Lewis Acid-Catalyzed 1,3-Dipolar Cycloaddition of Bicyclobutanes with Isatogens: Access to Indoxyl-Fused Bicyclo[3.1.1]heptanes

The 'escape from flatland' concept has gained significant traction in modern drug discovery, emphasizing the importance of three-dimensional molecular architectures, which serve as saturated bioisosteres of benzenoids. Bicyclo[1.1.0]butanes (BCBs), known for their high ring strain and numerous reactivity, offer a simple yet effective method for synthesizing these bicyclic frameworks. Although (3+2) annulations involving BCBs have been extensively studied, the 1,3-dipolar cycloaddi-tion of BCBs leading to (3+3) annulation has received limited attention. Herein, we report the Lewis acid-catalyzed 1,3-dipolar cycloaddition of BCBs with isatogens allowing the synthesis of biologically relevant indoxyl-fused bicy-clo[3.1.1]heptanes. Moreover, the reaction can be performed in one-pot by the in-situ generation of isatogens from 2-alkynylated nitrobenzenes. Additionally, preliminary mechanistic and photophysical studies of the (3+3) annulated prod-ucts, and experiments towards asymmetric version of this reaction are also provided.