N-α-Functionalization Of Tetrahydroisoquinoline Bioactive Molecular Skeleton

Among a large number of clinical drugs,nitrogen-containing heterocycles are the core skeleton of many drugs,in which tetrahydroisoquinoline derivatives are relatively general nitrogen-containing heterocyclic compounds with rich species and wide distribution and pharmacological activities.Tetrahydroisoquinoline is extracted from animals and plants and hase good pharmacological activity,however,when applied to the treatment of some diseases,its applications are limited and also suffered from the biological toxicity.With the development of methodology and biology,it has shown that after structural modifications,the tetrahydroisoquinoline skeleton can exhibit antihypertensive,anti-tumor,anti patkinson,anticonvulsant,anticoagulant,insecticidal and other activities in pharmaceutics.Therefore,the design and synthesis of functionalized tetrahydroisoquinoline derivatives and developing more efficient synthetic routes have been the focus of chemists’ research.Based on three parts of study,a series of efficient synthesis of functionalized tetrahydroisoquinoline derivatives was developed,which enriches the method library for the subsequent synthesis of related drugs.The details are as follows:1.Using antimony trichloride as an oxidant,an oxidative dehydrogenation coupling between tetrahydroisoquinoline and diethyl phosphite(DEP)was realized under aerobic reaction conditions,introducing the phosphorous ester groups into the N-α-position of tetrahydroisoquinolines.2.Using CBr4 as a HB donor as well as a tribromomethylation reagent,HB-triggered anα-functionalization of THIQ phosphorous esters was achieve under mild reaction conditions,providing a series of α-tribromomethyltetrahydroisoquinoline derivatives in good yields.Through a one-pot mode,the reaction can be further extended to the construction of dibenzopyrroline alkaloid framework.3.On the basis of C-H bond activation relay strategy,a series of 4-chloro and 4-iodo isoquinolone derivatives were successfully synthesized under the optimized reaction conditions.Through the classical cross coupling reactions,the functionalization of isoquinolone derivatives was smoothly realized.In future research,we will attempt to introduce a fluorine atom and CN into the 4-position of isoquinolone.