Ruthenium-Catalyzed C–F Bond Arylation of Polyfluoroarenes: Polyfluorinated Biaryls by Integrated C–F/C–H Functionalization

Fluorine-containing molecules are central motifs in pharmaceuticals, agrochemicals, and functional materials owing to the unique properties engendered by carbon–fluorine bonds. However, the chemoselective synthesis of multifluorinated biaryls, a motif extensively exploited in drug discovery, is challenging because of the difficulty in controlling selective fluorination. Herein, we report a site-selective arylation of C–F bonds in polyfluoroarenes enabled by a ruthenium catalyst system. The present C–F bond arylation proceeds exclusively at the ortho-position of polyfluorinated arenes through ruthenium(0) chelation to a readily modifiable directing group. A variety of broadly available polyfluoroarenes and organoboranes are applicable to this C–F bond functionalization, furnishing polyfluorinated biaryls featuring a readily removable aldehyde functional handle. Notably, the present conditions enable a programmed synthesis of multifluorinated biaryls by integrated C–F/C–H functionalization by the same ruthenium catalyst. This approach is characterized by broad scope and functional group tolerance to build complex multifluorinated biaryls. The synthetic utility of this approach is highlighted by the synthesis of polyfluorinated ligands, heterocycles, pharmaceuticals, and porphyrin analogues. DFT studies provide insight into the key selectivity of C–F bond activation. We fully expect that this approach will facilitate the implementation of C–F defluorination in the synthesis of polyfluorinated molecules utilizing molecules with high fluorine content.