AbstractA highly efficient, robust and scalable protocol for the synthesis of multifunctional ketones through Fukuyama coupling, i.e., cross‐coupling of thiol esters with zinc reagents, has been developed. Treatment of thiol esters with alkylzinc iodides or dialkyl zincs in the presence of palladium on activated carbon (Pd/C) or palladium acetate [Pd(OAc)2] furnished the corresponding ketones in high yields. Evaluation of the properties‐activities relationship of the Pd/C‐catalyzed reaction has proven that oxidic Pd/C is much more potent than reduced Pd/C in the reaction of thiolactone 1a with zinc reagent 2a. Based on the dependence of the Pd/C‐catalyzed reaction on the nature of Pd/C in combination with the extent of the Pd leaching from Pd/C to the solution, a dual reaction mechanism for the Pd/C‐catalyzed Fukuyama coupling reaction, which includes heterogeneous and homogeneous catalytic cycles, was proposed. The marked reduction of the zinc reagents and the use of Pd(OAc)2 in much smaller amounts were achieved when zinc bromide was added. This supports a hypothesis where a shift of the Schlenk equilibrium from inactive dialkylzincs (R2Zn) to active organozinc species, such as alkylzinc halides (RZnX) and three‐coordinate species [(RZnX2)−⋅ (ZnX)+], and generation of the stabilized monomeric Pd complexes during the reaction, may facilitate the reaction.