Sulfoximines, the monoaza analogues of sulfones, have recently gained considerable recognition as a new and versatile structural motif in the life sciences and the synthetic methodology for their preparation has progressed significantly over the last decade. In contrast, sulfonimidamides, the mono aza-analoges of sulfonamides have been neglected in the life sciences so far, even though they seem to offer very interesting properties, such as high stability, favourable physicochemical properties, multiple hydrogen-bond acceptor/donor functionalities, and structural diversity. It can be speculated that the use of sulfonimidamides in the life sciences has been hampered substantially by the lack of commercial availability and limited synthetic methods available. In this context, a recent publication caught our attention, in which Bull and Luisi described that mixing ammonium carbamate with bis-acetoxyiodobenzene directly converts sulfoxides into NH sulfoximines. We wondered if these reaction conditions could also be useful for the facile synthesis of NH sulfonimidamides (4) by NH transfer to sulfinamides (3). Indeed we have now demonstrated that unprotected tertiary sulfonimidamides 4 can be prepared from tertiary sulfinamides 3 in a one-pot transformation mediated by commercially available reagents in methanol in good to excellent yields. A wide range of functional groups common in medicinal chemistry were tolerated and initial results indicate that the NH transfer reaction is stereospecific. Moreover, sulfonimidamides offer an additional point for substitution, the =NH group, in contrast to sulfonamides. In this contest we have now developed new methods for the functionalization of this NH group by Pd-catalyzed arylation and KOH mediated alkylation reactions giving the desired complex products in good to excellent yields.

Novel methods for the synthesis of sulfonimidamides: New pharmacophores for the medicinal chemist’s toolbox

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.