The Fluorination of C-H Bonds: Developments and Perspectives

Abstract

This Review summarizes advances in fluorination by C(sp² )-H and C(sp³ )-H activation. Transition-metal-catalyzed approaches championed by palladium have allowed the installation of a fluorine substituent at C(sp² ) and C(sp³ ) sites, exploiting the reactivity of high-oxidation-state transition-metal fluoride complexes combined with the use of directing groups (some transient) to control site and stereoselectivity. The large majority of known methods employ electrophilic fluorination reagents, but methods combining a nucleophilic fluoride source with an oxidant have appeared. External ligands have proven to be effective for C(sp³ )-H fluorination directed by weakly coordinating auxiliaries, thereby enabling control over reactivity. Methods relying on the formation of radical intermediates are complementary to transition-metal-catalyzed processes as they allow for undirected C(sp³ )-H fluorination. To date, radical C-H fluorinations mainly employ electrophilic N-F fluorination reagents but a unique Mn^III -catalyzed oxidative C-H fluorination using fluoride has been developed. Overall, the field of late-stage nucleophilic C-H fluorination has progressed much more slowly, a state of play explaining why C-H ¹⁸ F-fluorination is still in its infancy.

Keywords: C−H activation; fluorination; radical chemistry; radiochemistry; transition-metal catalysis.