Synthesis of non-equivalent diamides and amido-esters via Pd-catalysed carbonylation

Abstract Given the widespread use of amides in chemistry and biology, the development of methods for their synthesis remains important. Although the construction of amide bonds has in principle been known since Wöhler’s urea synthesis, the direct and atom-efficient preparation of amides, especially with multiple amido groups, continues to be difficult. To address this challenge, we developed an efficient access to heterobifunctional compounds through linking amines as well as alcohols with specific molecular pincers in the presence of advanced carbonylation catalysts. In detail, we describe the synthesis of non-symmetrical diamides and amido-esters from available propargylic acetates using selective palladium-catalysed diamino- and amino-alkoxy carbonylations. Mechanistic studies and control experiments reveal a cascade process with allenoic amides, allylic amine and dienamide as crucial intermediates. The generality of this protocol is showcased by the highly selective synthesis of >100 heterobifunctional molecules including many pharmaceutically relevant products.