The Preparation of Gamma- Arylated Ketones via Palladium-Catalyzed Cross-Coupling of Cyclopropanol - Derived Homoenolates with Benzyl Chlorides

The first palladium-catalyzed cross-coupling reaction of cyclopropanol-derived ketone homoenolates with benzyl halides, was developed to prepare a variety of γ-arylated ketones. One of the major challenges of this cross-coupling reaction was the competing cleavage of the cyclopropanol starting material to the ring-opened ketone under the reaction conditions. Through systematic optimization studies involving screens of base, ligands, solvents, temperature, Pd sources, conditions for the high yielding cross coupling of 1-phenethylcyclopropanol with 4-methyl benzyl chloride were found. With optimized conditions excellent yields were obtained for the cross-coupling of various electron rich and neutral benzyl chlorides. Moreover, these conditions were also used to successfully cross couple a variety of cyclopropanols to 4-methyl benzyl chloride. This reaction is also shown to work with a low catalyst loading of 1 mol % and in gram-scale without any reduction in yield.