Hydrogen-Bond-Directed Highly Stereoselective Synthesis of Z-Enamides via Pd-Catalyzed Oxidative Amidation of Conjugated Olefins

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 σ-alkylamidopalladium intermediates, leading to Z- and
E-isomeric enamide products, respectively, was calculated to be 4.18 kcal/mol. The β-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.