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4CzlPN (2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile) can
promote this reaction (see the Supporting Information,
Table S1). Examination of the base showed that Li2CO3
provided higher yields than other carbonate salts. Likewise,
a catalytic amount of CsF (20 mol%) could also promote the
reaction in high yields, possibly explained through the
fluoride relay shown in Scheme 2 (see Supporting Informa-
tion, Table S2). Evaluation of solvents revealed DMSO as
best solvent. A lower yield (from 93% to 70%) was observed
when the reaction was set up in wet DMSO with 10 equiv of
H2O (see the Supporting Information, Table S3). Control
experiments proved that light irradiation, photocatalyst, and
base are each essential to this transformation (see the
Supporting Information, Table S4).
Two equivalents of perfluorobenzene is enough for
reactions with sufficiently nucleophilic radicals such as that
derived from N-Boc glycine but higher loading of perfluor-
oarenes are required with substrates that produce carbon
radicals with lower nucleophilicity[21] (see the Supporting
Information, Table S5 and S6). Due to its low cost, we
employed perfluorobenzene in access (5–10 equiv) for eval-
uation of the substrate scope with respect to the carboxylic
acid, which resulted in higher product yield and shorter
reaction time (Table 1). A variety of structurally and func-
tionally complex carboxylic acids are compatible with the
mild reaction conditions. a-Amino acids (7), a-oxy-substi-
tuted carboxylic acids (11 and 12), and aliphatic carboxylic
acids that result in the formation of secondary radicals (2, 3, 4,
and 6) are tolerated. Di-perfluoroarylation is achievable with
di-carboxylic acids (16). The reaction tolerates hydroxyl
groups (8 and 10), carbonyl groups (20), thiazoles (9),
amides (4), and indoles (5). Late-stage functionalization of
natural products (21) and drug molecules (13 and 17) is
possible as well. Carboxylic acids that result in the formation
of less nucleophilic, primary radicals (15) afford lower yield[21]
when compared to the transformations through secondary
and tertiary carbon radicals (14), respectively.
Several simple polyfluoroarenes are suitable for the
decarboxylative polyfluoroarylation (Table 2). While higher
yields are observed with higher fluorine substitution, alky-
lated arenes with as few as three fluorine atoms, in the
absence of other substituents, are achievable as demonstrated
by reaction with N-Boc glycine (27). Constitutional isomers
that resulted from addition at different positions for unsym-
metric fluoroarenes could all be purified chromatographically
(23, 24, 25, 26, 31, 32, and 33). The observed selectivity is
reminiscent to that observed in other radical addition
reactions to (het)arenes.[22] The reaction is chemoselective:
chloro-fluoro arenes reacted exclusively with fluorine sub-
stitution (23, 28, and 30), which is in contrast to the reactivity
observed by the Weaver group.[11,13]
Scheme 2. a) Perfluorobenzene as radical acceptor. b) Our reaction
design.
fluorobenzene in cyclohexane or in methanol in the presence
of benzophenone led to simple alkylated pentafluorophenyl
derivatives in product mixtures.[16] Radical addition to per-
fluoroarenes results in neutral radicals that would need to
formally lose a fluorine radical for productive alkylation. This
À
process is inefficient due to the large C F bond dissociation
energy (BDE = 145 kcalmolÀ1 in C6F6[17]), and results in
competing dimerization and hydroalkylation, which is the
reason that defluorinative alkylation through radical addition
to fluoroarenes is of little synthetic value so far. Perfluoroar-
enes and related electron-deficient arenes can be reduced to
the corresponding radical anions by excited photoredox
catalysts from which the carbon fluoride bond can be more
readily cleaved heterolytically by elimination of fluoride to
generate a synthetically useful aryl radical, as shown by
Weaver for addition of the aryl radical to p systems.[11,13] Our
reaction design is conceptually different in that we hypothe-
sized to add a radical to the perfluoroarene, and subsequently
reduce the resulting radical to an anion, from which fluoride
could be readily eliminated. Based on this hypothesis, we
designed a process, in which a photoredox catalyst, reduced in
its excited state by a carboxylate,[18,19] has appropriate redox
potential to reduce the initially formed radical adduct
to an anion (Scheme 2b). Consequently, we have employed
a cationic photoredox catalyst that is less reducing in its
excited state than the catalysts used for fluoroarene reduction
chemistry[11a] (Eox(IrIV/*IrIII) = À1.17 V vs. SCE in MeCN[20]).
The ability of our system to also furnish fluoroarenes with
smaller fluorine content such as trifluoroarenes is likely
a consequence of the different reduction potentials compared
to catalysts employed in other, related transformations that
function through arene reduction. On the other hand,
pentafluoropyridine that works well in reactions that reduce
the arene cannot be used as reagent in our reaction possibly
because it is too oxidizing.
Preliminary experiments to elucidate the mechanism of
the transformation are consistent with our original reaction
design (Scheme 2b). A Stern–Volmer analysis revealed that
photoexited [IrIII] was quenched by carboxylate rather
than perfluorobenzene (see the Supporting Information,
Scheme S3). Reductive quenching of photoexcited [IrIII]
(Ered(*IrIII/IrII) = 1.48 V vs. SCE in MeCN[20]) by carboxylates
(Eox(carboxylate) ranges from 0.95 V to 1.25 V vs. SCE in
Ir(dFFppy)2(dtbpy)PF6 was identified as the most suitable
photoredox catalyst, while neither Mes-Acr-Me·ClO4 nor
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