Palladium-Catalyzed Synthesis Of Substituted Quinoline/Isoquinoline Derivatives And Mechanism Study

With the development of the society,the amounts of chemical products increasing rapidly,the traditional chemical industry has given human survival ecological environment serious pollution and destruction.Protecting the environment,strengthen the pollution control has become a major event for the entire world.In order to effectively control the chemical pollution,the development of new efficient,low toxicity,environmental-friendly drugs,optimize the production process route is an effective method.Quinoline/isoquinoline compounds were widely used as drugs because of their significant biological activity.The traditional method for the synthesis of quinoline/isoquinoline compound has been raised from several decades of history,there are still many ways less efficient,more pollution and other issues,have been far from meeting the requirements of today,the development of new synthetic methods are imperative.The cyclization of alkynes containing proximate nucleophilic centers promoted by organopalladium complexes is a most effective strategy for heterocyclic ring construction.This chemistry provides a straightforward approach to the synthesis of functionalized carbo-and heterocycles through the regio-and stereoselective addition of a nucleophile and an unsaturated carbon unit across the carbon-carbon triple bond.The biggest advantages of this approach is to streamline the steps of synthesis of quinoline compounds,not only can improve the atom economy,also to improve the overall efficiency of the continuous multi-step synthesis.In this context,we have systematically studied the palladium-catalyzed aryl azide compounds,benzyl azides,2-alkynylbenzaldoximes compounds to react accordingly quinoline/isoquinoline compounds,and also to investigate the feasibility for the synthesis of multi-substituted quinolines via palladium-catalyzed aryl azide compounds and organic halides.The details are summarized as following:（1）Palladium-catalyzed synthesis of allylated quinolines from aryl azides.Allylation reactions are an important class of organic reactions,and the synthesis of allylated quinolines become a research hotspot because of the special biological activity.Herein we developed a new one-pot method for the synthesis of allylated quinolines,this reaction proceeds smoothly with 10 mmol%Pd（PPh₃）₄ and 5 eq K₃PO₄ in DMF at 100 ^oC and provides moderate yield.The results showed that3,4-diallylquinolines or 3-allylquinolines can be obtained by adjusting the allylsubstituent on the methylene position.Based on the mechaism,the most important point of the present Pd methodology,compared to the previous Au⁺and I⁺methods,is perhaps that the Pd-catalyzed azide-alkyne cyclization is able to incorporate another organic ligand of Pd,which is allyl in present,into quinoline framework.（2）Palladium-catalyzed synthesis of allylated isoquinolines from benzyl azides.Generally,the traditional methods always use higher temperature,longer reaction times to achieve good yields.Herein we developed a new one-pot method for the synthesis of 4-allylisoquinolines and 1,4-diallylisoquinolines,this reaction proceeds smoothly with 5 mmol%Pd（PPh₃）₄ and 5 eq K₃PO₄ in DMF at 100 ^oC and provides high yield.The substituted groups on the benzyl play an important role for the formation of 4-allylisoquinolines or 1,4-diallylisoquinolines.In this study,the presence of azides group with strong electron-withdrawing effect plays a decisive role for the reaction.（3）Palladium-catalyzed synthesis of 3,4-dihyrisoquinoline N-oxides from2-alkynylbenzaldoximes.Isoquinoline N-oxides are an important class of compounds because of their wide utility.Developments of new methods for the synthesis of isoquinoline N-oxide are still have important significance.Herein we developed a new method for the synthesis of 3,4-dihyrisoquinoline N-oxides,this reaction proceeds smoothly with 10 mmol%Pd（PPh₃）₄ and 40 mmol%PhCOOH at 100 ^oC and provides high yield.The reaction can proceed by using different substrates under optimized reaction conditions.From our study,the palladium/acid catalyst systems can effectively promote the reaction.We also studied the mechanism of the reaction,and the role of the benzoic acid in the reaction was also discussed.（4）Palladium-catalyzed synthesis of multi-substituted quinolines from aryl azides and organic halides.Development of an efficient,utility method for the synthesis of multi-substituted quinolines has been a hot topic in heterocyclic chemistry.Herein we reported a new method for the synthesis of multi-substituted quinolines.The reaction conditions were optimized,and the optimized conditions are 20 mmol%Pd（PPh₃）₄and 5 eq NaHCO₃ in DMF at 100 ^oC and the yield is 25%.The mechanism of the reaction was also discussed.The reactions with various substrates are in progress.