C(sp3)-C(sp3) bond formation via electrochemical alkoxylation and subsequent Lewis acid promoted reactions

A new and practical two-step transition metal-free methodology for the C(sp3)-C(sp3) functionalisation of saturated N-heterocyclic systems is disclosed. First, aminal derivatives are generated through the anodic oxidation of readily accessible carboxylic acids. Then, in the presence of BF3·OEt2, iminium ions are unmasked and rapidly alkylated by organozinc reagents under flow conditions. Secondary, tertiary and quaternary carbon centers have been successfully assembled using this new methodology. Such an approach is especially relevant to drug discovery since it increases C(sp3)-functionalities rapidly within a molecular framework. As proof of concept, our new methodology was applied to derivatization of peptides and an API.