Potassium Iodide → 6-Amino-4-(3-methoxypropyl)-2H-1,4-benzoxazin-3(4H)-one

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Reaction Conditions

Reaction Steps

A mixture of 6-nitro-4H-benzo[1,4]oxazin-3-one (5 g, 25.8 mmol) and NaH (˜60% moistened with oil, 911 mg, ˜23 mmol) in DMA (30 ml) is stirred at 5° C. for 30 min. Toluene-4-sulfonic acid 3-methoxy-propyl ester (6.87 g, 28.1 mmol) in DMA (10 ml) is added, followed by potassium iodide (4.67 g, 28.1 mmol). The ice-bath is removed and the mixture stirred for 3 h at 60° C. The solvent is distilled off in vacuo and the residue partitioned between H2O and ethyl acetate. The organic layer is dried (Na2SO4) and the solvent evaporated. Part of the crude product (5 g, 18.8 mmol) is dissolved in a mixture of acetic acid (50 ml) and ethyl acetate (50 ml). The solution is added dropwise to a suspension of Fe powder (6 g, 107 mmol) in 5% aqueous acetic acid (50 ml). The resultant mixture is kept at 70° C. for 5 h. After cooling to RT, the Fe powder is filtered off, and the filtrate diluted with H2O. The aqueous layer is extracted with ethyl acetate. The organic layer is washed with NaHCO3 solution, dried (Na2SO4) and evaporated. The residue is purified by column chromatography (SiO2, CH2Cl2/CH3OH 100:0-80:20) to afford 6-amino-4-(3-methoxy-propyl)-4H-benzo[1,4]oxazin-3-one as a dark brown oil. MS: 237.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 2.66 min. Part of this intermediate (1 g, 4.2 mmol) is diluted with methanol (15 ml). Acetaldehyde (166 μl, 2.94 mmol), acetic acid (480 μl, 8.4 mmol) and NaBH3CN (396 mg, 6.3 mmol) are added. The mixture is stirred for 1.5 h at RT, quenched with 5% KHSO4 solution and extracted with ethyl acetate. The organic layer is washed with NaHCO3 solution and brine, dried over Na2SO4 and evaporated in vacuo. Purification of the product by column chromatography (SiO2, CH2Cl2/CH3OH) affords the title compound as a purple oil. MS: 265.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 3.41 min

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