DUAL CATALYSIS
Merging photoredox with nickel
catalysis: Coupling of α-carboxyl
sp3-carbons with aryl halides
Zhiwei Zuo, Derek T. Ahneman, Lingling Chu, Jack A. Terrett,
Abigail G. Doyle,* David W. C. MacMillan*
Over the past 40 years, transition metal catalysis has enabled bond formation between
aryl and olefinic (sp2) carbons in a selective and predictable manner with high functional
group tolerance. Couplings involving alkyl (sp3) carbons have proven more challenging.
Here, we demonstrate that the synergistic combination of photoredox catalysis and nickel
catalysis provides an alternative cross-coupling paradigm, in which simple and readily
available organic molecules can be systematically used as coupling partners. By using
this photoredox-metal catalysis approach, we have achieved a direct decarboxylative
sp3–sp2 cross-coupling of amino acids, as well as a-O– or phenyl-substituted carboxylic
acids, with aryl halides. Moreover, this mode of catalysis can be applied to direct
cross-coupling of Csp3–H in dimethylaniline with aryl halides via C–H functionalization.
Visible light photoredox catalysis has emerged in recent years as a powerful technique in organic synthesis. This class of catalysis makes use of transition metal polypyridyl complexes that, upon excitation by visible
light, engage in single-electron transfer (SET) with
common functional groups, activating organic molecules toward a diverse array of valuable transformations (1–5). Much of the utility of photoredox
catalysis hinges on its capacity to generate nontraditional sites of reactivity on common substrates
via low-barrier, open-shell processes, thereby fostering the use of abundant and inexpensive starting materials.
Over the past century, transition metal-catalyzed
cross-coupling reactions have evolved to be among
the most used C–C and C–heteroatom bond-forming reactions in chemical synthesis. In particular, nickel catalysis has provided numerous
avenues to forge carbon–carbon bonds via a variety
of well-known coupling protocols (Negishi, Suzuki-Miyaura, Stille, Kumada, and Hiyama couplings,
among others) (6, 7). The broad functional group
tolerance of these reactions enables a highly modular building block approach to molecule construction. Organometallic cross-coupling methods
are traditionally predicated on the use of aryl or
vinyl boronic acids, zinc halides, stannanes, or
Grignard fragments that undergo addition to a
corresponding aryl or vinyl halide partner.
We recently questioned whether visible-light
photoredox and nickel transition metal cataly-
sis might be successfully combined to create a
dual catalysis platform for modular C–C bond
formation (Fig. 1) (8–14). Through a synergistic
merger of these two activation modes, we hoped
to deliver a mechanism by which feedstock chem-
icals that contain common yet nontraditional
leaving groups (Csp3–CO2H or Csp3–H bonds)
could serve as useful coupling partners. Among
many advantages, this multicatalysis strategy
would enable a modular approach to sp3–sp2
or sp3–sp3 bond formations that is not currently
possible by using either photoredox or transi-
tion metal catalysis alone. We sought to develop a
general method that would exploit naturally
abundant, inexpensive, and orthogonal functional
handles (e.g., C–CO2H, C–H with C–Br, or C–I).
We proposed that two interwoven catalytic
cycles might be engineered to simultaneously
generate (i) an organometallic nickel(II) species
via the oxidative addition of a Ni(0) catalyst to an
aryl (Ar), alkenyl, or alkyl halide coupling partner
and (ii) a carbon-centered radical generated through
a photomediated oxidation event (Fig. 2). Given
that organic radicals are known to rapidly com-
bine with Ni(II) complexes (15, 16), we hoped
that this dual catalysis mechanism would success-
fully converge in the form of Ni(III)(Ar)(alkyl)
that, upon reductive elimination, would deliver
our desired C–C fragment coupling product. One
of our laboratories has demonstrated that photo-
redox catalysis affords access to a-amino radicals
by two distinct methods: via decarboxylation of a
carboxylic acid or by an oxidation, deprotonation
sequence with N-aryl or trialkyl amines (17, 18).
The other laboratory has explored Ni-catalyzed
cross-coupling reactions with iminium ions that
proceed via a putative a-aminonickel intermediate
(19–21). Given our respective research areas, we
sought to jointly explore the capacity of a nickel
(II) aryl species to intercept a photoredox-generated
a-amino radical, thereby setting the stage for the
fragment coupling. We recognized that the sum
of these two catalytic processes could potentially
overcome a series of limitations that exist for each
of these catalysis methods in their own right.
A detailed description of our proposed mechanistic cycle for the decarboxylative coupling is
outlined in Fig. 2. We presumed that initial
irradiation of heteroleptic iridium(III) photocatalyst
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] (1)
would produce the long-lived photoexcited *IrIII
state 2 (exposure time t = 2.3 ms) (22). Deprotonation of the a-amino acid substrate 3 with base
and oxidation by the excited-state *IrIII complex
{E1/2red [*IrIII/IrII] = +1.21 V versus saturated
calomel electrode (SCE) in CH3CN} (22) via a
SET event would then generate a carboxyl radical, which upon rapid loss of CO2 would deliver
Merck Center for Catalysis at Princeton University, Princeton,
NJ 08544, USA.
*Corresponding author. E-mail: agdoyle@princeton.edu (A.G.D.);
dmacmill@princeton.edu (D. W.C.M.)
Fig. 1. The merger of photoredox and nickel catalysis yields access to direct sp3-sp2
cross-coupling. R, alkyl group.
