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

Abstract

A one-pot, two-step method to prepare 3-halohydrofurans efficiently by TfOH-catalyzed hydroxylation/halocyclization of cyclopropyl methanols with H(2)O 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.

Lewis and Br??nsted acid-catalyzed reactions of alcohol pro-electrophiles as novel synthetic strategies for C-X (X = C, N, O, S) bond formation

“…More recently, Chan and co-workers reported a TfOH-catalyzed one-pot, two-step synthetic method for the preparation of 3-halohydrofurans 142 from cyclopropylmethyl alcohols 139 (Scheme 1.46). 91 The reaction was shown to be efficient for a variety of cyclopropyl alcohols in the presence of TfOH at a low catalyst loading of 1 mol%. After hydroxylation, halocyclization of the resultant homoallylic alcohols 141 formed in situ with NIS gave the desired substituted 3-iodofurans 142 were obtained in up to 98% yield and with complete cis selectivity.…”

Ferrocenium Cations as Catalysts for the Etherification of Cyclopropyl‐Substituted Propargylic Alcohols: Ene‐yne Formation and Mechanistic Insights

“…Cyclopropyl‐substituted radicals 6 (Scheme c) may ring‐open to form alkenes, but carbocation 5 may also have this tendency (vide infra). As exemplified in Scheme c, ene‐ynes 7 can form through rearrangement if a cyclopropyl‐substituted propargylic alcohol 4 is employed . The employment of cyclopropyl‐substituted propargylic alcohols in reactions with alcohols to give conjugated, achiral enynes has been reported previously only four times, utilizing Yb(OTf) 3 ,[36a] triflic acid (TfOH),[36b] HAuCl 4 [36c] and ruthenium complexes[36d] as catalysts.…”

Silver Triflate Catalyzed Tandem Heterocyclization/Alkynylation of 1‐((2‐Tosylamino)aryl)but‐2‐yne‐1,4‐diols to 2‐Alkynyl Indoles

“…Lewis and Brønsted acid-catalyzed reactions of unsaturated alcohols have emerged over the years as efficient and convenient synthetic strategies for C À C and C À X (X= N, O, S) bond formation. [4][5][6] For example, we recently reported a method for the synthesis of indenyl-fused and 2,3-disubstituted indoles that relied on the cycloisomerization of 2-tosylaminophenylprop-1-yn-3-ols in the presence of a gold(I) catalyst. [2b] We subsequently demonstrated that the synthetic method could be fine-tuned to provide 1H-indole-2-carbaldehydes and (E)-2-(iodomethylene)indolin-3-ols by introducing N-iodosuccinimide into the reaction conditions.…”