[Synthesis]
Step 5: Synthesis of 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carboxaldehyde (9) and 6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine-3-carboxaldehyde: A mixture of 2-bromo-3-hydroxyacrylaldehyde (4.1 g), p-toluenesulfonic acid monohydrate (52 mg) and 2-propanol (5.2 mL) in cyclohexane ( The mixture in 42 mL) was subjected to azeotropic dehydration until the vapor temperature rose to 80 °C. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in anhydrous ethanol (50 mL). Subsequently, a mixture of anhydrous ethanol (200 mL) solution of 3-iminomorpholine hydrochloride (3.4 g) and 28% methanol solution of sodium methanolate (4.8 g) was added to this solution at room temperature. The reaction mixture was stirred at room temperature for 2 hours before the solvent was removed under vacuum. The residue was dissolved in chloroform (125 mL), triethylamine (3.5 mL) was added, and then the reaction mixture was heated to reflux for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (300 mL) and washed with 50% aqueous K2CO3 (2 x 100 mL). The organic layer was dried over anhydrous MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CHCl3-acetone (4:1) as eluent to afford the target product 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carboxaldehyde (light orange solid, 1.4 g, 36.3% yield) and the by-products 6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine-3-carboxaldehyde (light orange solid, 609 mg, 16.1% yield). 1H NMR (CDCl3) data of the target product: δ 4.08-4.15 (m, 4H), 4.88 (s, 2H), 7.58 (s, 1H), 9.85 (s, 1H). 1H NMR (CDCl3) data of the by-product: δ 4.06 (t, 2H, J = 5.2Hz), 4.40 (t, 2H, J = 5.2Hz), 4.90 (s, 2H), 7.75 (s, 1H), 9.72 (s, 1H). |