Reaction Steps
To a solution of 7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one (EXAMPLE 22) (0.183 g, 0.448 mmol) in 4.8 mL THF was added Tebbe reagent (0.99 mL, 0.49 mmol) at 0° C. After 1 h, ether (22 mL) and MeOH (0.32 mL) were added sequentially and the mixture was allowed to warm to rt. The slurry was filtered through Celite and concentrated, and the resultant residues was filtered through a short plug of basic alumina (4:1 hexanes:EtOAc) to afford 0.20 g of (±)-2,3-dihydro-7-isopropoxy-2-methylene-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline. This residue was dissolved in 2.2 mL THF, and BH3THF solution (1M, 0.49 mL, 0.49 mmol) was added dropwise at 0° C. After 15 min, the mixture was allowed to warm to rt, whereupon 0.1 mL MeOH was added and the solution allowed to stir for 16 h. The solvent was removed in vacuo, and the residue was redissolved in 2.2 mL THF and 0.45 mL MeOH, whereupon 0.10 mL 6N NaOH and a 35% H2O2 solution (0.055 mL, 60.9 mg, 0.63 mmol) was added. A precipitate was formed which was filtered with 20 mL THF. The filtrate was concentrated, and the resultant solid was dissolved in 1 mL MeOH, acidified with 0.05 mL conc. HCl, and the solution concentrated in vacuo. The residue was treated with 0. 1 mL 6N NaOH, and partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. Flash chromatography (2:1 hexanes:EtOAc) afforded 91 mg (48%) of (±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a light amber oil. Data for (±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: Rf 0.34 (2:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 7.17 (broad s, 1H), 7.01 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.50 (dd, 1H, J=11.1, 1.6), 4.12-4.25 (m, 1H), 3.96-4.09 (m, 1H), 3.78-3.90 (m, 2H), 3.61-3.67 (m, 1H), 1.71 (t, 1H, J=5.1), 1.38 (d,6H, J=6.2).
