Abstract
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
Key words
heterocycles - fluorination - medicinal chemistry - C–H functionalization - heterobenzylic
fluorides
