Curran Dara T, Szydło Marcin, Müller-Bunz Helge, Nikitin Kirill, Byrne Peter A
Centre for Synthesis & Chemical Biology, School of Chemistry, University College Dublin Belfield Dublin 4 Ireland
SSPC, the Research Ireland Centre for Pharmaceuticals Ireland.
Chem Sci. 2025 Mar 4;16(16):6991-7003. doi: 10.1039/d4sc06203e. eCollection 2025 Apr 16.
A new method has been established for formation of ethers from aldehydes and alcohols - a net reductive etherification. Reactions of these entities with phosphines in the presence of acid enable formation of α-(alkoxyalkyl)phosphonium salts, which, upon hydrolysis, result in formation of ether products in isolated yields of 63-92%. Formation and hydrolysis of the α-(alkoxyalkyl)phosphonium salts were done in an efficient telescoped two-step, one-pot process that does not require inert atmosphere conditions. Formation of the key phosphonium salt intermediates was found to occur in preference to acetal formation and is proposed based on both experimental and computational evidence to involve interception of oxocarbenium ions formed by reaction of the aldehyde, alcohol and acid by phosphine. This method represents the first instance in which net reductive etherifications have been achieved without the requirement for use of hydrides or hydrogen as reductants, and exhibits excellent functional group tolerance, thus enabling facile hydride-free synthesis of ethers. These are amongst the most important functional groups in organic synthesis. The new etherification method also enables deuteride-free synthesis of deuterated ethers.
已建立了一种由醛和醇形成醚的新方法——净还原醚化反应。这些物质在酸存在下与膦反应可生成α-(烷氧基烷基)鏻盐，水解后可得到醚产物，分离产率为63% - 92%。α-(烷氧基烷基)鏻盐的形成和水解在高效的两步一锅法中完成，该过程不需要惰性气氛条件。发现关键的鏻盐中间体的形成优先于缩醛的形成，并且基于实验和计算证据提出，这涉及通过膦拦截由醛、醇和酸反应形成的氧鎓离子。该方法是首次在不使用氢化物或氢气作为还原剂的情况下实现净还原醚化反应，并且具有出色的官能团耐受性，从而能够轻松地进行无氢化物的醚合成。这些是有机合成中最重要的官能团之一。新的醚化方法还能够实现无氘化物的氘代醚合成。
