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Outlook

http://pubs.acs.org/journal/acscii

Photoredox Catalysis Unlocks Single-Electron Elementary Steps in

Transition Metal Catalyzed Cross-Coupling
Mark D. Levin, Suhong Kim, and F. Dean Toste*
Department of Chemistry, University of California, Berkeley, California 94720, United States

ABSTRACT: Since initial reports, cross-coupling technologies employing photoredox

catalysts to access novel reactivity have developed with increasing pace. In this Outlook,
prominent examples from the recent literature are organized on the basis of the elementary
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transformation enabled by photoredox catalysis and are discussed in the context of relevant
historical precedent in stoichiometric organometallic chemistry. This treatment allows
mechanistic similarities inherent to odd-electron transition metal reactivity to be generalized
to a set of lessons for future reaction development.
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■ INTRODUCTION
The ability for transition metal catalysts to forge bonds between
manner. Examination of a generalized photoabsorption scheme
reveals that such an activation mode is a natural means of
ligated fragments has become a cornerstone of modern accessing odd-electron intermediates (Figure 2). As noted by
synthetic chemistry. Cross-coupling methodologies allow access early studies on these photoredox catalysts, excited states
to a variety of carbon−carbon and carbon−heteroatom coupled become both stronger single-electron oxidants and stronger
products via straightforward retrosynthetic disconnections, and single-electron reductants.4−6 By employing catalysts with
the systematic exploration of this paradigm has expanded the absorption bands in the visible region of the spectrum (rather
canon of accessible reactivity to cover a wide swath of chemical than in the ultraviolet), the source of open shell intermediates
space.1 can be effectively controlled.7,8
The vast majority of these methodologies rely on the same The rapid pace of recent developments combining photo-
three two-electron elementary steps as a means to accomplish catalysis with transition metal catalysis has prompted a survey
their target transformation: oxidative addition, transmetalation, of the field.9 We have endeavored here, for instructive purposes,
and reductive elimination (Figure 1). The centrality of these to organize these landmark examples by virtue of the
reactions is underscored by the numerous mechanistic studies elementary step in which the photocatalyst is engaged, as the
conducted that outline the influence of the metal catalyst and guiding principles and mechanistic homologies of this new field
its ligand environment. Despite the attention given to these are clearer when the catalyzed elementary steps are delineated.
polar mechanisms, many worthwhile challenges remain in this In each case, we aim to tie these novel catalytic methodologies
field.2 back to their prior stoichiometric analogues as a means to both
rationalize the observed reactivity and inspire the next
generation of technologies.
The key development in recent It is prudent to note that, in many cases, the photocatalysts
reports has been the implemen- may serve as chain initiators, with chain lengths measured for
tation of visible-light photocata- many photoredox processes exceeding one.10 As such, we have
lysts as a means to induce the chosen to abstract the involvement of these catalysts to the
level of a photoinduced electron transfer (signified by an
desired redox processes in a mild electron), rather than imply the specific species involved in any
and selective manner. given reduction or oxidation event.11 This Outlook is not
meant as a comprehensive review12−15 but rather as a tutorial,
and the lessons involved do not hinge on the presence or
Meanwhile, it has long been known that the chemistry of 17- absence of chain processes.16

■
and 19-electron transition metal complexes is marked by
dramatically faster rates compared to their even-electron PHOTOCATALYSIS OF OXIDATIVE ADDITION
congeners for virtually all elementary transformations.3 Despite
the wealth of stoichiometric precedent in this area, translation Oxidative addition involves the formation of bonds between a
of odd-electron organometallic reactivity into mild catalytic metal and an electrophilic substrate concomitant with the
reactions remained, until recently, far rarer than the two- formal two-electron oxidation of the metal center.2 In cross-
electron analogues. coupling this step typically involves concerted oxidative
The key development in recent reports has been the
implementation of visible-light photocatalysts as a means to Received: March 31, 2016
induce the desired redox processes in a mild and selective Published: May 3, 2016

© 2016 American Chemical Society 293 DOI: 10.1021/acscentsci.6b00090

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Figure 1. Generalized mechanism for cross-coupling and representative nucleophiles and electrophiles. Tf = trifluoromethanesulfonyl.

Figure 2. Simplified photoabsorption scheme and commonly employed photoredox catalysts.

Figure 3. Stoichiometric precedent: radical chain oxidative addition to Pt(II) and Au(I).

addition of a carbon−halogen or carbon−pseudohalogen bond catalysts kinetically incompetent for such an initiation on their
to generate the oxidized organometallic species. However, own. In the most general scheme, an electrophilic reagent is
many metals and electrophiles undergo prohibitively slow reduced by a photoexcited species, leading to its radical
reactions by this mechanism. congener. Subsequent addition to the metal species followed by
On the other hand, the facile addition of alkyl radicals to oxidation yields the net oxidative addition product. In this way,
transition metals in both chain and nonchain processes has the photocatalyst catalyzes the oxidative addition (Figure 4).
been studied in detail for a variety of complexes (Figure 3).17 One of the earliest examples of this activation mode in the
For example, photochemical initiation to generate isopropyl context of catalysis is in Pd-catalyzed directed C−H
radical was shown to accelerate the oxidative addition of functionalization (Figure 5).21 Sanford and co-workers showed
isopropyl iodide to Pt(II) via a radical chain process.18 that, in contrast to much harsher methods for accessing Pd(IV),
Fluoroalkyl iodides similarly undergo radical chain oxidative which require elevated temperature, the use of aryldiazonium
additions to Au(I).19,20 These precedents highlight the ability of cations in combination with a photoredox catalyst allowed for
otherwise sluggish oxidative addition processes to be facilitated the generation of the high-valent intermediate at room
by injection into a radical manifold. temperature. This was found to be broadly applicable with
With a photoredox catalyst, the involvement of a photo- respect to the directing group employed and to the diazonium
chemical process allows for the generation of the intermediate structure. Subsequent studies expanded this manifold to
radical species in milder fashion and with transition metal diaryliodonium electrophiles.22
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C−O40 forming reactions. Recent mechanistic studies have

shown that the copper-mediated pathway involves photo-
induced electron transfer from the nucleophile−cuprate
complex followed by in-cage radical recombination to afford
the coupled product, though oxidative addition and outer-
sphere recombination could not be distinguished (Figure 7).41
As such, it remains unclear the extent to which these precedents
are analogous to other photoredox-catalyzed oxidative
additions. Nonetheless, a recent study demonstrated an
Figure 4. Generalized scheme for photoredox catalysis of oxidative enantioselective variant of this process for C−N bond
addition. formation.42
In addition to these illustrative examples, several other
reports have emerged utilizing photoredox catalysis to enable
Beyond the mechanistic novelty oxidative addition. Notably, the combination of photoredox
in these processes, a striking catalysts with copper has enabled mild C-fluoroalkyl and C−N
feature of all systems developed coupling reactions to occur.43,44
to date is that the nucleophiles
employed are all air-stable, easily ■ PHOTOCATALYSIS OF REDUCTIVE ELIMINATION
Reductive elimination involves the formation of a new bond
prepared, and yet still capable of between ligands bound to a metal with concomitant 2-electron
effectively delivering sp3 nucleo- reduction of the metal center.2 As the key bond-forming step in
philes to transition metal centers. cross-coupling reactions, this process has been widely explored
for diverse combinations of metals and ligands, and virtually all
classes of reductive elimination are precedented in the
This same strategy employing diazonium electrophiles was literature. Nonetheless, there remain examples for which
subsequently applied in the context of gold catalysis by the bond formation is prohibitively slow.
Glorius and Toste groups, providing access to highly reactive Again, the literature surrounding single-electron processes
Au(III) intermediates in a straightforward fashion.23,24 Initial provides a potential solution;45,46 seminal studies by Kochi and
studies focused on the activation of alkenes to provide oxy- and Hillhouse showed that complexes that are inert to reductive
aminoarylated as well as ring expanded products (Figure 6).25 elimination or undergo unselective decomposition can be
Mechanistic investigations including time-resolved FT-IR, coaxed to perform the desired bond-forming process by single-
labeling studies, and DFT support a mechanism in which electron oxidation with a diverse array of oxidants (Figure
photocatalysis generates the Au(III)−aryl intermediate prior to 8).47,48
intervention of the unsaturated substrate.23,26 Subsequent On the basis of these precedents, it is conceivable that a
studies have expanded the scope to a wide variety of Au- photoredox catalyst can be applied to accomplish such a
catalyzed reactions of alkynes,27−30 allenes,31 and heteroatom transformation in a dual catalytic process. “Temporary”
nucleophiles32 allowing arylation to terminate catalytic cycles oxidation of the metal catalyst allows photocatalysis of the
typically closed via protodeauration. desired reductive elimination, which is followed by rereduction
Finally, a variant on this activation mode was demonstrated of the catalyst, as outlined in Figure 9.
by Fu and Peters in which a copper catalyst serves as both the A powerful realization of this activation strategy was
photocatalyst and ultimate bond-forming agent, albeit with UV employed by the Macmillan group in a nickel-catalyzed C−O
rather than visible light in most cases. These processes vary in coupling aided by an iridium photocatalyst (Figure 10).49 In
their nucleophiles and electrophiles, encompassing both aryl addition to demonstrating the scope of this process for a range
and alkyl halide substrates in C−S,33 C−N,34−37 C−C,38,39 and of coupling partners, stoichiometric experiments on an isolated

Figure 5. Catalytic application: palladium-catalyzed C−H functionalization at room temperature via Pd(IV) intermediates generated by photoredox
catalysis.

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Figure 6. Catalytic application: gold-catalyzed arylative ring expansion of vinylcyclobutanols via aryl−Au(III) intermediates generated by photoredox
catalysis.

These challenges should be taken

as a call to action, as the power
demonstrated in the reports thus
far suggests a wealth of untapped
reactivity. Most tantalizingly, the
involvement of a photoprocess
suggests that endergonic trans-
formations may be possible in
Figure 7. Catalytic application: copper-catalyzed C−S bond formation these catalytic reactions.
via photoinduced electron transfer. Mechanistic experiments have not
distinguished the two potential pathways.
A second example from Jamison and co-workers concerns
the synthesis of indolines via the coupling of ortho-iodoaniline
derivatives with alkenes (Figure 11).50 Having observed that
small amounts of the desired indoline product were formed
upon exposure of the reaction mixture to air, they employed a
photoredox catalyst to serve as a reversible means to access the
requisite Ni(III) intermediate. The proposed mechanism bears
many similarities to the example in Figure 10.

■ PHOTOCATALYSIS OF TRANSMETALATION
Transmetalation involves the formation of a bond between a
nucleophilic substrate and a metal, with no change in formal
oxidation state of the metal.2 These reactions typically involve
Figure 8. Stoichiometric precedent: oxidatively induced reductive displacement of a metal halide, and are mechanistically the
elimination from Fe(IV) and Ni(III). Cp = cyclopentadienyl. most complex of the steps discussed herein. Despite several in-
depth studies into the underlying elementary steps, many
transmetalation processes remain poorly understood.51−53
Worse yet, transmetalation of sp3 alkyl fragments is typically
challenging, requiring the use of sensitive reagents or harsh
conditions.
In this arena, limited stoichiometric precedent employing
open-shell intermediates has been reported; as such, the
simultaneous discovery by the Macmillan, Doyle, and Molander
groups that photoredox catalysis can be used to enable mild
transmetalation from otherwise weakly nucleophilic coupling
Figure 9. Generalized scheme for photoredox catalysis of reductive partners is perhaps even more impressive.54,55
elimination. Though many mechanisms have been proposed, the general
scheme for such a photocatalyzed transmetalation can be
conceived as follows: single-electron oxidation of a nucleophile
Ni(II)−aryl alkoxide complex clearly demonstrate the crucial and subsequent reduction of a transition metal complex
influence of the photoredox catalyst on the desired reductive generates complementary odd-electron species that can then
elimination process. efficiently undergo recombination (Figure 12). The order of
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Figure 10. Catalytic application: nickel-catalyzed etherification with C−O reductive elimination enabled via photoredox catalysis.

Figure 11. Catalytic application: nickel-catalyzed Larock-type indoline synthesis with C−N reductive elimination enabled via photoredox catalysis.
IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.

which a Ni(0) intermediate combines with the nascent radical

species to generate the corresponding Ni(I) alkyl.73,74 The
overall cycle is then closed via oxidative addition of the sp2
halide coupling partner, reductive elimination from Ni(III), and
single-electron reduction to regenerate the Ni(0) complex.
Two representative examples are shown in Figure 13, including
a recently reported enantioselective method leveraging this
protocol to generated enantioenriched benzylic amines in a
stereoconvergent fashion.75
Figure 12. Generalized scheme for photoredox catalysis of trans- An interesting application of the carboxylate nucleophiles has
metalation. been reported in which the carboxylate moiety is generated by
oxidative addition to palladium forming a π-allyl intermedi-
these two steps can likely be inverted, and other elementary ate.76,77 Other photoredox-facilitated transmetalations in cross-
coupling have also been reported.78−80

■
steps can intervene, but the sense of redox is likely maintained
regardless of the conditions employed.
Beyond the mechanistic novelty in these processes, a striking CONCLUSIONS AND OUTLOOK
feature of all systems developed to date is that the nucleophiles The leveraging of single-electron chemistry via the enabling
employed are all air-stable, easily prepared, and yet still capable technology of photoredox catalysis has clearly opened new
of effectively delivering sp3 nucleophiles to transition metal doors in the realm of transition metal catalyzed cross-coupling.
centers. Four main classes of photoredox-activated alkyl The motifs outlined herein are only some of the powerful new
nucleophiles have been developed: carboxylates,54,56−59 alkyl strategies accessed by this fruitful marriage of catalytic
trifluoroborates,55,60−65 alkyl silicates,66−70 and α-heteroatom modes.81−85 For example, several reports have employed
C−H bonds.54,71,72 In each, oxidation generates an alkyl radical photoredox catalysts to access oxidative cross-couplings with
via a subsequent fragmentation process, generating CO2, BF3, a variety of transition metals.86−93
bis(catecholato)silane, or acid, respectively. Moreover, there still exist stoichiometric precedents in
The most comprehensive mechanistic experiments and DFT single-electron acceleration of reactivity that have yet to be
calculations have been carried out for the nickel-catalyzed realized in a catalytic sense. One potentially instructive example
variants of these processes, and the studies support a process in of an accelerated migratory insertion is the documented
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Figure 13. Catalytic applications: nickel-catalyzed Csp3−Csp2 coupling reactions of alkyltrifluoroborates (racemic) and amino acids
(enantioselective). TBAI = tetrabutylammonium iodide, DME = 1,2-dimethoxyethane, Boc = tertbutoxycarbamoyl.

catalysis of alkyl carbonylation at iron via single-electron

oxidation (Figure 14); a dual catalytic coupling reaction making
use of this behavior is likely possible by some combination of
photoredox and transition metal catalysts.94

Figure 15. Stereoconvergence and diastereoselectivity in nickel-

+
Figure 14. Redox catalysis of migratory insertion. Fc = ferrocenium. catalyzed radical cross-coupling.

Though the power of open-shell intermediates to provide

rapid turnover has evidently been demonstrated, there are a displayed between transition metal catalysts and supramolecular
number of challenges that lie ahead. For one, while the catalysts.98
stereoconvergent nature of radical addition to transition metals Furthermore, the combination of more than one of the
has allowed the development of enantioselective processes,75 it activation modes presented herein, though challenging,
also imposes limitations in the diastereoselectivity for radical promises to enable progressively more complex transformations
transmetalation,62 making the synthesis of mismatched stereo- to be developed. To date, no sp3−sp3 C−C coupling protocols
isomers a more complex problem (Figure 15).95 have taken advantage of the newly discovered photoredox
These challenges should be taken as a call to action, as the manifolds, but such an advance, not to mention many others, is
power demonstrated in the reports thus far suggests a wealth of undoubtedly on the horizon.

■
untapped reactivity. Most tantalizingly, the involvement of a
photoprocess suggests that endergonic transformations may be AUTHOR INFORMATION
possible in these catalytic reactions.96
Additionally, there are a wide variety of photoredox catalysts Corresponding Author
and metals yet to be engaged in dual catalytic reactions. Recent *E-mail: [email protected].
reports of photoinduced electron transfer from supramolecular Notes
host complexes97 are particularly intriguing given the synergy The authors declare no competing financial interest.
298 DOI: 10.1021/acscentsci.6b00090
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■
Outlook

ACKNOWLEDGMENTS (20) Winston, M. S.; Wolf, W. J.; Toste, F. D. Photoinitiated

Oxidative Addition of CF3I to Gold(I) and Facile Aryl-CF3 Reductive
We gratefully acknowledge NIHGMS (RO1 GM073932) for Elimination. J. Am. Chem. Soc. 2014, 136, 7777−7782.
financial support. M.D.L thanks the NSF GRFP and ARCS (21) Kalyani, D.; McMurtrey, K. B.; Neufeldt, S. R.; Sanford, M. S.
foundation for graduate research fellowships. We thank Richard Room-Temperature C−H Arylation: Merger of Pd-Catalyzed C−H
Thornbury and Roman Sarott for helpful discussions. Functionalization and Visible-Light Photocatalysis. J. Am. Chem. Soc.

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