A General Strategy for N-(Hetero)arylpiperidine Synthesis Using Zincke Imine Intermediates
Jake D. Selingo, Jacob W. Greenwood, Mary Katherine Andrews, Chirag Patel, Andrew J. Neel, Barbara Pio, Michael Shevlin, Eric M. Phillips, Matthew L. Maddess, Andrew McNally
Abstract
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.