Incorporation
of C(sp3)–F bonds in biologically
active compounds is a common strategy employed in medicinal and agricultural
chemistry to tune pharmacokinetic and pharmacodynamic properties.
Due to the limited number of robust strategies for C(sp3)–H fluorination of complex molecules, time-consuming de novo syntheses of such fluorinated analogs are typically
required, representing a major bottleneck in the drug discovery process.
In this work, we present a general and operationally simple strategy
for site-specific β-C(sp3)–H fluorination
of amine derivatives including carbamates, amides, and sulfonamides,
which is compatible with a wide range of functional groups including N-heteroarenes. In this approach, an improved electrochemical
Shono oxidation is used to set the site of functionalization via net
α,β-desaturation to access enamine derivatives. We further
developed a series of new transformations of these enamine intermediates
to synthesize a variety of β-fluoro-α-functionalized structures,
allowing efficient access to pertinent targets to accelerate drug
discovery campaigns.