Mechanochemical Regioselective N -Functionalization of Hydroxypyridines

Abstract The development of solvent-free methodologies for the practical synthesis of N-functionalized heterocycles is crucial for the preparation of active pharmaceutical ingredients (APIs), particularly 2- and 4-pyridones. Mechanochemical tools provide a sustainable strategy to achieve this; however, the regioselective functionalization of N- vs O-remains a challenge. Herein, we report a robust and practical mechanochemical protocol for the regioselective N-functionalization of 2- and 4-pyridones through ball-milling techniques. A wide range of substrate scopes, including N-benzylated, N-alkylated, and N-acylated compounds, featuring electron-rich/deficient moieties, were furnished in moderate to excellent yields. Remarkably, N-alkylation of an electron-deficient tertiary acetate halide alluded to an uncommon mechanism for solid-state N-alkylation; an in situ side product was successfully isolated and revealed to be N-,O-dibenzylated pyridinium, adding credence to an unconventional mechanochemical reaction pathway. These mechanistic insights lay a foundation for future design of N-functionalization methodologies in solvent-free mechanochemical conditions. This mechanochemical N-functionalization system provides a new green strategy to obtain bioactive heterocycles, with high functional group tolerance and straightforward operation.