Three step procedure for the preparation of aromatic and aliphatic difluoromethyl ethers from phenols and alcohols using a chlorine/fluorine exchange methodology

•Synthesis of difluoromethyl ethers.•Synthesis of dichloromethyl ethers.•Chlorine/fluorine exchange.•Use of HF-Lewis base media for fluorination.

Difluoromethyl ethers are prepared from phenols in three steps via their respective formate ester derivatives. The formates are first converted to dichloromethyl ethers by treatment with PCl5. These ethers are then induced to undergo chlorine/fluorine exchange to form the respective difluoromethyl ethers. The chlorine/fluorine exchange is carried out by either a room temperature, solvolytic process using THF-5HF or Et3N-3HF as exchange medium, where HF is the ultimate source of fluorine, or by a direct displacement process in sulfolane at 125 °C, where KF is the source of fluorine. By one or another of these processes, virtually all phenols, electron-rich and electron-poor, can be converted to their respective difluoromethyl ethers in good yields. Aliphatic alcohols are also able to be converted to their difluoromethyl ether derivatives using the Et3N-3HF exchange medium.

Graphical abstractAryl difluoromethyl ethers have been prepared in three steps from phenols via their formate esters by conversion of the formate esters to dichloromethyl ethers followed by chlorine/fluorine exchange.Figure optionsDownload full-size imageDownload as PowerPoint slide