A New, Practical One‐Pot Synthesis of Unprotected Sulfonimidamides by Transfer of Electrophilic NH to Sulfinamides

Abstract

Unprotected tertiary sulfonimidamides have been prepared in good to excellent yields in a one‐pot transformation from tertiary sulfinamides through NH transfer. The reaction is mediated by commercially available (diacetoxyiodo)benzene and ammonium carbamate in methanol under convenient conditions. A wide range of functional groups are tolerated and initial results indicate that the NH transfer is stereospecific. A small molecule X‐ray analysis of NH sulfonimidamide 2 a and its behavior in selected in vitro assays in comparison to the matched sulfonamide are also reported. This new reaction provides a safe, short and efficient approach to sulfonimidamides, which have been the subject of recent, growing interest in the life sciences.

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

“…[13] In 2016, we reported af acile metal-free protocol for the direct synthesis of NH-sulfoximines from sulfoxides in high yields and with good functional group compatibility. [15] We,a nd others, recently reported related conditions for the conversion of sulfides into sulfoximines in ao ne-pot process through ahighly chemoselective NH and Ot ransfer. Our approach has been recently extended by Stockman and Lücking to form sulfonimidamides,u sing closely related conditions to effect NH transfer to sulfinamides (Scheme 1c).…”

Exploration of Novel Chemical Space: Synthesis and in vitro Evaluation of N‐Functionalized Tertiary Sulfonimidamides

“…Triggered by our experience that the use of uncommon functional groups, such as sulfoximines 4 , can be crucial for overcoming hurdles in lead optimization, we also became interested in sulfonimidamides 2 as a neglected but potentially versatile pharmacophore for drug discovery. Due to the limited synthetic methodology available, we developed a new, practical one‐pot synthesis of tertiary =NH sulfonimidamides 2 a by transfer of electrophilic NH to sulfinamides 3 (Scheme ) . The reaction is mediated by commercially available (diacetoxyiodo)benzene and ammonium carbamate in methanol at room temperature and tolerates a wide range of functional groups.…”

“…Originally, these reaction conditions had been newly reported by Bull, Luisi and co‐workers for the conversion of sulfoxides into sulfoximines 4 . Moreover, we investigated a variety of in vitro properties, relevant to medicinal chemistry, of =NH sulfonimidamide 2 aa in comparison to its matched sulfonamide analogue 1 aa and did not identify any intrinsic flaw of the =NH sulfonimidamide group with respect to its application in the life sciences …”

“…Therefore, we set course to investigate the N‐functionalization of tertiary =NH sulfonimidamides 2 a . To test the desired transformations, we selected =NH sulfonimidamide 2 aa as a model compound, which had been prepared from the corresponding sulfinamide 3 on a gram scale by the one‐pot NH‐transfer method (Scheme ) …”