镍催化的芳基硼酸偕二氟炔丙基化反应

Nickel-Catalyzed Cross-Coupling of gem-Difluoropropargyl Bromide with Aryl Boronic Acids

偕二氟炔丙基取代的芳烃是一类非常重要的化合物,但传统合成该类化合物的方法却存在很大局限性.以过渡金属催化直接向芳烃偕二氟炔丙基化是一种高效简洁制备上述化合物的方法.以廉价易得的Ni(NO3)2?6H2O为催化剂,首次实现了镍催化下芳基硼酸与α,α-二氟炔丙基溴的偶联反应.该反应不仅温和高效、原料廉价易得、官能团兼容性良好,而且还能进行克量级放大和对生物活性分子的后期氟修饰,从而为新药研发提供了一种有效手段.

The gem-difluoropropargylated arenes play an important role in life and material sciences owning to the unique properties of the difluoromethylene group(CF2). The traditional method to access such a kind of fluorinated structure relies on conversion of carbonyl group with aminosulfurtrifluorides, such as DAST and Deoxofluor. However, these reactions suffer from the use of expensive and toxic fluorinated reagents and the important functional group incompatibility. Hence, it is highly desirable to develop new and efficient strategies and methods to prepare gem-difluoropropargylated arenes. As part of our ongoing interest in transition-metal-catalyzed difluoroalkylation reactions, herein, we report a nickel-catalyzed cross-coupling of gem-difluoropropargyl bromide with aryl boronic acids. The reaction uses low-cost Ni-catalyst and proceeds under mild reaction conditions with high efficiency and good functional group compatibility. It is also possible for gram-scale reaction and late stage gem-difluoropropargylation of bioactive natural product, thus providing a facile route for application in drug discovery and development. A representative procedure for nickel-catalyzed cross-coupling of gem-difluoropropargyl bromide with aryl boronic acids is as following: Phenylboronic acid 1a(1.5 equiv.), Ni(NO3)2·6H2O or Ni Cl2·dppe(2.5 mol%), bpy(2.5 mol%), and K2CO3(2.0 equiv.) were subsequently added to a 25 m L of Schlenck tube.The resulting mixture was then evacuated and backfilled with Ar(3 times). gem-Difluoropropargyl bromide 2(0.6 mmol, 1.0equiv.) and 1,4-dioxane(4 m L) were then added. The Schlenck tube was screw capped and put into a preheated oil bath(80 ℃). After stirring for 24 h, the reaction mixture was cooled to room temperature. The yield was determined by 19 F NMR before working up. If necessary, the reaction mixture was diluted with Et OAc and filtered with a pad of cellite. The filtrate was concentrated, and the residue was purified with silica gel chromatography(100% Petroleum ether) to give product 3a.