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2.6 C—F Bond-Forming Reactions

DOI: 10.1055/sos-SD-208-00368

McMurtrey, K. B.; Sanford, M. S.Science of Synthesis: Cross Coupling and Heck-Type Reactions, (20132551.

General Introduction

Aromatic C—F bonds are a critical feature of numerous pharmaceuticals, agrochemicals, radiotracers, and organic materials. Traditional methods for accessing these linkages are highly limited due to the requirements for corrosive reagents and elevated temperatures as well their modest substrate scope and functional group tolerance. Transition-metal-catalyzed coupling reactions would provide an alternative and potentially highly complementary route to fluorinated aromatic compounds. However, such transformations have historically proven challenging due to the low kinetic reactivity of aryl(fluoro)metal complexes toward the C—F bond-forming reductive elimination step required for product release. As discussed in this chapter, research in the field has focused on two approaches to address this challenge. The first (detailed in Section 2.6.1) involves the use of electrophilic fluorinating reagents to access highly reactive oxidation states of the catalysts [e.g., palladium(III) or -(IV), silver(II) or -(III)]. These high-valent organometallic intermediates are typically very unstable, which facilitates low-energy pathways for C—F coupling. A second approach (discussed in Section 2.6.2) involves delivery of fluorine from nucleophilic fluoride sources. In these systems, efforts have focused on promoting reductive elimination from lower-valent palladium species [e.g., aryl(fluoro)palladium(II) complexes] through modification of supporting phosphine ligands.