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

• Published in: Journal of organic chemistry Vol. 71; no. 4; pp. 1493 - 1501
• Main Authors: Miles, R. Brandon, Davis, Chad E, Coates, Robert M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.02.2006; Amer Chemical Soc
• Subjects: Acids; Alcohols - chemical synthesis; Chemistry; Chemistry, Organic; Chlorohydrins - chemical synthesis; Cyclization; Cycloparaffins; Ketones - chemistry; Physical Sciences; Science & Technology; Stereoisomerism; EPOXIDES; KETONES; ALDEHYDE; DIASTEREOSELECTIVE SYNTHESIS; PI-CYCLIZATIONS; STEREOCHEMISTRY; ALPHA; COPE REARRANGEMENT
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo052142n

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.