Synthesis of 2,3,4-Trisubstituted 2,5-Dihydrofuran Derivatives

Abstract

Recently, synthesis of methylenetetrahydrofurans has received much attention due to their versatile usefulness in organic synthesis. The compounds were prepared most frequently either by the Zn(II)/amine-catalyzed coupling reaction of alkylidenemalonates with propargyl alcohol or Michael addition of propargyl alcohol to alkylidenemalonates followed by a palladium-mediated exo-dig cyclization. Methylenetetrahydrofurans can be used for the synthesis of polysubstituted tetrahydrofurans or furans. However, chemical transformations of these valuable compounds were not reported much. Very recently we reported the synthesis of 2,5-dihydrofuran derivatives by the sequential introduction of propargyl alcohol at the primary position of the Baylis-Hillman adducts, radical cyclization, iodolactonization, and finally decarboxylation strategy (Scheme 1). During the investigations we reasoned that we could prepare 2,4-disubstituted 2,5-dihydrofuran derivative (B) by following the similar protocol from the methylenetetrahydrofuran 3a (Scheme 2). Starting methylenetetrahydrofuran 3a was prepared in 51% yield from the reaction of benzylidenemalonate 1a and propargyl alcohol (2a) in the presence of n-BuLi (1.1 equiv) and CuI (30 mol%) in THF by following the reported method, which described the reaction with propargyl amines instead of propargyl alcohol. With the starting material 3a, we examined the hydrolysis of ester groups. Initially we tried the hydrolysis with LiOH in aq THF at room temperature. From the reaction, we obtained a mixture of starting material 3a and ethyl 2-phenyl-4-methyl-2,5dihydrofuran-3-carboxylate (4a). After many trials we found that the use of excess LiOH (3 equiv) at elevated temperature (50-60 C) gave 5a in good yield (75%) instead