Photoredox-Catalyzed Amidyl Radical Insertion to Bicyclo[1.1.0]butanes

Abstract

Heteroaromatic rings play a prominent role in medicinal chemistry, featuring in numerous biologically relevant molecules. However, unlike benzene ring the saturated and structurally rigid bioisosteric mimetics of heteroaromatic rings are rarely known, mainly due to the inherent challenges associated with the stability and synthesis of heteroatom-substituted C(sp3)-rich polycyclic hydrocarbons. We envisioned that the strategic and highly selective insertion of different heteroatomic units to bicyclo[1.1.0]butanes (BCBs) could offer an ideal platform to access diverse heterobicyclo[n.1.1]alkanes. Herein, by circumventing the intrinsic challenges associated with the reaction of BCBs with heteroatomic radicals, we report a photoredox-catalyzed highly regio- and chemoselective insertion of amidyl radicals to BCBs, which provided direct access to 2-oxa-4-azabicyclo[3.1.1]hept-3-enes. Detailed experimental and computational studies have been carried out to underpin the mechanistic paradigm of this reaction. The newly synthesized heterobicyclic motifs are structurally rigid and exhibit well-defined exit vectors, the two important molecular properties in medicinal chemistry. Moreover, various downstream transformations were carried out with these compounds, highlighting their utility as versatile building blocks in synthetic chemistry.