regard was found in the work of Sanford and
Glorius, who had demonstrated that cooperative catalysis between transition metals and
photoredox catalysts is indeed possible (15–17).
Potassium organotrifluoroborates were identified as promising partners in this new class of
cross-couplings, as previous reports have documented their ability to function as carbon radical
sources upon single-electron oxidation (18, 19).
Furthermore, Akita and co-workers have used
Ir[dFCF3ppy]2(bpy)PF6 (dFCF3ppy = 2-(2,4-
difluorophenyl)-5-(trifluoromethyl)pyridine; bpy =
bipyridine) as a catalyst for the oxidation of activated potassium organotrifluoroborates, demonstrating the feasibility of their implementation
in the proposed single-electron transmetalation
manifold (20, 21).
Studies were initiated with nickel as a result
of its high reactivity toward organic halides and
its favorable single-electron redox potentials.
We anticipated that the combination of a monomeric Ni(0) catalyst 1 and an aryl halide 2 would
result in rapid oxidative addition, generating
Ni(II) species 3. Concomitantly, visible-light
irradiation of Ir[dFCF3ppy]2(bpy)PF6 4 would
generate the excited-state complex 5, the reduction potential of which is sufficiently high [electrochemical potential of reduction Ered = +1.21 V
(22, 23)] to induce single-electron oxidation of an
activated alkyltrifluoroborate 6 [electrochemical
potential of oxidation Eox = –1.10 V (20)], affording the desired alkyl radical 7 upon fragmentation. Subsequent capture of the alkyl radical
at Ni(II) would then yield high-valent Ni(III)
intermediate 9, which was expected to undergo
reductive elimination to generate the desired cross-coupled product 10 and Ni(I) complex 11. From
here, reduction of 11 [Ered > –1.10 V (24, 25)] by the
reduced form of the photocatalyst 8 [Eox = +1.37 V
(21)] would regenerate both the Ni(0) catalyst
1 and the Ir catalyst 4, closing the dual catalytic cycle.
As a proof of concept, this dual catalytic single-electron transmetalation approach was applied
to the cross-coupling of benzylic trifluoroborates
and aryl bromides (Fig. 2). Our efforts were quickly
rewarded, as a catalytic system consisting of photocatalyst 4, Ni(COD)2 (COD = 1,5-cyclooctadiene),
4,4-di-tert-butyl-2,2′-bipyridine (dtbbpy) as ligand, and 2,6-lutidine as an additive effected the
cross-coupling of potassium benzyltrifluoroborate and bromobenzonitrile in 89% yield upon
exposure to visible light from a 26-W compact
fluorescent light bulb at room temperature for
24 hours. Control reactions performed in the
absence of photocatalyst, Ni catalyst, or light
resulted in no detectable product formation,
confirming the essential role of each of these
components in the dual catalytic process (26).
We next analyzed the scope of the reaction with
regard to both the benzylic trifluoroborate and
aryl halide. As expected, electronic modification
of the trifluoroborate component had a mod-
erate effect on reaction yield, with more electron-
rich, and thus more highly stabilized, radical
precursors (16 and 18) performing better than
those substituted with electron-withdrawing
groups (15 and 17). Substrates possessing an
ortho substituent were well tolerated, as evi-
denced by isolation of product 13 in 82% yield.
The reaction also exhibited increased efficiency
on a larger scale, as diarylmethane 12 was isolated
in 97% yield on a 5.5-mmol scale with reduced
catalyst loading [1 mol 4 and 1.5 mol of Ni
(COD)2 and ligand].
High levels of versatility and functional group
tolerance were observed with regard to the aryl
halide partner. Substrates bearing electrophilic
functional groups that would be incompatible
with more highly reactive organometallic nucleo-
philes were well tolerated. Protic functional
groups, including amide 27, sulfonamide 39,
phenol 26, pyrazole 32, and -NHBoc 28, could
also be used. Substrates possessing substituents
ortho to the halide (25, 37) were tolerated, albeit
in diminished yield. The absence of a strong base
permitted the coupling of amino acid derivative
28 with no observable epimerization, demon-
strating the potential utility of this method for
late-stage functionalization of peptides or for use
with molecules containing other base-sensitive
functional groups.
A variety of nitrogen-containing heteroaryl
bromides—classically challenging yet highly valued
substrates because of their prevalence in biolog-
ically active compounds (27)—performed well un-
der the optimized reaction conditions. Pyridine
substrates were coupled in all possible regioiso-
meric configurations (29, 30, 31, 33). Other
important N-heterocycles, including pyrimidine
34, indole 35, and quinoline 37, proved to be
competent partners. Although five-membered
heterocyclic bromides generally exhibited poor
reactivity, electron-deficient thienyl bromides
were coupled in moderate yields, leading to 38
and 39.
Several practical and more sustainable fea-
tures derive from this approach to cross-coupling.
Previous approaches to the cross-coupling of
benzylboron compounds with aryl halides have
required excess (3 equiv) aqueous base and tem-
peratures no lower than 60°C (28–30). Further-
more, the present reaction makes use of air-stable
and inexpensive bipyridine ligands with low
loading of the Ni catalyst. A derivative of photo-
catalyst 4 has recently been made commercially
available and is similarly effective in promot-
ing the desired reactivity.
The reported cross-coupling reactions generally exhibited levels of efficiency and functional
group tolerance equal to or surpassing those of
traditional cross-coupling reactions on similar
substrates. Most reactions cleanly afforded the
desired product, with the remaining mass balance
consisting of only unreacted aryl halide. Competing homocoupling of the trifluoroborate to
afford bibenzyl derivatives was undetectable by
crude high-performance liquid chromatography
analysis, allowing use of only a slight excess (1.2
equiv) of this reaction partner, which is typical
in traditional Suzuki-Miyaura cross-couplings.
Also of note is the compatibility of this reaction
manifold with functional groups susceptible to
ν
δ
h
Fig. 1. Comparison of transmetalation in the palladium-catalyzed Suzuki-Miyaura cross-coupling
and the proposed single-electron transmetalation in photoredox/nickel cross-coupling. Ir =
Ir[dFCF3ppy]2(bpy)PF6, R = generic organic subunit, Ar = aryl group.
