<p>Functional group interconversions are particularly sought after by medicinal chemists as a means to enable both lead optimization and library diversification. Here we report SO₂ insertion into the C–N bond of primary amines, enabling the direct synthesis of primary sulfonamides without preactivation and effectively inverting the nitrogen’s properties (acidity, hydrogen bonding and so on). The key to this transformation is the implementation of an anomeric amide as a dual-function reagent that both serves to cleave the initial C–N bond and delivers 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 that reacts with the anomeric amide to forge the S–N bond. 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.</p><p></p>