Late-Stage N-Adamantylation of Pyridines.

Pyridines are among the most prevalent heterocyclic motifs in approved pharmaceuticals. A general strategy enabling direct functionalization of the pyridine nitrogen in structurally complex molecules would provide a powerful means to diversify existing drugs into pyridinium salts and piperidines with minimal synthetic effort. However, current approaches typically require N-functionalization to be performed on simple pyridines, with molecular complexity introduced at later stages, where the available synthetic repertoire is limited. Here, we report a general strategy for the direct N-adamantylation of structurally more complex pyridines, including numerous drug molecules. The method is operationally simple and proceeds through the treatment of pyridine substrates with adamantyl acetate and Me3SiOTf. Mechanistic studies support initial N-silylation, followed by reaction with the alkyl acetate. Beyond pyridine adamantylation, the method extends to other N-heterocycles (pyrimidines, pyrazines, quinoxalines, and quinazolines) and alkyl groups, including systems that are too unstable to participate in conventional carbocation-based N-alkylation. Subsequent dearomatization provides access to N-alkyl piperidines. Evaluation of these previously inaccessible compounds for their in vitro ADME properties shows adequate solubility, permeability, and metabolic stability, supporting their potential utility in medicinal and agrochemical contexts.