623564-42-1

623564-41-0

623564-42-1

623564-43-2

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 (42 mL ) in a mixture 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). To this solution was added a mixture of a solution of 3-iminomorpholine hydrochloride (3.4 g) in anhydrous ethanol (200 mL) and a methanol solution of 28% sodium methanol (4.8 g) 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 the reaction mixture was subsequently 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 magnesium sulfate 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 another regional isomer 6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine-3 -formaldehyde (light orange solid, 609 mg, 16.1% yield). 1H NMR (CDCl3) δ of the target product: 4.08-4.15 (m, 4H), 4.88 (s, 2H), 7.58 (s, 1H), 9.85 (s, 1H). 1H NMR (CDCl3) δ of the regional isomer: 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).