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

Abstract

Summary: 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.

Keywords

• bridging C–H activation
• isocyanide insertion
• palladacycle
• mechanistic studies
• synthetic application