Lithium Hexamethyldisilazide → N-(3-bromo-1,2,4-thiadiazol-5-yl)-N-(4-methoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide

Participants

Reaction Steps

A 25-mL round-bottom flask was charged with 3-bromo-N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (INTERMEDIATE K) (157 mg, 0.522 mmol) and THF (2.6 mL) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (653 μl, 0.653 mmol) was added dropwise. The resulting clear solution was stirred for 20 min, then a solution perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate (INTERMEDIATE E) (157 mg, 0.261 mmol) in THF (1 mL with a 0.5 mL vial/syringe wash) was added dropwise over 1 min. The resulting solution was stirred for 10 min, then the flask was lowered into an ice bath for 2.5 h. The reaction mixture was quenched with saturated aq ammonium chloride solution, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were concentrated, and the crude product was purified by chromatography on silica gel (0 to 60% EtOAc/Heptane) N-(3-bromo-1,2,4-thiadiazol-5-yl)-N-(4-methoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide (136.87 mg, 0.191 mmol, 73.1% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ=8.09 (d, J=1.8 Hz, 1 H), 7.96-7.83 (m, 2 H), 7.79 (d, J=1.4 Hz, 1 H), 7.66-7.49 (m, 2 H), 7.39 (d, J=1.9 Hz, 1 H), 7.31 (s, 1 H), 7.26 (d, J=8.8 Hz, 2 H), 6.86-6.79 (m, 2 H), 6.33 (d, J=1.9 Hz, 1 H), 5.08 (s, 2 H), 3.83 (s, 3 H), 3.68 (s, 3 H), 3.24 (s, 3H). m/z (ESI) 717.2 (M+H)+.

Provenance & Evidence