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

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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.
Funding Information
  • Genentech
  • Camille and Henry Dreyfus Foundation
  • National Institute of General Medical Sciences (R01GM130928)
  • National Defense Science and Engineering Graduate

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