Lithium Hexamethyldisilazide → 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide

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Reaction Steps

A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (50.3 mg, 0.200 mmol) and THF (1 mL) to give a clear, light-orange solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a suspension. Lithium bis(trimethylsilyl)amide (1M in THF) (200 μl, 0.200 mmol) was added dropwise. After about 5 min, a solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (INTERMEDIATE LLL; 100 mg, 0.182 mmol) in THF (0.5 mL with a 0.25 mL syringe/vial wash) was added drop wise. After another 2 min, the flask was placed in an ice-water bath. The mixture was stirred for another 20 min, then diluted with saturated aq ammonium chloride and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g column, 10 to 50% EtOAc/Heptane). The desired product was collected with some of the excess amine to give a white foam. The solid was taken up in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with methanol and concentrated. The crude product was purified by chromatography on silica gel (12-g column, 0 to 10% MeOH/DCM) to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (56.9 mg, 0.122 mmol, 67.0% yield) as a white powder: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.73 (d, J=5.7 Hz, 1H), 8.61 (d, J=1.9 Hz, 1H), 8.51 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.89 (dd, J=1.9, 8.9 Hz, 1H), 7.74 (d, J=8.9 Hz, 1H), 7.61-7.43 (m, 3H), 3.75 (s, 3H). m/z (ESI) 467.2 (M+H)+.

Provenance & Evidence