Synthesis of Novel Heterocycle-fused Furo[3,4-d]isoxazoles via Ring Transformation of 2-Isoxazoline-2-oxides by Lewis Acid

Abstract

Reaction of five-membered heterocycle-substituted 2-isoxazoline-2-oxides (2,3, and 4) with titaniumtetrachloride afforded novel heterocycle-fused furo [3,4-~isoxazoles (5, 6 and 7), respectively.This transformation was applied to indole-substituted 2-isoxazoline-2-oxide (8) to give the corresponding fused furo [3,4-d]isoxazole (9) and indolo[2,3-b]-1-pyrroline-1-oxide (10).In continuation of our studies of the synthesis of benzofuro[3,4-djisoxazole derivatives2 through the ring transformation of 2-isoxazoline-2-oxides by Lewis acid,3 we investigated the reaction of heterocycle-substituted 2-isoxazoline-2-oxides (2, 3,4, and 8) with titanium tetrachloride4 and now report the preparation of heterocycle-fused furo[3,4-dJisoxazoles (5,6, 7, and 9), which are novel heterocyclic ring systems.The heterocycle-substituted 2-isoxazoline-2-oxides (2, 3, 4, and 8) were prepared by the reaction of the corresponding aldehydes, i.e., 3-furaldehyde, 2-furaldehyde, l-ptoluenesulfonyl-2-pyrrolecarbaldehyde, and 1-p-toluenesulfonyl-2-indolecarbaldehyde, with two molar amount of methyl nitroacetate (1 ) in the presence of ammonium a ~e t a t e .~ When furan-substituted 2-isoxazoline-2-oxides (2 and 3) were allowed to react with titanium tetrachloride at O0C, tetrahydrofuran-fused furo [3,4-d]isoxazoles (5 and 6) were isolated from the reaction mixture in 33 and 28 % yields, respectively.Furthermore, pyrrole-substituted isoxazoline-2-oxide (4) reacted with titanium tetrachloride to afford the corresponding pyrrolidine-fused furo [3,4-d]isoxazole (7) in 40 % yield.The structures of 5,6, and 7 were deduced on the basis of 'H-nmr analysis.The 'H-nmr