Mechanically Activated N-Deformylation,Cross-Dehydrogenative Coupling Reactions Applied To The Synthesis Of Quinolines And Tetrahydroisoquinolines

With the rapid development of the pharmaceutical and chemical industry, current dependence on solvents appears increasingly unsustainable since it is wasteful of fossil-derived materials, environmentally problematic, hazardous and energy-demanding with regard to solvent production, purification and recycling. Solvent-free reactions avoid the dangers, toxic and costs-increase posed by the use of solvents, become one of the hot-spot recently. As a new way to promote solvent-free reactions, mechanical milling has various advantages and becomes an effective tool for organic synthesis reactions.In this thesis, investigations are focused on the deformylation and cross dehydrogenation coupling reaction under mechanical milling condition. The main contents include the following five aspects.(1) Briefly describes the development of the mechanical chemistry, the overview of mechanical milling in organic synthesis as well as various influencing factors.(2) Under high speed ball milling conditions, using solid base to realize the deformylation and aromatization reaction of N-formyl-1,2-dihydroquinolines. With solid NaOH as base, PEG2000as additive, NaCl as grinding aid, this solvent-free reaction providing a fast, convenient and environmentally friendly route for the preparation of2-aryl(heteroaryl)-quinolines. Compared with traditional deformylation methods, the reaction did not require any toxic organic solvents, Also, short reaction time, high yields, wide generality and simple isolation of the production all make this method fully embodied the concept of green chemistry. Additionally, additives and grinding aids used in the reaction could be reused many times with a high reaction activity.(3) Under high speed ball milling conditions, using DDQ to promote the cross-dehydrogenative coupling reaction (CDC) between tetrahydroisoquinoline (sp3C-H) with three different type of hybrid substrates (sp C-H, aryl-sp2C-H, sp3C-H). Mechanical milling technique has been first applied to the cross-dehydrogenative coupling reaction. DDQ, a safe, stable and easy-store oxidant was used in these reactions. For nitroalkanes and malononitrile, R-C-H-functionalized products were obtained without any metal catalyst. For alkynes and indoles, copper balls were used both as the reacting catalyst and milling balls; the recovery of the catalyst would be as simple as removing the copper ball from the reaction media. Such reactions have both the characteristic of high atom economy of CDC reaction, and the advantages of fast, efficient and solvent-free of mechanical milling reaction. This method provides a reasonable approach for the preparation of tetrahydroisoquinoline derivatives having potential anti-tumor activity.(4) Under high speed ball milling conditions, asymmetric alkynylation of prochiral sp3C-H bonds for the preparation of optically active tetrahydroisoquinolines was achieved by using PyBox as chiral ligand. Although High Speed Ball-Milling (HSBM) technique has been increasingly used in synthetic organic chemistry to promote several solvent-free reactions, only a few enantioselective reactions have been explored under HSBM conditions. The present work is attractive in the search of the application of this nonconventional methodology for the preparation of optically active tetrahydroisoquinoline derivatives through asymmetric CDC reactions. This could represent an interesting challenge for the development of enantioselective reactions in a ball mill. Fast, simple operation and easy to reuse the catalyst are advantages of the reaction.(5) Mechanically activated cross-dehydrogenative coupling reaction was applied for the preparation of praziquantel intermediates, while a derivative reaction was studied. Mechanically promoted CDC reaction was firstly applied to prepare the key intermediates of praziquantel, the reaction is more rapid and efficient. N-(4-methoxyphenyl) tetrahydroisoquinoline was used as the substrate, through cross-dehydrogenative coupling, catalytic hydrogenation, and oxidative deprotection three-step reactions to give1-aminomethyl-1,2,3,4-tetrahydroisoquinoline intermediates, which providing a novel and effective method for constructing praziquantel and its analogues intermediates. In addition, during the design and optimization process in praziquantel synthetic routes, a new type of solvent-free oxidative ring-opening reaction of N-acyl-tetrahydroisoquinoline under ball mill condition was discovered. In this reaction, a relative comprehensive study was carried out on the range of substrate, reaction conditions, selectivity and mechanism. For comparison, the reaction was also carried out in the traditional condition.