Research On The CC Bond Construction Of Indoline And Indole Derivatives Involving Organolithium

Organolithiums play an important role in modern organic synthetic chemistry,based on their wild application and power to create new C-C bonds.The chararceristircs of the high activity and solubility in various non-polar solvents makes organolithiums a perferable reagants rather than other organometallic compounds.Therefore,the organolithium chemistry attracts chemsits to develop and explore novel strategies in oraganic synthetic chemistry.Meanwhile,many boacitve natural products contain indoline and indole core structures.The investigation of green synthesis methods for the syntheisis of these nitrogen-containing heterocyclic compounds has been a hot topic for synthetic chemists.Thus in,attempts to develop new methods of the synthesis of heterocylic compounds containing indoline and indole motifys by the lithiation-substitution and the lithiation-lithium-zinc exchange-Negishi couplingreactions were explored.This thesis mainly focuses on the following several parts:1.The method for the synthesis of racemic 2-substituted-N-Boc-2-arylindolines by the lithiation-substitution reaction directed by Boc group was studied.The conjugation between the carbonyl group of the Boc group and the lone pair of electrons on the adjacent nitrogen atom in N-Boc-2-arylindolines makes the rotation of the C-N bonds slower than normal C-N,so there is a pair of rotamers in the substrate.In addition to the effects of lithiation and the electron-effect of the 2-aryl group,the rate of interconversion of the rotamers also affects the yield of the lithiation-substitution reaction.The temperature of the reaction has the major effort on the rate of the inverconveration of the rotamers.Once the lithiation is complete,the organolithium intermediate reacts with the added electrophile to give the substituted product.Therefore,we optimized the reaction temperature,lithiation time.It was found that the best condition was deprotonating the substrate at-50℃ in dry THF by using n-BuLi.After 4 min,the addition of n-BuBr as electrophile gave N-Boc-2-n-butyl-2-phenylindoline in high yield.16 racemic 2-substitut-N-Boc-2-arylindolines were successfully prepared by using this optimized method,and the yields were about 30～90%.At the same time,the kinetic resolution of N-Boc-2-phenylindoline was investigated by using chiral base formed from the complextion of chiral ligands with n-BuLi.This method provides an idea about efficient synthesis of enantioenriched N-Boc-2-arylindolines and 2-substitut-N-Boc-2-arylindolines.2.Lithiation-lithium-zinc exchange-Negishi coupling reaction was used to the synthesis of N-methyl-2-arylindole derivatives.Firstly,the lithiation condition was optimized by alkylation of N-methyindole.It was found that n-BuLi can be used to successfully deprotonate at the 2-position of N-methylindole at room temperature.After 1.5 hours,n-BuBr and other electrophiles were added to respectively finish the lithiation-substitution reaction,resulting in N-methyl-2-n-butyl-indole and other four derivatives,yield 74 to 97%.Based on this result,we explored the condition of the time for lithium-zinc exchange,different types and amounts of catalysts and ligands,additives and solvents by using N-methylindole as substrate.When the lithiation step was completed,anhydrous ZnCl2 was added to the reaction mixture at room temperature followed by the addition of bromobenzene,the catalyst Pd2(dba)3 and the ligand X-Phos in one portion after 30 min.The Negishi cross coupling was then reacting smoothly to give N-methyl-2-phenylindole in a yield of 88%after 2.5 h.By using this optimized condition,30 N-methyl-2-arylindole derivatives were efficiently synthesized,and the yield was about 57 to 94%.The reaction condition is mild and features functional group compatibility,this method can be applied to the 2-arylation of benzofuran.3.Most of the complex organolithium intermediates are obtained in cryogenic condition.We unexpectedly obtained 2-lithium-N-methylindole in dry THF at room temperature.The crystal structure was identified by culturing crystals and X-ray single crystal diffraction data analysis.This organolithium intermediate was found to exist as a dimer of Ar2Li2·4THF complex,in which the heteroaryl groups are three-center two-electron bonded to two Li atoms.Besides,we studied the reaction mechanism by means of GC-MS and found that there was a secondary metal exchange process in the Negishi coupling reaction,resulting in the formation of the homocoupling byproduct of N-methylindole in the reaction.In summary,a method for the synthesis of racemic 2-substituted-N-Boc-2-arylindo-lines by lithiation-substitution reaction was established,which laid foundation for the subsequent study of asymmetric synthesis of chiral indoline derivatives.In addition,in this thesis,2-arylation of indoles was efficiently achieved at room temperature by a lithiation-lithium-zinc exchange-Negishi coupling reaction.This reaction has the advantages of mild reaction conditions,high yield,and wide range of substrate scopes.