Zwitterionic π-Allyl-Pd Species Enabled [2σ+2π] Cycloaddition Reactions of Vinylbicyclo[1.1.0]butanes (VBCBs) with Alkenes, Carbonyls, and Imines

Abstract

Transition-metal-catalyzed cycloaddition reactions of strained small-ring compounds are powerful methods for constructing carbo- and heterocyclic structures of medicinal interest. However, the application of this strategy to bicyclo[1.1.0]butanes (BCBs), which are among the most strained carbocycles known, remains underdeveloped. Herein, we report vinylbicyclo[1.1.0]butane (VBCB) as a platform synthon for palladium-catalyzed formal [2σ+2π] cycloaddition reactions with various 2π-components, enabling the synthesis of BCHs, oxa-BCHs, and aza-BCHs under identical reaction conditions. The zwitterionic π-allyl-Pd species generated through the palladium-catalyzed activation of VBCBs is the key to circumventing potential carbene reactivity and serves as a common intermediate for cycloadditions with diverse 2π-systems, including alkenes, aldehydes, ketones, and imines. Notably, by utilizing Pd₂(dba)₃ and an anthracene-derived Trost ligand, a wide array of BCHs bearing two vicinal chiral centers has been prepared in a highly diastereo-, and enantioselective manner. The generality and practicality of this method have been demonstrated by a broad substrate scope, scale-up reactions, and the versatile transformation of multiple functional groups into BCH scaffolds. Preliminary mechanistic studies support the formation of the π-allyl-Pd species.