Silver-Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Expedient Access to Indoline Fused Bicy-clo[2.1.1]hexanes

Abstract

Bicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but are difficult to access. Here a novel silver-catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N-unprotected in-doles and bicyclobutane precursors is described. This strain-release dearomative cycloaddition operates under mild conditions, tolerates a wide range of functional groups and is capable of forming BCHs bearing three quaternary carbon centers with up to 99% yield, a longstanding challenge in the field. In addition, a scale-up experi-ment and the synthetic transformations of the cycloadducts further highlighted the synthetic utility.