從5-溴-1,2,3-三嗪一鍋化靈活合成嘧啶衍生物

Abstract

三嗪是含有三個氮的六員芳香雜環化合物，存在於各種生物活性分子中。根據其氮原子的位置不同，可分為1,2,3-三嗪(1,2,3-triazines)，1,2,4-三嗪(1,2,4-triazines)和1,3,5-三嗪(1,3,5-triazines)。博格(Dale L. Boger)和他的研究團隊系統性的研究1,2,3-三嗪與各種胺類(amine)相關的親二烯體(dienophile)的環加成反應，為合成含氮雜環天然產物提供了新的見解方向。在本論文中，我們以5-溴-1,2,3-三嗪作為起始物，提出了一種有效合成多種官能基化的嘧啶衍生物的方法，反應過程通過一鍋化依序建立新的碳‒氧鍵和進行逆電子需求的狄耳士—阿爾德反應(inverse electron demand Diels–Alder reaction)。在反應中只需要利用碳酸銫促進反應，5-溴-1,2,3-三嗪即可直接與各種苯醇進行碳‒氧偶合，並與脒進行隨後的[4+2]環加成反應，以溫和的反應條件下生成良好到優異產率的相對應嘧啶衍生物。該方法同時展示反應基質的可用性、簡易實驗操作和原子經濟性等優點，提供了一鍋化合成嘧啶的有效途徑。The triazines are three nitrogen-containing six-membered aza-aromatic compounds, which are present in various biologically active molecules. According to the different positions of their nitrogen atoms can be divided into 1,2,3-triazines, 1,2,4-triazines, and 1,3,5-triazines. Boger and coworkers have systematically investigated the cycloaddition reactions of 1,2,3-triazines with various amine-related dienophiles and provided new perspectives into the synthesis of nitrogen-containing heterocyclic natural products. In this thesis, we present a practical one-pot approach for the synthesis of functionalized pyrimidines from 5-bromo-1,2,3-triazine via sequential direct C‒O coupling and amidine-based inverse electron demand Diels–Alder reaction. The reactions utilize Cs2CO3 to promote direct C‒O coupling of 5-bromo-1,2,3-triazine with various aryl alcohols and subsequent amidine cycloaddition to generate the corresponding pyrimidines in good to excellent yields under mild reaction conditions. The reaction was mediated by cesium carbonate under transition metal-free conditions. This protocol also showed the merits of substrate availability, simple operation, and atom economy. It provided an efficient route for straightforward one-pot synthesis of pyrimidines.