Solvent- and Catalyst-Controlled Regioselective <i>O</i>- and <i>N</i>-Alkylation of 2-Pyridones by 2<i>H</i>-Azirines

The synthesis of <i>O</i>-substituted 2-hydroxypyridines and <i>N</i>-substituted 2-pyridones, crucial for many bioactive compounds and drugs, faces challenges due to the tautomeric nature of 2-pyridones, which complicates selective alkylation. Here we developed an efficient method for regioselective <i>O</i>- and <i>N</i>-alkylation of 2-pyridones using Bro̷nsted acid-catalyzed ring opening of 2<i>H</i>-azirines. The process involves triflic acid for <i>O</i>-alkylation and <i>p</i>-toluenesulfonic acid for <i>N-</i>alkylation, achieving high yields under optimized conditions. For <i>O</i>-alkylation, a variety of 2-pyridones and 2<i>H</i>-azirines were used, resulting in significant yields of the desired products. Similarly, for <i>N</i>-alkylation, the optimized conditions produced excellent yields, highlighting the method's versatility. This methodology was further demonstrated through scaled-up syntheses and subsequent transformations, showcasing its practicality for complex molecular architectures. The proposed mechanism involves the protonation of 2<i>H</i>-azirine, followed by a regioselective S_N2-type attack and acid-catalyzed hydrolysis, leading to the desired alkylated products. This innovative approach, emphasizing Bro̷nsted acid catalysis and careful control of reaction conditions, represents a significant advancement in the selective alkylation of 2-pyridones, with broad implications for medicinal chemistry.