Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:11]1[N:16]=[CH:15][C:14]([O:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1>CS(C)=O.C(OCC)(=O)C.[Cu]>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:16][CH:15]=2)=[CH:25][CH:24]=1)#[N:23]
A mixture of ethyl 2-bromo-2,2-difluoroacetate (22.13 mL, 109.05 mmol) and copper (13.85 g, 218.1 mmol) in dry dimethylsulfoxide (DMSO) (80 mL) was stirred at room temperature (rt) for 4 h. 4-((6-Bromopyridin-3-yl)oxy)benzonitrile (10 g, 36.35 mmol) was added and the mixture heated at 50° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with 200 mL of ethyl acetate (EtOAc) and stirred for 10 min. The mixture was filtered through a plug of Celite® and the filtrate was washed with saturated NH4Cl solution to remove any remaining copper. The solution was dried (Na2SO4) and solvent was removed under reduced pressure to give the title compound as brown oil (6.5 g, 56.5%): IR (thin film) 2229, 1767 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J=2.7 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.73-7.64 (m, 2H), 7.49 (dd, J=8.6, 2.7 Hz, 1H), 7.16-7.07 (m, 2H), 4.39 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H); ESIMS m/z 319 ([M+H]+).
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