Divergent isoindolinone synthesis through palladium-catalyzed isocyanide bridging C–H activation

Abstract

The formation of thermodynamically accessible metallacycle is crucial to achieve site-selective C–H bond activation. Here, we report an isocyanide-bridging C–H activation through the formation of a five-membered palladacycle. As such, a proximal C–H bond in aldehyde moiety is activated selectively. The subsequent palladium shift and intramolecular C=N bond insertion construct a valuable isoindolinone framework. Compared with conventional isocyanide-promoted C–H bond activation, both carbon and nitrogen atoms in isocyanide are engaged in new bond formations. Notably, three types of isoindolinones can be obtained selectively by variations of the reaction conditions. Mechanistic studies shed light on the reaction pathways. Moreover, the synthetic potential of current methodology is demonstrated by providing concise routes to key intermediates of indoprofen, indobufen, aristolactams, lennoxamine, and falipamil. • Isocyanide-bridging C–H activation • A new reaction mode for C–H bond functionalization • Divergent preparation of isoindolinone derivatives • Potential applications in bio-active molecule synthesis Metallocycles are commonly used to direct C–H bond activation. Here, Zhang et al. describe a palladium-catalyzed isocyanide-bridging C–H activation in which the isocyanide moiety not only acts as a bridging unit to facilitate a proximal C–H bond activation but also serves as a two-atom building block to construct the three different substituted isoindolinone derivatives.