Reductive Transamination of Pyridinium Salts to N‑Aryl Piperidines

• Published in: Journal of organic chemistry Vol. 89; no. 13; pp. 9352 - 9359
• Main Authors: Chen, Zhenyu, Song, Geyang, Qi, Leiming, Gunasekar, Ramachandran, Aïssa, Christophe, Robertson, Craig, Steiner, Alexander, Xue, Dong, Xiao, Jianliang
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.07.2024; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; PALLADIUM; AMINATION; POTENT; PYRROLIDINES; COUPLING REACTIONS; LEVULINIC ACID; AMINES; COPPER; ASYMMETRIC HYDROGENATION; CATALYST
• ISSN: 0022-3263; 1520-6904; 1520-6904
• DOI: 10.1021/acs.joc.4c00493

Saturated N-heterocycles are found in numerous bioactive natural products and are prevalent in pharmaceuticals and agrochemicals. While there are many methods for their synthesis, each has its limitations, such as scope and functional group tolerance. Herein, we describe a rhodium-catalyzed transfer hydrogenation of pyridinium salts to access N-(hetero)­aryl piperidines. The reaction proceeds via a reductive transamination process, involving the initial formation of a dihydropyridine intermediate via reduction of the pyridinium ion with HCOOH, which is intercepted by water and then hydrolyzed. Subsequent reductive amination with an exogenous (hetero)­aryl amine affords an N-(hetero)­aryl piperidine. This reductive transamination method thus allows for access of N-(hetero)­aryl piperidines from readily available pyridine derivatives, expanding the toolbox of dearomatization and skeletal editing.