Study On [3+2] Cycloaddition Of 1,4-benzodiazepin-2-one-based Azomethine Ylides

1,4-Benzodiazepine-2-one has thermodynamically stable conformational chirality as a class of advantageous drug skeletons,and its spatial and chemical structure is unique.Its derivatives have a wide range of biological activities and medicinal value such as sedation,hypnosis,anti-depression,anti-Alzheimer's,anti-tumor,anti-HIV and anti-malaria biological activities.At present,there exist certain limitations for the structural modification of 1,4-benzodiazepine-2-one.Therefore,designing a new type of organic synthetic building block based on1,4-benzodiazepine-2-one to construct a new and complex spiro/fused ring system of1,4-benzodiazepine by using asymmetric cycloaddition reaction is of great significance not only to enrich and develop organic synthesis methodology about1,4-benzodiazepine-2-one,but also to the research and development of new chiral spiro/fused 1,4-benzodiazepines as drug candidates.In this paper,the azomethine ylides,which is generated in situ by3-amino-1,4-benzodiazepine-2-ones and aldehydes under the catalysis of proton acid,react with azodicarboxylic acid derivatives forming a kind of novel chiral spiro1,4-benzodiazepine-2-ones with complex and diverse structure efficiently and stereoselectively through the[3+2]cycloaddition reaction.The main research contents of this paper are listed as follows(1)Designing a three-component model reaction of3-amino-1,4-benzodiazepine-2-one,aldehyde and azodicarboxylic acid derivatives and then constructing the optimal conditions for the reaction by screening the solvents,additives,temperature and substracts ratio.(2)Extending the substrates synthesized by the[3+2]cycloaddition reaction under optimal condition and investigating the substrates universality by changing the structure and position of the substituents on the reaction substrate,synthesizing kinds of structurally novel and diverse spiro1,4-benzodiazepine-2-one with a moderate to excellent yield(59-98%)and excellent diastereoselectivity(dr>20:1).(3)The target products were characterized by corresponding means(~1H NMR,¹³C NMR,HRMS),the relative configuration of the product was determined by X-ray single crystal diffraction,and the[3+2]cycloaddition reaction mechanism was proposed.