Synthesis of Heterobenzylic Fluorides

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

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