Arylthianthrenium Salt-Based Synthesis Of Pyrrolidine And Tetrahydrofuran Derivatives

Pyrrolidine and tetrahydrofuran as important drug intermediates are ubiquitous in drugs and there are many existing methods for synthesizing these two heterocyclic derivatives,but these methods possess apparent shortcomings such as harsh conditions and difficult application in the late-stage functionalizaiton of drug molecules.In this thesis,starting from aryl thianthrenium salts,2-arylmethylenepyrrolidine and tetrahydrofuran derivatives were synthesized after reaction condition optimization.At same time,the optically pure compounds were synthesized by using chiral ligands.This thesis is mainly divided into three parts:1.Synthesis of pyrrolidine derivatives from aryl thianthrenium salts.First,30 different aryl thianthrenium salts were synthesized using trifluoromethanesulfonic anhydride or tetrafluoroborate ethyl ether complex and trifluoroacetic anhydride as Lewis acid,and acetonitrile as the solvent.Then,the cyclization reaction conditions of 1-toluenesulfondoline thianthrenium trifluoromethanesulfonate with Ts and Boc protected 4-pentene-1-amino groups were explored and screened,and the optimal conditions for the reaction were obtained as:Allyl palladium chloride dimer as the palladium source,CPhos as the ligand,lithium tert-butoxide as base,trifluorotoluene as the solvent,reacting under room temperature for 12 hours.Then,the substrates of mono-substituted or multi-substituted aryl thianthrenium salts,aryl thianthrenium salts of complex molecules and drug molecules were expanded.A total of 33 substrates were synthesized with a separation yield of 39%-96%,and the structure was identified by NMR,HRMS,IR and other methods.Completed the amplification reaction.Through deuterium substitution experiments,it was determined that this reaction was carried out through the syn mechanism,and an asymmetric reaction was achieved using chiral SadPhos phosphine ligands.2.Synthesis of tetrahydrofuran derivatives from aryl thianthracene salts.First,the cyclization reaction conditions of tolylthianthrenium trifluoromethanesulfonate and 4-penten1-ol were explored and screened,and the optimal reaction conditions were obtained:allylpalladium chloride as palladium source,CPhos as the ligand,lithium tert-butoxide as the base,trifluorotoluene as the solvent,and the reaction is carried out at room temperature or 50℃.The total 26 products were synthesized with the yield ranging from 32%to 79%.The structures were identified by NMR,HRMS,IR and other methods,and the asymmetric synthesis was explored.Through deuterium substitution experiments,it was determined that this reaction was carried out through both syn and syn mechanisms simultaneously,and asymmetric reactions were also achieved using chiral SadPhos phosphine ligands.3.Synthesis of pyrrolidine and tetrahydrofuran rings from allyl azide mixture.This chapter is dedicated to discovering a synthetic method of 3-azido-2-arylidenetetrahydropyrrole and tetrahydrofuran derivatives by means of the rearrangement reaction of allyl azide and the reaction rate difference of different alkene isomers of allylic azides in the palladium-catalyzed cyclization reaction.First,two types of allyl azide mixtures were synthesized.By screening different gold catalysts(ligands and anions),reaction solvents,ratios between reactants,reaction temperatures,different types of aryl raw materials,finally the target product can be obtained with 33%separation yield and 3:1 dr under the conditions of gold as the catalyst,phenylboronic acid as the aryl source,and Selectfluor as the oxidant.The reaction conditions need to be further optimized.