Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Nov 7;90(44):15790-15803.
doi: 10.1021/acs.joc.5c02077. Epub 2025 Oct 29.

Sulfoximine N-Functionalization with N-Fluorobenzenesulfonamide

Žan Testen  1 , Črtomir Podlipnik  1 , Marjan Jereb  1
Affiliations

Sulfoximine N-Functionalization with N-Fluorobenzenesulfonamide

Žan Testen et al. J Org Chem. .

Abstract

An operationally simple, convenient, mild, metal-free, and scalable transformation of sulfoximines with N-fluorobenzenesulfonamide is presented. A wide range of structurally different NH-sulfoximines were prepared and reacted with N-fluorobenzenesulfonamide in the presence of TMP (2,2,6,6-Tetramethylpiperidine) and in the environmentally friendly EtOAc to obtain the desired products, mostly in yields above 75%. The method also supports various amine, hydrazide, phenol, and amino acid substrates as well as scale-up to gram reactions with minimal to no modification of the process. The products formed from the sulfoximines were structurally analyzed by NMR and X-ray crystallography and investigated for their stability and further reactivity as substrates in Suzuki-Miyaura coupling, methylation, and bromination reactions. In addition, DFT calculations were carried out with regard to the energy profile and mechanism of the reaction.

PubMed Disclaimer

Figures

1
1
Selection of biologically active sulfoximines.
1
1. Recent N–S Functionalizations of Sulfoximines
2
2. Initial Experiments with NFSI
3
3. Reaction of Modified Cholesterol and 2
4
4. Gram-Scale Reaction
5
5. Reaction of Benzoic Acid and 2
6
6. Methylation of 3a
7
7. Suzuki-Miyaura Coupling Reactions
8
8. Bromination of 3a in Different Solvents
9
9. Proposed Mechanism for the Formation of 3a and Its Crystal Structure
2
2
Calculated Changes of the Gibbs Free Energies for the Reaction of 1a and 2.
See this image and copyright information in PMC

References

    1. Han Y., Xing K., Zhang J., Tong T., Shi Y., Cao H., Yu H., Zhang Y., Liu D., Zhao L.. Application of Sulfoximines in Medicinal Chemistry from 2013 to 2020. Eur. J. Med. Chem. 2021;209:112885. doi: 10.1016/j.ejmech.2020.112885. - DOI - PubMed
    1. Frings M., Bolm C., Blum A., Gnamm C.. Sulfoximines from a Medicinal Chemist’s Perspective: Physicochemical and in Vitro Parameters Relevant for Drug Discovery. Eur. J. Med. Chem. 2017;126:225–245. doi: 10.1016/j.ejmech.2016.09.091. - DOI - PubMed
    1. Mäder P., Kattner L.. Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry. J. Med. Chem. 2020;63:14243–14275. doi: 10.1021/acs.jmedchem.0c00960. - DOI - PubMed
    1. Lücking U.. Neglected Sulfur­(VI) Pharmacophores in Drug Discovery: Exploration of Novel Chemical Space by the Interplay of Drug Design and Method Development. Org. Chem. Front. 2019;6:1319–1324. doi: 10.1039/C8QO01233D. - DOI
    1. Sirvent J. A., Lücking U.. Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates. ChemMedChem. 2017;12:487–501. doi: 10.1002/cmdc.201700044. - DOI - PMC - PubMed

LinkOut - more resources