Selective Late‐Stage Sulfonyl Chloride Formation from Sulfonamides Enabled by Pyry‐BF₄

Abstract

Reported here is a simple and practical functionalization of primary sulfonamides, by means of a pyrylium salt (Pyry‐BF4), with nucleophiles. This simple reagent activates the poorly nucleophilic NH2 group in a sulfonamide, enabling the formation of one of the best electrophiles in organic synthesis: a sulfonyl chloride. Because of the variety of primary sulfonamides in pharmaceutical contexts, special attention has been focused on the direct conversion of densely functionalized primary sulfonamides by a late‐stage formation of the corresponding sulfonyl chloride. A variety of nucleophiles could be engaged in this transformation, thus permitting the synthesis of complex sulfonamides, sulfonates, sulfides, sulfonyl fluorides, and sulfonic acids. The mild reaction conditions and the high selectivity of Pyry‐BF4 towards NH2 groups permit the formation of sulfonyl chlorides in a late‐stage fashion, tolerating a preponderance of sensitive functionalities.

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

“…The high chemical and metabolic stability [6, 7, 22] combined with the interesting physicochemical properties [23] makes sulfonamide functionalities highly important in bioactive molecules [3, 22] . For this reason, extensive research effort has been put into the development of more efficient syntheses of sulfonamides [24] …”

Metallfreie, elektrochemische Synthese von Sulfonamiden direkt aus (Hetero)arenen, SO2 und Aminen

“…Die hohe chemische und metabolische Stabilität [6, 7, 22] in Verbindung mit den interessanten physikochemischen Eigenschaften [23] machen Sulfonamide in bioaktiven Molekülen zu wichtigen funktionellen Gruppen [3, 22] . Aus diesem Grund wurde viel Forschungsanstrengung in effizientere Synthesen von Sulfonamiden gesteckt [24] …”

“…[3,22] Aus diesem Grund wurde viel For-schungsanstrengung in effizientere Synthesen von Sulfonamiden gesteckt. [24] Traditionell werden Sulfonamide direkt durch Reaktion eines Amins mit einem Sulfonylchlorid hergestellt (Schema 2). Sulfonylchloride sind jedoch feuchtigkeitsempfindlich, [25] und einige davon sind nicht für eine Langzeitlagerung geeignet.…”

Synthesis of Sulfonyl Fluorides from Sulfonamides

“…We have recently reported on the use of Pyry‐BF 4 ( 1 ), as a highly chemoselective reagent for the modification of amino groups . One particular application is the selective activation of sulfonamides by Pyry‐BF 4 ( 1 ) thus converting them into the corresponding sulfonyl chloride in the presence of MgCl 2 (Figure B) . Although great electrophiles, sulfonyl chlorides suffer from high instability and fast hydrolysis rates, which results in troublesome isolation procedures .…”