Work

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

Year: 2026

Type: article

Abstract: 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.

Source: ACS Catalysis

DOI: 10.1021/acscatal.6c02785

Authors: Matteo Balletti, Leonardo Pagliano, Marcos G. Suero

Institutions: Institut Català d'Investigació Química, Barcelona Institute of Science and Technology, Universitat Rovira i Virgili, Institució Catalana de Recerca i Estudis Avançats

Language: English

Topic: Cyclopropane Reaction Mechanisms

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: hybrid

Estimated APC paid: $4,500