Iridium(III)-Catalyzed Ionic Hydrogenation of Pyridines to Multi-Substituted Piperidines

Piperidine and pyridine are highly prominent nitrogen heterocyclic motifs in pharmaceuticals and of high relevance. The direct reduction of flat pyridines into piperidines with high sp3-carbon content is of strong appeal producing high-value products and broadening structural space. However, direct hydrogenation of pyridines with homogenous catalysts is challenging due to its aromatic stability and catalyst-poisoning abilities. We describe a robust and selective iridium(III)-catalyzed ionic hydrogenation of pyridines to corresponding functionalized piperidines. Important highly reduction-sensitive groups including nitro-, azido-, bromo-, alkenyl- and alkynyl are inert enabling access to a broad range of multi-substituted piperidines in high yields, substantially expanding the available chemical space for this relevant scaffold. The method requires low catalyst loadings, is scalable to decagrams, and delivers the most synthetically valuable free secondary amines as easily isolable and stable piperidinium salts. Applied in a complex late-stage setting, the pyridine motif in several FDA-approved drugs were successfully and selectively hydrogenated.