Rapid Generation Of Tetrahydropyridine And Tetrahydroquinoline Derivatives By Dearomatization

Tetrahydropyridines are widely present in various natural products and have strong biological activity and potential druggability.For example,1,2-tetrahydropyridine compounds have a strong inhibitory effect on α-mannosidase,and have potential medicinal value as immunosuppressants and antiviral agents.Tetrahydroquinoline compounds act as important template building blocks in organic synthesis.At the same time,these compounds also have good hypoglycemic,antibacterial,antitumor and other activities,and drug synthesis workers often use them for drug research and development..Although there are many reports on the synthetic methods of tetrahydropyridine and tetrahydroquinoline,these methods have disadvantages such as harsh reaction conditions,the use of highly toxic reagents,and poor substrate applicability,which do not meet the requirements of green chemistry.In this paper,the dearomatization synthesis methods of tetrahydropyridines and tetrahydroquinolines were studied,and a green and efficient synthetic route was developed.In this thesis,pyridine or quinoline compounds are used as raw materials and tetrahydrofuran is used as solvent.First,under the catalysis of Lewis acid,Grignard reagent is added to the C-4 position of pyridine or quinoline.Under the action of silane and trifluoroacetic acid,the nucleophilic addition reaction at the C-2 position occurs to obtain the amino nitrile intermediate,and then the addition and elimination reaction occurs rapidly with various Grignard reagents to generate tetrahydropyridine and tetrahydroquinoline products.The experimental method used in this paper has the advantages of simple operation,wide application of substrates and high yield.In this thesis,it is proposed for the first time that amino nitrile intermediates are used as masked imide cations,which can react with various Grignard reagents and greatly enrich the range of derivatives of tetrahydropyridine and tetrahydroquinoline.A total of 23 cyanamide intermediates,26 2,4-disubstituted tetrahydropyridine and tetrahydroquinoline compounds,and 2 application examples were synthesized in this project,all of which are new compounds.The corresponding structures of all final products were confirmed by H NMR,C NMR,IR,and high-resolution mass spectrometry.The synthetic method designed in this paper realizes the dearomatization of quinoline or pyridine.There are few reports at home and abroad to synthesize 2,4-disubstituted tetrahydropyridine or tetrahydroquinoline,etc.Cyclic compounds with remarkable innovation.In terms of basic theory,the dearomatization of nitrogen-containing aromatic heterocycles has been greatly expanded and has broad application prospects.