Synthesis of 3a,4,5,6-Tetrahydroimidazo-[1,5-b]isoxazoles

Significance

Described is the 1,3-dipolar cyclo-addition of perfluoro-2-alkynoates with cyclic ­nitrones to afford 2-perfluoroalkyl-3a,4,5,6-tetra­hydroimidazo[1,5-b]isoxazoles. The reaction occurs under mild conditions and in short reaction times. Yields are good (R^² = electron-withdrawing) to ­excellent (R^² = electron-donating). The authors ­attribute the high efficiency in the reaction to the strong electron-withdrawing nature of R_F according to the FMO theory. The reaction is highly regio-selective resulting in the formation of a single ­regioisomer with R_F at position 2 of the tetra­hydroimidazo[1,5-b]isoxazole. The reaction is also highly diastereospecific due to the approach of the alkynoate from the less sterically hindered side of the plane, affording a pair of enantiomers with a cis stereochemistry (Ph and R^² on the same side).