Hydrogen Bromide → 2-Bromo-5-(trifluoromethyl)-1,3,4-thiadiazole

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To 3 mL of 48% aqueous HBr was added 1.0 g (5.9 mmol) of 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine with stirring. The mixture was cooled in a salt ice-water bath, and 2.27 mL (44 mmol) of bromine was added slowly dropwise. The salt ice-water bath was replaced with an ice-water bath and a solution of 1.05 g (15 mmol) of sodium nitrite in 1.5 mL of water was added slowly dropwise. The reaction mixture was stirred for 1 h and then let warm to room temperature. The mixture was neutralized with 5M aqueous sodium hydroxide, and the resulting precipitate was filtered off. The filtrate was extracted with chloroform, and the extract was dried over magnesium sulfate before being concentrated to afford 750 mg (54%) of 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole, 330 mg (1.4 mmol) of which was added to a solution of 240 mg (1.6 mmol) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride and 0.73 mL (4.2 mmol) of N,N-diisopropylethylamine in 5 mL of isopropanol. The reaction mixture was heated at reflux for 2 h, and then concentrated. The residue was purified by silica gel chromatography eluting with 0.3:9.7 methanol dichloromethane to afford 328 mg (88%) of (3S)-4,4-dimethyl-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-pyrrolidinol. 1H NMR (300 MHz, DMSO-d6) δ 5.31 (d, J=5 Hz, 1H), 3.89-3.76 (m, 2H), 3.40-3.22 (m, 3H), 1.02 (s, 3H), 1.00 (s, 3H). Cl-LCMS m/z 268 (M+H).

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