Rapid Access to Halohydrofurans via Brønsted Acid-Catalyzed Hydroxylation/Halocyclization of Cyclopropyl Methanols with Water and Electrophilic Halides

A one-pot, two-step method to prepare 3-halohydrofurans efficiently by TfOH-catalyzed hydroxylation/halocyclization of cyclopropyl methanols with H2O and N-halosuccinimide (NXS, X=1, Br, Cl) or Selectfluor is described. The reactions proceed rapidly under mild and operationally straightforward conditions with a catalyst loading as low as 1 mol % and afford the 3-halohydrofuran products in moderate to excellent yields and, in most cases, with preferential cis diastereoselectivity. The method was shown to be applicable to cyclopropyl methanols containing electron-withdrawing, electron-donating, and sterically demanding functional groups and electrophilic halide sources. The mechanism is suggested to involve protonation of the alcohol substrate by the Brønsted acid catalyst and ionization of the starting material. This results in ring-opening of the cyclopropane moiety and in situ formation of a homoallylic alcohol intermediate, which undergoes subsequent intramolecular halocyclization on treating with the electrophilic halide source to give the halohydrofuran. The observed cis product selectivity is thought to be determined by the reaction proceeding through an in situ generated unsaturated alcohol intermediate that contains a (Z)-alkene moiety under the kinetically controlled conditions.

本文报道了一种以三氟甲磺酸（TfOH）为催化剂，以水（H₂O）与N-卤代丁二酰亚胺（NXS，X=I、Br、Cl）或选择性氟试剂（Selectfluor）为试剂，通过环丙基甲醇的羟基化/卤代环化反应，高效制备3-卤代四氢呋喃的一锅两步法。该反应在温和且操作简便的条件下快速进行，催化剂负载量可低至1 mol%，目标产物3-卤代四氢呋喃的产率处于中等至优异水平，且多数情况下表现出优先的顺式非对映选择性。该方法适用于带有吸电子基团、供电子基团、空间位阻较大官能团以及亲电卤源的环丙基甲醇底物。研究表明，反应机理为：布朗斯特酸催化剂（TfOH）先对醇底物进行质子化，使原料发生电离，进而引发环丙烷结构开环，原位生成高烯丙基醇中间体；随后该中间体在亲电卤源作用下发生分子内卤代环化，最终得到卤代四氢呋喃产物。观测到的顺式产物选择性，被认为是由于反应在动力学控制条件下，经由原位生成的含(Z)-烯烃结构单元的不饱和醇中间体进行所导致的。