Due to the unique properties of fluorine atom(s), the introduction of fluorinated functional groups into molecules has become one of the powerful strategies in the discovery of new pharmaceuticals, agrochemicals, and advanced functional materials. Consequently, considerable efforts have been made to develop new and efficient methods for preparing organofluorine compounds. Among the fluorine functionalities, the gem-difluoroallyl group represents one of the attractive moieties due to the unique properties of the difluoromethylene group (CF₂) and the synthetic versatility of the carbon-carbon double bond. Over the past decade, important progress has been made in the catalytic gem-difluoroallylation reactions. However, the efficient methods for the preparation of gem-difluoroallyl arenes remain limited despite their important applications in medicinal chemistry. Here, we report a palladium-catalyzed gem-difluoroallylation of heteroaryl bromides with gem-difluoroallylboronates. The reaction proceeds under mild conditions with high efficiency, high functional group tolerance, and excellent regioselectivity. A series of heteroaryl bromides are applicable to the reaction, providing facile access to gem-difluoroallyl heteroarenes of medicinal interest. A representative procedure for the palladium-catalyzed cross-coupling of heteroaryl bromides with gem-difluoroallylborons is as following: heteroaryl bromide (0.40 mmol, 1.0 equiv.) and (P(t-Bu)₂Ph)₂•PdCl₂ (3.0 mol%) were added to a 25 mL of Schlenck tube. The tube was then evacuated and backfilled with Ar (3 times). CsF (2.0 equiv.), gem-difluoroallylboron (0.44 mmol, 1.1 equiv.), and 1,4-dioxane (2.0 mL) were added under Ar. The tube was screw capped and put into a preheated oil bath (100 ℃). After stirring for 2 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (2.0 mL). The yield was determined by ¹⁹F NMR using fluorobenzene (1.0 equiv.) as an internal standard before working up. If necessary, the reaction mixture was diluted with EtOAc and filtered with a pad of cellite. The filtrate was concentrated, and the residue was purified with silica gel chromatography to give product 11.

Key words: palladium catalysis, gem-difluoroallylation, heteroaryl bromides, cross-coupling