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

PdCl 2 (PPh 3 ) 2 , in combination with HCl, is highly active in the alkoxycarbonylation of α,β-ketocycloolefins to 3-oxocycloalkanecarboxylic acid esters. The reaction is region specific. The catalytic system is stabilized by addition of PPh 3 , which depresses the activity but prevents decomposition to inactive palladium metal. Typical reaction conditions are: Pd/P/cyclohexenone/HCl=1/2–4/200–600/50–100; [Pd] = 0.1−1·10 −2 mol l −1 ; P CO = 100 atm; temperature 100°C; solvent dioxane, THF, or benzene. With 2-cyclohexen- 1 -one the effect of the following variables on the yield has been examined: temperature, pressure of carbon monoxide, concentration 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, concentration of catalyst at constant Pd P ratio, and temperature. The yield passes through a maximum when increasing the concentration of HCl and EtOH, after which the yield decreases because the catalyst decomposes 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 bulkyness 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. (i) The starting Pd II precursor is reduced to a Pd 0 complex which gives oxidative addition of HCl with formation of a Pd-hydride species; (ii) cyclohexenone inserts into a PdH bond giving a β-ketocyclohexyl-Pd intermediate; (iii) this inserts CO with formation of the corresponding carbonyl derivative; (iv) alcoholysis of this intermediate yields the final product with regeneration of the hydride. The reaction is region specific because of the keto group which directs the anti-Markownikoff addition of PdH to the conjugated CC double bond.