1234319-14-2

51776-71-7

73183-34-3

1234319-14-2

General procedure for the synthesis of 4-(difluoromethyl)phenylboronic acid pinacol ester from 1-bromo-4-(difluoromethyl)benzene and pinacol ester of biphenylboronic acid: B. Synthesis of 2-[4-(difluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (25.25 g, 34.5 mmol) was added in a single step to 1-bromo-4-(difluoromethyl)benzene (160 g, 0.77 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborolane (392.5 g, 1.55 mol) and potassium acetate (303 g, 3.09 mol) in a degassed mixture of 1,4-dioxane (2.42 L). The reaction mixture was heated to 100 °C and kept for 18 hours. After completion of the reaction, the mixture was cooled to room temperature and filtered through diatomaceous earth and washed with ethyl acetate (3 L). The filtrate was concentrated in vacuum to give a dark brown oil. This process was repeated three times on batches of 50 g, 160 g and 156 g of 1-bromo-4-(difluoromethyl)benzene (total raw material, 526 g, 2.54 mol) and all the crude products were combined. Two purifications by silica gel chromatography (gradient: 0% to 3% ethyl acetate in heptane solution) gave a yellow-white solid (803 g). The solid was recrystallized from methanol (1.6 L) at -20 °C, the filtrate was concentrated to half its original volume, cooled and the resulting solid was collected by filtration. The combined solids (426 g) were recrystallized from heptane (500 mL) at -20 °C, then melted and poured into methanol (200 mL) cooled in a methanol-ice bath. The mixture was crushed and filtered to give the target product as a solid. Yield: 250.7 g, 0.987 mmol, 39% yield. 1H NMR (400 MHz, CDCl3) δ 1.37 (s, 12H), 6.65 (t, J = 56.4 Hz, 1H), 7.52 (br d, J = 8.1 Hz, 2H), 7.92 (br d, J = 8.0 Hz, 2H).