Study On The C(Sp~3)-H Bond Functionalization/Cyclization Of Ketene To Construct Multifunctional 1,5-Dihydro-2H-Pyrrol-2-Ones

1,5-Dihydro-2H-pyrrol-2-ones derivatives,as significant class of γ-lactam rings,are basic components of many important natural products,drug molecules,enzyme receptor inhibitors,catalysts,and materials.Traditionally synthesis of this compounds have a relatively single type of starting substrate,which to some extent limits the adaptability of the substrate.For example,many reactions used compounds such as propargylamide,enamine ketone(or in situ formation)as starting materials.Consequently,the development of simple,green and efficient synthetic methods to synthesize 1,5-dihydro-2H-pyrrol-2-one derivatives are primarily focus of pharmaceutical chemists.Enaminone had been widely applied as a key intermediate in drug synthesis,which have simple preparation methods and multiple reaction sites.However,based on the long-term study of ketamine chemistry,we found that N1 and C3 of ketamine reaction easily occurs,but C5 and C6 of ketamine had not been investigated by scientists.To synthesis the construction of 1,5-dihydro-2H-pyrrol-2-one skeleton via enaminone,it’s necessary to directly apply C(sp~3)-H bond functional group/cyclization reaction between C5 and C6 positions and two easily reactive sites N1 and C3 don’t participate in the reaction.Based on long term research of enaminone,a series of 1,5-dihydro-2H-pyrrole-2-one derivatives were prepared with enaminone as the reaction intermediates via environmentally synthetic method to solve the above problems.Preliminary screening for anticancer and antioxidant activity was also performed.The paper mainly includes four chapters:Chapter Ⅰ.According literatures research,the applications of 1,5-dihydro-2H-pyrrole-2-one derivatives on the biological,pharmaceutical and different synthesis strategies of 1,5-dihydro-2H-pyrrole-2-one derivatives via different catalytic modes are reviewed.The research contents and innovations of this paper are proffered.Chapter Ⅱ.More substituted 2,4-pentanedione,primary amine and sodium sulfinate,with KI,TBHP as catalysts,anisole and acetic acid as solvents,reacted at room temperature for 24 h to synthesize 5-sulfonyl-1,5-dihydro-2H-pyrrole-2-one derivatives.This strategy achieves regional selectivity and chemoselectivity of enamine via C(sp~3)-H bond functional group/cyclization reaction.Chapter Ⅲ.Based on the feasibility of the reaction in chapter Ⅰ,the selenium and sulfur free radical and double bond coupling were applied to synthetize 1,5-dihydro-2H-pyrrol-2-ones.The reaction conditions were as follows:Na I and CHP as catalysts,DCE and Ac OH as solvents,and the products were obtained at a yield of up to 78%.Chapter Ⅳ.1,5-Dihydro-2H-pyrrol-2-ones,containing not only a conjugated ring system but also nucleophilic sites such as NH,α-C,have the possibility of further modification.We realize diphenoxyphosphating,benzoylation,alkoxylatation,and thiocyanation of 1,5-dihydro-2H-pyrrol-2-ones via constructing of C-S,C-C,and C-P bonds.According reduction,benzylation,lactam ring derivatives are also obtained and of 1,5-dihydro-2H-pyrrol-2-one were systematically studie.The representative compounds were also screened for Anti-PDE4D enzyme and antioxidant activities.