Stereoselective Synthesis of Tetrahydrofurans via the Palladium-Catalyzed Reaction of Aryl Bromides with γ-Hydroxy Alkenes:  Evidence for an Unusual Intramolecular Olefin Insertion into a Pd(Ar)(OR) Intermediate

Abstract

A new, stereoselective method for the synthesis of substituted tetrahydrofurans from gamma-hydroxy alkenes that forms both a C-C and a C-O bond with diastereoselectivities of up to >20:1 is described. Initial mechanistic studies that suggest the reactions proceed via the intramolecular insertion of an olefin into a Pd(Ar)(OR) intermediate are discussed.

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

“…Treatment of the analogous substrate bearing a deuterium atom at C-6 (31) with 4-bromobiphenyl under identical conditions afforded a 75:20:5 ratio of the two diastereomeric tetrahydrofurans 32 and 33, along with the 3-aryl-2-ethyltetrahydrofuran regioisomer 30. The outcome of this transformation was similar to that described above, with the major diastereomer bearing the deuterium atom at the expected C1′ position, the minor diastereomer bearing the majority of the deuterium label at C2, and the (4) regioisomer deuterated exclusively at C1′ (eq 4). As above, unreacted starting material isolated from a reaction stopped at partial conversion (63%) was deuterated only at C-6.…”

“…In addition, small amounts of arenes that derive from reduction of the aryl bromide substrates are also observed in reactions of both 3 and 9. 21 Transformations of substrates bearing internal alkenes required higher temperatures (110 °C) than analogous transformations of substrates bearing terminal alkenes (65 °C), 4,5 and gemdisubstitution of the C-1 position was necessary for successful conversion of internal alkene substrates to tetrahydrofuran products. For example, the reaction of 4-hexen-1-ol (8) with 4-bromobiphenyl provided only products derived from oxidation/reduction processes (Table 1, entry 1).…”

“…3 We recently reported a new method for the stereoselective synthesis of tetrahydrofurans from reactions of aryl or vinyl bromides with γ-hydroxyalkenes. 4,5,6,7,8,9 These reactions lead to the formation of both a C-O and a C-C bond in a single step, and transformations of substrates bearing substituents at the 1-or 3-position afford trans-2,5-or trans-2,3-disubstituted tetrahydrofurans with diastereoselectivities of up to ≥20:1. 4,5 Our preliminary studies indicated that reactions of substrates bearing internal alkenes afford products that derive from synaddition of the aryl group and the oxygen atom across the double bond.…”

“…4,5 Our preliminary studies indicated that reactions of substrates bearing internal alkenes afford products that derive from synaddition of the aryl group and the oxygen atom across the double bond. 4 For example, treatment of internal cyclic alkene 1 with 4-bromoanisiole in the presence of NaOtBu and a Pd 2 (dba) 3 / P(o-tol) 3 catalyst provided bicyclic product 2 in 69% yield with >20:1 diastereoselectivity (eq 1). The analogous coupling of acyclic internal alkene substrate 3 with 4-bromobiphenyl afforded tetrahydrofuran 4a in 73% yield with modest (5:1) diastereoselectivity for the product of syn-addition.…”

Iridium-Catalyzed, Intermolecular Hydroetherification of Unactivated Aliphatic Alkenes with Phenols

“…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.…”