New Take On C-F Activation

The first examples of Suzuki-type cross-coupling involving perfluorinated arenes has been reported by Udo Radius and his coworkers at Karlsruhe University, in Germany (J. Am. Chem. Soc.,DOI: 10.1021/ja064068b).

Chemists have taken a great interest in C-F bond activation reactions in part to synthesize fluorinated analogs of active pharmaceutical ingredients. The very strong C-F bond helps modulate the lipophilicity of a drug to improve its bioavailability and helps control drug metabolism. So far, most cross-coupling reactions have involved converting monofluorinated arenes into nonfluorinated derivatives, while fluorinated arene products have remained elusive.

Radius' group has developed a nickel catalyst stabilized by an N-heterocyclic carbene ligand (an imidazolylidene) that selectively activates the C-F bond para to the electron-withdrawing CF₃ group in perfluorotoluene or C₆F₅ group in perfluorobiphenyl. The catalyst then mediates coupling of the intermediate with a phenyl or biphenyl boronic acid to form polyfluorinated biphenyl or triphenyl products.

The efficient metal-catalyzed C-F activation with C-C bond formation is general, Radius notes, and his group is in the process of expanding the scope of the reaction.