Solvent- and Catalyst-Controlled\nRegioselective <i>O</i>- and <i>N</i>‑Alkylation\nof 2‑Pyridones\nby 2<i>H</i>‑Azirines

The synthesis of <i>O</i>-substituted 2-hydroxypyridines\nand <i>N</i>-substituted 2-pyridones, crucial for many bioactive\ncompounds and drugs, faces challenges due to the tautomeric nature\nof 2-pyridones, which complicates selective alkylation. Here we developed\nan efficient method for regioselective <i>O</i>- and <i>N</i>-alkylation of 2-pyridones using Bro̷nsted acid-catalyzed\nring opening of 2<i>H</i>-azirines. The process involves\ntriflic acid for <i>O</i>-alkylation and <i>p</i>-toluenesulfonic acid for <i>N-</i>alkylation, achieving\nhigh yields under optimized conditions. For <i>O</i>-alkylation,\na variety of 2-pyridones and 2<i>H</i>-azirines were used,\nresulting in significant yields of the desired products. Similarly,\nfor <i>N</i>-alkylation, the optimized conditions produced\nexcellent yields, highlighting the method’s versatility. This\nmethodology was further demonstrated through scaled-up syntheses and\nsubsequent transformations, showcasing its practicality for complex\nmolecular architectures. The proposed mechanism involves the protonation\nof 2<i>H</i>-azirine, followed by a regioselective S<sub>N</sub>2-type attack and acid-catalyzed hydrolysis, leading to the\ndesired alkylated products. This innovative approach, emphasizing\nBro̷nsted acid catalysis and careful control of reaction conditions,\nrepresents a significant advancement in the selective alkylation of\n2-pyridones, with broad implications for medicinal chemistry.