EFFICIENT SYNTHESIS OF TRIFLUOROMETHYL-SUBSTITUTED 5,6-DIHYDRO-4H-1,2-OXAZINES BY THE HETERO-DIELS-ALDER REACTION OF 1,1,1-TRIFLUORO-2-NITROSO-2-PROPENE AND ELECTRON-RICH OLEFINS

1,1,1-Trifluoro-2-nitroso-2-propene (1) was generated in situ by treatment of the alpha-bromo oxime 5 with base. Moderate to excellent yields of the 3-trifluoromethyl-substituted 1,2-oxazines 17-27 were obtained from the reaction of 1 and the silyl enol ethers 6-16, respectively. Other dienophiles, i.e., allyltrimethylsilane, cyclopentadiene, furan, and dihydropyran, upon reaction with 1 provided the cycloadducts 31-34, respectively, in good yield. The results demonstrated that 1 is probably the most reactive heterodiene that has so far been employed in this type of Diels-Alder reaction (i.e., Diels-Alder reaction with inverse electron demand). The mechanism of the reaction and diastereoselectivity of the cycloadditions are discussed. The reaction of 1 with indole and acetyl acetone afforded the oxime 38 and a mixture of the isomers 40-42, respectively. Also, ring openings and other transformations of the trifluoromethyl-substituted 1,2-oxazines were effected. Acid-induced desilylation of the silylated 1,2-oxazines provided oximes like 46 and 48 or 6-hydroxy-1,2-oxazines like 47. Treatment of the 1,2-oxazines with Mo(CO)6 in the presence of trifluoroacetic acid produced 2-trifluoromethyl-substituted pyrroles (e.g., 18 --> 50). The reduction of the 1,2-oxazines afforded either gamma-hydroxy oximes (e.g., 19 --> 51) or amino alcohols (e.g., 32 --> 52, 31 --> 55). The reduction of the indole derivative 38 by LiAlH4 provided the trifluoromethyl-substituted tryptamine 56. The results of these explorative studies demonstrated that readily available trifluoromethyl-substituted 1,2-oxazines could be efficiently converted into other compounds that bear a trifluoromethyl group.