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F
CN
CN
N
N
PdIV
N
N
CD3CN
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N
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F
–
3
BF4
*
3a
5 equiv.
2′
1 equiv.
4a
63%, 66:34
+
2
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N
N
N
PdII
N
CN
CN
N
–
2
BF4
X
Cl
N
5 mol%
MeCN
+
N
F
F
–
2
BF4
*
3a
1 equiv.
4a
Selectꢀuor
2 equiv.
X = H (1′): 40%, 69:31
X = Cl (1): 80%, 71:29†
Figure 4 | Comparison of the positional selectivity of stoichiometric
and catalytic fluorinations using 2′. Top, stoichiometric fluorination;
bottom, catalytic fluorination. †5 equiv. of 4-cyanobiphenyl (3a) and
1 equiv. of Selectfluor were used.
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species. Reported examples of such a mechanism for aromatic C–H
oxidation, however, are rare, and are proposed to involve metal-
nitrene or aminyl-radical transfer to the arene, although evidence for
the proposed modes of action in these cases is indirect30,31. To the best
of our knowledge, the aromatic fluorination reaction reported here
is the only example so far of a synthetic method for aromatic C–H
functionalization in which oxidation reactivity between a high-valent
catalytic intermediate and arenes has been directly scrutinized.
The other examples of aromatic and aliphatic C–H oxidation reac
-
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tions proceeding through ‘oxidation-first’ mechanisms mentioned
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reaction for complex molecule synthesis. Science 318, 783–787 (2007).
to a mechanism of oxidation that is not available to the starting
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31. Paudyal, M. P. et al. Dirhodium-catalyzed C–H arene amination using
reagents, such as a radical-rebound mechanism in the case of hydrox-
ylation through metal–oxo intermediates. We have shown here data
that support the interpretation that catalyst 2 provides access to a
fluoride-coupled electron-transfer mechanism that is not accessible to
electrophilic fluorinating reagents such as Selectfluor.
We anticipate that the direct electrophilic C–H fluorination of arenes
hydroxylamines. Science 353, 1144–1147 (2016).
reported here will be a useful tool in medicinal chemistry; indeed,
the reaction has already found use in the late-stage derivatization of
drug molecules. Furthermore, the unusual mechanism of catalysis by
Acknowledgements We thank L. Gitlin for HPLC purification, R. Goddard,
S. Palm and J. Rust for X-ray crystallographic analysis, C. Farès for NMR
spectroscopy, and M. Blumenthal, D. Kampen and S. Marcus for mass
spectrometry. We thank UCB Biopharma for funding and compound separation,
complex 1, in which a high-valent transition-metal intermediate under-
goes group transfer to arenes, may become the basis for a new approach
to the catalysis of C–H functionalization reactions.
the Japan Society for the Promotion of Science and L’Oréal-UNESCO Japan for
Data Availability Data are available from the corresponding author on
reasonable request.
graduate fellowships to K.Y., the Fonds der Chemischen Industrie for a graduate
fellowship for J.D.R., and the German Academic Exchange Service, DAAD for an
Otto-Bayer fellowship to J.C.B.
received 21 March; accepted 17 December 2017.
Author Contributions K.Y. designed catalyst 1 and optimized the fluorination
reaction. K.Y. and J.D.R. conducted mechanistic studies. K.Y. and G.B.B.
developed the conceptual approach to the project. J.L., J.A.O.G., J.C.B., K.Y. and
J.D.R. explored the substrate scope. J.D.R. performed DFT calculations with
input from M.v.G. and F.N. G.B.B. wrote the manuscript with input from all other
authors. C.G. and J.J. supported development towards useful examples. K.Y., J.L.,
J.A.O.G., G.B.B., J.D.R. and T.R. analysed the data. T.R. directed the project.
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