C(sp3)-C(sp3) Bond Formation via Electrochemical Alkoxylation and Subsequent Lewis Acid Promoted Reactions

A two-step transition metal-free methodology for the C(sp(3))-C(sp(3)) 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 center dot 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 methodology. Such an approach is especially relevant to drug discovery since it increases C(sp(3))-functionalities rapidly within a molecular framework. As proof of concept, our methodology was applied to derivatization of peptides and an API.

Automated summary

This two-step methodology involves the generation of aminal derivatives through anodic oxidation of carboxylic acids, followed by rapid alkylation of iminium ions under flow conditions using organozinc reagents in the presence of BF3 center dot OEt2. It successfully assembles secondary, tertiary, and quaternary carbon centers and can enhance C(sp(3))-functionalities within a molecular framework, making it relevant to drug discovery.