catalysis, a reaction involving a putative radical intermedi-
ate via Ag(III)-assisted single-electron transfer followed by
fluorine atom transfer.11 This method tolerates a range of
functional groups but is not applicable to aryl carboxylic
acids. We questioned whether the incorporation of a di-
fluoromethylene unit between the aryl group and the
carboxylic acid functionality could lead to a new class of
reactive substrates since the R,R-difluorobenzyl radical is a
well characterized aryl-stabilized species known to adopt
an all planar geometry.12 Herein, we report that R,R-
difluoroarylaceticacidsrespond tosilver-catalyzedfluoro-
decarboxylation in the presence of Selectfluor; this meth-
od, which offers access to aryl CF3 through late-stage
fluorination, was extended to the preparation of difluoro-
methylated arenes and was found suitable for [18F]-
labeling using [18F]Selectfluor bis(triflate) (Scheme 2).
Scheme 1. Retrosynthesis of Aryl CF3 (LG = Leaving Group)
precursors armed with a suitable leaving group have been
considered to access the aryl [18F]CF3 motif. More com-
monly, bromide, chloride, and fluoride are displaced in halex
exchange processes with [18F]fluoride; these reactions require
harsh reaction conditions and could suffer from narrow
substrate scope and low specific activity, especially for radio-
tracers obtained by isotopic exchange or carrier-added
methods.6 Given the importance of decarboxylative fluorina-
tion to access alkyl fluorides, we were surprised that the
displacement of a carboxylic acid functionality has never been
considered for the construction of trifluoromethylated arenes
from R,R-difluoroaryl acetic acid precursors (Scheme 1).
Several groups have made seminal contributions toward
Scheme 2. Ag-Catalyzed Fluorodecarboxylation of Carboxylic
Acids
7
fluorodecarboxylation of carboxylic acids with F2 and
XeF2.8 Following these discoveries, Sammis and co-workers
established that milder reagents can be used for the
fluorination of alkyl radicals via the decomposition of
tert-butyl peresters of carboxylic acids; these reagents
include NFSI (N-fluorobenzenesulfonimide) and Select-
fluor (1-chloromethyl-4-fluorodiazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)).9 More recently, Li and co-workers10a
have shown that aliphatic carboxylic acids underwent
fluorodecarboxylation with Selectfluor under AgNO3
We initiated our studies with the fluorodecarboxylation
of biphenyl-4-yl(difluoro)acetic acid 1a, a substrate readily
prepared in two steps from the corresponding aryl iodide
and ethyl bromodifluoroacetate adapting a literature
procedure (Table 1).13,14 Gratifyingly, exposure of 1a to
AgNO3 (20 mol %) and 2 equiv of Selectfluor, in 1:1
(v/v) acetone/H2O under reflux, gave the trifluoromethylated
arene 2a in >95% yield (entry 1). The reaction monitored
by 19F NMR was completed within 1 h (100% conversion
of 1a); it required AgNO3 to proceed (entry 2) and was
found to be equally successful using Selectfluor bis(triflate)
(entry 3). Alternative reagents were not suitable. The use of
NFSI gave no reaction under the standard reaction con-
ditions and the use of 5 equiv of NFSI in MeCN at 100 ꢀC
afforded the acyl fluoride 3a15 in 30% yield along with
trace amount of 2a (entries 4 and 5). The treatment of 1a
(5) For methods toward [18F]CF3 and [18F]CF2CF3, see: (a) Josse, O.;
ꢀ
Labar, D.; Georges, B.; Gregoire, V.; Marchand-Brynaert, J. Bioorg.
Med. Chem. 2001, 9, 665–675. (b) Dolbier, W. R., Jr,; Li, A.-R.; Koch,
C. J.; Shiue, C.-Y.; Kachur, A. V. Appl. Radiat. Isot. 2001, 54, 73–80. (c)
Riss, P. J.; Aigbirhio, F. I. Chem. Commun. 2011, 47, 11873–11875. (d)
Riss, P. J.; Ferrari, V.; Brichard, L.; Burke, P.; Smith, R.; Aigbirhio, F. I.
Org. Biomol. Chem. 2012, 10, 6980–6986.
(6) For halex-exchange processes toward [18F]CF3, see: (a) Angelini,
G.; Speranza, M.; Shiue, C.-Y.; Wolf, A. P. J. Chem. Soc., Chem.
Commun. 1986, 924–925. (b) Kilbourn, M. R.; Pavia, M. R.; Gregor,
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€
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Stone-Elander, S. J. Label Compd. Radiopharm. 1995, 36, 537–547.
(e) Suehiro, M.; Yang, G.; Torchon, G.; Ackerstaff, E.; Humm, J.;
Koutcher, J.; Ouerfelli, O. Bioorg. Med. Chem. 2011, 19, 2287–2297.
(7) Grakauskas, V. J. Org. Chem. 1969, 34, 2446–2450.
(8) (a) Patrick, T. B.; Johri, K. K.; White, D. H. J. Org. Chem. 1983,
48, 4158–4159. (b) Patrick, T. B.; Johri, K. K.; White, D. H.; Bertrand,
W. S.; Mokhtar, R.; Kilbourn, M. R.; Welch, M. J. Can. J. Chem. 1986,
64, 138–141. (c) Patrick, T. B.; Khazaeli, S.; Nadji, S.; Hering-Smith, K.;
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(9) (a) Rueda-Becerril, M.; Sazepin, C. C.; Leung, J. C. T.; Okbinoglu,
T.; Kennepohl, P.; Paquin, J.-F.; Sammis, G. M. J. Am. Chem. Soc. 2012,
134, 4026–4029. For a photofluorodecarboxylation, see: (b) Leung, J. C. T.;
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Sammis, G. M. Angew. Chem., Int. Ed. 2012, 51, 10804–10807.
(10) (a) Yin, F.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134,
10401–10404. For an early example of Ag(I)-catalyzed oxidative decarbox-
ylation of acids by peroxydisulfate, see: (b) Anderson, J. M.; Kochi, J. K.
J. Am. Chem. Soc. 1970, 92, 1651–1659.
(11) For a recent account on free-radical approaches for Csp3ÀF
bond formation, see: Sibi, M. P.; Landais, Y. Angew. Chem., Int. Ed.
2013, 52, 3570–3572.
(12) Kispert, L. D.; Liu, H.; Pittman, C. U., Jr. J. Am. Chem. Soc.
1973, 1657–1659. For an account on the heat of formation of difluoro-
methylene, see: Gozzo, F.; Patrick, C. R. Nature 1964, 202, 80.
(13) (a) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. J. Fluorine
Chem. 2004, 125, 509–515. (b) Fujikawa, K.; Fujioka, Y.; Kobayashi,
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(14) Details provided in the Supporting Information.
(15) The formation of benzoyl fluoride upon fluorodecarboxylation
of benzoic acid has been reported. See ref 8.
B
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