Potassium Bisulfite’s Role in Developing a Robust Platform for Enantioenriched <i>N</i> -Alkylpyridinium Salts as Piperidine Precursors

Piperidines are prominent scaffolds in medicinal chemistry. However, methods that incorporate chiral <i>N</i>-alkyl substituents on piperidine remain limited. Here, we report a platform for the synthesis of enantioenriched <i>N</i>-(α-chiral)alkylpyridinium salts from commercially available pyridines and enantiopure primary amines; the resulting pyridinium salts serve as versatile precursors to stereoenriched <i>N</i>-(α-chiral)alkylpiperidines via established reduction protocols. We discovered potassium metabisulfite as a reaction additive that significantly enhanced the robustness of the pyridinium formation reaction. Mechanistic and computational studies reveal that potassium metabisulfite deconjugates Zincke imines, enabling a lower-energy polar cyclization pathway to pyridinium formation compared to a pericyclic one. We performed high-throughput experimentation that demonstrated a broad scope for both coupling partners, providing a robust, general platform for generating libraries of piperidine precursors relevant to medicinal chemistry.