Acidity Controlled Formal Nucleophilic Substitution of Hydrofluoroolefin-based Iodonium Salt with O-nucleophiles: Synthetic Application and Mechanistic Study.

Abstract

The development and mechanistic investigation of a novel O-fluoroalkylation of phenol derivatives using a hypervalent fluoroalkyliodonium salt, derived from hydrofluoroolefin gas (HFO-1234yf) as bulk fluorous feedstock, is reported. Optimization of the reaction conditions enabled versatile and efficient synthetic applications, and the synthetic study revealed phenol acidity-dependent selectivity of the O-fluoroalkylation process. The mechanistic behavior of phenols was supported by both experimental studies and DFT calculations. As a result, we showed that more acidic phenols (pKa < 5) undergo direct O-alkylation, while reactions of the fluoroalkyliodonium salt involving less acidic phenol substrates proceed via a base-assisted chloride elimination and substitution pathway. Deuterium-labeling and halide competition experiments further validated the proposed mechanism. This practical and scalable method provides access to structurally diverse fluoroalkyl ethers and holds significant potential for applications in medicinal and materials chemistry.