Study On The Synthesis Methods Of α-halogenated Imines And Indole Derivatives

α-haloimines are a class of organic compounds with halogen atoms at the alpha site at the position.They are important intermediates in the design of drug molecules,capable of introducing halogens and nitrogen-containing blocks.In recent years,due to the significant role of haloimines in halogen-containing drugs,the establishment of efficient synthesis methods of α-haloimines has attracted more and more attention from medical researchers.At present,the traditional reactions for synthesizing α-functionalized halogenated imines are direct halogenation of the imine at the α position or dehydration condensation ofα-halogenated ketone and amine.However,these methods are limited due to their tedious operation,low yields and narrow substrate scope.This subject aims at solving these problems,and designs a new method to synthesize α-haloimines,which is subsequently applied to the synthesis of indole derivatives,providing a potent method to the design and synthesis of drug molecules,as well as the halogenated functionalization of drug candidates.The thesis is composed of three parts.The first part is the synthesis and application of α,α-difluoroimide compounds.From ethyl benzoylaceta,a straight-forward method was developed to synthesize the template substrate,which was further used to evaluate solvents and fluorine sources and their amount.A series of α,α-difluoroimines were synthesized under the optimized condition.At the same time,some of the compounds were were employed to study the reaction mechanism,while some others were applied to further transformation.The newly obtained compounds were all confirmed by NMR analysis.The results showed that the best reaction conditions include: 2.5 equiv.of Selectfluor,acetonitril,0 ℃.Twenty-six α,α-difluoroimine compounds were synthesized,and some compounds were further derivatized to obtain corresponding nitrogen-containing geminal difluoro derivatives.Mechanistic studies indicate that the reaction proceed via an α-monofluroenamine intermediate.The above mentioned method features wide substrate scope,mild conditions and high yields,which is of great significance for the structural modification of traditional Chinese medicinal substances.The second part focuses on the synthesis and application of α,α-dichloroimine and α,α-dibromoimine.Inspired by the work of the first part,almost the same substrates were synthesized and applied to the synthesis of α,α-dihaloemines under the optimized conditions.It can smoothly synthesize 26 α,α-dichloroimine compounds and 23 α,α-dibromoimine compounds.Compounds selected underwent some useful transformation to afford nitrogen containing heterocycles and building blocks.All the new compounds were checked by NMR and IR analysis.It has the advantages of wide substrate scope,mild conditions and high yields,which has of great significance for the synthesis of 1H-indole derivatives and other nitrogen heterocyclic compounds.The third part concerns the synthesis of 3H-indole derivatives.Based on the above two parts of work,a series of α-monohalogenated imines were prepared.Among them,α-monobromo imines can be transformed to 3H-indole derivatives via copper mediated intramolecular cyclization.All the compounds were confirmed by NMR analysis and compared with literature reported.The results show that α-haloimines are an important intermediate for the synthesis of pharmaceutical molecules.This method can provide reference for the synthesis of indole alkaloid core skeleton.