α,β-Desaturation and Formal β-C(sp³)–H Fluorination of N-Substituted Amines: A Late-Stage Functionalization Strategy Enabled by Electrochemistry

Abstract

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.