Studies On The Synthetic Method Of Tterahydropyridine And Tetrahydroquinoline Derivatives Via Dearomatization Reaction

Tetrahydroquinolines are widely present in many natural products and have a wide range of biological activities.Among them,1,2,3,4-tetrahydroquinolines can prevent and treat diseases such as arteriosclerosis,hyperlipidemia,anti-tumor and arrhythmia.Tetrahydropyridines are an important synthetic precursor for many pharmaceutical or functional materials,many of which contain this structure.Although there are many reports on the synthesis methods of tetrahydroquinolines,these methods have the disadvantages of poor substrate suitability,low economic efficiency and harsh reaction conditions.This thesis focuses on the synthesis of tetrahydroquinolines and tetrahydropyridines via dearomatization reactions.In this project,a new one-pot synthesis method for synthesizing tetrahydropyridine and tetrahydroquinoline derivatives with high selectivity was established by two consecutive nucleophilic addition dearomatization reactions.Using a cheap and readily available quinoline or pyridine as the starting material,tetrahydrofuran as the solvent,dearomatization of the substrate was realized by boron trifluoride etherate and a Grignard reagent to form an intermediate with nucleophilic addition at C-4,followed by a second nucleophilic addition reaction at C-2 to afford tetrahydroquinoline or tetrahydropyridine product.The second nucleophilic addition reaction was carried out by treating the intermediate with a solution of 1-methy indole in methanol and trifluoroacetic acid.The synthesis method designed in this project has high stereoselectivity,and the chirality of the product produced can be controlled by different reaction temperatures.The trans product is formed at low temperature,whereas the cis product is produced at room temperature.We first discovered two dicarbocations,which are the synthons of the target product tetrahydroquinoline and tetrahydropyridine,respectively.The corresponding equivalent reagents are quinoline and pyridine.This is also the first synthetic method for preparing tetrahydropyridine and tetrahydroquinoline by dearomatization reaction which directly forms two C-C bonds with two dicarbocation synthons.This synthetic method is simple and convenient.It has wide substrate scope,and has very good regio-and stereoselectivity.From the green chemistry perspective,the atomic economy and step economy of the reaction are high,and its efficiency can be compared with the classical Diels-Alder reaction.Two C-C bonds,one C-H bond and one N-H bond are formed in the reaction,and two chiral carbons are formed with high stereoselectivity;at the same time,a C=C bond,a C=N bond and a C-H bond are broken.At present,there is no report on using C-C bond forming dearomatization reaction to synthesize a nitrogen-containing heterocyclic compound such as tetrahydropyridine or tetrahydroquinoline,which is remarkable in innovation.In terms of basic theory,it greatly enriches the dearomatization reaction of nitrogen-containing aromatic heterocyclic rings,and has broad application prospects.