Ring expansion of bicyclo[1.1.0]butyl ketones to bicyclo[2.1.1]hexenes using ketone as both activating and reacting groups

Bicyclo[n.1.1]alkyl skeletons are of significant interest as bioisosteres of phenyl groups for lead drug modification. Common strategies for their synthesis utilize bicyclo[1.1.0]butanes, wherein the electron-withdrawing groups serve solely as activating groups to facilitate the cleavage of the bridged σ bond, leading to ring expansion by an insertion manner. In this work, we utilize ketones in bicyclo[1.1.0]butane as both activating and reacting groups, promoting a tandem nucleophilic addition/intramolecular Horner-Wadsworth-Emmons olefination process by a distinct exo-cyclic annulation manner. The approach enables the synthesis of diverse bicyclo[2.1.1]hexenes (52 examples, up to 96% yield). A series of transformations have been carried out on bicyclo[2.1.1]hexenes to synthesize bicyclo[2.1.1]hexane/hexene analogues of sonidegib, and the physicochemical properties and anti-tumor activities of these analogues have been investigated. In addition, this approach enables the discovery of aggregation-induced emission properties in this distinctive ring skeleton.