Base-Promoted Chemodivergent Construction of 2H-Chromen-2-one and Chromeno[2,3-c]pyrrole Scaffolds from para-Quinone Methides and α-Alkylidene Succinimides

Abstract

Herein, we evolve a base-promoted synthesis of 2H-chromen-2-one and chromeno[2,3-c]pyrrole scaffolds via (4 + 2) annulation of α-alkylidene succinimides with 2-hydroxyphenyl-substituted para-quinone methides (p-QMs). Extremely selective and switchable cyclizations were obtained by modifying the base. This metal-free protocol is highlighted by its mild reaction conditions and broad substrate scope, and the viability of the existing protocol was additionally illustrated by gram-scale synthesis and further modification. Several control experiments were performed to understand the reaction mechanism.A mong the useful class of oxygen-based heterocycles, 2Hchromen-2-one and 2H-chromene are practical motifs found in various classes of natural products and pharmaceuticals. 1,2 2H-Chromen-2-one scaffold-based molecules represent a generous range of biological and pharmacological activities, 3 including anti-inflammatory, 3a anticancer, 3b anticholinesterase, 3c etc. For example, warfarin, 3d a prominent 2H-chromen-2one-based drug molecule, is used to treat thromboembolic disorders (Figure 1a). A series of 2H-chromene-based compounds, such as iclaprim, have been used to treat respiratory infections due to their notable specific inhibitory action on microbial dihydrofolate reductase. 4a A powerful 2Hchromene-based non-steroidal antiestrogen drug called EM-800 4b is used to treat breast cancer (Figure 1b).Conversely, pyrrolidine-2,5-dione scaffolds are the building blocks for many alkaloids and a wide range of synthetic compounds with various biological activities. 5 Owing to their importance in biological systems, it is crucial to discover new methods for creating these multi-substituted peculiar structures. Over the past few decades, synthetic communities have devised several effective methods to formulate strategies for creating 2H-chromen-2-one 6 and 2H-chromene 7 motifs. Until now, only a few reports are available for synthesizing chromeno[2,3-c]pyrrole scaffolds. 8