Efficient Multicomponent Synthesis of Novel Rhodanine Based Amide Derivatives

Abstract

Multicomponent reactions (MCRs) have become important tools for the synthesis of highly functionalized organic molecules. This is due to their convergence, simplicity, atom economy, and green characteristics. MCRs are quicker and cheaper than conventional reactions, since they are performed by mixing compounds together in one pot, without separating any intermediate. Isocyanide-based MCRs (IMCRs) are especially significant, because of their diversity and flexibility. Rhodanine (2-thioxothiazolidin-4-one) is a privileged scaffold and is found in a variety of biologically active compounds, including some with antiviral, antibacterial, antifungal, antitubercular, anticancer, anticonvulsant, and hypnotic activities. Following our interests in isocyanide-based reactions and our studies towards the development of new directions for the synthesis of novel organic compounds with biological activities, we now provide a preliminary report on our exploration of the multicomponent reaction of aromatic aldehydes 1 in the presence of aniline 2, rhodanine-N-acetic acid 3 and isocyanides 4 in THF. The reaction affords rhodanine-based amides 5 in good yields (Scheme 1). Initially we examined the reaction of benzaldehyde 1a (1 (R 1⁄4 H), 1.0mmol), aniline 2 (1.0mmol), rhodanine-N-acetic acid 3 (1.0mmol), and tert-butyl isocyanide 4a (4 (R 1⁄4 t-Bu), 1.0mmol) in tetrahydrofuran (THF) at room temperature as a model reaction. This condensation reaction did not afford the expected Ugi product 6a (6, R 1⁄4 H, R 1⁄4 t-Bu). Instead, 2-(5-benzylidene-4-oxo-2-thioxo-thiazolidin-3-yl)-N-tertbutyl-acetamide 5a, was obtained in 90% yield (Scheme 1, see Experimental Section for full structural characterization). In fact, it seems clear that the Knoevenagel condensation between benzaldehyde and rhodanine-N-acetic acid in the presence of aniline proceeds much faster than the Ugi reaction. Even with 2.0mmol benzaldehyde in the model reaction under reflux conditions, we found compound 5a as the main product (91%) with only a trace amount of the Ugi product 6a. In the absence of aniline, even after 24 h at reflux, only starting materials were recovered. Additionally, the reaction of