TiCl4-promoted direct N-acylation of sulfonamide with carboxylic ester

N‐acylsulfonamides: Synthetic routes and biological potential in medicinal chemistry

“…[14][15][16] This synthetic route generally works well, affording desired acylated products in satisfactory yields. [18] This methodology was further applied to a wider panel of esters, allowing the synthesis of N-acylsulfonamides of pharmaceutical interest. [17] Some reports from the literature describe the use of esters as acylating agents of sulfonamides, in the presence of Lewis acids.…”

“…X-ray structure analysis revealed a different binding mode of 17 in LBD, accounting for the partial agonism. Recent studies showed for F I G U R E 1 0 N-acylsulfonamides targeting PPARs: PPARγ agonists (16,17) and PPARα antagonists (18,19) 19 antiproliferative effects in glioblastoma, pancreatic, and colorectal cancer models. In a similar way, fibrate-based N-acylsulfonamides were found PPARα antagonists, especially derivatives more hindered in the sulfonimidic portion.…”

An efficient FeCl3‐promoted O‐alkyl cleavage of esters to carboxylic acids

“…Recently, we found that TiCl 4 could efficiently enhance the direct N-acylation of sulfonamide using carboxylic esters as acylating agents, and further studies on the reaction mechanism indicated that carboxylic esters were first transformed to their corresponding acids via O-alkyl cleavage and then condensed with sulfonamide to form N-acylated sulfonamide. [14] Therefore, we present an alternative ester cleavage method using Lewis acids as promoters under mild conditions.…”

N-Monoacylation of Sulfonimidamides

“…To avoid the formation of N,N-diacylated sulfonamide byproducts, an acid-catalyzed reaction of carboxylic acid anhydrides or esters with amines is often applied. [14][15][16][17] As noted, we thought that the TBS-deprotected compound 2 could be diacylated to afford the undesired compound 4; therefore, the TBS-protected compound 1 was used in this work. Considering the undesired lability of 1 under acidic conditions, we focused on finding other acylating systems, using either benzoic acid or benzoyl chloride under basic conditions (Scheme 2).…”