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A round bottom flask with magnetic stirrer was charged with 3-methyl-isoxazole-5- carboxylic acid ethyl ester (900 mg, 5.8 mmol) in tetrahydrofuran (2.0 mL). To the reaction was added a solution of sodium hydroxide (465 mg, 11.6 mmol) in water (2 mL), followed by methanol (4 mL). The reaction was stirred at room temperature for 18 - 20 hours under an argon atmosphere. The reaction was transferred to a separatory funnel and the pH adjusted to 2 via addition of IN hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 35 mL) and the combined extractions were washed with brine (1 x 50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield S-methyl-isoxazole-S-carboxylic acid as a white solid (660 mg, 90percent). The solid was used without purification in the next reaction.
To a solution of 1 (5g) in EtOH(100mL) was added thionyl chloride(3.44mL), and the resulting solution was stirred at 50 °C. After termination of this reaction, the solution was cooled to room temp. and the volatile was removed under reduced pressure. The residue was dissolved in EtOAc and partitioned between Na2CO3 soln. and EtOAc, then extracted with EtOAc. The extraction was washed with water, brine and dried with MgSO4 and concentrated in vacuo to give ethylester(6.3g). To a solution of tetramethylammonium nitrate(6.81g) in CH2Cl2 (40mL)was added trifluoromethanesulfonic acid anhydride(8.41mL). Ethylester(5.17g) in CH2Cl2 (15ml)was added to the solution and the resulting mixture was refluxed overnight. The reaction mixture was cooled to room temp. and added sat. NaHCO3 soln., then partitioned between water and EtOAc and extracted with EtOAc. The extraction was washed with water and brine, dried with MgSO4 and concentrated in vacuo. The residue was purified by silicagel columnchromatography to give 16 (5.38g).
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