Late-stage diversification of indole skeletons through nitrogen atom insertion

Compared with peripheral late-stage transformations mainly focusing on carbon-hydrogen functionalizations, reliable strategies to directly edit the core skeleton of pharmaceutical lead compounds still remain scarce despite the recent flurry of activity in this area. Herein, we report the skeletal editing of indoles through nitrogen atom insertion, accessing the corresponding quinazoline or quinoxaline bioisosteres by trapping of an electrophilic nitrene species generated from ammonium carbamate and hypervalent iodine. This reactivity relies on the strategic use of a silyl group as a labile protecting group that can facilitate subsequent product release. The utility of this highly functional group-compatible methodology in the context of late-stage skeletal editing of several commercial drugs is demonstrated.

Automated summary

Reliable strategies for directly editing the core skeleton of pharmaceutical lead compounds are still scarce despite recent developments in the field. This study presents a method for skeletal editing of indoles through nitrogen atom insertion, demonstrating its utility in late-stage skeletal editing of several commercial drugs.