Syn- and Anti-Selective Prins Cyclizations of δ,ε-Unsaturated Ketones to 1,3-Halohydrins with Lewis Acids

Ten acyclic and monocyclic δ,ε-unsaturated ketones, with and without methyl substituents on the double
bond, underwent halide-terminated Prins (halo-Prins) cyclizations under anhydrous conditions in the
presence of Lewis acids. TiCl4, TiBr4, BCl3, and BBr3 promoted syn-selective cyclizations to sterically
congested chloro- and bromohydrins, while SnCl4, SnBr4, InCl3, ZrCl4, and several other Lewis acids
effected highly anti-selective reactions to furnish the corresponding trans halohydrins. The stronger Lewis
acids (TiX4 and BX3) favor the syn process that involves axial delivery of a halide ligand. Competition
experiments showed that substitution at the δ carbon (methallyl enones) led to increased rates (40−50-fold), while substitution at the ε position (cis and trans crotyl enones) retarded the rate and eroded the
selectivity of the cyclizations. The trends in syn vs anti selectivity, reactivity, and effects of different
Lewis acidic metal halides are rationalized by competitive reaction pathways proceeding through syn
carbocation−halide ion pairs and a higher order transition state that leads to inversion of configuration
and formation of trans halohydrins, along with cyclic olefins arising from proton elimination.