Hydrochloric Acid → 3-Methoxy-5-(trifluoromethyl)benzene-1-sulfonyl chloride

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Reaction Conditions

Reaction Steps

3-methoxy-5-trifluoromethyl-phenylamine (10 g, 54 mmol) was added to trifluoroacetic acid (100 mL) in a 250 mL flask, and the mixture was cooled to 0° C. Concentrated hydrochloric acid (10 mL) was then added slowly to the reaction mixture, followed by the dropwise addition of a solution of sodium nitrite (4.7 g, 68 mmol) in water (5 mL) over 20 min. The mixture was stirred for another 10 minutes at 0° C., and then poured into a stirred mixture of acetic acid (120 mL), sulfurous acid (0.94 N aqueous sulfur dioxide solution, 120 mL, 113 mmol), copper(II) chloride (9.2 g, 68 mmol) and copper(I) chloride (100 mg, 1 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 15 hours, and then treated with water (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered through a glass funnel and concentrated in vacuo. The residue was purified by column chromatography (20% ethyl acetate in petroleum ether) to afford 3-methoxy-5-trifluoromethyl-benzenesulfonyl chloride (3.9 g, 27%) as a white solid [reference: Cherney, R. J. et al., J. Med. Chem. 46 (2003) 1811]. 1H NMR (400 MHz, CDCl3) δ ppm 7.89 (s, 1H); 7.70 (s, 1H); 7.50 (s, 1H); 4.00 (s, 3H).

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