Hydrogen-bond-directed highly stereoselective synthesis of Z-enamides via Pd-catalyzed oxidative amidation of conjugated olefins.J Am Chem Soc. 2006 Oct 04; 128(39):12954-62.JA
An efficient procedure for the preparation of Z-enamides has been developed, involving the reaction of primary amides with conjugated olefins using a Pd/Cu cocatalyst system. It was found that certain additives, such as phosphine oxides and phosphonates, increase the efficiency of the reaction in nonpolar solvents under an oxygen atmosphere, thus producing a variety of Z-enamides in high yields with excellent stereoselectivity under Wacker-type conditions. The oxidative amidation reaction has a broad substrate scope, allowing alkyl, aryl, and vinyl amides to react with olefins conjugated with ester, amide, phosphonate, and ketone groups. The notable preference for the formation of Z-enamides is presumably due to the presence of an intramolecular hydrogen bond between the amido proton and the carbonyl oxygen. The energy difference between two plausible sigma-alkylamidopalladium intermediates, leading to Z- and E-isomeric enamide products, respectively, was calculated to be 4.18 kcal/mol. The beta-hydride elimination step is assumed to be a stereochemistry-determining step in the overall oxidative amidation process, with the energy level for the transition state leading to the Z-enamide being 5.35 kcal/mol lower than that leading to the E-isomer. The efficiency of photoisomerization between Z- and E-enamides was observed to be largely dependent on the substrates' substituents, and certain E-enamides could be obtained in synthetically useful yields by photoirradiation of Z-isomers. Synthetic application of the present method was successfully demonstrated by a direct formal synthesis of cis-CJ-15,801.