Cl[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[F:11][C:8]1[CH:9]=[N:10][C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[C:3]([CH:7]=1)[C:4]([O:6][CH3:20])=[O:5]A mixture of 2-chloro-5-fluoronicotinic acid (2.61 g, 14.9 mmol), 4-fluorophenol (2.02 g, 18 mmol), potassium carbonate (4.56 g, 33 mmol), copper bronze (211 mg, 3.3 mmol), and cuprous iodide (230 mg, 1.2 mmol) in N,N-dimethylforamide (40 mL) was heated under reflux in an oil bath for 6 h. The reaction mixture was filtered through a pad of Celite®. The filtrate was partitioned between ethyl acetate (200 mL) and 2 N hydrochloric acid (200 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic extracts were washed with brine (50 mL) and dried (sodium sulfate). After removal of solvent, the residual oil was dissolved in methanol (50 mL). To the solution were added conc. hydrochloric acid (1 mL) and the mixture was heated under reflux for 4 h. The volatile components were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (3/1) to afford 2.63 g (67%) of the title compound: 1H-NMR (CDCl3) δ 8.11 (1H, d, J=3.1 Hz), 8.02 (1H, dd, J=7.7, 3.1 Hz), 7.11–7.07 (4H, m), 3.96 (3H, s); MS (ESI) m/z 266 (M+H)+.
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