the reaction was conducted in tetrahydropyran.
Some non-ethereal substrates were also found to afford cross-
coupled products. N-Methylpyrrolidinone underwent α-aryla-
tion with good yield and regioselectivity for the endocyclic
Based upon the unexpected results of our control experiments,
we probed the reaction mechanism to achieve a better
understanding of the nature of this C−H functionalization
B
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Communication
Scheme 2. THF/d8-THF Kinetic Isotope Effect Experiment
Scheme 3. (A) Plausible Catalytic Cycle, (B) Pathway A:
Intermolecular C−H Abstraction, and (C) Pathway B:
a
Concerted Ni−Br Homolysis/C−H Abstraction
Table 4. Reactions of Ni(II) Oxidative Addition Complexes
with THF
a
EnT = triplet−triplet energy transfer.
process. First, the optimized reaction was performed in a 1:1
mixture of THF and d8-THF (Scheme 2) to observe the effect of
heavier hydrogen isotopes on the reaction rate. The ratio of 2 to
25 was 6:1 by 1H NMR spectroscopy. Kinetic isotope effects of
this magnitude are typically consistent with a near-thermoneutral
radical C−H abstraction (Scheme 2).10
their longer emission wavelengths. Although energy transfer has
been employed in some visible light photocatalytic processes,1a,13
there is limited precedent of this mechanism operating
cooperatively with transition metal catalysis.14
We next undertook a series of experiments aimed at studying
the reactivity of stable, isolable Ni(II) oxidative addition complex
26. We first confirmed that treatment of one equivalent of this
complex with 1 equiv of photocatalyst 1 in THF under visible
light irradiation leads to formation of the C−H cross-coupling
product (Table 4, entry 1). Importantly, exposure of the Ni
complex to visible light in the absence of photocatalyst leads to
no product formation (Table 4, entry 4). We first suspected that
the photocatalyst engages the Ni(II) complex in single electron
transfer (SET), generating a Ni(III) complex that could catalyze
C−H functionalization by homolysis of the bromine−nickel
bond to generate a bromine radical. Nocera has observed an
analogous Ni−Cl homolysis from an excited-state Ni(III)
complex.11 To probe this hypothesis, we treated 26 with more
strongly oxidizing photocatalysts Ru(bpz)3·2PF6 (excited state
ERed = +1.45 V vs SCE)1a and (9-MesAcr)ClO4 (excited state
ERed = +2.06 V vs SCE).12 To our surprise, no C−H cross-
coupled product was observed when these catalysts were
employed with visible light irradiation. These experiments
suggest that a mechanism involving oxidation of Ni(II) to
Ni(III) may not be operative in these reactions.
In light of these experiments, we began to suspect that a
mechanism involving triplet−triplet energy transfer from the
excited-state photocatalyst to the Ni(II) complex might be
operative. Importantly, this mechanism would be consistent with
our stoichiometric experiments, because, under this manifold,
reactivity should be correlated with triplet state energy (i.e.,
emission wavelength) rather than with excited-state oxidation
potential. Indeed, all of the photocatalysts tested exhibit
significantly lower triplet-state energies than 1, as evidenced by
The absorption spectrum of 26 exhibits broad, low-intensity
features between 400 and 600 nm, which we attribute to Ni d →
d* transitions.15 The failure of visible light irradiation to promote
the C−H cross-coupling reaction in the absence of photocatalyst
suggests that the operative triplet state is not accessible from
these excited states. A more intense band appears in the UV
region at ∼300 nm. We suspected that irradiation of this
absorption band might permit access to the triplet state from
which C−H functionalization occurs. Supporting this hypoth-
esis, UV-B irradiation (290−315 nm) of 26 resulted in
observation of the arylated tetrahydrofuran product 27 (Table
4, entry 5). A unified mechanistic picture consistent with these
data involves a catalytically active triplet excited state that is
accessible by two pathways: (1) direct sensitization via triplet−
triplet energy transfer in the presence of visible light and
photocatalyst 1 (Scheme 3A) or (2) excitation into a higher
energy singlet excited state via UV irradiation, which undergoes
intersystem crossing and relaxes nonradiatively to the same active
excited state. Importantly, in this circumstance, the operative Ni
excited state would be inaccessible in the presence of
photocatalysts with insufficiently energetic triplet states or by
irradiation with insufficiently energetic wavelengths of light (i.e.,
visible light).
Although we are at this point unsure of the exact nature of the
C−H functionalization event, the observed KIE suggests that this
complex leads to the formation of a bromine radical through Ni−
Br bond homolysis. This radical would then engage the substrate
in HAT to form a stabilized carbon-centered radical that adds to
the nickel catalyst. The product can be subsequently generated
by reductive elimination. We suspect this may occur by one of
C
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Journal of the American Chemical Society
Communication
two different pathways: the first involving the discrete formation
of a Ni(I) complex and a bromine radical (Scheme 3B), and the
other involving a concerted four-centered transition structure
(Scheme 3C). This proposal is consistent with a variety of our
experimental observations. Specifically, the weakness of the H−
Br bond provides only a mild thermodynamic driving force for
abstraction of an H atom from THF, consistent with the
measured KIE and our limited ability to engage stronger C−H
bonds in this reaction.
for iridium salts used in the preparation of the photoredox
catalysts. Dr. Rakesh Kohli (University of Pennsylvania) is
acknowledged for collection of HRMS data.
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catalyzed C(sp3)−H arylation are achieved through the use of an
Ir photocatalyst, substoichiometric benzophenone-derivative
additive, and visible light. A variety of aryl- and heteroaryl
halides are tolerated, including those containing weak C(sp3)−H
bonds. Background reactivity in the absence of the presumed co-
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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.6b04789.
■
S
Experimental details and data (PDF)
AUTHOR INFORMATION
Corresponding Author
*gmolandr@sas.upenn.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was generously supported by the NIGMS (R01-
GM-113878) and the NSF (CHE-1362841). J.C.T. was
supported by a Bristol-Myers Squibb Graduate Fellowship. We
thank Professors Joseph Subotnik and Jessica Anna (University
of Pennsylvania) for enlightening discussions. We thank Aldrich
D
DOI: 10.1021/jacs.6b04789
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX