Access to bis-heterocyclic architectures via enol-Ugi reactions of privileged scaffolds

Bis-heterocycles are hybrid molecular compounds involving two heterocyclic frameworks covalently linked either directly or through a spacer moiety. Such structures are prevalent in numerous natural products and pharmacologically active compounds. Two biologically relevant structural motifs are the pyrrolidinone and indane-1,3-dione cores, which are present in a wide range of bioactive compounds and pharmaceuticals. Multicomponent reactions involving enols and bifunctional reagents represent an efficient approach to accessing these complex structures. In previous work, biscumarins were successfully obtained through a double enol-Ugi reaction. This methodology has now been extended to enols derived from pyrrolidinone and indane-1,3-dione systems, enabling the synthesis of highly functionalized bis-heterocycles based on privileged scaffolds. The optimized reaction conditions allow the simple and sustainable generation of complex architectures such as bis-pyrrolidinones and bis-indanones, which opens new and promising avenues in drug discovery. Importantly, these bis-heterocyclics exhibit remarkable stability, making them attractive precursors for the future development of macrocyclic systems. The versatility of this synthetic route demonstrates the potential of the enol-Ugi reaction in modern organic chemistry, facilitating the rapid construction of libraries of compounds with therapeutic relevance. This approach not only simplifies synthetic processes but also provides a robust framework for structural exploration in medicinal chemistry and other areas.