Accessing Sulfonamides via Formal SO2 Insertion into C–N Bonds

Functional group interconversions of abundant substructures that accommodate the often-complex molecular architectures seen in pharmaceuticals are particularly sought after by medicinal chemists as a means to enable both lead optimization and library diversification. Here, we report a conceptually new strategy that enables net SO2-insertion into the C–N bond of primary amines, enabling the direct synthesis of primary sulfonamides without pre-activation and effectively inverting the nitrogen’s properties (acidity, hydrogen bonding, etc.). The key to realizing this overall transformation is the implementation of an anomeric amide as a dual-function reagent which both serves to cleave the initial C–N bond and deliver a nitrogen atom to the product after SO2 incorporation. The process tolerates a wide array of functionalities and can be run in an automated fashion thus allowing libraries of amines to be viable progenitors to highly desirable sulfonamides. Mechanistic studies support an isodiazene radical chain mechanism that generates an intermediate sulfinate which reacts with the anomeric amide to forge the S–N bond. As a proof of concept, our protocol was used to conduct a high-throughput library diversification campaign, was applied to the synthesis and modification of approved active pharmaceutical ingredients and was used to enable a net CO-to-SO2 “isosteric replacement” approach. Conceptually, this successful translation of a reagent originally developed for atom deletion into a protocol for atom insertion has important implications for skeletal editing.