Serendipitous synthesis of 2-alkenyl- and 2-aryl-4-thiazolidinones using dithiodiglycolic anhydride

Cyclic anhydrides, including sulfur-embedded anhydrides such as thiodiglycolic anhydride, are useful dipolar synthons for the synthesis of complex organic molecules through formal cycloaddition reactions with imines ( i.e. , the Castagnoli-Cushman Reaction (CCR)). Here, we disclose that a disulfide-embedded anhydride ( i.e. , dithiodiglycolic anhydride) unexpectedly underwent an efficient formal cycloaddition with aryl aldimines to afford functionalized 4-thiazolidinones, without complications arising from the CCR. Importantly, when 1,3-azadienes were employed, the 2-alkenyl-4-thiazolidinones were obtained without complications stemming from the sulfa-Michael reaction or the Tamura reaction. These 4-thiazolidinones constitute the core of several pharmaceuticals that display a broad spectrum of biological activities, including anti-HIV and anticancer. The current tactic obviates the need for thioglycolic acid, an alternative annulation partner associated with a strongly unpleasant odor. The ensuing N,S -heterocycles are then engaged in several selective fragment growth processes, including oxidation to sulfoxides, sulfones, and epoxysulfones. Dithiodiglycolic anhydride undergoes an efficient formal cycloaddition with imines to afford functionalized 4-thiazolidinones, without complications arising from the anhydride-imine reaction or the sulfa-Michael reaction (in the case of 1,3-azadienes).