Iron-Catalyzed Cross-Coupling of Diarylzinc or Aryl Grignard Reagents with Difluoroalkyl Bromides

The demanding of discovering new, pharmaceuticals, agrochemicals and advanced functional materials have triggered extensive efforts on efficient synthesis of fluorinated compounds. Over the past decade, the transition-metal-catalyzed fluoroalkylation has emerged as an efficient and straightforward strategy for the synthesis of organofluorine compounds. Despite the importance of the reported synthetic methods, the development of environmentally benign and cost-efficient fluoroalkylation reactions with base metals as catalysis and widely available fluoroallcyl halides as fluoroalkyl sources continues to attract great interest. Here, we reported the first example of iron-catalyzed cross-coupling of diarylzinc reagents with gem-difluoropropargyl bromides. The reaction proceeds under mild reaction conditions and provides a facile access to gem-difluoropropargyl arenes. Additionally, this iron-catalytic system can also be applied to the cross-coupling of aryl Grignard reagents with difluoroalkyl bromides. Applications of the method led to modified bioactive molecules efficiently, offering potential opportunities in medicinal chemistry. Preliminary mechanistic studies reveal that a single electron transfer pathway is involved in the reaction. A representative procedure for iron-catalyzed cross-coupling of diarylzincs with gem-difluoropropargyl bromide is as following: Fe(acac) 3 (10 mol%) was added to a 25 mL of Schlenck tube, the tube was then evacuated and backfilled with Ar (3 times). gem-Difluoropropargyl bromide 2 (0.3 mmol, 1.0 equiv.), TMEDA (0.45 mmol, 1.5 equiv.) and THF (1 mL) were then added, the reaction mixture was stirred at room temperature for 10 min and cooled to -20 C. A solution of diarylzinc reagent (0.45 mmol in 1.5 mL of THF, 1.5 equiv.) was added dropwise. After stirring for 4 h at -20 degrees C, the reaction mixture was quenched with saturated NH4Cl solution. 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 to give product 3.