Synthesis 2018; 50(06): 1228-1236
DOI: 10.1055/s-0036-1589159
short review
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Heterobenzylic Fluorides

Michael Meanwell
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada   Email: rbritton@sfu.ca
,
Robert Britton*
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada   Email: rbritton@sfu.ca
› Author Affiliations
R.B. acknowledges support from an NSERC Discovery Grant and a MSFHR­ Career Investigator Award. M.M. is supported by an NSERC Postgraduate Scholarship and a Simon Fraser University Fellowship.
Further Information

Publication History

Received: 25 November 2017

Accepted after revision: 27 November 2017

Publication Date:
23 January 2018 (eFirst)

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

 
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