Chlorotrimethylsilane → 3-(3-(Pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol

Participants

Reaction Conditions

Reaction Steps

To a stirred solution of 2,2,6,6-tetramethylpiperidine (Preparation 63D, 0.354 mL, 2.096 mmol) in anhydrous THF (1 mL) in a flame-dried flask at 0° C. was added a 2.5 M solution of butyl lithium in hexane (0.839 mL, 2.10 mmol) dropwise. The resulting dark yellowish reaction mixture was stirred for 30 min. at 0° C. To a solution of (E)-6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate I-1, 0.131 g, 0.699 mmol) and Hunig's Base (0.220 mL, 1.258 mmol) in anhydrous THF (2.0 mL) at 0° C. was added TMS-Cl (0.089 mL, 0.699 mmol) dropwise. The resulting off-white suspension was stirred for 60 min. at 0° C. The reaction mixture was cooled to −78° C., the above LiTMP solution was added dropwise, and the mixture was stirred for 30 min. at −78° C. To the reaction mixture was added ethyl 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylate (0.69 M in THF) (1.01 mL, 0.699 mmol), and the resulting orange mixture was then stirred at −78° C. for 30 min. The dry-ice bath was removed, and the reaction mixture was slowly warmed to 0° C. over 25 min. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (˜4.0 mL), and the mixture was diluted with dichloromethane (40 mL), washed with a 1:1 mixture of saturated aqueous solution of ammonium chloride and water, dried over anhydrous sodium sulfate, and concentrated to give a dark red residue, which was purified by flash silica gel chromatography using a mixture of ethyl acetate and hexane (5%-12%-20%) to give 3-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol (0.080 g, 0.187 mmol, 26.8% yield) as a yellow oil. The product had an HPLC ret. time=2.76 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=427.9.

Provenance & Evidence