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2.6.2 C—F Coupling Reactions with Nucleophilic Fluorinating Reagents

DOI: 10.1055/sos-SD-208-00368

McMurtrey, K. B.; Sanford, M. S.Science of Synthesis: Cross Coupling and Heck-Type Reactions, (20132562.

The use of a nucleophilic source of fluorine (e.g., a fluoride salt) in metal-catalyzed cross coupling is of particular interest due to the low cost of metal fluorides compared with the electrophilic fluorinating reagents discussed above. Nucleophilic fluorination reactions are also advantageous from the perspective of applications in 18F PET imaging. [18F]Fluoride has dramatically higher specific activity than the synthetic precursor to electrophilic fluorinating reagents, [18F]F2. However, despite the great potential advantages of metal-catalyzed nucleophilic fluorination, this type of transformation has historically proven extremely challenging for a number of reasons. First, fluoride typically has low nucleophilicity in solution due to the formation of strong hydrogen bonds with adventitious water. Second, fluoride salts are generally poorly soluble in organic solvents. Third, low-valent metal fluorides have largely proven inert to C—F bond-forming reductive elimination reactions. Instead, coupling of fluoride with a coordinated phosphine ligand is often a lower-energy competing pathway.[‌10‌]