Assembly of polyfunctional arenes with three contiguous and different substituents by Pd-catalyzed four-component reactions

Abstract

The innovation of versatile multi-component reaction modes for one-pot assembly of polyfunctional arenes is a highly challenging and important goal in organic synthesis. Here, we report that polyfunctional arenes with three contiguous and different substituents can be assembled efficiently under mild conditions in a one-pot, four-component modular way by orchestrating mechanistically sequential and compatible palladium-catalyzed domino carbopalladation of arynes and norbornene (NBE)-mediated Catellani processes. Optimization of the reaction conditions reveals that balancing the reaction parameters in general, and loading amount of NBE especially, is a linchpin for the reaction. Studies of the reaction scope indicate a wide selection of functional groups, including complex natural product-derived substructures, can be tolerated, making it appealing for early- and late-stage assemblies. Post-transformations show that not only the newly installed substituents but also the parent aromatic nucleus can be derived conveniently, enabling polyfunctional arenes with diverse substitutions in a concise manner. General one-pot, four-component modular domino synthesis Three contiguous and different substituents Benzenes with up to six substituents Shen et al. describe a general, palladium-catalyzed, four-component reaction that can incorporate different functional groups onto three successive positions of benzene rings. The reaction tolerates complex natural product structures, and the products can be derived diversely.