Synthesis Of 1-aryl-substituted Isoquinoline Compounds

Isoquinolines and their derivatives are widely found in nature and are an important source of drugs and drug-like molecules.There are about 10,000 alkaloids in nature,about 60 of which are classified according to their chemical structures,and the largest group is isoquinoline-like alkaloids.Isoquinolines are widely regarded as efficiently pharmacological groups with complex and diverse structures,which have a wide range of pharmacological activities including anti-inflammatory,antiseptic,hypotensive,antidiabetic and antidepressant.Isoquinolines are widely distributed in natural plants.In addition,isoquinolines are also found in animals and humans,and these compounds are generally used as neuromodulators to regulate the activity of various enzymes in the body,which play an irreplaceable role in the normal life of human beings.For the reason,the synthesis of isoquinolines and their derivatives in an efficient and direct manner are always a hot research topic for medicinal chemists.Therefore,in order to explore the activity of isoquinolines,a series of1-aryl-substituted isoquinolines were designed and synthesized.This dissertation is divided into two parts.The Chapter 1 the thesis presents a literature review on the research progress of isoquinolines.By summarizing the biological activities and synthesis methods of isoquinolines,it is found that their existing synthesis methods have disadvantages such as raw materials not easily available,long reaction steps,use of precious metal catalysis,low yields or the need to use oxidizing agents（or dehydrogenating agents）for aromatization.Therefore,the present work is intended to design a simple,applicable and brief synthetic route for 1-aryl-substituted isoquinolines,which will lay a solid foundation for further research and application of isoquinolines in the future.In the chapter 2 the synthetic route of 1-aryl-substituted isoquinolinne was designed based on the Bischler-Napieralski reaction : the intermediate amide was generated by the condensation reaction of benzoic acid compounds with substituted2-aminoacetophenone,and the target compound 1-aryl isoquinolines were obtained by ring closure with the dehydrating agent trichloroxaphos.We tried the synthetic route using 3,4-dimethoxybenzoic acid and 2-aminoacetophenone as starting materials to obtain the intermediate amide followed by the Bischler-Napieralski reaction in the presence of trichloroxaphos,and we obtained smoothly the target compound1-phenylisoquinoline.Subsequently,conditions of the ring closure reaction was attempted,and the reaction rate could be improved when trichloroxaphos was used as a solvent during ring closure.Then the reaction mechanism was also speculated.Subsequently,scope of the substrate was examined,and the electron cloud density of the benzene ring on the aromatic acid showed little effect on the reaction,but the substituted position of the aromatic acid have great impact on the reaction.In summary,the synthesis of 1-phenylisoquinolines was successfully achieved by the Bischler-Napieralski reaction through the ring closure reaction,which possess some advantages,such as simply synthetic route,high yields.and there is no need to use expensive transition metals or oxidative dehydrogenation agents.These will lay the foundation for further studies of isoquinolines.