Synthesis Of Tetrahydroquinoline-fused Ring Compounds Through [4+2] Cycloaddition

Tetrahydroquinoline compounds are one of the most important nitrogen heterocyclic compounds in organic synthesis,which are widely present in natural products and drug molecules.Tetrahydroquinoline compounds usually have good biological activities,such as antibacterial,anti-inflammatory,anti-tumor and so on.Due to the importance of tetrahydroquinoline compounds,its efficient synthesis is not only one of the hottest topics in organic synthesis but also a very meaningful research field.aza-ortho quinine methides(aza-o-QMs)as important 1,4-dipoles in organic synthesis,have the characteristics of short life,high reactivity and multi-function.It is widely used in organic chemistry,material chemistry,biology and other fields.Its reaction with different electrophiles in cycloaddition reaction could rapidly construct five-,six-,and seven-membered nitrogen heterocyclic compounds.In this thesis,we mainly focus on the formation of aza-o-QMs 1,4-dipoles from N-(ortho-chloromethyl)aryl amides under different conditions,which can intermolecular react with nucleophiles such as furans,bicyclo alkenes and indoles through[4+2]cycloaddition reaction to efficiently construct tetrahydroquinoline-fused ring compounds.At the same time,a series of tetrahydroquinoline compounds containing several chiral centers were developed.This thesis includes the following six parts:In the first part,we focused on the core framework of tetrahydroquinolines.The current strategies for constructing tetrahydroquinoline compounds were introduced,such as intramolecular amination,transition metal catalytic reduction of quinoline,C-H bond activation,Diels-Alder reaction,ring expansion and other strategies.N-(Ortho-chloromethyl)aryl amides as important precursors for the formation of aza-o-QMs 1,4-dipoles can participate in the cycloaddition reaction to efficiently construct tetrahydroquinoline compounds.Therefore,this section also reviews the recent progress in the[4+2]cycloaddition reaction of N-(ortho-chloromethyl)aryl amides to construct tetrahydroquinoline compounds.In the second part,We devopled an metal-free intermolecular[4+2]cycloaddition the to select synthesize two types of furo[3,2-b]quinolines and furo[2,3-b:4,5-b?]diquinolines by the use of N-(ortho-chloromethyl)aryl amides and furans as raw materials,and sodium carbonate as the base.The reaction could be obtained in good yields and high regioselectivity,and good functional group tolerance.preliminary mechanistic studies have showed that[4+2]cycloaddition was a concerted process,not a stepwise process by control experiments and ¹H NMR trace experiments.In the third part,We developed a Cu₂O and neocuproine as catalysts to catalyze the[4+2]cycloaddition reaction between N-(ortho-chloromethyl)aryl amides and bicyclic alkenes to costruct epoxybenzo[b]acridine compounds containing multiple stereocenters.The preliminary control experiments showed that the formation of aza-o-QMs 1,4-dipoles by N-(ortho-chloromethyl)aryl amides under catalysis of Cu₂O and neocuproine was a radical process.Cu(I)catalyst not only accelerates the formation of aza-o-QMs in the reaction but also accelerates the[4+2]cycloaddition reaction.The obtained epoxybenzo[b]acridine compound can be chemically transformed to synthesize a variety of tetrahydroquinoline skeleton compounds.The preliminary asymmetric reaction test can afford an enantioselectivity of 10% ee,which provides an experimental basis for further realization of its asymmetric cycloaddition reaction.In the fourth part,We developed a Cu(OAc)₂/1,10-Phen-catalyzed the three-component[4+2]cycloaddition reaction of two molecules of N-(ortho-chloromethyl)aryl amides and N-methylindoles.The tetrahydroquinolines bearing a C₃-quaternary carbon center were obtained in good yields and high diastereoselectivity.The study of the mechanism by the separation of intermediates showed that the reaction underwent two intermolecular substitution reactions and subsequent intramolecular cyclization.The reaction tolerated a wide range of substrates,good functional groups,and can be performed at gram scales showing high atomic economy.In the fifth part,a three-component reaction of N-(ortho-chloromethyl)aryl amides,2,3-dihydrofuran,and aryl trifluoromethanesulfonate was developed to synthesize a series of tetrahydrofuro[2,3-b]tetrahydroquinolines bearing three chiral centers through Heck reaction/[4+2]cycloaddition cascade by palladium and axial chiral bisphosphine ligand.The products can be obtained in good yields,excellent enantioselectivity,diastereoselectivity and regioselectivity(?90% ee,20:1 dr).The reaction tolerated a wide range of substrates,showed good functional group compatibility,and can be performed in gram scale.The developed method can also be applied to modify drug molecules and achieved a rapidly introduction of a chiral fragment containing tetrahydrofuro[2,3-b]tetrahydroquinoline in high yield,high enantioselectivity and diastereoselectivity.In the sixth part,a three-component reaction of chloro-sbustituted oximes,2,3-dihydrofuran,and aryl trifluoromethanesulfonate was also achieved to prepare a series of tetrahydrofuro[3,2-d]isoxazolines containing three chiral centers through heck reaction/[3+2]cycloaddition cascade.This cascade can also afford the desired tetrahydrofuro[3,2-d]isoxazolines in good yield and high enantioselectivity and diastereoselectivity(?90% ee,3:1 to 20:1 dr).This strategy can also rapidly introduced tetrahydrofuro[3,2-d]isoxazoline fragments containing three chiral centers with high enantioselectivity and diastereoselectivity(?90% ee,3:1 to 20:1 dr)in to the drug molecules.