Methods
to synthesize diverse collections of substituted piperidines
are valuable due to the prevalence of this heterocycle in pharmaceutical
compounds. Here, we present a general strategy to access N-(hetero)arylpiperidines using a pyridine ring-opening and ring-closing
approach via Zincke imine intermediates. This process generates pyridinium
salts from a wide variety of substituted pyridines and (heteroaryl)anilines;
hydrogenation reactions and nucleophilic additions then access the N-(hetero)arylpiperidine derivatives. We successfully applied
high-throughput experimentation (HTE) using pharmaceutically relevant
pyridines and (heteroaryl)anilines as inputs and developed a one-pot
process using anilines as nucleophiles in the pyridinium salt-forming
processes. This strategy is viable for generating piperidine libraries
and applications such as the convergent coupling of complex fragments
