Fluorination of organic molecules often leads to enhanced efficacy in a variety of pharmaceuticals and agrochemicals, and thus, developing new fluorinated motifs is desirable to both academia and industry. Fluorinated epoxides, which are key building blocks for α-fluoroketones and structurally more complicated heterocycles, can be easily diversified. Current synthetic routes toward fluorinated epoxides include substitution reactions of halogenated epoxides with fluoride, Darzens reactions, oxidation of vinyl fluorides, Johnson–Corey–Chaykovsky reactions, and use of carbenoid intermediates. However, preparations of these active fluorinated epoxides are still limited by incompatibilities of functional groups and/or synthetic reagents. In this presentation, we will outline a new method to prepare fluorinated epoxides using hexamethylborazine stabilized fluoroalkyl synthons and carbonyl electrophiles (ketones, acyl chlorides, and esters). The mechanism was investigated by kinetics analysis using in situ 19F NMR spectroscopy. A variety of unprecedented α-fluorinated epoxides and multi-fluorinated epoxides can be synthesized and isolated via this route, showing good compatibility with commonly used functional groups including –CN, –Br, –OMe, and 2-pyridyl. Furthermore, the prepared fluorinated epoxides were used as precursors for ring-opened intramolecular fluoride migration, nucleophilic substitution, as well as the construction of heterocycles.

Preparation of fluorinated epoxides by fluoroalkylation of carbonyl electrophiles

ACS Spring 2022

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