Green synthesis of a 4-hydroxydithiocoumarin-imidazole bis-heterocycle scaffold, and its antiproliferative study and unusual single-crystal XRD pattern

Abstract

This study introduces a catalyst-free, highly efficient synthetic strategy for constructing hitherto unreported tetra-substituted imidazole-bound bis-heterocyclic (BHC) derivatives via a pseudo-five-component reaction. The method provides selective reactivity at the C3 position of 4-hydroxydithiocoumarin, rather than the expected CS, in which one equivalent each of 4-hydroxydithiocoumarin, isocyanide, and ammonium acetate and two equivalents of aryl aldehyde participate to form two C–C and two C–N bonds in a single operation. This protocol is distinguished by its remarkable atom economy (83.4%), an exceptionally low environmental factor (E-factor = 0.19), and environmentally benign reaction conditions. Moreover, this one-pot process affords good yields without the need for column chromatographic separation, thereby reducing the use of additional auxiliaries. Notably, the resulting BHC derivatives, 5l and 5m, exhibit promising antiproliferative activities, highlighting the potential impact of this sustainable synthetic approach. In addition, the newly developed product exhibits an unusual structural pattern, as observed by single-crystal XRD.