Scaffold hopping of furans into 3-cyanopyridines
TL;DR
A scaffold-hopping strategy in which a cyanosulfenylcarbene selectively cleaves furan cores, generating dienone intermediates bearing an intrinsic thioaryl leaving group, and provides a conceptually distinct approach to the controlled remodeling of heterocycles is reported.
Abstract
Furans are economically accessible bulk chemicals largely derived from lignocellulosic biomass. Although the furan motif is widely found in natural products, it remains underrepresented in FDA-approved therapeutics owing to its metabolic instability. This gap underscores the need for strategies that diversify and functionalize furan scaffolds for drug discovery. Here, we report a scaffold-hopping strategy in which the cyano-sulfenylcarbene selectively cleaves the furan core, generating dienone intermediates bearing an intrinsic thioaryl leaving group. A subsequent reaction with a nitrogen source restores aromaticity and yields pyridines, a privileged and pharmaceutically indispensable heterocycle. This metal-free process exhibits broad functional-group tolerance, enables 15N-incorporation, and provides a conceptually distinct approach to the controlled remodeling of heterocycles. Mechanistic studies, supported by density functional theory calculations, highlight the critical role of the cyano-group in the ring-opening step of furan and uncover an unusual ring-closing pathway that proceeds via a cyclopropane-fused pyrrole, ultimately yielding an unexpected pyridine regioisomer. The authors report a scaffold-hopping strategy in which a cyanosulfenylcarbene selectively cleaves furan cores, generating dienone intermediates bearing an intrinsic thioaryl leaving group. A subsequent reaction with a nitrogen source restores aromaticity and yields pyridines, a privileged and pharmaceutically indispensable heterocycle.