Palladium-Catalyzed Synthesis of 2,1‘-Disubstituted Tetrahydrofurans from γ-Hydroxy Internal Alkenes. Evidence for Alkene Insertion into a Pd−O Bond and Stereochemical Scrambling via β-Hydride Elimination

Abstract

Palladium-catalyzed reactions of γ-hydroxy internal acyclic alkenes with aryl bromides afford 2,1′-disubstituted tetrahydrofurans in good yields with diastereoselectivities of 3-5:1. The analogous transformations of substrates bearing internal cyclic alkenes afford fused bicyclic and spirocyclic tetrahydrofuran derivatives in good yields with excellent diastereoselectivities (>20:1). A series of deuterium labeling experiments indicate that the origin of the modest diastereoselectivity in reactions of acyclic internal alkene substrates likely derives from a series of reversible β-hydride elimination and σ-bond rotation processes that occur following a rare intramolecular syn-alkene insertion into an intermediate Pd(Ar)(OR) complex. In addition, these studies shed light on the chemoselectivity of insertion, suggesting that the alkene inserts into the Pd-O bond in preference to the Pd-C bond.

Migratory Insertion of Alkenes into Metal–Oxygen and Metal–Nitrogen Bonds

“…The stereochemistry of the products from the palladium-catalyzed reaction of aryl bromides with g-hydroxy alkenes indicated that these reactions also occur by a syn addition of the palladium and the oxygen atom across the alkene (Scheme 6). [43][44][45] These reactions are highly regio-and stereoselective, thus forming the trans-2,5-disubstituted furan products. The selectivity of these products is inconsistent with a mechanism involving trans hydroxypalladation of the alkene.…”

Palladium‐Catalyzed Carboetherification and Carboamination Reactions of γ‐Hydroxy‐ and γ‐Aminoalkenes for the Synthesis of Tetrahydrofurans and Pyrrolidines

“…[27a, 29,30] In contrast, the analogous reactions of cycloalkene substrates provide bicyclic or spirocyclic products with excellent stereocontrol (Ͼ20:1). The observed products derive from syn addition of the alkene and the aryl unit across the C-C double bond, which is complementary to the anti addition stereochemistry that is typically observed in the Pd II -catalyzed carbonylative carboetherifications described above.…”

“…[29] The observed product stereochemistry derives from syn-oxypalladation through an organized cyclic transition state in which the substrate substituents assume pseudoequatorial orientations to avoid 1,3-diaxial interactions. The intermediacy of the (aryl)(alkoxide)palladium complex 38 is supported by the observation of side products that derive from β-hydride elimination or C-O bond forming reductive elimination of this species.…”

“…[29] As shown below (Scheme 8), the Pd-catalyzed carboetherification of 40 afforded a 4:1 mixture of 41 and 42; [30] the minor diastereomer (42) was deuterated at C2 rather than the expected benzylic carbon. The minor diastereomer 42 is generated through β-hydride elimination of 43 to afford 44, which undergoes reinsertion of the alkene into the Pd-H bond with the opposite regiochemistry to provide 45.…”

Unexpected ring contraction of 1-aryl-cyclohexa-2,5-dienes under palladium catalysis

“…Mechanisms have recently been put forward by Wolfe for such heterocyclizations, assuming the formation of a Pd-heteroatom bond preceding the cyclization, the C-Ar bond being generated through reductive elimination. [18][19] Based on these premises, we started a study on the reactivity of arylcyclohexadienes 3 with aryl iodides 4 in the presence of a Pd(II) catalyst. We report herein the addition of aryl halides onto dienes 3 and the unusual reactivity of the latter, which afford under these conditions cyclopropanes 5.…”