Lithation Substitution Of N-methyltetrahydroisoquinoline And Negishi-type Arylation Reaction

Tetrahydroisoquinolines are a class of alkaloids widely distributed in nature.For their multiple physiological activities,the synthesis and structural derivatization of tetrahydroisoquinoline compounds have attracted much attention.The organolithium compounds have strong nucleophilicity and basicity.Meanwhile,compared with other organometallic compounds,organolithium species possess higher reacitivity.Therefore organolithiums can be wildly used in the construction of carbon-carbon bonds,carbon-heteroatom bonds.Besides,organolithiums can also be transmetallated to organozinc or organotin compounds to initiate cross coupling reaction.As one of the classiscal cross coupling reactions,Negishi coupling reaction has the advantages of good selectivity,wide substrate range,high reaction efficiency,mild reaction conditions.On the other hand,the organozinc compound is easy to prepare and more reactive than organotin and organoboron respectively used in the Stille and Suzuki reactions.These characteristics have made the Negishi coupling reaction become essential tools for the synthesis of many important organic compounds.This study aimed to find new methods for the synthesis of 4-substituted N-methyltetrahydroisoquinolines by using organolithium chemistry.A variety of 4-substituted N-methyltetrahydroisoquinolines were obtained by regioselective deprotonation of N-methyltetrahydroisoquinoline with butyllithium at the C-4 position to form the corresponding organolithium intermediate;followed by direct electrophilic quenching;simlply transmetallation of corresponding orgnaolithium intermediate to organozinc reagenat,following by the Negishi type cross coupling reactions,a broad range of C-4 aryalted N-methyltetrahydroisoquinolines can be assessed.This thesis mainly includes the following contents.1.n-Butyllithium and s-butyllithium were screened as alkaline reagents to explore the lithiation-substitution reaction between substrate N-methyltetrahydroisoquinoline and electrophile n-bromobutane.The result showed that the C-4 lithiation can be achieved by simply protecting the tetrahydroisoquinoline with methyl group.Then the formed organolithium intermediate was quenched with electrophile n-bromobutane to successfully generate 4-butyl-N-methyltetrahydroisoquinoline.By further conditions optimization,it was found that better conidition is to use 1.2 equiv of s-BuLi as base to deprotonate N-methyltetrahydroisoquinoline at-50? for 30 min,followed by the addition of 1.2 equiv of n-bromobutane gave 88%yield of 4-butyl-N-methyltetrahydro-isoquinoline.The reaction scope was expanded under the optimized conditions,it was found that the reaction could be adapted to various substrates and electrophiles with moderate to good yield by using different electrophiles(43-88%).2.Based on the optimized lithiation conditions of N-methyltetrahydroisoquinoline,the transmetalation of the formed organolithium intermediate with ZnCl2 gave an organozinc intermediate,followed by a Negishi type cross coupling reaction with bromobenzene were investigated in order to find a new synthetic method of 4-aryl-N-methyltetrahydroisoquinoline derivatives.After optimization of the transmetalation and coupling reaction conditions,the 4-lithium-N-methyltetrahydro-isoquinoline intermediate was exchanged with 2.4 equiv of anhydrous ZnCl2 at-50?for 30 min and then the mixture was treated with 2 equiv of bromobenzene in the presence of Pd2(dba)3 and phosphine ligand X-Phos at room temperature for 5 hours to yield 4-phenyl-N-methyltetrahydroisoquinoline in 50%.Therefore,10 racemic 4-aryl-N-methyltetrahydroisoquinolines were synthesized in a yield of 28?50%through the expansion of reaction substrate and aryl halide.The results indicated that the corresponding target products could be obtained from various aryl halides with both the electron-donating and electron-withdrawing group by the method.3.On the basis of the preparation of racemic 4-aryl-N-methyltetrahydro-isoquinolines,the Negishi cross-coupling reaction after transmetalation was also investigated in the presence of chiral ligands to explore an asymmetric synthesis method of chiral 4-aryl-N-methyl tetrahydroisoquinolines.Further study is under investigation.