<i>N</i> , <i>N</i> -Difluoroarylsulfonamides: A Reagent for Chemodivergent Trifunctionalization of Unactivated Alkenes to Construct Quinoline Isosteres

Although the replacement of aromatic rings with C(sp3)-rich isosteres has proven essential for improving the reactivity of drug candidates, the development of aza-arene-related isosteres, especially for privileged quinolines, remains limited due to the lack of efficient and controllable synthetic methods. Herein, we report a cost-effective Cu(I)-catalyzed chemodivergent trifunctionalization protocol for unactivated alkenes, which leverages the integrated versatile chemical reactivity of N,N-difluoroarylsulfonamides. This strategy enables the de novo synthesis of two types of topologically complex bridged sultams that are otherwise difficult to access using existing methods. The synthetic utility of our approach is demonstrated through the late-stage functionalization of biologically relevant targets and the synthesis of 15N-labeled molecules. More essentially, preliminary biological studies have identified that the synthesized bridged sultams serve as three-dimensional isosteres of quinoline, exhibiting enhanced bioactivity for cancer treatment. Comprehensive mechanistic studies further elucidate this reaction pathway.