The Fluorination of C-H Bonds: Developments and Perspectives

Area of Science:

• Organic Chemistry
• Catalysis
• Fluorination Chemistry

Background:

• C-H activation enables direct functionalization of typically inert C-H bonds.
• Fluorination is crucial for modifying molecular properties in pharmaceuticals and materials.
• Developing selective and efficient fluorination methods remains a significant challenge in synthetic chemistry.

Purpose of the Study:

• To review recent advancements in fluorination via C(sp2)-H and C(sp3)-H activation.
• To highlight the role of transition-metal catalysis in site- and stereoselective fluorination.
• To discuss the current landscape and limitations of late-stage C-H fluorination strategies.

Main Methods:

• Transition-metal-catalyzed C-H activation using palladium and other metals.
• Exploitation of high-oxidation-state transition-metal fluoride complexes.
• Use of directing groups (transient and external ligands) for site selectivity.
• Radical-mediated C-H fluorination approaches.
• Development of methods combining nucleophilic fluoride sources with oxidants.

Main Results:

• Palladium catalysis enables selective fluorination at C(sp2) and C(sp3) sites.
• External ligands enhance control in C(sp3)-H fluorination.
• Radical methods offer complementary undirected C(sp3)-H fluorination.
• Electrophilic fluorination reagents are widely used, but nucleophilic methods are emerging.
• Late-stage nucleophilic C-H fluorination and C-H 18F-fluorination are still underdeveloped.

Conclusions:

• Significant progress has been made in transition-metal-catalyzed C-H fluorination.
• Electrophilic fluorination remains the dominant strategy, with growing interest in nucleophilic and radical pathways.
• Further research is needed to advance late-stage C-H fluorination, particularly for radiolabeling applications.