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. 2019 Apr 10;141(14):5664-5668.
doi: 10.1021/jacs.9b02266. Epub 2019 Mar 28.

Sulfonamide Synthesis through Electrochemical Oxidative Coupling of Amines and Thiols

Gabriele Laudadio  1 , Efstathios Barmpoutsis  1 , Christiane Schotten  1   2 , Lisa Struik  1 , Sebastian Govaerts  1 , Duncan L Browne  2 , Timothy Noël  1
Affiliations

Sulfonamide Synthesis through Electrochemical Oxidative Coupling of Amines and Thiols

Gabriele Laudadio et al. J Am Chem Soc. .

Abstract

Sulfonamides are key motifs in pharmaceuticals and agrochemicals, spurring the continuous development of novel and efficient synthetic methods to access these functional groups. Herein, we report an environmentally benign electrochemical method which enables the oxidative coupling between thiols and amines, two readily available and inexpensive commodity chemicals. The transformation is completely driven by electricity, does not require any sacrificial reagent or additional catalysts and can be carried out in only 5 min. Hydrogen is formed as a benign byproduct at the counter electrode. Owing to the mild reaction conditions, the reaction displays a broad substrate scope and functional group compatibility.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Development of a direct synthesis of sulfonamides starting from thiols and amines. (A) Established routes toward sulfonamides requiring prefunctionalized reagents. (B) Direct use of commodity chemicals to yield sulfonamides requires two steps. (C) Optimization of the electrochemical sulfonamide synthesis using thiophenol and cyclohexylamine. Reaction Conditions (Entry 1): thiophenol (2 mmol), cyclohexylamine (3.0 mmol), Me4NBF4 (0.2 mmol), CH3CN/0.3 M HCl (20 mL, 3:1 v/v), C anode/Fe cathode, 5 min residence time, 700 μL reactor volume.
Figure 2
Figure 2
Synthesis of sulfonamides. Substrate scope for the electrochemical sulfonamide synthesis by direct anodic coupling of thiols and amines. All yields are isolated and reproduced at least two times. Reaction conditions: thiol (2 mmol), amine (3.0 mmol), Me4NBF4 (0.2 mmol), CH3CN/0.3 M HCl (20 mL, 3:1 v/v), C anode/Fe cathode, 5 min residence time, 700 μL reactor volume. 1Reaction carried out in a batch reactor. Reaction conditions: thiol (3 mmol), amine (4.5 mmol), Me4NBF4 (3 mmol), CH3CN/0.3 M HCl (30 mL, 3:1 v/v), C anode/Fe cathode, 24 h reaction time. 2Pyridine (2.0 mmol) was added as an additive. 3The corresponding disulfide was used as starting material. 410 min of residence time instead of 5 min.
Figure 3
Figure 3
Mechanistic investigation of the electrochemical sulfonamide synthesis. (A) Kinetic experiment. (B) Cyclic voltammetry. See Supporting Information for more details. (C) Radical trapping experiments and intermediate evaluation. ‡GC Yield (biphenyl as internal standard). (D) Proposed mechanism.
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References

    1. Petkowski J. J.; Bains W.; Seager S. Natural Products Containing a Nitrogen–Sulfur Bond. J. Nat. Prod. 2018, 81, 423–446. 10.1021/acs.jnatprod.7b00921. - DOI - PubMed
    1. Forster M. O.; Kunz E. CLXIII.—Studies in the camphane series. Part XXXV. Isomeric hydrazoximes of camphorquinone, and some derivatives of aminocamphor. J. Chem. Soc., Trans. 1914, 105, 1718–1733. 10.1039/CT9140501718. - DOI
    1. Autenrieth W.; Koburger J. Ueber die Einwirkung aromatischer Amine auf Aethylendisulfochlorid und über Vinylsulfonderivate. Ber. Dtsch. Chem. Ges. 1903, 36, 3626–3634. 10.1002/cber.190303603162. - DOI
    1. Schmitt A.-M. D.; Schmitt D. C.. Chapter 13. Synthesis of Sulfonamides. In Synthetic Methods in Drug Discovery: Volume 2; Blakemore D. C., Doyle P. M., Fobian Y. M., Eds.; RSC Drug Discovery Series; Royal Society of Chemistry, 2016; pp 123–138.
    1. Sohrabnezhad S.; Bahrami K.; Hakimpoor F. High yielding protocol for direct conversion of thiols to sulfonyl chlorides and sulfonamides. J. Sulfur Chem. 2019, 1.10.1080/17415993.2019.1570196. - DOI - PubMed

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