Studies On (Catalytic Aza-)Wittig Reaction And Its Application In Synthesis Of Biologically Active Heterocycles

Scientists have expressed great concern about pesticides because of their significance to foodstuffs safety in production. Most of pesticides are heterocyclic compounds. Therefore, how to quickly and efficiently synthesis diverse and multi-substitued heterocyclic compounds to find out new pesticides has always been an important area of organic chemistry and medicinal chemistry research. In this dissertation, a series of fully substituted oxazoles were synthesized by a sequential Passerini/Staudinger/intramolecular aza-Wittig reaction. We also prepared a series of 2,3-dihydro-1H-2-benzazepin-1-ones and 3H-2-benzoxepin-1-ones via the tandem Ugi reaction or Passerini reaction and intramolecular Wittig reaction. A series of 4(3H)-quinazo lines, 1,4-benzodiazepin-5-ones and isoquinolin-1(2H)-ones were synthesized via catalytic intramolecular aza-Wittig reaction or catalytic intramolecular Wittig reaction. Furthermore, we designed and prepared three series of new skeleton 1,2,4-triazole derivatives. The spectral properties of the target compounds and the conditions of the synthesis were discussed. We also measured the fungicidal activity of target compounds against Gibberella saubinetii, Magnaporthe grisea, Penicillium digitatum, Penicillium italicum and Rhizoctonia solani at the 50 mg/L concentration. Detailes were summarized as follows: 1. The latest development and applications of the Wittig rection and aza-Wittig reaction in synthesis of heterocyclic compounds were reviewed.2. A series of fully substituted oxazoles were synthesized via the sequential Passerini/Staudinger /intramolecular aza-Wittig reaction. The spectral and synthesis conditions of 2,4,5-trisubstitued oxazoles were studied. The antibacterial activities of the target compouneds Ⅱ-4 were tested. The results show that compound Ⅱ-4 has good inhibitory activities on Penicillium digitatum, Penicillium italicum and Rhizoctonia solani, which show the best inhibitory on Rhizoctonia solani. Most of compounds inhibition rate is about 70%. When the group of R2 contains Cl, the compound shows better inhibitory activities. In summary, the compounds of fully substituted oxazoles Ⅱ-4 show great potential in inhibitory activities. Following are the synthetic routes.3. A series of 2,3-dihydro-1H-2-benzazepin-l-ones and 3H-2-benzoxepin-1-ones were synthesized via a tandem Ugi reaction or Passerini reaction and intramolecular Wittig reaction. The structures of the target compounds 2,3-dihydro-1H-2-benzazepin-1-ones and 3H-2-benzoxepin-l-ones were characterized by 1H NMR,13C NMR, MS, and elemental analysis. We also tested the antibacterial activities of the target compouneds Ⅲ-4 and Ⅲ-7. The results show that compound Ⅲ-4 has good inhibitory activities on Penicillium digitatum, Penicillium italicum and Rhizoctonia solani, which also show moderatamente inhibitory activities on Gibberella saubinetii and Magnaporthe grisea. We also got a compound of Ⅲ-4f which has good inhibitory activities. While, the compound 7 has no significant inhibition. Following are the synthetic routs.4. The catalytic aza-Wittig reaction based on phosphine(Ⅲ)/phosphine(Ⅴ) oxide catalytic cycle has been developed. A variety of 4(3H)-quinazolinones Ⅳ-3 was obtained via the catalytic aza-Wittig reaction with triphenylphosphine used in catalytic amount, and the air-stable and inexpensive tetramethyldisiloxane (TMDS)/Ti(OiPr)4 used as reductant. This protocol also facilitated the synthesis of natural product (S)-vasicinone with >99% ee. We also tested the antibacterial activities of the 4(3H)-quinazolinones Ⅳ-3. The results show that compound Ⅳ-3 has good inhibitory activities on Penicillium digitatum, Penicillium italicum and Rhizoctonia solani, Gibberella saubinetii and Magnaporthe grisea. We also got a compound of Ⅳ-3h which has good inhibitory activities on Rhizoctonia solani with the inhibition rate of 94%. Following are the synthetic routes.5. A series of 1,4-benzodiazepin-5-ones Ⅴ-5 were efficiently prepared via catalytic aza-wittig reaction. The spectral properties of the target compound were studied. We also tested the antibacterial activities of the 1,4-benzodiazepin-5-ones Ⅴ-5. The results show that target compound Ⅴ-5 has general inhibitory activities on Penicillium digitatum and Rhizoctonia solani, while only has poor inhibitory activities on Gibberella saubinetii and Magnaporthe grisea. Following are the synthetic routes.6. The first catalytic intramolecular Wittig reaction based on phosphine(Ⅲ)/phosphine(Ⅴ) oxide catalytic cycle has been developed. A variety of isoquinolin-1(2H)-ones Ⅵ-4 were obtained via the catalytic intramolecular Wittig reaction with organophosphorus reagent used in catalytic amount, and the air-stable and inexpensive tetramethyldisiloxane (TMDS)/Ti(OiPr)4 used as reductant. The structures of the target compounds were characterized by’H NMR,13C NMR and HRMS. The results of the tested the antibacterial activities show that target compound Ⅵ-4 only has poor inhibitory activities. Following are the synthetic routes.7. Three series of new skeleton 1,2,4-triazole derivatives were designed and synthesized. The fungicidal activity of target compounds against Gibberella saubinetii, Magnaporthe grisea, Penicillium digitatum, Penicillium italicum and Rhizoctonia solani at the 50 mg/L concentration were measured. The initial results show the compound Ⅶ-3 has good inhibitory activities on Penicillium digitatum, Penicillium italicum, Rhizoctonia solani, Gibberella saubinetii and Magnaporthe grisea. The compound Ⅶ-4 has general inhibitory activities on Penicillium digitatum and Rhizoctonia solani. The compound Ⅶ-5 has good inhibitory activities on Penicillium digitatum, Penicillium italicum and Rhizoctonia solani, such as compound Ⅶ-5e has 89% inhibition rate on Rhizoctonia solani. Following are the synthetic routes.