Nucleophilic Fluorination by Light-mediated Radical Oxidation

Abstract

Aliphatic organofluorine compounds are valuable synthetic products, as they are well represented in pharmaceuticals, agrochemicals, and materials, with many valuable biological and physical properties imparted due to the presence of fluorine. The value of fluorine incorporation has made the late-stage addition of fluorine a longstanding objective. Traditional incorporation of fluorine arises from the use of highly reactive electrophilic fluorine reagents or low reactivity nucleophilic fluoride reagents. Different mechanistic models and approaches have been developed around these dissimilar reactivity patterns, however, nucleophilic techniques are valued due to their more facile translation to radiochemical applications with [18F]fluoride. Unfortunately, the conventional reactivity of fluoride has limited the incorporation pathways of fluoride to bimolecular nucleophilic substitution, more commonly known as SN2, and is thus confined to the preparation of activated or unhindered aliphatic fluorides.

Herein is described a photomediated, unimolecular pathway for fluorine addition into aliphatic molecules. This reaction platform allows for the synthesis of a variety of hindered and unactivated aliphatic fluoride compounds, with complementary reactivity to traditional displacement chemistry. The methodology is extended towards the synthesis of radiolabeled compounds with [18F]fluoride as a demonstration for application in development of pharmaceuticals via radiochemical techniques. Mechanistic investigation provides evidence for a proposed radical oxidation with observations consistent with both radical and carbocation intermediacy. This mild reaction platform is extended beyond the synthesis of carbon-fluorine bonds to the construction of carbon-oxygen and carbon-carbon bonds and provides a strategic blueprint for a variety of novel transformations.