Ruthenium Catalyzed Aromatic C-H Methylation With Methyl Ester

Since the " magic methyl effect " was proposed to the present,installing methyl groups into molecules has been increasingly concerned by synthetic chemists and drug developers,which has become a hot topic.In particular,the installation of methyl groups into aromatic rings is widely used in new drug development and drug modification.Among various methylation methods,C-H bond methylation is the simplest and most efficient strategy.Although important progress has been made in metal-catalyzed carbon-hydrogen bond methylation reactions,these methods usually use highly reactive and highly toxic methyl iodide and highly hazardous peroxides,or expensive methyl metal reagents,which are greatly limited wide application of these methods.Therefore,developing a cheap,green and economical methylation reagent is still a difficult problem to be solved in this field.In this paper,the selective methylation of benzene,naphthalene and heterocycles was achieved by ruthenium-catalyzed C-H bond and C-O bond cross-coupling strategy using cheap and readily available alkyl carboxylate methyl esters as methylation reagents.1.Ruthenium-Catalyzed C-H Methylation of Biaryls with Methyl Acetate as Methylating ReagentWe first report methyl acetate as a novel methylation reagent,through ruthenium catalysed C-O bond activition to achieve the ortho-C-H methylation of biaryl phosphines,modified a series of phosphine ligands with methyl group.Methyl acetate and mesitylene were used as co-solvents to promote the reaction nicely.Our strategy shortens the synthesis steps of commercialized Me Ph-Phos and reduces its synthesis cost;And by adjusting the reaction temperature and the amount of catalyst,the chemical selectivity of the reaction is controlled,and the controllable synthesis of mono-and bis-methylated products is realized.This method has important application prospects in the design and synthesis of phosphine ligands.2.Ruthenium-catalyzed C-H methylation of fused-ring aromatic hydrocarbons with methyl acetate as methylating reagentWe extended the ruthenium-catalyzed cross-coupling strategy of C-H bonds and C-O bonds to polycyclic aromatic compounds,and accomplished the selective methylation of naphthalene rings and aromatic heterocycles.Synthesis of a series of ipso-methyl-substituted naphthalene ring compounds in which substrates with biologically active molecules such as menthol and cholesterol were also methylated with high efficiency under our conditions,which makes our method promising for application In the fields of new drug synthesis and modification.3.Methyl palmitate as methylating reagent of aromatic C-H methylationOn the basis of previous work,we further realized the synthesis of ruthenium-catalyzed CH bond methylation of aromatic rings with low equivalent of methyl palmitate as the methylating reagent,with high selectivity(mono/di > 20:1).Series of monomethyl substituted biarylphosphine ligands.The method reduces the amount of methylation reagent from 90 equiv.to 5 equiv.further reduces the cost of the reaction,has extremely high greenness and economy,and has a good industrial application prospect.