| Isoxazole, pyridine, triazole, 1,4-dihydropyridine, pyrazole and their derivatives are not only very important organic heterocyclic compounds, but also important building blocks of natural products and biological activity molecules, which were widely applied in medicine, pesticide and organic synthesis. At present, many methods for synthesizing isoxazole, triazole, 1,4-dihydropyridine and pyrazole derivatives have been reported in literatures, which exist some disadvantages, such as more reaction steps, harsh reaction conditions, low yields, complicated operation,poor economic performance and so on. Therefore, developing a simple method for synthesizing isoxazole, triazole, 1,4-dihydropyridine and pyrazole derivatives is much significant. In particular, the N?O bond of isoxazole ring was opened in alkaline or other conditions, which resulted in isoxazole derivatives have unique pharmacological properties and biological activities, and show good application prospects in the new agrochemical and pharmaceutical fields. With the development of technology,ultrasonic and microwave technology have been widely used in organic synthesis,because of its simple operation, environmental protection and energy conservation.In this work, the novel synthesis and their potential pharmacological activities of bis-isoxazole derivatives and some 1,2,3-triazole, 1,4-dihydropyridine and pyrazole derivatives bearing isoxazole group were explored, and their potential pharmacological activities were investigated.First, 3-substituted phenyl isoxazolyl-5-methanols were synthesized starting from substituted benzaldehyde oximes NCS and propargyl alcohol by one-pot traditional heating method using ZnCl2 as catalyst via 1,3-dipolar cycloaddition reaction. Further,3-substituted phenyl isoxazolyl-5- methanols were selectively oxidated to3-substituted phenyl isoxazolyl-5- carbaldehydes and etherified into 3-substituted phenyl isoxazolyl-5-ether alkynes. Herein, the effects of the reaction factors on the yields of target product were explored. The yield of target product has been improved,and the reaction conditions have been optimized, which became relatively mild, andmore convenient to operate and easy for post processing compared with the reported synthesis conditions.Second, a series of novel bis-isoxazole ether compounds were synthesized by employing 3-substituted phenyl isoxazolyl-5-ether alkynes and 3-pyridyl chloro oxime with a good pharmaceutical active group. The effects of different catalysts ZnCl2, FeCl3, CuI, SnCl2, Fe, Zn, and Cu/CuSO4 on the yield of the products were investigated. The results showed that the coordination catalysis of zinc powder with zinc chloride generated in the process of reaction could prevent the complexation of3-pyridyl chloro oxime with Zn2+, and the yield of the target product was highest.Under the optimal reaction condition, ten novel 3-substituted phenyl-5-(((3-(pyridin-3-yl)isoxazol-5-yl)methoxy)methyl)isoxazole derivatives and fifteen novel 3-(3(4)-nitrophenyl)-5-(((3-substituted phenylisoxazol-5-yl)methoxy)methyl) isoxazole derivatives were synthesized with 48–77% and 63–83% yields,respectively. The effects of different substituent groups on the yield and applicability of the catalyst were discussed. The inhibition and killing effects of the synthesized compounds on bacteria and fungus were investigated by in vitro antibacterial test. The results showed that bis-isoxazole derivatives had a good inhibitory effect for candida albicans(C. albicans ATCC 10231), but the antibacterial effect was not obvious.Third, under the condition of ultrasonic-assisted, a series of novel 1,2,3-triazole compounds were synthesized starting from 3-substituted phenyl isoxazolyl-5-ether alkynes and azide substituted thymidine. Through investigating different catalysts,solvents and heating methods on the yields of the obtaining target compound, the optimum reaction conditions were determined that the catalyst was copper acetate and sodium ascorbate, the best reaction solvent was i-Pr OH/H2O=2:1(V/V), and ultrasonic heating temperature was 45 oC. Twelve novel 4-hydroxy thymidine-1,2,3-triazole derivatives and seven novel 5-hydroxy methyl thymidine-1,2,3-triazole derivatives were synthesized with 84?96% and 87?96% yields, respectively. The effects of different substituent groups on the yield were analyzed. The yield of target products by ultrasonic heating is increased about 10% compared with conventional heating.Besides, reaction time was shorter, and by-product was less and the reaction conditionwas more friendly. Additionally, the quorum sensing inhibitory activity of the synthesized compounds on gram negative bacteria were evaluated by drop method compared with a positive control C10-HSL using chromobacterium violaceum as model. The results showed that compounds 8a, 8c and 8f have good inhibitory effects on cell quorum sensing activity for chromobacterium violaceum(C. violaceum CV026) without affecting the growth of bacteria.Last, one-pot method for the synthesis of 1,4-dihydropyridines and4-substituted-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-aryl-isoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-ones was respectively developed on solid support SiO2 under solvent-free conditions using microwave irradiation starting from various3-substituted isoxazolyl-5-carbaldehydes, ethyl acetoacetate and ammonium acetate/or substituted hydrazinobenzene. Through the investigation of the effect of microwave reaction temperatures, reaction times and solid supports on yield of target products,the optimum reaction conditions were determined. Ten novel4-substituted-isoxazolyl-1,4-dihydropyridines and fifteen novel 4-substituted-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-aryl-isoxazol-5-yl)methyl)-5-methyl-1H-py razol-3(2H)-ones derivatives were synthesized with 86–96% and 78–97% yields,respectively, and the effects of different substituents on the yield were discussed. The molecule structure, single molecule space configuration, hydrogen bonding interaction and intermolecular interaction of the compound diethyl4-(3-(2-methoxyphenyl)isoxazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbox ylate(5c) and 2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-methyl-1Hpyrazol-4-yl)(3-phenylisoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-one(5a)were determined by single crystal structure analysis, which further proved the structure of the synthesized product. In addition, the effect of silica reutilized was evaluated. It suggested that the yield had perfect reproducibility. Simultaneously,expanding experiment showed that this method also has good applicability to other aromatic aldehydes. In conclusion, the microwave heating reaction can not only improve the yield, shorten the reaction time, but also reduce the environment pollution and save energy, which possesses the prospect of industrialization.Besides, the synthesized compounds were characterized and analyzed by infrared spectroscopy FT-IR, 1H and 13 C NMR and HRMS. The structure of the synthesized compounds were confirmed.In summary, a series of heterocyclic compounds containing nitrogen with isoxazole groups were synthesized in one-pot, solvent-free solid-phase synthesis and ultrasonic radiation and microwave radiation technologies. With the development of technology, I believe that ultrasonic radiation and microwave radiation technologies because of shorter reaction time, milder conditions, easier post-processing and higher yield, along with the reutilization of solid silica will obtain broad application. |
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