The adoption of unusual functional groups into medicinal and agrochemical research programmes provides enhanced coverage of both chemical and intellectual property space. In this regard, sulfoximines and sulfonimidamides, the mono-aza analogues of sulfones and sulfonamides respectively are receiving considerable attention as bioisosteres in drug design. However, restrictive synthetic methods have, in part, limited the utility of these motifs in the life sciences. Here, we report the development of a new strategy for the direct synthesis of NH-sulfonimidamides from sulfenamides as stable and previously unexplored substrates. This sequence enables access to sulfonimidamide scaffolds in just two straightforward steps from commercially available starting materials (A). A highly selective one-pot NH and O transfer is achieved using a hypervalent iodine reagent, iodosobenzene, as an oxidant, along with ammonium carbamate as an easy-to-handle source of ammonia. These conditions are mild and selective and allow for a broad variety of sulfonimidamides to be synthesised, including late stage functionalisation reactions on amine containing drugs desipramine and fluoxetine (B). The method was used in the synthesis of an aza-analogue of the sulfonamide drug probenecid, demonstrating the utility of the methodology for medicinal chemistry (C). Detailed mechanistic studies have been carried out and in the absence of added acid, an unprecedented alkoxy-amino-l6-sulfanenitrile is isolated as a reaction intermediate. These newly formed alkoxy-amino-l6-sulfanenitriles act as powerful alkylating agents to a range of acidic nucleophiles (D).

Synthesis of sulfonimidamides from sulfenamides via an unprecedented alkoxy-amino-l6-sulfanenitrile intermediate

ACS Fall 2020 Virtual Meeting

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