Straightforward Access to Polyfunctionalized δ-Lactams via Domino Aza–Michael/Thia–Michael/Aldol Sequence

Domino reactions are powerful tools for the straightforward synthesis of complex molecules with a particular emphasis on functionalized azacycles. We report a contribution in this field, implemented via a new thia-Michael/aldol sequence between readily accessible <i>N</i>-alkoxyacrylamides and α,β-unsaturated carbonyls, for access to polysubstituted δ-lactams with acceptable-to-good yields and good selectivity. This method, initially developed in a two-component approach and characterized by the mildness of its reaction conditions, was shown to be compatible with various thiophenol derivatives and to employ a simple pre-thiasilylation step in a one-pot process. This further extension to the monotype aza-Michael/thia-Michael/aldol sequence establishes a proof-of-concept that acrylamides can react as both 1,3-bis-nucleophiles and 1,4-electrophiles in a single flask operation.