[Synthesis]
Scheme 1 outlines the synthetic route to 2-methyl-6-nitrobenzoxazole in the following detailed steps:(a) 2-amino-5-nitrophenol (7.70 g, 50.0 mmol) and pyridine (3.96 g, 50.0 mmol) were dissolved in dry xylene (150 mL) at 0 °C, and acetyl chloride (4.32 g, 55.0 mmol) was added slowly and dropwise. The reaction mixture was stirred at room temperature for 2 hours. Subsequently, p-toluenesulfonic acid (1.72 g, 10.0 mmol) was added and the mixture was refluxed until no water was drained. After cooling to room temperature, the organic layer was washed sequentially with water (100 mL x 3) and saturated NaCl solution (50.0 mL). The organic phase was collected, dried with Na2SO4, and the solvent was evaporated under reduced pressure to afford the crude product 2-methyl-6-nitrobenzoxazole (light-colored solid, 8.80 g, 95% yield), which could be used in the next reaction without further purification. (b) 2-Methyl-6-nitrobenzoxazole (3.92 g, 22.0 mmol) was dissolved in methanol (60.0 mL) and a solution of NH4Cl (11.77 g, 220 mmol) in water (40.0 mL) and iron powder (4.48 g, 80.0 mmol) was added. The mixture was stirred at 70 °C for 4 h until the feedstock was completely consumed (TLC monitoring). After completion of the reaction, it was cooled to room temperature, filtered and the filtrate was extracted with ethyl acetate (30.0 mL x 3). The organic phases were combined, dried with Na2SO4 and the solvent was evaporated under reduced pressure to give crude 2-methylbenzoxazol-6-amine (2.77 g, 85% yield), which was used directly in the next reaction. (c) 2-Methylbenzoxazol-6-amine (2.66 g, 18.0 mmol) was dissolved in methanol (30.0 mL) and formaldehyde (37%, 12 mL, 144 mmol) and NaBH3CN (2.27 g, 36.0 mmol) were added. The reaction mixture was stirred at room temperature for 36 hours until the feedstock was completely converted (TLC monitoring). The reaction solution was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The organic phases were combined, dried with Na2SO4, concentrated and purified by fast column chromatography (eluent: petroleum ether/ethyl acetate=10/1, v/v, Rf=0.11) to afford 2-methyl-6-(N,N-dimethylamino)benzoxazole (2.50 g, 79% yield). |