N-Monoacylation of Sulfonimidamides

Abstract

N-Monoacylated sulfonimidamides, the aza analogue of Nacylsulfonamides which are a common motif in drug discovery, were exclusively synthesized by using a 1:1-premixed mixture of an acyl chloride and pyridazine as the acylating agent, while diacylation exclusively occurred when N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) was used as the coupling agent. The monoacylation is fast, easy to operate, and applicable to both aromatic and aliphatic acyl chlorides to give the corresponding products in moderate or high overall yields. A two-step N,N′-diacylated product exemplifies that the sulfonimidamide moiety provides one more handle than its sulfonamide isostere. This stepwise functionalization approach can be used to fine-tune the desired properties of compounds in medicinal chemistry.

An Improved Synthesis of 1λ6,2,4,6‐Thiatriazine‐1,3,5‐trione Derivatives – the Sulfonimidamide‐featured Triazinones

“…As previously reported, sulfonimidamide 1 is prone to diacylation, even though 1 equiv. of acylating reagent is used [5b] . To achieve full conversion of 1 to 6 , 2 equiv.…”

“…Our research focuses on the synthesis and functionalization of sulfonimidamides [5] . Due to the nucleophilicity of the two N atoms in a sulfonimidamide, di‐acylated by‐products were usually formed as main products when common coupling reagents, such as TBTU, were applied [5b] . To prepare the mono‐acylated derivative, we developed a protocol using a mixture of acyl chloride and pyridazine as the acylating reagents [5b] .…”

“…Due to the nucleophilicity of the two N atoms in a sulfonimidamide, di‐acylated by‐products were usually formed as main products when common coupling reagents, such as TBTU, were applied [5b] . To prepare the mono‐acylated derivative, we developed a protocol using a mixture of acyl chloride and pyridazine as the acylating reagents [5b] . Inspired by these results, we used pyridazine as the base for mono N‐carbamoylation and reported a one‐pot approach to access 1λ 6 ,2,4,6‐thiatriazine‐1,3,5‐trione derivatives, the sulfonimidamide‐featured triazinones through a sequential carbamoylation‐acylation‐cyclization approach ( 5 , Scheme 1) in our previous work [5d] …”

Synthesis of Sulfonimidamide‐Based Amino Acid Building Blocks with Orthogonal Protecting Groups

“…As mentioned above, the one‐pot method demonstrated by Chen started from TBS‐protected sulfonamides that were treated with simple ammonia, primary and secondary amines . Thus, only protecting groups lacking UV/Visible chromophore groups have been explored in this synthetic route making the analysis of UV inactive sulfonimidamide compounds, e.g., methanesulfonimidamide, difficult , . Our first investigations had two primary goals: firstly, to see if the more stable, UV‐active and more sterically demanding TBDPS‐protection is compatible with the one‐pot SIA formation, and secondly to investigate the outcome of amino acid esters as amine nucleophiles.…”

“…Also, single atom alterations are well‐known to sometimes considerably improve the activity of the parent molecule . Exploration of novel synthetic methods to enrich the SIA chemistry as well as its application in drug discovery projects is one of the ongoing projects in our laboratory, , and with our industrial collaborators …”