Study On The Synthesis Of Ethyl 2-alkyl-2-arylcyanoacetate And Dauricine By Ullmann Coupling Reaction

The cross-coupling reaction catalyzed by copper has been firstly reported by Ullmann in 1901,which was the coupling reaction by formation of carbon-carbon bond between two aryl halides initially and was restricted to the synthesis of diphenyl.In 1903,there were reports about the formation of the aryl carbon-nitrogen bond and the aryl carbon-oxygen bond.In 1906,Goldberg reported the coupling reaction of the aryl carbon-acyl nitrogen bond.In 1929,Hurtley reported the coupling reaction between.the aryl carbon-carbon(active methylene).It is assumed that the cross-coupling reaction catalyzed by copper can be widely used in the formation of aryl carbon-carbon bond,arbon-acyl nitrogen bond,aryl carbon-oxygen bond,aryl carbon-sulfur bond,etc.All these cross-coupling reactions are typed as Ullmann reaction customarily.Ullman coupling reaction provided an important method in organic synthesis.Howerer,the backdraw of traditional Ullman coupling reaction,such as necessity of chemometry or excessive copper as catalyst,strong alkali and high reaction temperature,passivation to the electronic-donoring aryl halides,difficulty in the post-treatment,complex of the products and low yield,limited the popularization of this reaction.With the emergence of lots of new ligands,Ullmann cross-coupling reaction has a rapid development by introducing these new ligands to the catalytical copper.It has been widely reported that many effective ligands can promote the bond formation of carbon-nitrogen,carbon-oxygen,carbon-sulfur and carbon-carbon catalyzed by the copper.Therefore,some Ullmann cross-coupling reactions which were difficult to achieve come to the sights of researchers in the field of chemical synthesis.The progress on the study of the ligands in Ullman coupling reaction and the coupling reaction in aryl halides and active methylene compounds was sumarrized in this thesis.The coupling reaction of aryl halides and a-substituted cyanoacetates catalyzed by CuI/sodium picolinate was carried out at 60 ? in the presence of Cs2CO3 and 4A molecular sieve,affording 2-alkyl-2-arylcyanoacetates in good to excellent yields.The reaction has a wide scope,as demonstrated by that electron-rich aryl iodides,electronic-deficient aryl iodides and some functionalized a-substituted cyanoacetates were compatible with the reaction conditions.Intensive attention on the applicable value of the methodology in the synthesis of drugs and natural products has been received.Dauricine is an important bibenzyl tetrahydroisoquinoline alkaloid.The formation of aryl ether bond is the key step in the synthesis of dauricine.Refering to synthetic methods in the literatures,we efficiently constracted the aryl ether bond by using Ullmann cross-coupling reaction catalyzed by CuI and N,N-dimethyl glycine and got the phenyl acetic acid by Wilgerodt-Kindler reaction.The quinoline ring was synthesized by Bischler-Napieralski reaction with chiral auxiliary and the tandem reduction reaction with sodium borohydride.Finally,we accomplished the synthesis of dauricine in 12 steps of reaction with the total yield of 20%.In addition,we synthesized 30 dauricine derivatives.The in vitro antitumor activity of the 30 compounds were evaluated by MTT method,in which the A431(Human squamous cell carcinoma cell line)is used as the cell line,and the Tetrandrine serves as the positive control.14 compounds and dauricine exhibited potent anti-tumor activity.Among them,compound X-20,X-21 showed the best activity in potent anti-tumor activity.We make a preliminary study on the structure and antitumor activity relationship of the bibenzyl tetrahydroisoquinoline alkaloids.