Reaction Steps
To a small reaction tube fitted with a screw cap is placed (4S,5S)-4-(3-methoxyphenyl)-5-(prop-2-ynyl)oxazolidin-2-one (50 mg, 0.22 mmol) in tBuOH/water (1:1, 1.5 mL). Successively, copper(II) sulfate pentahydrate (2 mg, 0.012 mmol), sodium ascorbate (12 mg, 0.06 mmol), potassium bicarbonate (92 mg, 0.92 mmol), and the freshly prepared product described above are then added. After stirring at room temperature for 2 h, the reaction is then quenched with sat. ammonium chloride, and extracted with EtOAc. The combined organics are washed with brine, dried over MgSO4, filtered, and concentrated to give the crude product, which is carried forward without purification. Next, in a small reaction tube fitted with a screw cap is placed the crude intermediate, acetonitrile (1 mL), 4-chloro-1-iodobenzene (62 mg, 0.26 mmol), copper iodide (3 mg, 0.04 mmol), N,N′-dimethylethylenediamine (9.3 μL, 0.08 mmol), and cesium carbonate (143 mg, 0.44 mmol). The vessel is evacuated and back-filled with nitrogen, then heated to 85° C. for 4 h. The reaction is then cooled to room temperature and quenched with sat. ammonium chloride, extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The title compound is obtained after purification by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)). 1H NMR (acetone-d6, 400 MHz) 5 (mixture of diastereomers) 8.67 (overlp s, 1H), 7.50-7.43 (m, 2H), 7.30-7.27 (m, 2H), 6.97-6.96 (m, 2H), 6.90-6.87 (m, 1H), 5.45 (d, J=4.8 Hz, 0.2H), 5.40 (d, J=5.8 Hz, 0.8H), 4.92-4.89 (m, 0.2H), 4.68-4.63 (m, 0.8H), 4.05 (m, 1H), 3.97-3.68 (m, 7H), 2.34-2.01 (m, 2H); HPLC-MS calculated C23H23ClN2O5 (M+H+) 455.1, found 455.1. For references to Copper catalyzed synthesis of 3,5-disubstituted isoxazoles, see Hansen, T. V.; Wu, P.; Fokin, V. V. J. Org. Chem. 2005, 70, 7791-7764; Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210-216.
