Scope and mechanistic studies involving the palladium-catalyzed olefin carboetherification reaction.

Abstract

Studies on the scope and mechanism of the palladium-catalyzed synthesis of tetrahydrofurans from gamma-hydroxy alkenes and aryl or vinyl halides are described. Diastereoselectivities of up >20:1 have been obtained in the preparation of <italic>trans</italic>-2,5-disubstituted tetrahydrofurans and <italic> trans</italic>-2,3-disubstituted tetrahydrofurans, whereas lower diasteroselectivities (c.a. 2:1) have been observed for the formation of 2,4-disubstituted tetrahydrofurans. Modest diastereocontrol (5:1) is achieved in stereospecific cyclizations of acyclic internal olefin-containing substrates, whereas transformations of substrates bearing cyclic internal olefins proceed with >20:1 diastereoselectivity. The major products in each case result from <italic>syn</italic>-addition of the alcohol and aryl or vinyl group across the alkene. Mechanistic studies are consistent with a pathway involving initial formation of a Pd(Ar)(OR) intermediate that undergoes intramolecular <italic>syn</italic>-oxpalladation of the alkene followed by reductive elimination to afford the heterocyclic product. Deuterium labeling studies suggest that the modest diastereoselectivity observed in reactions of substrates bearing acyclic internal olefins results from reversible beta-hydride elimination that occurs after the initial oxypalladation step. The scope of the reaction has also been expanded include the synthesis of 5-benzyl isoxazolidines from <italic>N</italic>-butenyl hydroxylamines. This process affords a variety of monoand fused bicyclic <italic>N</italic>-alkyl isoxazolidine products with good to excellent levels of diastereoselectivity from easily accessible unsaturated hydroxylamine substrates.