Carboxylic acids as alternative electrophiles in ether synthesis

醚是有机化学中重要的官能团，存在于大量的天然产物中，也存在于溶剂、聚合物和精细化学品中。农用化学品和制药工业尤其依赖芳醚，最近发表的化合物库中约有35%含有芳醚。尽管它们储量丰富，但只有少数几个反应可以用于商业规模的合成醚。其中最多产的是威廉姆森醚合成，其中强亲电试剂如烷基卤化物或伪卤化物被醇取代。虽然稳定且产率高，但该方法使用强的化学计量碱，并且通常需要较少的可持续溶剂，如DMF，以最大限度地减少竞争消除反应。此外，烷基卤化物具有致癌性，通常由相应的醇在另一个步骤中制成，这降低了整体效率。在追求更可持续的过程中，还原过程已成为杂原子烷基化的有前途的新策略。在醚合成的背景下，大多数方法的发展都集中在羰基亲电试剂的使用上，然而涉及酮/醛的反应通常具有非常有限的底物范围，选择性酯还原需要额外的步骤来形成适当的起始材料。本项目旨在使用羧酸作为亲电试剂在威廉姆森醚合成的还原变化。类似的策略最近已发展为胺合成，然而，尽管这些方法的实用性，氧类似物的探索远远少于。该方法的主要优点是用羧酸代替烷基卤化物，羧酸丰富、稳定且价格低廉。

Ethers are vital functional groups in organic chemistry and occur across a plethora of natural products as well as in solvents, polymers and fine chemicals. The agrochemical and pharmaceutical industries are particularly reliant on aryl ethers, which feature in around 35% of recently published library compounds. Despite their abundance, only a select few reactions are can be used to synthesise ethers on a commercial scale. One of the most prolific is the Williamson ether synthesis, in which strong electrophiles such as an alkyl halide or pseudohalide is substituted by an alcohol. Whilst robust and high yielding, this procedure uses strong, stoichiometric bases and often requires less sustainable solvents such as DMF to minimise the competing elimination reaction. Additionally, alkyl halides are carcinogenic and are often made from corresponding alcohols in an additional step which reduces overall efficiency.In the pursuit of more sustainable processes, reductive procedures have emerged as promising new strategies for heteroatom alkylation. In the context of ether synthesis, most method development has focussed on use of carbonyl-based electrophiles, however reactions involving ketones/aldehydes typically have a very limited substrate scope and a selective ester reduction requires an additional step to form the appropriate starting material.This project aims to use carboxylic acids as electrophiles in a reductive variation of the Williamson ether synthesis. Similar strategies have recently been developed for amine synthesis, however despite the practicality of these methods, the oxygen analogue is far less explored. The key advantage of this methodology would replacement of alkyl halides with carboxylic acids, which are abundant, bench stable and inexpensive.