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

Abstract

An unprecedented set of structurally diverse sulfonimidamides (47 compounds) has been prepared by various N‐functionalization reactions of tertiary =NH sulfonimidamide 2 aa. These N‐functionalization reactions of model compound 2 aa include arylation, alkylation, trifluoromethylation, cyanation, sulfonylation, alkoxycarbonylation (carbamate formation) and aminocarbonylation (urea formation). Small molecule X‐ray analyses of selected N‐functionalized products are reported. To gain further insight into the properties of sulfonimidamides relevant to medicinal chemistry, a variety of structurally diverse reaction products were tested in selected in vitro assays. The described N‐functionalization reactions provide a short and efficient approach to structurally diverse 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

“…It was found that in the case of chloroacetyl chloride, N ‐benzoylisothiocyanate, phenylisocyanate, methyl and benzyl chlorocarbonate, and mesyl chloride, the corresponding products 24 – 29 were obtained in 63–100 % yields (Scheme ). Unlike the corresponding sulfonimidamides, compound 20 did not react with bromobenzene and with 1‐bromo‐3‐iodobenzene under the Buchwald–Hartwig reaction conditions (Pd(OAc) 2 or Pd 2 dba 3 , Xantphos, Cs 2 CO 3 , dioxane or toluene, 100 °C). Therefore, imidosulfuric diamides are somewhat less nucleophilic than sulfonimidamides.…”

Modern Stereoselective Synthesis of Chiral Sulfinyl Compounds

“…In 2018, 47 N -functionalized tertiary sulfonimidamides were prepared by Lücking and co-workers by arylation, alkylation, trifluoromethylation, cyanation, sulfonylation, alkoxycarbonylation, and aminocarbonylation of the =NH group. 388 Their hydrolytic and metabolic stability were checked, indicating the potential of application in biological systems.…”

Accessing Perfluoroaryl Sulfonimidamides and Sulfoximines via Photogenerated Perfluoroaryl Nitrenes: Synthesis and Application as a Chiral Auxiliary

“…During the last decades, the utility of sulfonimidamides (SIAs) − and sulfoximines (SOIs) − has been demonstrated in synthesis, agrochemical applications, and as bioisosteres in medicinal chemistry due to their notable properties, such as basicity, nucleophilicity, and solubility in polar solvents. The classical synthetic routes to access SIAs usually rely on the formation of sulfonimidoyl chloride as a precursor, followed by an amidation reaction (Figure ).…”