Synthesis of Heterobenzylic Fluorides

Fluorination at heterobenzylic positions can have a significant impact on basicity, lipophilicity, and metabolism of drug leads. As a consequence, the development of new methods to access heterobenzylic fluorides has particular relevance to medicinal chemistry. This short review provides a survey of common methods used to synthesize heterobenzylic fluorides and includes fluoride displacement reactions of previously functionalized molecules (e.g., deoxyfluorination and halide exchange) and electrophilic fluorination of resonance-stabilized heterobenzylic anions. In addition, recent advances in the direct fluorination of heterobenzylic C(sp3)–H bonds and monofluoromethylation of heterocyclic C(sp2)–H bonds are presented. 1 Introduction 2 Heterobenzylic Fluorides 2.1 Deoxyfluorination 2.2 Halide Exchange 2.3 Electrophilic Fluorination of Heterobenzylic Anions 2.4 Late Stage C–H Bond Fluorination 2.5 Monofluoromethylation of C(sp2)–H Bonds 3 Conclusions