US EPA

3443246 

Journal Article 

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

Xiao Yulan; Pan Qiang; Zhang Xingang 

2015 

Yes 

Huaxue Xuebao / Acta Chemica Sinica
ISSN: 0567-7351 

73 

5 

383-387 

Chinese 

10.6023/A15010042 

WOS:000357389800001 

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)center dot 6H(2)O or NiCl2 center dot dppe (2.5 mol%), bpy (2.5 mol%), and K2CO3 (2.0 equiv.) were subsequently added to a 25 mL of Schlenck tube. The resulting mixture was then evacuated and backfilled with Ar (3 times). gem-Difluoropropargyl bromide 2 (0.6 mmol, 1.0 equiv.) and 1,4-dioxane (4 mL) were then added. The Schlenck tube was screw capped and put into a preheated oil bath (80 degrees C). After stirring for 24 h, the reaction mixture was cooled to room temperature. The yield was determined by F-19 NMR 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 (100% Petroleum ether) to give product 3a. 

nickel; aryl boronic acids; gem-difluoropropargyl bromide; cross-coupling reaction