Contra-thermodynamic Hydrogen Atom Abstraction in the Selective C-H Functionalization of Trialkylamine N-CH₃ Groups

We report a simple one-pot protocol that affords functionalization of N-CH₃ groups in N-methyl-N,N-dialkylamines with high selectivity over N-CH₂R or N-CHR₂ groups. The radical cation DABCO^+•, prepared in situ by oxidation of DABCO with a triarylaminium salt, effects highly selective and contra-thermodynamic C-H abstraction from N-CH₃ groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH₃ groups. Chemoselectivity, scalability, and recyclability of reagents are demonstrated, and a mechanistic proposal is corroborated by computational and experimental results. The utility of the transformation is demonstrated in the late-stage site-selective functionalization of natural products and pharmaceuticals, allowing rapid derivatization for investigation of structure-activity relationships.