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. 2021 Mar 1;60(10):5056-5062.
doi: 10.1002/anie.202016164. Epub 2021 Feb 2.

Metal-Free Electrochemical Synthesis of Sulfonamides Directly from (Hetero)arenes, SO2 , and Amines

Stephan P Blum  1 , Tarik Karakaya  1 , Dieter Schollmeyer  1 , Artis Klapars  2 , Siegfried R Waldvogel  1
Affiliations

Metal-Free Electrochemical Synthesis of Sulfonamides Directly from (Hetero)arenes, SO2 , and Amines

Stephan P Blum et al. Angew Chem Int Ed Engl. .

Abstract

Sulfonamides are among the most important chemical motifs in pharmaceuticals and agrochemicals. However, there is no methodology to directly introduce the sulfonamide group to a non-prefunctionalized aromatic compound. Herein, we present the first dehydrogenative electrochemical sulfonamide synthesis protocol by exploiting the inherent reactivity of (hetero)arenes in a highly convergent reaction with SO2 and amines via amidosulfinate intermediate. The amidosulfinate serves a dual role as reactant and supporting electrolyte. Direct anodic oxidation of the aromatic compound triggers the reaction, followed by nucleophilic attack of the amidosulfinate. Boron-doped diamond (BDD) electrodes and a HFIP-MeCN solvent mixture enable selective formation of the sulfonamides. In total, 36 examples are demonstrated with yields up to 85 %.

Keywords: electrochemistry; green chemistry; oxidation; radical reactions; sulfonamides.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Sulfonamide‐containing drugs.
Scheme 2
Scheme 2
Selected strategies for the synthesis of sulfonamides. DABSO=1,4‐diazabicyclo[2.2.2]octane–bis(sulfur dioxide) adduct; DIPEA=N,N‐diisopropylethylamine.
Scheme 3
Scheme 3
General reaction scheme for the electrochemical synthesis of sulfonamides during the optimization process. [a] The 6:1 regioisomeric ratio was determined according to the crude NMR of entry 9 (Table 1).
Scheme 4
Scheme 4
Sulfonamide substrate scope of different (hetero)arenes. Grey background: isolated regioisomers. [a] Reaction conditions: arene substrate (0.6 mmol, 0.1 m), morpholine (3 equiv.), DIPEA (4 equiv.), SO2 (1.5 m), HFIP/MeCN=1:1, divided cell (glass frit), r.t., BDD electrodes, j=12 mA cm−2, Q=3.5 F.
Scheme 5
Scheme 5
Sulfonamide substrate scope of different amines. [a] Reaction conditions: 1,4‐dimethoxybenzene (0.6 mmol, 0.1 m), amine substrate (3 equiv.), DIPEA (4 equiv.), SO2 (1.5 m), HFIP/MeCN=1:1, divided cell (glass frit), r.t., BDD electrodes, j=12 mA cm−2, Q=3.5 F; [b] l‐proline methyl ester hydrochloride (3 equiv.) and DIPEA (5 equiv.) were used.
Scheme 6
Scheme 6
Scale‐up reaction. Comparison between screening cell (normal scale) and H‐type glass cell (scale‐up reaction).
Scheme 7
Scheme 7
Postulated reaction mechanism.
Scheme 8
Scheme 8
Cyclic voltammetry results. Black graph: morpholine (0.3 m), DIPEA (0.4 m), SO2 (1.5 m), HFIP/MeCN=1:1.
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