tert-Butyl 3-amino-4-hydroxybenzoate → tert-butyl 2-(2-methoxy-2-oxoethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

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Reaction Steps

To a stirred solution of tert-butyl 4-hydroxy-3-aminobenzoate (3 g, 14.35 mmol) in methanol (20 mL) sodium hydrogen carbonate (1.5 g) was added and a solution of methyl-4-bromo crotonate (3 mL, 17 mmol) in methanol (5 mL) was added dropwise in 30 minutes and the resulting suspension was stirred 4 h at room temperature. The reaction mixture was concentrated in vacuo and taken up with ethyl acetate (250 mL) and water (300 mL). The organic phase was separated and the aqueous phase was extracted with more ethyl acetate (2×250 mL). The combined extracts were dried (Na2SO4) evaporated and the resulting oil dissolved in ethanol (25 mL), potassium carbonate (1 g) was added and the resulting suspension was stirred 4 h at room temperature. The reaction mixture was evaporated in vacuo and the resulting oil was diluted with dichloromethane (150 mL) and washed with water (3×100 mL), the organic solution was then extracted whit hydrochloric acid 1N (150 mL) and separated, the aqueous solution was neutralized with 1N sodium hydroxide and extracted with ethyl acetate (3×150 mL). The combined extract were dried (Na2SO4) evaporated to dryness in vacuo, the resulting crude was purified by flash chromatography on silica gel (n-hexane/ethyl acetate 3:1) to afford tert-butyl 2-(2-methoxy-2-oxoethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (5.4 g) as a white solid.

Provenance & Evidence