Synthesis Of Biologically Active N-Heterocycles By Sequential IMCR/aza-Wittig Reaction

Chemists have expressed great concern about N-heterocycles because of their good biological activities, such as broad-spectrum, efficient and low toxicity. The study of N-heterocycles chemistry have found a great deal of compounds with good prospects in pesticide、fungicide、herbicide、anti-Virus、anti-inflammatory and anti-tumor drugs. Some of them have been used as pesticide and medicine, the research on the synthesis and evaluate their biological activities of new N-heterocycle compounds is very active. In this dissertation we applied sequential IMCR/Staudinger/aza-Wittig reaction to design and synthesize 4-aminocarbonyl substituted 4H-3,1-benzoxazines,3,4-dihydro-2,3,4-trisubstitued quinazolines and indolo[1,2-c]quinazolines. And a series of unreported 1,2,4-triazole derivatives were designed and synthesized using Ugi reaction with the aim of evaluating their biological activities. Furthermore, novel 3-azolyl-quinoline derivatives were designed and synthesized using Friedlander reaction based on the lead compound "Diniconazole", a commercial triazole fungicide. The conditions of the syntheisis and the mechanism of the reaction were discussed, and the spectral properties of the target molecules were researched. The fungicidal activities of partial compounds were also tested. It may be summarized as follows:1. The utilization of IMCR in the synthesis of heterocycles and the development of aza-Wittig reaction of recent years were reviewed, and a few commercial fungicides of triazole derivatives and imidazole derivatives were briefly introduced.2.4-Aminocarbonyl substituted 4H-3,1-benzoxazine derivatives were synthesized using sequential Passerini/Staudinger/aza-Wittig reaction. The synthetic conditions and properties of the target compounds were studied and discussed. The unexpected phenomena of the reaction while pyruvic acid was used in the Passerini reaction were explained, and using further intermolecular aza-Wittig reaction via iminophosphoranes and isocyanates also give 4-aminocarbonyl substituted 4H-3,1-benzoxazine derivatives through carbodiimides and nucleophilic addition reaction. The synthetic routes could be used as new method to construct 4H-3,1-benzoxazines not only due to the easily accessible starting materials, but also for the simple operation, mild reaction conditions and the high yields. Following are the synthetic routes. (?) (?)3.A series of 3,4-dihydro-2,3,4-trisubstitued quinazoline derivatives were synthesized using sequential Ugi/Staudinger/aza-Wittig reaction,and the structures of the target compounds were characterized via IR,1HNMR,13CNMR,MS and elemental analysis,and the spectral properties were also studied.Furthermore,the structure of the qninazoline derivatives was further confirmed and analysised through X-Ray single crystal diffraction by one representative compound.Through the structure analysis of the target molecules,a possible mechanism for the formation of the 3,4-dihydroquinazolines is proposed.It is the first report that N,N-disubstituted amides(containing no N-H moiety)could react with carbodiimides,and 3,4-dihydroquinazolines were formed through the further rearrangement of acyl group.The influence on the reaction of substituents was also studied, and following is the synthetic route. (?)4.A sequential Ugi/Staudinger/aza-Wittig/nucleophilic addition reaction was developed to construct indolo[1,2-c]quinazoline derivatives,starting from carboxylic acid,2-azidobenzaldehyde, 2-acylaniline and isocyanide.And the structures of the compounds were characterized through IR, 1HNMR,13CNMR,MS and elemental analysis,the spectral properties were also discussed.The structure of the indolo[1,2-c]quinazoline derivatives was further established through X-Ray single crystal diffraction by one representative compound.Through the structure analysis of the target molecules,a possible mechanism for the formation of indolo[1,2-c]quinazolines is proposed.And this is the first report of the cyclization of the Ugi adduct to give indole ring system via the nucleophilic addition reaction of the methine group to the carbonyl group. Furthermore, the influence of substituents on the reaction was studied,and it is confirmed that the quinazoline ring together with the indole ring were formed sequentially through controlled reactions.Following is the synthetic route. (?) 5.A series of unreported 1,2,4-triazole derivatives were designed and synthesized using Ugi reaction.And based on the lead compound"Diniconazole",a commercial triazole fungicide,novel 3-azolyl-quinoline derivatives were designed and synthesized using Friedlander reaction,on the assumption that introduce the chainlike-Diniconazole into heterocycles.Following are the synthetic routes. (?) (?)6.The fungicidal activities against Penicilium digitatum of partial target compounds were tested, and initial screening show that the some compounds have activities against Penicilium digitatum.For example,compound 30n exhibited 90% inhibition activity against Penicilium digitatum in 50 ppm. Further fungicidal activity test found that the compound 30n still exhibited 99% inhibition activity against Septoria nodorum even in 10 ppm. (?)■...