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

Abstract

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.

Electrode Materials in Modern Organic Electrochemistry

“…The concept of forming electrogenerated bases (EGBs, Figure A) in situ from a pro‐base for utilisation in a synthetic transformation was first reported in 1967 . Using electrochemistry allows the concentration and basicity of the reaction to be carefully controlled, and changing the counterion influences both the stability and reactivity of the EGB …”

Advances in Asymmetric Organotransition Metal-Catalyzed Electrochemistry

“…First, oxoammonium species (TEMPO + ) 17 is formed via anodic oxidation of TEMPO. Upon hydride transfer, [30] iminium intermediate 20 is generated from 13, with the concomitant formation of TEM-PO-H 16, which can be converted into 17 by anodic oxidation. Addition of the chiral acetylide species 19 (derived from Cu(I) and alkyne 14 in the presence of base) to electrophilic 18 results in the formation of product 15.…”

Merging Photochemistry with Electrochemistry: Functional‐Group Tolerant Electrochemical Amination of C(sp3)−H Bonds

“…FeiW ang and Shannon S. Stahl* Abstract: Direct amination of C(sp 3 ) À Hb onds is of broad interest in the realm of C À Hf unctionalization because of the prevalence of nitrogen heterocycles and amines in pharmaceuticals and natural products.R eported here is ac ombined electrochemical/photochemical method for dehydrogenative C(sp 3 ) À H/N À Hc oupling that exhibits good reactivity with both sp 2 and sp 3 N À Hb onds.T he results show howu se of iodide as an electrochemical mediator,i nc ombination with light-induced cleavage of intermediate NÀIbonds,enables the electrochemical process to proceed at low electrode potentials. This approach significantly improves the functional-group compatibility of electrochemical CÀHamination, for example, tolerating electron-richa romatic groups that undergo deleterious side reactions in the presence of high electrode potentials.…”

“…Important challenges,h owever,m ust be overcome to expand the utility of these methods.F or example,h igh electrode potentials required to initiate electron transfer from an organic molecule can lead either to decomposition or oxidative side reactions of ancillary functional groups in the molecule.W eh ave been exploring strategies to enable electrochemical oxidation reactions to proceed at lower electrode potentials. [3] Use of an electron-proton transfer mediator,such as an aminoxyl or imidoxyl species,r epresents one appealing strategy,a st hese mediators enable oxidations to proceed at electrode potentials more than 1V lower than analogous nonmediated processes. [3b,c] In spite of this progress,a dditional strategies are needed.…”