Solvent- and Catalyst-Controlled Regioselective O- and N-Alkylation of 2-Pyridones by 2H-Azirines

The synthesis of O-substituted 2-hydroxypyridines and N-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 O- and N-alkylation of 2-pyridones using Bro̷nsted acid-catalyzed ring opening of 2H-azirines. The process involves triflic acid for O-alkylation and p-toluenesulfonic acid for N-alkylation, achieving high yields under optimized conditions. For O-alkylation, a variety of 2-pyridones and 2H-azirines were used, resulting in significant yields of the desired products. Similarly, for N-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 2H-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.