One‐Pot, Three‐Component Sulfonimidamide Synthesis Exploiting the Sulfinylamine Reagent N‐Sulfinyltritylamine, TrNSO

Abstract

Sulfonimidamides are increasingly important molecules in medicinal chemistry and agrochemistry, but their preparation requires lengthy synthetic sequences, which has likely limited their use. We describe a one-pot de novo synthesis of sulfonimidamides from widely available organometallic reagents and amines. This convenient and efficient process uses a stable sulfinylamine reagent, N-sulfinyltritylamine (TrNSO), available in one step on 10 gram scale, as a linchpin. In contrast to classical approaches starting from thiols or their derivatives, our TrNSO-based approach facilitates the rapid assembly of the three reaction components into a variety of differentially substituted sulfonimidamides containing medicinally relevant moieties, including pyridines and indoles. Analogues of the sulfonamide-containing COX-2 inhibitor Celecoxib were prepared and evaluated.

Sulfonimidamides and Imidosulfuric Diamides: Compounds from an Underexplored Part of Biologically Relevant Chemical Space

“…A number of methods for the synthesis of sulfonimidamides have been reported in the literature in the last five years. These approaches include: (i) reaction of sulfinamides with ammonium carbamate and PhI(OAc) 2 ; (ii) copper‐catalyzed oxidative S−C/S−N bond interconversion in the corresponding sulfones; (iii) sulfur(VI)–fluoride exchange (SufFEx) reactions in the corresponding sulfonimidoyl fluorides 1 (Figure ); (iv) nucleophilic substitution in unstable sulfonimidoyl chlorides 2 (Scheme ) . Many of these methods were either limited in scope or relied on the use of unstable and/or difficult‐to‐operate (e.g., gaseous or explosive) reagents.…”

Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy‐amino‐λ6‐sulfanenitrile Intermediate

“…[9] Selected examples include Willissu se of Nsulfinyltritylamine as al inchpin for the addition of Grignard reagents and amines,v ia sulfonimidoyl chlorides. [6] Sharpless and co-workers described the use of thionyl tetrafluoride (SOF 4 )a sauseful reagent for sulfur fluoride exchange (SuFEx) click chemistry,u sing sulfonimidoyl fluorides as precursors to sulfoximines,s ulfonimidates,a nd sulfonimid-amides. [10] TheB olm group has reported copper-catalyzed methods to form sulfonimidamides involving across-coupling of sulfinamides [11] and the oxidation of methyl sulfoximines.…”

Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy‐amino‐λ6‐sulfanenitrile Intermediate

“…[2,3] High metabolic and chemical stability,along with hydrogen bond donor/acceptor capabilities,can impart improved physicochemical properties to these aza derivatives. [5] Thes ulfonimidamide group on the other hand has been less developed, but presents similar opportunities.B iologically active examples of sulfonimidamides include the aza analogues of the sulfonamides celecoxib [6] and tasisulam, [7] as well as asodium channel inhibitor published by Genentech in ap atent application (Scheme 1b). [5] Thes ulfonimidamide group on the other hand has been less developed, but presents similar opportunities.B iologically active examples of sulfonimidamides include the aza analogues of the sulfonamides celecoxib [6] and tasisulam, [7] as well as asodium channel inhibitor published by Genentech in ap atent application (Scheme 1b).…”

“…[8] This interest has prompted several recent synthetic advances (Scheme 1c). [6] Sharpless and co-workers described the use of thionyl tetrafluoride (SOF 4 )a sauseful reagent for sulfur fluoride exchange (SuFEx) click chemistry,u sing sulfonimidoyl fluorides as precursors to sulfoximines,s ulfonimidates,a nd sulfonimid-amides. [6] Sharpless and co-workers described the use of thionyl tetrafluoride (SOF 4 )a sauseful reagent for sulfur fluoride exchange (SuFEx) click chemistry,u sing sulfonimidoyl fluorides as precursors to sulfoximines,s ulfonimidates,a nd sulfonimid-amides.…”