Facile Methodologies For The Synthesis Of Benzolactam Derivatives From Simple Precursors

Nitrogen compounds are present in various drugs,agricultural chemicals and functional materials.Specially,among the 200 hot-selling drugs,the content of nitrogen-containing drug molecules exceeds 80%.Benzolactams,such as isoindolinones,quinolinones,and isoquinolinones,are common predominant structures in pharmaceutical molecules and are widely found in natural products and bioactive molecules.Therefore,it is of practical significance to develop a simple and easy method for synthesizing benzolactam.This thesis consists of two parts.The first part is the selective synthesis of spiro structures and tandem heterocycles of isoindolinones by the reactions of propargyl alcohols derived from phthalimides with 1,3-ketones or the related derivatives.In the second part,the work focuses on the mechanism of aerobic oxidation of N-alkylimmonium salts and the total synthesis of natural alkaloid norketoyobyrine by the use of this reaction as the key step.In the first part of the work,by carefully adjusting the reaction performance of nucleophiles,in the presence of Br(?)nsted acid,a form(3 + 2)cyclization reaction with phthalimyl-derived propargyl alcohol was carried out to selectively construct the spiro-ring structure and tandem heterocyclic structure of isoindolinone are presented.The highest yield is 94%,the reaction conditions are mild,and the operation is simple.In the second part of this paper,the reaction mechanism of alkali-promoted air oxidation of N-alkylimmonium salts to benzene unsaturated lactams was studied and successfully applied to the simple and total synthesis of natural alkaloid norketoyobyrine.Early research in the laboratory found that in the presence of inorganic bases,without the addition of other catalysts or additives,azaaromatic ring salts can be rapidly oxidized by air to the corresponding unsaturated lactams,but the reaction mechanism is unclear.On the basis of this,the mechanism was studied through control experiments,supplemented by nuclear magnetic resonance and high-resolution mass spectrometry,and a more reasonable reaction mechanism was proposed.Using this reaction,the commercially available isoquinoline was used as a starting material to complete the synthesis of the natural alkaloid norketoyobyrine with a total yield of 61%.