Regio- and Stereoselective Alkyl enol Ether Synthesis via Microwave-Promoted, Base-Catalysed Alkyne Hydroalkoxylation

Abstract

The diverse reactivity presented by alkyl enol ethers underpins a wide range of synthetically significant processes. Their synthesis is often achieved by atom-economical alkyne hydroalkoxylation (i. e., addition of an alcohol across an alkyne), either using superbasic conditions or transition metal catalysis. Unfortunately, the harsh conditions of the former approach limit substrate tolerance whilst the latter approach often requires inert, anhydrous conditions and exotic, expensive catalysts. In order to pursue more convenient, general and sustainable methodology for enol ether synthesis, we have developed microwave-promoted alkyne hydroalkoxylation as an attractive solution. Our optimised conditions employ caesium carbonate as a mild base catalyst and the required alcohol as solvent and reagent, with reaction temperatures from 20–150 °C and reaction times from 10–60 minutes. We have demonstrated that the reaction shows broad tolerance of diverse substrate functionality (e. g., ester, ether, carboxylate, nitrile, nitro, halide), including examples of terminal, internal, aryl and alkyl alkynes. Greatest reactivity is observed with electron-poor alkyne substrates, and the reaction shows near-complete anti-Markovnikov regioselectivity and a very strong stereochemical bias towards Z-configured enol ether products. These observations are consistent with a polar mechanism proceeding via a vinyl anion intermediate, and we provide empirical and computation evidence in support of this.