A regio- and stereocontrolled approach to the synthesis of 4-CF3-substituted spiro[chromeno[3,4-c]pyrrolidine-oxindoles] via reversible [3+2] cycloaddition of azomethine ylides generated from isatins and sarcosine to 3-nitro-2-(trifluoromethyl)-2H-chromenes

Abstract

A one-pot three-component reaction of azomethine ylides generated in situ from isatins and sarcosine with 3-nitro-2-(trifluoromethyl)-2H-chromenes in i-PrOH at 55–60 °C leads to the kinetically controlled products – exo-spiro[chromeno[3,4-c]pyrrolidine-3,3′-oxindoles]. When this reaction is carried out in 1,4-dioxane under reflux, the thermodynamically controlled endo-spiro[chromeno[3,4-c]pyrrolidine-1,3′-oxindoles] are preferably formed. The isomerization of the kinetic products in DMSO solution at different temperatures has been studied by NMR spectroscopy and the stepwise mechanism of reversible [3+2] cycloaddition has been confirmed. The cytotoxic activity of some CF₃-substituted spiro[chromeno[3,4-c]pyrrolidine-oxindoles] against the HeLa cell line was evaluated by the MTT test.