Selective Fluorination of Complex Molecules: Late-Stage Functionalization

It has been more than 160 years since chemists first performed fluorination reactions on organic molecules. Scores of fluorination reagents and hundreds of worthwhile methods have been developed over the intervening years. Meanwhile, workers in the field are increasingly aware of the benefits of incorporating fluorine atoms into bioactive molecules. Therefore, the emergence of “late-stage fluorination” in the first decade of the 21st century is both natural and well-justified─an extant compound, off the shelf, can be converted more efficiently to a fluorinated product than through a de novo approach. It is worth noting that chemists’ attempts to fluorinate complex molecules began sporadically decades ago before the concept of “late-stage” was first proposed. In this Perspective, we aim to present a comprehensive series of late-stage fluorination strategies, with the spotlight primarily focused on single-atom modifications of complex molecules (although incidental examples of polyfluorination are addressed), including natural products, analogues, and pharmaceuticals. Both the nucleophilic and electrophilic sources of fluorine are examined.