Skeletal editing of indoles and benzofurans to give indazoles, benzimidazoles, benzoxazoles and benzisoxazoles

Skeletal editing comprises the structural reorganization of compounds. Such editing can be achieved through atom swapping, atom insertion, atom deletion or reorganization of the compound's backbone structure. Conducted at a late stage in drug development campaigns, skeletal editing enables diversification of an existing pharmacophore, enhancing the efficiency of drug development. Instead of constructing a heteroarene classically from basic building blocks, structural variants are ready accessible directly starting from a lead compound or approved pharmacophore. Herein we present C to N atom swapping in indoles at the C2 position to give indazoles through oxidative cleavage of the indole heteroarene core and subsequent ring closure. Reactions proceed through ring-opened oximes as intermediates. Importantly, these ring deconstructed intermediates can also be diverted into benzimidazoles resulting in an overall C to N atom swapping with concomitant skeletal reorganization. The same structural diverting strategies are equally well applicable to benzofurans leading to either benzisoxazoles or benzimidazoles. All heteroarene classes accessible through these structural diversification processes belong to important compound classes.