Study On The Novel Methods Of Transition-metal-catalyzed Synthesis Of Indoles And Indolizines

Nitrogen-containing heterocyclic compounds are important organic mo lecules that exist widely in medicines,dyes,and materials.As important nitrogen-containing heterocyclic compounds,indoles and indolizines possess potential biological activity and are core structural units in many pharmaceutical molecules.The synthesis and derivation of these two important compounds have attracted considerable concern from organic and medicinal chemists.Therefore,the development of novel methods for the synthesis of indoles and indolizines is of importance in academia and potential application prospects.In the dissertation,novel methods via transition-metal-catalyzed transformation toward the synthesis of indoles and lindolizines were studied.First,nickel-catalyzed intramolecular addition of aryl halides to ketones was carried out to obtain indole compounds.On the base of this research,the addition and coupling reaction between aryl triflates and aldehydes were developed.Through the control of reaction conditions,a range of diarylmethanols and diarylketones were isolated.Next,the three-component cascade annulation of pyridinyl enynes,allyl halides,and nucleophiles has been studied,which afforded densely functional 1,2,3-trisubstituted indolizines via Michael addition,cyclization,and Heck reaction by using Pd?CH3CN?2Cl2 as a catalyst.Nucleophilic addition reaction of halogenated hydrocarbons to carbonyls is one of the most important methods to form C-C bond.Conventional methods employ active organometallic reagents,prepared from organohalides,as nucleophiles;however,the substrates bearing sensitive groups are very limited as the usage of sensitive organometallic reagents.Accordingly,it's attractive to develop efficient and green process for the direct addition of halogenated hydrocarbons to carbonyls to avoid the preparation of organometallic reagents and the use of poisonous reagents to broaden substrate scope.In chapter II,nickel-catalyzed intramolecular addition of aryl halides to carbonyls was first studied.The intramolecular addition of 2-aminoaryl bromides to ketones was conducted with N i?dppe?Br₂ as a catalyst and Zn powder as the reducing agent.Through systematic optimization,the optimal reaction condition was determined as the following: 10 mol% N i?dppe?Br₂,2.5 equiv of Zn powder,and 0.2 mmol of 2-??2-bromophenyl?amino?-1-arylethanones in DME?2 mL?at 100 oC for 48 hours.During the study,28 starting materials and indole products were prepared,which included 22 unknown compounds that characterized by 1H NMR and 13 C NMR and HRMS analysis.Indole products were isolated in the yields from 38 to 90% under the optimal condition.On the base of the above study,nucleophilic addition of aryl triflates to aldehydes was studied in chapter III.The reaction between aryl triflates and aldehydes proceeds smoothly in MeOH solvent by using N i?dppe?Br₂ as the catalyst and Zn powder as reducing agents.The optimal reaction condition was found as the following: 0.2 mmol of aryl triflates,0.4 mmol of aldehydes,10 mol% N i?dppe?Br₂ and 2.5 equiv of Zn powder in 2.0 mL of MeOH at 75 oC for 48 hours.Under this condition,aryl triflates react with aldehydes smoothly to afford diarylmethanols in the yields from 11 to 84% for a series of 14 examples,including 3 unknown compounds.Meanwhile,it was found that aryl triflates can couple with aldehydes under the same catalyst system through the simple change fo the solvent from MeOH to THF.Diarylketones in 15 examples were afforded in the yields from 21 to 92%,including 4 unknown compounds.The reaction mechanism of the nickel-catalyzed nucleophilic addition of aryl halides or triflates carbonyls was discussed.In chapter ?,pyridyl enynes were synthesized and applied in the cascade annulation with electrophiles and nucleophiles.With Pd?CH3CN?2Cl2 as the catalyst,K2CO3 as the base in acetonitrile solvent,the reaction proceeds smoothly at room temperature to obtain indolizine compounds for 19 examples in the yields from 55 to 85%,which provide a novel efficient method for the synthesis of densely functionalized multisubstituted indolizines.In chapter ?,a catalyst-free aza-Baylis-Hillman reaction between enaminoester and azodicarboxylates was investigated.The reaction was promoted by water that led to a shorter reaction time,lower temperature,higher yield,and make it very attractive from the viewpoint of atom economy and green chemistry.The optimal reaction condition was determined as the following: enaminoester?1.0 mmol?,azodicarboxylate?1.0mmol?,and water?60 mL?at room temperature for 6 hours.In this chapter,23 kinds of novel Aza-Baylis–Hillman adducts were obtained in the yields from 70 to 99%.