Synthesis Of The Isoindolinone Derivatives Promoted By C₄F₉I/CS₂CO₃

Research background and purposeMost of the alkaloids have unique physiological and pharmacological activities,and they can be contributed for the clinical development of new drug after chemical modification.As an important member of alkaloids,isoindolinone derivatives not only widely exist in natural products,but also the core skeleton of many drug molecules,and at the same time could be vital intermediates in organic synthesis.In view of its important research value in the fields of biology,medicine,chemical engineering,etc.,researchers have drawn extensive attention to the synthesis of isoindolinone skeleton,and many effective strategies have emerged with the help of transition-metal catalysts.Given the consensus towards green chemistry,however,it is necessary to explore a new method which is simple,efficient,economical and environmentally friendly.Thus,we aim at pursuing a novel approach to the isoindolinone moiety.A series of isoindolinone derivatives would be synthesized concisely in good yield under mild conditions without the participation of transition-metal catalysts.Methods(1)To select the appropriate type of substrate,screen different reagent combinations,change the reaction conditions,and analyze the experimental results by using thin layer chromatography(TLC),gas chromatography/liquid chromatography-mass spectrometry(GC/LC-MS)and nuclear magnetic resonance spectroscopy(NMR);(2)Various functional group modifications were made to the model substrate to examine the substrate tolerance of the reaction combination;(3)The control experiments were performed,and then based on the results and literature studies,try to analyze the reaction mechanism.ResultsAfter screening the reaction conditions,when N-phenyl o-vinylbenzamide was used as the substrate,N,N-dimethylformamide as the solvent,and the cyclization reaction was carried out at room temperature with the aid of perfluorobutyl iodide and cesium carbonate.The isoindolinone product was obtained in a yield of 97%.After using various substrates modified with different functional groups for testing,the yields of the expected products ranged from 45%to 85%.All isoindolinone products were analyzed by NMR(1H,13C),HRMS and the melting point was tested.The mechanism of intramolecular cyclization of N-phenyl-o-vinylbenzamide via the EDA complex and iodonium ion pathway was proposedConclusionsBased on the C4F9I/Cs2CO3 reaction system,this study disclosed a new method for constructing the isoindolinone skeleton through intramolecular cyclization under mild conditions.It is facile,available,economical and environmentally friendly,and the yield can reach moderate to good.It provides new ideas and options for the synthesis and modification of isoindolinone alkaloids.