Late-stage diversification of indole skeletons through nitrogen atom insertion

• Published in: Science (American Association for the Advancement of Science) 2022-09, Vol.377 (6610), p.1104-1109
• Main Authors: Reisenbauer, Julia C., Green, Ori, Franchino, Allegra, Finkelstein, Patrick, Morandi, Bill
• Format: Article
• Language: English
• Subjects: Chemical reactions; Drug development; Functional groups; Indoles; Iodine; Nitrogen; Quinoxaline; Quinoxalines
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.add1383

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. Numerous pharmaceutical compounds contain five- or six-membered rings composed of carbon and nitrogen. Chemical reactions that interconvert these motifs can therefore be very helpful during drug development research. Reisenbauer et al . present a method to insert a nitrogen atom into the five-membered rings of silyl-protected indoles, thereby expanding them into six-membered quinazoline or quinoxaline compounds depending on their substitution pattern at the outset. The chemistry relies on nitrene generation using hypervalent iodine and is compatible with many common functional groups. —JSY Nitrene chemistry expands indole rings by inserting nitrogen.