H-phosphonates Mediated Synthesis Of 2-aminoquinoline Derivatives From Primary Amines And Quinoline-n-oxides

It is well known that, as an extremely important structural moiety, the quinoline(or pyridine) moiety exists in a wide range of pharmaceutical interest products.7 However, it has been found that quinine, a naturally occurring product for treatment of malaria, is easily detoxified in the body by oxidation to the 2-hydroxy derivative which has much less therapeutic activity. So lots of synthetic methods have been focused on introducing groups into the 2-position in order to block this mode of detoxification, A lot of works have done to functionalization quinoline at C-2 position to protect its activation. Thus, direct induction of amidogen groups into quinolines to obtain a kind of Quinoline derivatives which have better medical activation has been focused on. According to report the available methodologies for2-aminoquinoline derivatives mainly include the following:(1) Chichibabin-tapy amination from amine alkali;(2) Substitution of 2-prefunctionalized quinolines by an amine;(3) Cycloaddition with anilines as starting materials;(4)directly oxidation the 2-aminoquinoline. However, most of these methods suffer from some limitations such as relatively harsh reaction conditions, tedious procedures and so on. Therefore,a simple, cheap, mild condition method is badly needed.Based on our laboratory previous work, we report an efficient method for the synthesis of 2-aminoquinoline derivatives from primary amines and quinoline-N-oxides, using much cheap, easily available base-H-phosphonate catalytic system. And this was the first time primary amines were used as substrates to synthesize 2-aminoquinoline derivatives. Primary amine either aliphatic amine or aromatic amine with electron-donating or electron-withdrawing group all found work very well. The advantages of this work are obviously: metal free, mild reaction condition, higher atom economy, cheaper substrates, simple process, higher yield.The possible reaction mechanism was also investigated. Finally, we comprehensively expound the mechanism of the reaction by 31 P NMR stacks.This mainly discusses from the following several aspects:1. It’s mainly summary and conclusion that the nature of quinolines and quinoline derivatives, synthesis methods and practical application.2. With quinoline-N-oxides and Propylamine as template reaction. The investigations of optimal reaction condition regarding influence of reactions’ usage, solvents and reaction temperature, are carried out with a selected model reaction. Finally, the best reaction condition: 0.4 mmol quinoline-N-oxides,0.4mmol Propylamine,0.8 mmol H-diethyl phosphate, 2 equivalent K2CO3, 0.5m L CCl4 in DMF(1.0m L) was stirred at room temperature for 3 hours.3. Therewith, with the optimum reaction condition for expansion of the substrate,24 objective product were ultimately synthesized with structural elucidations by1 H NMR, 13 C NMR, HR MS.4. We comprehensively expound the mechanism of the reaction by 31 P NMR stacks.