Site-selective decarbonylative [4 + 2] annulation of carboxylic acids with terminal alkynes by C–C/C–H activation strategy and cluster catalysis†

Abstract

Cycloaddition and annulation strategies are among the most powerful methods for creating molecular complexity in organic molecules. In this manuscript, we report a highly site-selective palladium-catalyzed decarbonylative [4 + 2] cyclization of carboxylic acids with terminal alkynes by a sequential C–C/C–H bond activation. Most notably, this method represents the first use of carboxylic acids as the ubiquitous and underdeveloped synthons for intramolecular cycloadditions by decarbonylative C–C bond cleavage. The method provides a solution to the long-standing challenge of the regioselective synthesis of substituted naphthalenes by cycloaddition. Mechanistic studies show that this reaction occurs through a sequential process involving the formation of key palladacycle by a sequential C–C/C–H bond activation and highly regioselective alkyne insertion enabled by cluster catalysis. Wide substrate scope for both carboxylic acids and terminal alkynes is demonstrated with high functional group tolerance. Moreover, this reaction is scalable and applicable to the synthesis of functionalized molecules featuring bioactive fragments. This reaction advances the toolbox of redox-neutral carboxylic acid interconversion to cycloaddition processes. We anticipate that this approach will find broad application in organic synthesis, drug discovery and functionalized material research fields.