Late-stage diversification of indole skeletons through nitrogen atom insertion

Abstract

Advances in the field of late-stage functionalization have expedited lead-structure discovery and established new opportunities to access valuable molecules. Although many peripheral late-stage transformations, mainly focusing on C–H functionalizations, have been reported, reliable strategies to directly edit the core skeleton of lead compounds have remained scarce. Late-stage remodeling strategies of widely encountered and pharmaceutically relevant scaffolds, such as indoles, would offer enormous potential to expand accessible chemical space. Herein, we report the skeletal editing of indoles through nitrogen atom insertion, accessing their corresponding quinazoline or quinoxaline bioisosteres via trapping of an electrophilic nitrene species generated from ammonium carbamate and hypervalent iodine. This unique reactivity is unlocked through the strategic use of a silyl group which acts as a reactivity-controlling element to suppress the inherent nucleophilicity of the nitrogen in indoles. Importantly, the utility of this highly functional group-tolerant methodology in the context of late-stage skeletal editing of several commercial drugs is demonstrated.

Skeletal Metalation of Lactams through Carbonyl-to-Nickel Exchange Logic

“…Thus, developing a skeletal metalation platform for lactams, in which the carbonyl moiety could be directly exchanged by a metal, could facilitate such a transformation and even unlock more versatile atom swap or ring expansion processes that are particularly attractive for the structural remodeling of heterocycles. (15)(16)(17)(18)(19) Here we introduce a carbonyl-to-metal exchange logic for the skeletal metalation of 4-to 8membered lactams. The reaction employs an easily prepared Ni(0) precursor and occurs readily at room temperature, affording a versatile new class of well-defined organonickel reagents.…”