N-[(4-methoxyphenyl)methyl]-1,3-thiazol-2-amine → 6-bromo-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

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Reaction Steps

A 50-mL round-bottom flask was charged with 6-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (Enamine, Kiev, Ukraine, 1.002 g, 3.07 mmol), N-(4-methoxybenzyl)thiazol-2-amine (0.811 g, 3.68 mmol), and THF (15.34 ml) to give a thick suspension. The flask was cooled in a dry ice-acetone bath for 10 min. Lithium bis(trimethylsilyl)amide (1M in THF) (6.75 ml, 6.75 mmol) was added dropwise over 5 min. After another 5 min, the flask was transferred to an ice-bath. After 25 min, the mixture was diluted with saturated aq. ammonium chloride and water. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from DCM (2×, to help remove residual EtOAc and water). The flask was flushed with Ar (g), and the mixture was taken up in THF (15 mL) to give a thin suspension. Borane-tetrahydrofuran complex (1M in THF) (7.67 ml, 7.67 mmol) was added over 20 s, resulting in some bubbling and then a clear, amber solution. The mixture was stirred overnight for 16 h, then MeOH (ca. 20 mL) was added carefully. The resulting solution was stirred for 3 h, and the mixture was concentrated. The residue was concentrated from MeOH (1×), then from MeOH/DCM (3×). The residue was taken up in MeOH, which formed a partial slurry with some floating gummy solid. The mixture was sonicated for 2 min, then stirred vigorously for 4 h. The mixture was filtered, and the collected solids were washed with MeOH (2×), then dried under a stream of N2 (g) overnight. The material was dried further under high vac to give 6-bromo-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (391.2 mg, 0.788 mmol, 25.7% yield) as an off-white solid: m/z (ESI) 495.9 (M+H)+.

Provenance & Evidence