Electrochemical Direct Hydroxylation of Benzylic C–H Bonds Assisted by HFIP

Benzylic alcohols represent a privileged structural motif that is ubiquitous in bioactive natural products and pharmaceutical agents. Selective oxidative hydroxylation of benzylic C–H bonds is an efficient, atom-economical, and environmentally friendly methodology. However, the inherent obstacle of alcohol overoxidation still poses a significant challenge. Herein, we report an HFIP-assisted electrochemical oxidative hydroxylation of benzylic C–H bonds, utilizing green, benign H₂O as the hydroxyl source. This method exhibits remarkable compatibility with a broad range of substrates, including electron-rich, electron-neutral, and electron-deficient alkylarenes, alkylarenes bearing primary, secondary, and tertiary benzylic C–H bonds, and even pharmaceutical molecules. Notably, the method enables efficient synthesis of ¹⁸O-labeled biorelevant derivatives, highlighting its utility for isotopic-labeling studies. Furthermore, this electrochemical protocol has been shown to be readily scalable (up to 10 g under 200 mA/cm²), thus demonstrating its promising potential for industrial application. Mechanistic studies have revealed that benzylic alcohols can be stabilized by HFIP via hydrogen-bonding interactions, thereby reducing the electron density of the aromatic rings, subsequently deactivating its further oxidation and improving the selectivity of the reaction.