使用二叔丁基苯基膦预配位的氯化钯(P(t-Bu)₂Ph)₂•PdCl₂为催化剂, 实现了钯催化下偕二氟烯丙基硼试剂与杂芳基溴代物的偶联反应. 该方法不仅体系简单, 反应效率高, 区域选择性优秀, 可以克量级制备产物, 而且具有良好的官能团兼容性, 适用于一系列不同类型的杂环底物, 为合成偕二氟烯丙基杂芳烃化合物提供了一种高效方法.

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.