Development And Application Of Copper Catalyzed Oxidation Of N-Heterocyclic Compounds

This dissertation is mainly focused on oxidation reactions catalyzed by CuBr2 for the syntheis of nitrogenous heterocyclic compounds such as isoquinolines,?-carbolines,3,4-dihydroisoquinolines,3,4-dihydro-?-carbolines and 1,3,5-substituted pyrazoles.Furthermore,total syntheses of several alkaloids by applying the above method have also been performed.This thesis contains five parts as described below:Part one:Copper-catalyzed aromatizations of tetrahydroisoquinolines and tetrahydro-(3-carbolines:1,2,3,4-Tetrahydroisoquimolines were converted into corresponding isoquinolines in 71-96%yields via copper-catalyzed aerobic oxidative aromatization with DBU or EtONa as the base in DMSO at room temperature.1,2,3,4-Tetrahydro-?-carbolines were converted into corresponding ?-carbolines in 66-95%yields via copper-catalyzed aerobic oxidative aromatization with DBU as the base in DMSO at room temperature.Some advantages such as good tolerance of functional groups,use of cheap and low toxic copper salt as catalyst,and use of O2(air)as a clean oxidant would make the method very useful.Part two:Copper-catalyzed oxidation of tetrahydroisoquinolines and tetrahydro-?-carbolines for the syntheses of dihydroisoquinolines and dihydro-?-carbolines:Tetrahydroisoquinolines were converted into corresponding 3,4-dihydroisoquinolines in 73-93%yields via copper-catalyzed aerobic oxidation in DMSO at room temperature.Tetrahydro-?-carbolines were also converted into corresponding 3,4-dihydro-?-carbolimes in 72-91%yields via copper-catalyzed aerobic oxidation in DMF/EtOAc at room temperature.In comparison with the classic Bischler-Napieralski reaction,this method has some advantages such as use of cheap and low toxic copper salt as catalyst,and use of O2(air)as a clean oxidant.This method provides a general and efficient approach to 3,4_dihydroisoquinolines and 3,4-dihydro-?-carbolines.Part three:Base-promoted aromatization of 3,4-dihydroisoquinolines:3,4-dihydro-isoquinolines with electron-withdrawing substitutents were converted into corresponding isoquinolines in 79-93%yields with DBU as the base in DMSO at room temperature.In contrast,3,4-dihydroisoquinolines without electron-withdrawing substitutents were converted into corresponding isoquinolines in 84-97%yields with EtONa as the base in DMSO at room temperature.Some advantages such as mild reaction conditions,good to high yields,easy preparation of 3,4-dihydroisoquinolines and simple manipulation would make this method very useful.Part four:Copper-catalyzed oxidation of 1,3,5-trisubstituted pyrazolines to synthesize 1,3,5-trisubstituted pyrazoles:1,3,5-Trisubstituted pyrazolines were converted into coreesponding pyrazoles in 75-89%yields via copper-catalyzed aerobic oxidative aromatization in DMSO.In comparison with other oxidation methods,this method has some advantages such as use of low toxic and readily available CuBr2 as a catalyst,air as a clean oxidant.This method would provide an efficient and practical approach to 1,3,5-trisubstituted pyrazoles.Part five:The syntheses of several bioactive alkaloids:To showcase the synthetic utility Of above-described copper-catalyzed aromatization,we applied the protocol to concise total syntheses of some ?-carboline and isoquinoline alkaloids.Two ?-carboline alkaloids Perlolyrin and Flazin were thus synthesized by 3 or 4 steps from tryptamine or tryptophan methyl ester in 59%and 56%overall yields.The isoquinoline alkaloid O-methylmoschatoline was synthesized for the first time from 2,3,4-trimethoxyphenylethylamine by 5 steps in 49%overall yield.