Diisopropylamine → 1-(3-{[4-(Difluoromethoxy)phenyl]ethynyl}phenyl)-1,4-difluorobutane

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To a degassed solution of 13 mg (0.034 mmol) of bis(benzonitrile)dichloropalladium (II) in dioxane was added 0.145 gm (0.072 mmol) of a 10% (wt/wt) tri-t-butylphosphine in hexanes. The reaction mixture was stirred for 15 minutes at room temperature, treated with 4.3 mg of copper(I) iodide followed by 0.21 mL of diisopropylamine, stirred for 10 min, treated with 0.28 gm (1.14 mmol) of 1-bromo-3-(1,4-difluoro-butyl)benzene and 0.25 gm (1.48 mmol) of 1-difluoromethoxy-4-ethynylbenzene dissolved in 2 mL of dioxane. The reaction mixture was heated to 35° C. for 0.5 h, allowed to cool to room temperature, stirred at room temperature for 3 h, poured into EtOAc. The organic phase was separated, washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the concentrate on silica gel with a gradient of 0% to 25% EtOAc-hexanes afforded 1-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-1,4-difluorobutane as an oil, 0.314 gm (82% yield); 1H NMR (400 MHz, CDCl3) δ: 1.77-2.07 (m, 4H), 4.51 (m, 2H), 5.48 (dq, 1H, J=4.4, 47.6 Hz), 6.51 (t, 1H, J=73.5 Hz), 7.08 (d, 1H, J=8.6 Hz), 7.22-7.36 (m, 3H), 7.45-7.52 (m, 3H).

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