{"title":"Solvent- and Catalyst-Controlled Regioselective <i>O</i>- and <i>N</i>-Alkylation of 2-Pyridones by 2<i>H</i>-Azirines.","authors":"Subrata Biswas, Surajit Duari, Srabani Maity, Arnab Roy, Sourav Guchhait, Asma M Elsharif, Srijit Biswas","doi":"10.1021/acs.joc.4c01870","DOIUrl":null,"url":null,"abstract":"<p><p>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<sub>N</sub>2-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.</p>","PeriodicalId":57,"journal":{"name":"The Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Organic Chemistry","FirstCategoryId":"1","ListUrlMain":"https://doi.org/10.1021/acs.joc.4c01870","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/7 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, ORGANIC","Score":null,"Total":0}
引用次数: 0
Abstract
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 SN2-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.
期刊介绍:
The Journal of Organic Chemistry welcomes original contributions of fundamental research in all branches of the theory and practice of organic chemistry. In selecting manuscripts for publication, the editors place emphasis on the quality and novelty of the work, as well as the breadth of interest to the organic chemistry community.