Unified Approach to Benzo[d]thiazol-2-yl-Sulfonamides

Abstract

In this paper, we report a unified approach to N-substituted and N,N-disubstituted benzothiazole (BT) sulfonamides. Our approach to BT-sulfonamides starts from simple commercially available building blocks (benzo[d]thiazole-2-thiol and primary and secondary amines) that are connected via (a) a S oxidation/S−N coupling approach, (b) a S−N coupling/S-oxidation sequence, or via (c) a S-oxidation/S−F bond formation/SuFEx approach. The labile N−H bond in N-monoalkylated BT-sulfonamides (pK a (BTSO 2 N(H)Bn) = 3.34 ± 0.05) further allowed us to develop a simple weak base-promoted N-alkylation method and a stereoselective microwave-promoted Fukuyama−Mitsunobu reaction. N-Alkyl-N-aryl BT-sulfonamides were accessed with the help of the Chan− Lam coupling reaction. Developed methods were further used in stereo and chemoselective transformations of podophyllotoxin and several amino alcohols.Article pubs.acs.org/joc

Heteroaryl sulfonamide synthesis: scope and limitations

“…2C, entry 1). 23 Only traces of product 7a were observed. Detailed investigation and optimization of the reaction steps (sulfenamide formation (entry 2) and its oxidation to sulfonamide (entry 3)) and the isolation and purification of product 7a allowed us to prepare the desired sulfonamide in a reasonable 35% isolated yield (entry 4).…”

“…Previous observations and data obtained during our research in the field of benzothiazole-2-yl sulfones and sulfonamides showed that sulfone/sylfonamide-bearing C α carbon in the heterocycle is prone to nucleophilic attack. 24–26 We exploited this behaviour, for example, in amine synthesis; 23 however, it also caused the instability of sulfones and sulfonamides on silica gel. 24,27,28 For those reasons we wondered if the quasi-nonexistence of several classes of heteroaryl sulfonamides in the literature 19 might be caused by their instability.…”

“…5A). 23,35,36 Using such conditions, sulfonamide 7a was transformed into N , N -dialkylated benzoxazole sulfonamide (+)- 17f with a 48% yield. Pure (+)- 17f was found to be shelf stable for at least 3 months.…”

“…1D). 23 Simplicity of the developed protocol hand-in-hand with a quasi-nonexistent general method that would allow the synthesis of, for example, (benzo[ d ])oxazole-2-yl sulfonamides 19 led us to the idea of extending this method to other heterocyclic thiols.…”