Strategies for Nucleophilic C(sp3)-(Radio)Fluorination.

Abstract

This Perspective surveys the progress and current limitations of nucleophilic fluorination methodologies. Despite the long and rich history of C(sp3)-F bond construction in chemical research, the inherent challenges associated with this transformation have largely constrained nucleophilic fluorination to a privileged reaction platform. In recent years, the Doyle group─along with many others─has pursued the study and development of this transformation with the intent of generating deeper mechanistic understanding, developing user-friendly fluorination reagents, and contributing to the invention of synthetic methods capable of enabling radiofluorination. Studies from our laboratory are discussed along with recent developments from others in this field. Fluoride reagent development and the mechanistic implications of reagent identity are highlighted. We also outline the chemical space inaccessible by current synthetic technologies and a series of future directions in the field that can potentially fill the existing dark spaces.