Electrocatalytic Radical-Polar Crossover Hydroetherification of Alkenes with Phenols

We disclose a general electrocatalytic hydroetherification for modular synthesis of alkyl aryl ethers by utilizing a wide range of alkenes and phenols. The integration of the two involves an electrochemically instigated cobalt-hydride-catalyzed radical -polar crossover of alkenes that enable the generation of key cationic intermediates, which could readily be entrapped by challenging nucleophilic phenols. We highlight the importance of precise control of the reaction potential by electrochemistry in conjunction with the decisive role of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the co-solvent to obtain optimal and exclusive chemoselectivity. This reaction system is pertinent to late-stage functionalization of pharmacophores that contain alkyl aryl ethers which have constantly been challenged since traditionally unconventional methods.

Automated summary

We disclose a general electrocatalytic hydroetherification method for modular synthesis of alkyl aryl ethers. This method involves an electrochemically instigated cobalt-hydride-catalyzed radical-polar crossover of alkenes, resulting in the generation of cationic intermediates that react with nucleophilic phenols. Precise control of reaction potential by electrochemistry and the use of hexafluoro-2-propanol (HFIP) as the co-solvent are crucial for achieving optimal and exclusive chemoselectivity. This method is important for the late-stage functionalization of pharmacophores containing alkyl aryl ethers, which has been a challenge using traditional unconventional methods.