Diversity in a Bottle: Iminium Ions as a Platform for N-(Hetero)Aryl Piperidine Synthesis

Piperidines are prevalent throughout FDA-approved drugs and current drug candidates, thus robust methods for preparing these heterocycles are desirable for efficiently probing structure activity relationships (SAR) during drug discovery campaigns. N-heteroaryl piperidines are particularly important in pharmaceutical applications, but they remain problematic synthetic targets because traditional approaches based on transition metal catalyzed cross-coupling and or SNAr reactions routinely fail. We report here a general platform for the rapid synthesis of densely functionalized N-(hetero)aryl piperidine derivatives using a common precursor. First, we disclose an expeditious synthesis of bench-stable cyclic iminium salts starting from widely abundant heteroaryl amine and ketoacrylate feedstocks. We then show that these intermediates are readily elaborated into a wide variety of complex piperidines via derivatization reactions employing common reagents. This chemistry facilitates incorporation of trifluoromethyl, methyl, and cyano nucleophiles at C2, in addition to substitution at C3 using a variety of carbon electrophiles. Additionally, sequential C3 and C2 functionalization of the iminium salts allows for modular construction of piperidine derivatives having very complex substitution patterns. Finally, we show that the key iminium species can be generated and transformed in situ, providing access to desired compounds in a single-pot through-process.