Paul Bhaskar, Panja Dibyajyoti, Kundu Sabuj
Department of Chemistry, University of Oxford, Oxford, UK.
Department of Chemistry, Indian Institute of Technology Kanpur (IITK), Kanpur, India.
Nat Protoc. 2024 Dec;19(12):3640-3676. doi: 10.1038/s41596-024-01031-w. Epub 2024 Aug 22.
Nitrogen heterocycles are found in the structures of many biologically important compounds, as well as materials used in the synthesis of fine chemicals. Notably, ~59% of US Food and Drug Administration-approved small-molecule drugs contain nitrogen heterocycles. It is therefore meaningful to explore greener or more sustainable methods for their synthesis. The use of alcohols as reagents is attractive as they can be readily obtained from biomass derived natural resources. In the last two decades, alcohol dehydrogenative coupling reaction to synthesize various heterocycles were extensively explored which furnished hydrogen (H) and water (HO) as the two greener byproducts. In this protocol, we describe several efficient catalytic transformations to synthesize quinolines, 1,8-naphthyridines, quinoxalines, quinazolines, pyrimidines, benzimidazoles, pyrroles and pyridines, using alcohol as starting materials. We also describe the synthesis of several homogeneous iridium/ruthenium catalysts and heterogeneous cobalt/copper catalysts that can be used in these transformations. The reaction setup is simple; in a Schlenk/reaction tube with magnetic stir-bar, alcohol, corresponding coupling reagents (nucleophiles), catalyst, base and solvent (water or organic solvent such as toluene, dioxane or p-xylene) are added. The reaction mixture is refluxed at the specified temperature (110-150 °C)-either in air or under argon-to furnish these heterocycles. Synthesis of the catalysts takes 3-5 h and the coupling reactions take 4-5 h depending on the target product. The cobalt- and copper-based heterogeneous catalytic systems displayed an good catalyst recyclability.
氮杂环存在于许多具有重要生物学意义的化合物结构中，以及用于精细化学品合成的材料中。值得注意的是，美国食品药品监督管理局批准的小分子药物中约59%含有氮杂环。因此，探索更绿色或更可持续的合成方法具有重要意义。使用醇类作为试剂很有吸引力，因为它们可以很容易地从生物质衍生的自然资源中获得。在过去的二十年里，人们广泛探索了通过醇脱氢偶联反应合成各种杂环，该反应产生氢气（H）和水（HO）作为两种更绿色的副产物。在本方案中，我们描述了几种以醇为起始原料合成喹啉、1,8-萘啶、喹喔啉、喹唑啉、嘧啶、苯并咪唑、吡咯和吡啶的高效催化转化反应。我们还描述了几种可用于这些转化反应的均相铱/钌催化剂和多相钴/铜催化剂的合成。反应装置简单；在带有磁力搅拌棒的Schlenk反应管中，加入醇、相应的偶联试剂（亲核试剂）、催化剂、碱和溶剂（水或有机溶剂，如甲苯、二氧六环或对二甲苯）。反应混合物在指定温度（110-150°C）下回流——可在空气中或氩气气氛下——以合成这些杂环。催化剂的合成需要3-5小时，偶联反应根据目标产物的不同需要4-5小时。钴基和铜基多相催化体系表现出良好的催化剂可回收性。
