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Reaction of 5,5-dimethyl-8-nonene-2,4-dione catalyzed by PdCl2(CH3CN)2 (5 mol %) in the presence of CuCl2 (2.5 equiv) at room temperature for 3 h formed 2-acetyl-3,6,6-trimethyl-2-cyclohexenone in 96% isolated yield. Palladium-catalyzed intramolecular oxidative alkylation tolerated a range of substitution and was applicable to the synthesis of spirobicyclic compounds and to the cyclization of zeta-alkenyl beta-keto esters.

The development of a practical, asymmetric synthesis of the hepatitis C virus (HCV) protease inhibitor MK-5172 (1), an 18-membered macrocycle, is described.

Reaction of 7-octene-2,4-dione (3) with a catalytic amount of PdCl2(CH3CN)2 (4) (10 mol %) in dioxane at room temperature for 16 h formed 2-acetylcyclohexanone (5) in 81% yield as a single regioisomer. Byproducts in the conversion of 3 to 5 include 2,4-octanedione (13), 2-acetyl-2-cyclohexenone (14), 2-acetylphenol (15), (E)- and (Z)-6-octene-2,4-dione (17), (E)- and (Z)-5-octene-2,4-dione (18), the η3-β-diketonate chloride dimer {[η3-CH3CH2CH2CHCOHCHAc]Pd(Cl)}2 (12), and the π(allyl)palladium chloride dimer {[η3-CH3CHCHCHC(O)CH2Ac]Pd(Cl)}2 (16). The palladium-catalyzed cyclization of 3-butenyl β-diketones tolerated substitution at the terminal acyl carbon atom, the enolic carbon atom, and the terminal olefinic carbon atom. Deuterium-labeling studies, in conjunction with kinetic and in situ NMR experiments, supported a mechanism for the palladium-catalyzed hydroalkylation of 3-butenyl β-diketones initiated by 6-endo-trig attack of the enol carbon atom on a palladium-complexed olefin to form a palladium cyclohexanone species. Migration of the palladium atom from the C(4) to the C(6) carbon atom of the 2-acylcyclohexanone intermediate via iterative β-hydride elimination/addition followed by protonolysis of the resulting palladium C(6)-enolate complex released the cyclohexanone and regenerated the palladium dichloride catalyst.