Scope and Limitations in Palladium-Catalyzed Substitution Reactions of Unsaturated Fused Lactones

The palladium-catalyzed nucleophilic substitution of C-4-substituted 2-oxabicyclo[3.3.0]oct-7-en-3-ones (unsaturated, fused lactones) have been studied particularly in relation to how electronic and steric factors influenced the rate and efficiency of substitution reactions. Thus, a range of α-substituted lactones were prepared (X = H, Me, OH, OAc, Br, N3, NHCBZ) and subjected to palladium-catalyzed substitution reaction with diethyl sodiomalonate, and it was found that reaction rates increased with increasing electron-withdrawing ability of the substituent and that there was a strong correlation between rate and pK a of the corresponding substituted acetic acids (XCH2CO2H). The only exception to the correlation was with X = OH, in which case the endo isomer reacted considerably faster than expected and the exo isomer reacted much slower than expected. It was also found that the rates of reaction of the endo isomers were greater than the exo isomers. The increased rates have been accounted for by a shift in equilibrium between the lactone and the π-allyl palladium intermediate toward the latter species due to the increased stability of the carboxylate (electronic effects) or relief of steric hindrance in the starting lactone. The scope and limitations of the palladium-catalyzed substitution reaction were studied by reacting a range of lactones with a range of nucleophiles. Lactones with unactivated leaving groups such as 2 (X = H) coupled efficiently with good nucleophiles such as malonate but only poorly with less reactive nucleophiles such as azide. Lactones with activated leaving groups such as 4a (X = OH) coupled efficiently with a broad range of nucleophiles.