6-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide → 6-Cyano-4-(2-Methoxy-4-(Trifluoromethyl)Phenyl)-N-(Thiazol-2-Yl)-3,4-Dihydro-2H-Benzo[B][1,4]Oxazine-7-Sulfonamide

Participants

Reaction Steps

A vial was charged with 6-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (67 mg, 0.100 mmol), dicyanozinc (23.46 mg, 0.200 mmol), bis(tri-t-butylphosphine)palladium(0) (5.11 mg, 9.99 μmol), and zinc (1.960 mg, 0.030 mmol). The vial was flushed with Ar (g), then N,N-dimethylacetamide (500 μl) was added. The vial was sealed and placed in a 60° C. heating bath for 5 h. Additional portions of dicyanozinc (23.46 mg, 0.200 mmol) and bis(tri-t-butylphosphine)palladium(0) (ca. 8.5 mg) were added, and the vial was returned to the heat for 2 h. The mixture was diluted with EtOAc, then washed with water (2×), washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was taken up in DCM (1 mL) and TFA (0.5 mL). After 35 min, the mixture was diluted with MeOH and concentrated. The residue was purified by chromatography on 12-g Redi-Sep Gold column (20-70% EtOAc/Heptane, product eluted late) to give ca. 16 mg of a white solid. The material was rechromatographed twice on 12-g Redi-Sep Gold columns, once with 3% MeOH/DCM, then with 0-4% MeOH/DCM to give 6-cyano-4-(2-methoxy-4-(trifluoromethyl)phenyl)-n-(thiazol-2-yl)-3,4-dihydro-2h-benzo[b][1,4]oxazine-7-sulfonamide as a white solid that was about 91% pure by LCMS and NMR: 1H NMR (400 MHz, DMSO-d6) δ=12.91 (br. s., 1 H), 7.56 (d, J=8.1 Hz, 1 H), 7.49-7.40 (m, 2 H), 7.36 (s, 1 H), 7.28 (d, J=4.6 Hz, 1 H), 6.87 (d, J=4.6 Hz, 1 H), 6.60 (s, 1 H), 4.43-4.38 (m, 2 H), 3.87 (s, 3 H), 3.71 (t, J=4.3 Hz, 2 H); m/z (ESI) 497.2 (M+H)+.

Provenance & Evidence