Synthesis of -ketocycloalkanecarboxylic acid esters by regiospecific alkoxy carbonylation of ,-ketocycloolefinscatalyzed by palladium

PdCl2(PPh3)2, in combination with HCl, is highly active in the alkoxycarbonylation of ,-ketocycloolefins to 3- oxocycloalkanecarboxylic acid esters. The reaction is regiospecific. The catalytic system is stabilized by addn. of PPh3, which depresses the activity but prevents decompn. to inactive palladium metal. Typical reaction conditions were: Pd/P/cyclohexenone/HCl = 1/2-4/200-600/50-100; [Pd] = 0.1-1•10-2 mol l-1; PCO = 100 atm; temp. 100°C; solvent dioxane, THF, or benzene. With 2-cyclohexen-1-one the effect of the following variables on the yield was examd.: temp., pressure of carbon monoxide, concn. of cyclohexenone, ethanol, catalyst, Pd/P ratio, cyclohexenone/HCl ratio, reaction time, and solvent. As expected the yield increases with increasing reaction time, pressure of carbon monoxide, concn. of catalyst at const. Pd/P ratio, and temp. The yield passes through a max. when increasing the concn. of HCl and EtOH, after which the yield decreases because the catalyst decomps. to palladium metal. The yield is almost insensitive to the polarity of solvents such as dioxane, THF, or benzene, but it rather depends on the bulkiness of the alkanol as the reaction rate decreases in the order: MeOH>EtOH>n-PrOH>n-BuOH>s-PrOH. The proposed reaction mechanism proceeds through the following steps: the starting PdII precursor is reduced to a Pd0 complex which gives oxidative addn. of HCl with formation of a Pd-hydride species; cyclohexenone inserts into a Pd-H bond giving a -ketocyclohexyl- Pd intermediate; this inserts CO with formation of the corresponding carbonyl deriv.; alcoholysis of this intermediate yields the final product with regeneration of the hydride. The reaction is regiospecific because of the keto group which directs the anti-Markownikoff addn. of Pd-H to the conjugated C:C double bond.