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Accessing Sulfonamides via Formal SO2 Insertion into C–N Bonds

Myojeong Kim,1Carys E. Obertone,1Christopher B. Kelly,2,*Christopher A. Reiher,3,* Cristina Grosanu,4James C. Robertson,5 and Mark D. Levin1,*

1 Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States;

2 Discovery Process Research, Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania 19477, United States;

3 Parallel Medicinal Chemistry, Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania 19477, United States

4 High-Throughput Purification, Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania 19477, United States.

5 In Silico Discovery, Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania 19477, United States

—Nat. Chem. 2025, doi: 10.1038/s41557-025-01848-2

Recommended by Depei Meng_MC4

KEY WORDS:SO2 insertion, skeletal editing, N-deletion(响应类型),C(sp3)–S, S-N (成键), amines, amide, anomeric amide, DABSO (原料), primary sulfonamides (产品)

ABSTRACT: 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 pre-activation 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.

Overview of this study. a) Primary sulfonamides with therapeutic potential.b) Our goal and strategy for underdeveloped direct SO2-insertion. c)This work.

Substrate scope

Synthetic utility. a.Modification of Crenolanib and comparative docking study to PDGFR. The full kinase domain is also shown with key structural motifs highlighted. b.Synthesis of primary sulfonamide from amide, pKa prediction, and theoretical geometry comparison. c. Synthesis of tyrosine kinase inhibitor Pazopanib via SO2 insertion.

In summary, Prof. Mark D. Levin group and scientists from Johnson & Johnsonhave developed a direct SO2insertion into the C–N bondof primary amines driven by the synergy between an anomeric amide reagent and SO2. The dual role of the anomeric amide as a homolytic deaminating agent (cleaving the N–C bond) and as an effective electrophilic nitrogen trap (forging the S–N bond) allows for seamless assembly of sulfonamides under the conditions described here. This late-stage amenable approach affords the end-user the ability to tactically modify biologically relevant amines into sulfonamides in both a singleton (thus permitting point mutations on complex targets) or in parallel automated mode. The latter may be used to construct diverse arrays of sulfonamides whose currently mapped chemical space is only a fraction of their amine progenitors. Mechanistic data derived from both experiment and calculations, support the intermediacy of a sulfonyl radical which outcompetes C-centered radicals in HAT events involving isodiazines. More broadly, the implementation of a reagent originally designed for atom deletion to instead promote an overall atom insertion represents a generalizable approach that may have significant applications in skeletal editing.

（转自：康龙化成）

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