Study On Intramolecular Cyclization Of Alkynyl Quinazolinone

Heterocyclic compounds are already inseparable from our lives and are one of the largest organic compounds.Heterocyclic compounds have a wide range of applications in pharmaceuticals,agricultural chemistry,material science,and chemical raw materials.As an important component of heterocyclic compounds,nitrogen-containing heterocycles have attracted the attention of many organic synthetic chemists in recent years.Quinazolone,as an important nitrogen heterocyclic compound,has been widely reported in the field of medicinal chemistry and natural products.The pharmacological activities of quinazolone compounds mainly include anti-tumor,anti-inflammatory,anti-bacterial,anti-malarial,anti-hypertensive and sedative effects,and there are already 12 types of quinazolone drugs approved for marketing by the FDA.At present,more than 200 types of quinazolone compounds have been isolated from natural products,most of them have been proved to play important physiological roles in organisms.Therefore,the synthesis and application of quinazolones have become one of the hottest research topics of organic synthesis and pharmaceutical chemists.2,3-fused quinazolinones are widely present in quinazolinone alkaloids,such as Rutaecarpine,Luotonin,Tryptanthrine etc.,which has also attracted the widespread attention of many synthetic chemists.In this thesis,different types of 2,3-fused quinazolinones were obtained by transition metal catalyzed intramolecular cyclization with excellent regioselectivity and stereoselectivity from alkynyl-containing quinazolinones.This paper is divided into four sections:Part Ⅰ:The palladium catalyzed intramolecular dearomatization cyclization strategy of 2-alkynyl-N3-（4-methoxyphenyl）-4（3H）-quinazolone derivatives were developed,which realized the efficient construction of 2,3-fused spiroquinazolones.The experimental results show that the palladium acetate and monophosphine ligand generate a palladacycle species in situ.This cocatalysis of palladacycle species with boron trifluoride etherate delivered 5-endo spirocycization products in good to excellent yields.During the experiment,it was found that the regioselectivity of the cyclization reaction was related to the position of the methoxy on the N3-aryl moiety.However,when the position of the methoxy on the N3-aryl was changed,the reaction underwent 6-endo cyclization,and efficiently afforded six-membered cyclization products.The mechanistic studies showed that the alkynyl group was activated by palladacycle and methoxy group was activated by BF₃.Et₂O,which promoted the C-O bond cleavage of the methoxy group.This reaction had the characteristics of mild reaction conditions,simple operation,good functional group tolerance,and can be prepared at gram scales.Moreover,the prepared spiroquinolone skeleton can also undergo various transformations.In vitro cell experiments had shown that the synthesized spirocyclic compounds had certain anti-tumor activity.Part Ⅱ:A series of chiral spirocycloquinazolone derivatives were efficiently constructed by the asymmetric intramolecular dearomatization of N3-propargyl-2-（3-indolyl）-quinazolone derivatives catalyzed by chiral silver phosphate.Under standard conditions,a total of 35 chiral spiroquinolone derivatives were obtained in good to excellent yields（76%-99%yields）and high enantioselectivity（57%-99%ee）.The chiral products can be applied to the structural modification of natural products or drug molecules,and the enantioselectivity of the corresponding products were maintained.This strategy lays an important material foundation for developing the medicinal value of chiral spirocycloquinazolones.Part Ⅲ:A series of pseudorutaecarpine derivatives were efficiently prepared using N3-propargyl-2-（3-indolyl）-quinazolone derivatives as raw materials by gold catalyzed selective cyclization.The reaction had a wide range of substrates and excellent regioselectivity.Six-,seven-,and eight-membered cyclization products can all be obtained smoothly.According to the control experiments and literature reports,this reaction may undergo dearomatization cyclization of alkynyl and indolyl groups at the 3-position catalyzed by gold,and then afforded seven membered cyclization products by intramolecular migration;Alternatively,the direct cyclization of alkynyl and indolyl groups at the C2 position catalyzed by gold was also possible;In vitro cell experiments have shown that the obtained pseudorutaecarpine derivatives had better anti-inflammatory activity compared to indomethacin.Part Ⅳ:A biaryl monophosphine ligand derived from fused-quinazolinones with axial chirality was designed and synthesized.This ligand was applied to the gold catalyzed intramolecular cyclization reaction of alkynyl quinolinone,and a series of fused-quinolinone derivatives with axial chirality were efficiently synthesized.After comparison,the catalyst formed by this ligand and gold had higher catalytic activity for this cyclization reaction compared to common monophosphine ligand derived gold catalysts.The asymmetric cyclization of alkynylquinazolinone was realized under the action of chiral amide catalyst derived from quinine.After further conversion,the chiral fused-quinazolinone derived chiral monophosphine ligand was successfully constructed.The chiral ligand was applied to the asymmetric cyclization of alkynylquinazolinone and the asymmetric allylic substitution reactions,respectively.The results showed that the designed and synthesized axial chiral biaryl monophosphine ligands had certain asymmetric induction potential.