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.

10种双键上带有或不带有甲基取代基的无环及单环δ,ε-不饱和酮，在无水条件及路易斯酸（Lewis acid）存在下发生卤离子终止型普林斯（halo-Prins）环化反应。四氯化钛、四溴化钛、三氯化硼及三溴化硼可促进顺式选择性环化，生成空间位阻较大的氯代醇与溴代醇；而四氯化锡、四溴化锡、三氯化铟、四氯化锆及其他多种路易斯酸则可高效诱导反式选择性反应，生成对应的反式卤代醇。更强的路易斯酸（TiX4与BX3）更倾向于涉及卤离子配体轴向进攻的顺式反应路径。竞争实验表明，δ位碳上的取代（即甲基烯丙基烯酮类底物）可使反应速率提升40~50倍；而ε位上的取代（即顺式及反式巴豆基烯酮类底物）则会降低反应速率，并削弱环化反应的选择性。本研究通过两条竞争性反应路径对顺式与反式选择性、反应活性以及不同路易斯酸金属卤化物的影响规律进行了合理化阐释：一条路径经由顺式碳正离子-卤离子离子对进行，另一条则为高阶过渡态路径，后者可导致构型翻转并生成反式卤代醇，同时伴随质子消除产生的环烯烃副产物。