The Functionalization Reaction Of The C-H Bond Of Quinolines Derivatives

Quinoline is an important and versatile heterocyclic compound that widely exists in the fields of natural products,pharmaceuticals,agrochemicals,functional materials,etc.,as well as ligands in transition metal catalysts.Among the broad range of aza-heterocycles,quinolones have been explored more than any other aza-heterocycles,in organic and medicinal chemistry.Therefore,the research on the efficient synthesis of substituted quinolines is very important in the field of organic synthesis.The method for constructing a quinoline-heterocyclic skeleton using 2-methylquinoline as a raw material provides a green and efficient way for the synthesis of multifunctional bi-heterocyclic compounds.The method of constructing quinoline-heterocyclic compounds with 2-methylquinoline as C1 source provides a green and efficient way for the synthesis of multifunctional bi-heterocyclic compounds.Meanwhile,Csp2-H activation by quinoline compounds is the most efficient way to construct substituted quinolines,especially for C3 substituted quinolones.In this paper,a new method for the synthesis of quinoline-isoxazole,quinoline-benzothiophene,quinoline-thiophene,quinoline-thiazole,and 3-thioether quinoline compounds using 2-methylquinoline as raw material was developed.The specific research contents are as follows:1.A method for the efficient synthesis of various isoxazolines and isoxazoles by1,3-dipolar cycloaddition without metal catalysis was developed.In this reaction,TBN was used as an N-O source to convert in situ with 2-methylquinoline to nitrile oxide.A variety of functional groups such as halogen,acetyl and ester groups are compatible.This method provides a convenient route for the construction of quinoline-isoxazole or quinoline-isoxazoline structure.2.A convenient synthetic route to 2-heteroaryl-3-hydroxybenzo[b]thiophene derivatives via K₂CO₃-promoted multicomponent cyclization between o-halogenated benzaldehyde,2-methylquinolines and sulfur powder has been demonstrated.The reaction does not require transition metal catalysis and can be scaled up at the gram scale.The resulting functionalized benzothiophenes could be applied into organic synthesis and medicinal applications.3.This dissertation developed an acid-promoted three-component cyclization of 2-methylquinoline,elemental sulfur andα,β-unsaturated aldehyde to synthesize thiophene derivatives.First,2-methylquinoline is dehydrated withα,β-unsaturated aldehyde to form 1,3-diene,and then undergoes[4+1]cyclization with elemental sulfur.In this reaction,elemental sulfur acts as both a sulfur source and an oxidant.4.We report the synthesis of quinoline-thiazole derivatives by[3+1+1]cyclization using 2-methylquinoline,enamine esters and elemental sulfur as starting materials without metal catalysis.The method can be successfully scaled up to the gram scale,providing an effective alternative method for the synthesis of quinoline-isothiazole derivatives.5.For the first time,the electro-promoted C3-H activation of quinoline to generate C-S bond was reported.Boron trifluoride ether is an important additive for the reaction,which provides a green and environmentally friendly route to synthesize 3-thioether quinoline.It is worth noting that this method is also applicable to the construction of 3-selenoether quinolines.This method provides a new idea for the functionalization of quinoline C3-H.