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.