Regioselective synthesis of aza-saccharins via anionic [1,4] Fries-type rearrangement of aryl sulfonimidoyl fluorides

Abstract

A regioselective synthesis of aromatic and aliphatic aza-saccharins as cyclic sulfonimidamide derivatives is reported, starting from easily accessible aryl sulfonimidoyl fluorides and primary or secondary amines with broad functional group tolerance. The transformation is enabled by electron-withdrawing substituents and proceeds through an anionic [1,4] Fries-type rearrangement at cryogenic temperature, initiated by KHMDS-mediated ortho-deprotonation and rapid carbonyl migration. Mechanistic investigations indicate the formation of aryl sulfonimidoyl fluoridate anions, a distinct and previously unexplored motif in S(VI) and SuFEx chemistry. The involvement of these low-temperature-persistent intermediates is supported by cryogenic ¹⁹F/¹⁵N NMR studies of a ¹⁵N-labeled substrate, interception by acylation to give a stable adduct whose structure was confirmed by X-ray diffraction, and complementary DFT calculations indicating that the fluoridate anion is a viable low-energy intermediate. Regioselectivity follows predictable electronics-driven trends governed by meta-substituents, while selective aza-saccharin formation can be modulated by base choice and reagent addition order. Notably, the fluoridate anions are configurationally stable at sulfur, as demonstrated in a representative example, and subsequent amination via in situ SuFEx capture proceeds stereospecifically with inversion at sulfur. This synthetic method provides a mechanistically defined and stereocontrolled entry to chiral aza-saccharins with potential relevance to medicinal chemistry, agrochemical discovery and related disciplines.