Design And Synthesis Of Indolizines In Friedel-Crafts Reaction

Indolizines are an important class of aromatic heterocyclic compounds containing nitrogen,its structural units widely exist in natural drugs.Indolizines with different structures have different biological activities or medicinal values and are widely used in life medicines and drug syntheses.For example,indolizines have anticancer,antioxidant,anti-inflammatory,antibacterial and other effects.Therefore,the establishment of the synthetic methodology of indolizines is of great significance.Friedel-Crafts alkylation reaction is one of the important ways to synthesize indolizines.In this thesis,a new method for the synthesis of indolizines was studied.In the first chapter,we studied the asymmetric catalytic Friedel-Crafts reaction of indolizines withα,β-unsaturated ketene catalyzed by chiral-at-metal complexes.In the second chapter,we completed the design and green synthesis of indolizines andβ,γ-unsaturatedα-ketone esters,a new method for the synthesis of indolizines was developed.The specific contents are as follows:1.We studied the asymmetric catalytic Friedel-Crafts reaction of indolizines withα,β-unsaturated ketenes catalyzed by chiral-at-metal complexes.Through the selection and improvement of conditions,such as reaction solvents,metal-centric chiral catalysts,reaction time and reaction temperature,we finally get the optimal conditions.Under the action of 1.0 mol%catalyst,using dichloroethane as solvent,a series of expansion work containing different substituents of indolizine andα,β-unsaturated ketene were carried out at room temperature.With excellent yield（85-97%）and excellent enantioselectivity（95->99%ee）,30 chiral indolizines were obtained.When the reaction is scaled up to gram,the target product can still be obtained with good yield and enantioselectivity.The absolute configuration of the product was determined as S configuration by single crystal diffraction experiment.The reaction has excellent stereoselectivity and substrate universality,low catalyst loading,and can realize the diversity synthesis of indolizine derivatives,which provides a feasible synthesis methodology for drug screening of such compounds in the future.2.We designed and synthesized indolizines andβ,γ-unsaturatedα-ketone esters.Through the selection and improvement of reaction additives,reaction solvents,reaction temperature and reaction time and other conditions,we finally obtained the best reaction conditions.With 30 mol%H₂O as additive and methanol as solvent,a series of expansion work containing different substituents of indolizine andβ,γ-unsaturatedα-ketone esters was carried out at room temperature,nineteen heterocyclic compounds containing indolizine structural units were obtained with excellent yield（80-92%）.When the reaction scale is scaled up to gram,the target product can still be obtained with good yield.The reaction uses water as additive,which has the characteristics of environmental protection and low cost.Further studies show that the reaction is closely related to the hydrogen bonding of water,which provides a novel and practical catalytic system and has a broad application prospect.