Palladium-Catalyzed Suzuki-Miyaura Coupling Promoted By Mechanochemistry

Mechanochemistry is a solid-state grinding method promoted by mechanical energy,which is widely used in the field of biology,materials,pharmaceuticals,and other fields due to its advantages of solvent-free method or only a small amount of solvent,short reaction time and high efficiency.However,the traditional Suzuki-Miyaura coupling usually has the disadvantages of long reaction time,oxygen-free conditions and organic solvents.Therefore,it is of great significance to apply mechanochemistry to the transition metal-catalyzed SuzukiMiyaura coupling reaction.The main research contents of this paper are as follows:(1)The Pd-catalyzed Suzuki-Miyaura coupling via selective cleavage of CN bond under mechanochemistry was studied.Using 1-benzoylpiperidine-2,6dione and phenylboronic acid as model substrates,the optimal reaction conditions were selected and a series of ketone compounds were synthesized under the optimal conditions in a short time and high selectivity.Intermolecular competition experiments revealed that electron-deficient amides are significantly more reactive and electron-rich boronic acids are inherently more reactive,these results are consistent with oxidative addition of the N-C(O)bond to palladium and transmetallation as relevant steps in the reaction,respectively.The drug components Febuxotam and Probenecid were also successfully modified in the later stage,and the drug 17b-HSD2 for the treatment of osteoporosis was synthesized by two-step mechanochemistry,these studies demonstrate that N-C solid-state,mechanochemical cross-coupling may find broad utility in medicinal chemistry research.The reaction is the first mechanochemical solid-state crosscoupling of amides by N-C(O)bond activation.(2)The Pd-catalyzed Suzuki-Miyaura coupling via carbon-halide bond cleavage under mechanochemistry was studied.Using benzoyl chloride and phenylboronic acid as the model substrates,the mechanochemical reaction conditions were discussed,and a series of ketone compounds with good substrate compatibility were synthesized.Intermolecular competition experiments revealed that electron-deficient chlorides are significantly more reactive and electron-rich boronic acids are inherently more reactive,these results are consistent with the Pd(0)/(Ⅱ)catalytic cycle for acyl Suzuki-Miyaura cross-coupling.Two potent antitubulin agents were synthesized by the direct coupling of acyl chlorides and boronic acids,this solid-state method provides access to synthetically useful synthons.This method also features the application for ball milling at high temperature that can be applied in challenging cases,it is proved that heating operation is an effective and direct method to improve the reaction activity in solid coupling reaction.This method provides a novel strategy for C(acyl)-Cl bond cleavage.