Design and development of a deoxyfluorination method using transition metal fluorides

Abstract

The installation of a C–F bond in organic molecules is of significant importance to the scientific community due to its ability to modulate a compound’s physicochemical properties. For this reason, organofluorine compounds are valuable and widespread in the medicinal, agrochemical, and material industries.

Accordingly, research into developing new methods of C–F bond formation is a fast-paced field. A popular way of installing C(sp³)–F bonds is by deoxyfluorination whereby alcohols are converted to the corresponding fluorides. This particular transformation is attractive due to the fact that alcohols are readily available and inexpensive starting materials, and the reaction can proceed in a stereospecific manner. There have been a vast range of bespoke deoxyfluorination reagents which have been designed to facilitate this reaction, and whilst they are effective, they often have drawbacks associated with them such as cost and stability.

Of particular interest with regards to C–F bond formation is the use of metal fluorides. This poses a major challenge to organic chemists as the inherent properties of metal fluorides render them difficult to utilise as the fluoride is not easily accessible. Whilst this is an underdeveloped field, recently strategies are emerging which successfully aid the poor reactivity of metal fluorides such as hydrogen bonding catalysis, allowing them to successfully participate in fluorination reactions.

Enclosed is the development of a stereospecific deoxyfluorination reaction using CuF₂ enabled by a Lewis base activating group. The reaction design means that through a ligation approach, the inherent properties of metal fluorides can be circumvented which in turn allows for the chelate-directed delivery of fluoride. Ultimately, the development of this methodology and its generality towards a wide range of alcohol substrates will be discussed. In order to showcase the utility of this strategy, the translation of the system into a ¹⁸F-radiolabelling protocol is demonstrated.