Regio- and Stereoselective Catalytic Addition of Amides to Alkynes: Synthesis of the Enamide Substructure in the Most Atom-economic and Environmentally Friendly Way

The enamide moiety is an important substructure often encountered in biologically active compounds and synthetic drugs. Furthermore, enamides and their derivatives are versatile synthetic intermediates for polymerization, [4+2] cycloaddition, crosscoupling, Heck-olefinination, Halogenation, enantioselective addition or asymmetric hydrogenation. Traditional syntheses of this important substrate class involve rather harsh reaction conditions such as high temperatures and/or the use of strong bases. Based on previous work on the addition of secondary amides to alkynes, a new broadly applicable protocol for the catalytic addition of N-nucleophiles such as primary amides, imides and thioamides to terminal alkynes was developed. The choice of ligands and additives determines the regiochemical outcome so that with two complementary catalyst systems, both the E-anti-Markovnikov products and the Z-anti-Markovnikov products can be synthesized highly regio- and stereoselectively.