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.

Keywords: amines; heterocycles; nucleophilic addition; sulfonamides; synthetic methods.

Figure 1

The sulfonamide bond in medicinally relevant compounds.

Figure 2

A) Synthetic approaches to sulfonyl chlorides. B) Prior work on the application of Pyry‐BF₄ (1) in S_NAr with aminoheterocycles. C) State‐of‐the‐art of primary sulfonamide modification: electrophiles versus nucleophiles as coupling partners.

Figure 3

A) Derivatization of complex sulfonamides through the parent sulfonyl chloride. See the Supporting Information for conditions in each particular case. B) Formation of the sulfonyl chloride on gram scale.