Regiospecific Sp~2 C-H Methylation Of Naphthalene And Its Application In The Total Synthesis Of Natural Methylated Naphthalenes Compounds

The natural compounds containing naphthalene core include many active components of Traditional Chinese medicine with a wide range of pharmacological activities.At present,most of them are prepared through separation and extraction from plants,and few by chemical synthesis.Therefore,it is of great importance to develop efficient methods for these compounds,especially those with low plant content and certain pharmacological activity.C-H activation can selectively activate inert C-H bond and realize further functionalizations.Moreover,the advantages of atomic economy and step economy presented by the strategy are consistent with the concept of green chemistry,which provides a new idea for the total synthesis of effective components of Traditional Chinese medicine.Thus,a novel,highly regioselective C-H methylation of naphthalene has been developed,and this protocol can serve as a platform for the synthesis of natural methylated naphthalene compounds represented by methylated furanoeremophilones,and musizin:The first part is the peri-selective C-H methylation of 1-naphthaldehyde by transient ligand strategy.The C8-H selective methylation of 1-naphthaldehyde has been realized by using palladium acetate as the catalyst,glycine as the transient ligand,copper trifluoroacetate hydrate as the oxidant and potassium methyl trifluoroborate as the methylation reagent.This operationally simple and mild protocol displays a broad substrate scope and a broad spectrum of functional group tolerance,and provides an efficient method for the construction of 1,8-disubstituted naphthalenes.The mechanistic studies rationalize that the peri-methylation is controlled by the higher electronic density of peri-position of 1-naphthaldehyde as well as the formation of intermediary 5,6-fused bicyclic palladacycles.In addition,site-exchange substitutes of naphthalenes can also been achieved in symmetric environment,which enrich the structural diversity of naphthalenes.The second part is the transient ligand assisted ortho-selective C-H methylation of 1naphthaldehyde.The C2-H selective methylation of 1-naphthaldehyde has been implemented with pentamethylcyclopentadienyl iridium dichloride dimer as the catalyst,potassium methyl trifluoroborate as the methylation reagent,silver acetate as the oxidant,and meta-substituted electron deficient aniline as the transient ligand.This operationally simple,mild and fast protocol shows a broad substrate scope and good functional group tolerance.Experimental studies and theoretical calculations corroborate that a 5-membered iridacycle formed at the ortho-position of 1-naphthaldehyde leads to energetically favorable ortho-methylation via an interconversion between peri-iridacycle and ortho-iridacycle.To demonstrate the synthetic utility of this method,sequential C-H activation and the synthesis of vitamin K intermediate have been performed.In the third part,the total synthesis of some methylated furanoeremophilones and musizin have been achieved with the assistance of regioselective methylation.Three natural products,methylated furanoeremophilones(FE-7 and FE-17)and musizin,are obtained from the cheap and commercially available starting materials,1-bromo-2-naphthol and 1,8-dinaphthol respectively.The solution to FE-7 saves 6 steps and improves the total yield 4.5-fold compared with the previously reported route.In addition,FE-17 is synthesized for the first time.In contrast to the previous route of musizin,the process is shortened by 2 steps and the overall yields are comparative.The success of methylated furanoeremophilones and musizin indicate that regioselective methylation method has great potential and value in the total synthesis of natural methylated naphthalenes,and provides a variety of their derivatives for the study of the structureactivity relationship.