Scaffold Hopping of Isoxazole Enabled by an Oxidative Rh-Catalyzed Single-Carbon Insertion

High Resolution Image Download MS PowerPoint Slide Scaffold hopping is a key strategy in medicinal chemistry for lead optimization, but its application is often constrained by the need to synthesize each analogue from scratch. Single-atom skeletal editing offers an attractive alternative, yet methods for isoxazole scaffolds−especially in complex, medicinally relevant contexts−remain limited. Here, we present a scaffold hopping approach for isoxazoles based on an oxidative Rh-catalyzed single-carbon insertion using diazo-substituted hypervalent iodine(III) reagents and water. N−O bond cleavage by a Rh-carbynoid generates β-enaminones, versatile intermediates that can be transformed into oxazoles and pyrimidines. The method shows broad scope, high chemoselectivity, and strong functional-group tolerance. Extension to benzo[c]isoxazoles enables access to quinazolines, while late-stage modification of drug-like molecules demonstrates its value for medicinal chemistry.