Facile Access to Hindered Ethers via Photoinduced O-H Bond Insertions

Abstract

The synthesis of the hindered and polyfluorinated dialkyl ethers poses challenges owing to the bulkiness of tertiary alcohols and the low nucleophilicity of polyfluorinated alcohols. Additionally, associated competitive side reactions always provide poor reactivities. Although certain strategies, such as the electrocatalytic decarboxylation and hydroalkoxylation, have been explored, a straightforward method for obtaining ethers with structural diversity remains elusive. In this study, we proposed a photoinduced approach that involved the in-situ formation of singlet carbenes followed by O-H insertions to access the hindered and polyfluorinated ethers. This method successfully converted diverse congested alcohols and polyfluorinated alcohols into their corresponding challenging ethers. Moreover, other nucleophiles such as phenols, H2O, thiols, silanols, tributyltin hydride etc. were tolerable to obtain valuable products. The gram-scale synthesis of marketed drugs and the modification of complex molecules demonstrated the practicality of this approach. The detailed mechanistic studies have elucidated the key intermediates and reaction mechanisms.