Carbene Bridging C-H Activation:Isocoumarin Synthesis Through Palladium-catalyzed Reaction Of 2-Pseudohalobenzaldehydes With Aryl Diazoesters

Isocoumarin and its derivatives bearing six-membered lactone core structures are ubiquitous in nature.They are valuable compounds with the potential in the areas ranging from pharmaceutical to agriculture.Therefore,the development of efficient and selective method for the synthesis of isocoumarin derivatives would be valuable and in high demand.In the past decades,many methods have been developed for the synthesis of isocoumarin derivatives.Among them,approaches involving transition metal catalyzed C-H activation have received considerable attentions due to the high atom and step economies,which have the potential by using simple feedstock chemicals as starting materials.Transition metal-catalyzed reaction of benzoic acids and alkynes is a prominent example.Nevertheless,to achieve high regioselectivity is very challenging,especially when unsymmetric alkynes are employed.In this work,we have conceived a strategy on palladium-catalyzed carbene bridging C-H activation.A new method for isocoumarin synthesis is described.Mechanistically,the reaction of low valent palladium catalyst with2-pseudohalobenzaldehyde would generate a palladium(II)intermediate,which could further react with a proper diazo compound to generate a palladium carbene.Migratory insertion of the palladium carbene intermediate could deliver the palladium catalyst center to the reacting cite,hence promoting the C-H bond palladation of the aldehyde moiety.In this reaction,aryl diazoesters were acting as modular three-atom-units to construct the seven-membered palladacycles.Reductiveelimination would generate the final isocoumarin products.The salient features of this reaction are the mild conditions,easily accessible reactants,broad substrate scope with good functional group tolerance and complete regioselectivity.Moreover,the current method is applicable for late-modification of several natural products.We believe that a number of new reactions following the designed principle of this new concept on carbene bridging C-H activation will be discovered in the future.