Iridium(III)-catalysed ionic hydrogenation of pyridines to multisubstituted piperidines

Piperidine and pyridine are nitrogen heterocyclic motifs prominently used in pharmaceuticals and consequently of great importance. The direct reduction of planar pyridines into piperidines with high sp³-carbon content is highly attractive as this offers a route to producing high-value products and broadening the structural space. However, direct hydrogenation of pyridines with homogeneous catalysts is challenging due to their aromatic stability and catalyst-poisoning abilities. Here we describe a robust and selective iridium(III)-catalysed 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 multisubstituted 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 was successfully and selectively hydrogenated.