Introducing fluorine into organic molecules is a general strategy to improve performance in a wide variety of pharmaceuticals and agrochemicals, and thus, developing new fluorinated motifs has attracted broad interest. Fluorinated epoxides represent an easily diversifiable class of compounds that are important building blocks for α-fluoroketones and the construction of more complicated heterocycles. Existing methods to prepare fluorinated epoxides include Darzens reactions, Johnson–Corey–Chaykovsky reactions, as well as routes that proceed through oxidation of vinyl fluorides, fluoride substitution of halogenated epoxides, and usage of carbenoid intermediates. However, the synthesis of fluorinated epoxides is still limited by incompatibilities of functional groups and/or the instability of the products toward the reagents involved in the preparation. In this presentation, we will describe the development of a new synthetic approach to prepare fluorinated epoxides using Lewis acid (hexamethylborazine) stabilized fluoroalkyl synthons and carbonyl electrophiles (ketones, acyl chlorides, and esters). The mechanistic pathway was investigated by kinetics analysis of a key intermediate using in situ 19F NMR spectroscopy. A number of unprecedented α-fluorinated epoxides and multi-fluorinated epoxides can be synthesized and isolated via this route, and various commonly used functional groups (–CN, –Br, –OMe, and 2-pyridyl) are tolerated. Importantly, the fluorinated epoxides serve as versatile precursors that can be ring-opened concomitant with fluoride migration. Finally, we will demonstrate the utility of this strategy by using a tandem reaction sequence, wherein the epoxide ring-opening can be coupled with a nucleophilic substitution of fluoride to ultimately construct heterocycles.

Borazine masked fluoroalkyl synthons for the synthesis of fluorinated epoxides and subsequent rtsformations

ACS Spring 2022

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