Amide alpha-C-H Oxidative Coupling Reactions Enabled by Base-Promoted Halogen Transfer

A base-promoted protocol for the direct oxidative coupling of amide α-C-H bonds with common O-, S- and N-pronucleophiles is described. This process operates via a synergistic deprotonation, halogenation, and substitution sequence that is enabled by the use of mild bases with inexpensive 2-bromothiophenes as halogen oxidants. This strategy overcomes longstanding challenges associated with conventional two-step amide enolate formation/halogenation sequences that are generally ineffective. Furthermore, this route to α-substituted amides serves as a streamlined and modular alternative to traditional multistep syntheses that require preassembly of an α-functionalized carboxylic acid before amide coupling.