Electrochemical Aminoxyl-Mediated α‑Cyanation of Secondary Piperidines for Pharmaceutical Building Block Diversification

Secondary
piperidines are ideal pharmaceutical building blocks
owing to the prevalence of piperidines in commercial drugs. Here,
we report an electrochemical method for cyanation of the heterocycle
adjacent to nitrogen without requiring protection or substitution
of the N–H bond. The reaction utilizes ABNO (9-azabicyclononane N-oxyl) as a catalytic mediator. Electrochemical oxidation
of ABNO generates the corresponding oxoammonium species, which promotes
dehydrogenation of the 2° piperidine to the cyclic imine, followed
by addition of cyanide. The low-potential, mediated electrolysis process
is compatible with a wide range of heterocyclic and oxidatively sensitive
substituents on the piperidine ring and enables synthesis of unnatural
amino acids.