A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic) Alcohols - The Synthesis of Halogenated Tetrahydrofurans by Stereoselective Alkoxyl Radical Ring Closures

A new synthesis of bromo‐ and iodomethyl‐substituted tetrahydrofurans has been devised. The sequence starts with the conversion of aryl‐functionalized bis(homoallylic) alcohols 1 into N‐alkenoxythiazole‐2(3H)‐thiones 6 or pyridine‐2(1H)‐thiones 7. When photolyzed in the presence of appropriate trapping reagents, thiones 6 and 7 efficiently liberated substituted 4‐penten‐1‐oxyl radicals 2, which underwent synthetically useful 5‐exo‐trig cyclizations. Cyclized radicals 3 were trapped with BrCCl3 or an adequate iodine atom donor (either n‐C4F9I or diethyl 2‐iodo‐2‐methyl malonate) to provide halocyclization products 4 or 5. This strategy has been applied for the synthesis of 3‐, 4‐, or 5‐phenyl‐substituted 2‐(1‐bromo‐1‐methylethyl)tetrahydrofurans 4a−c (75−90%, 36−96% de), which were not attainable as major products from polar, for example NBS‐mediated, bromocyclizations. Aryl‐substituted 2‐iodomethyl tetrahydrofurans 5 (46−80%) were prepared in a similar way starting from N‐alkenoxypyridine‐2(1H)‐thiones 7 and a suitable iodine atom donor. Diastereomerically pure iodides cis‐5 and trans‐5 served as starting materials for a stereochemical analysis of disubstituted tetrahydrofurans by NMR spectroscopy and X‐ray diffraction analysis. The results of this investigation clarified that all new alkoxyl radical cyclizations followed in terms of regio‐ and diastereoselectivity the general guidelines which had been established for this type of ring‐closure reaction. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)