Studies On Novel Synthesis And Properties Of 8-Azaguanine Derivatives

A large number of 8-azaguanine (1,2,3-triazolo[4,5-d]pyrimidine) derivatives have been synthesized in view of their broad spectrum biological activities, such as antifungal, antiviral, anticancer and antiallergic properties. However, most of the reported synthetic methods involved harsh acid and the heating at high temperature. Over past twenty years, the utility of aza-Wittig reactions in the synthesis of nitrogen heterocyclic compounds have received increased attention due to the mild conditions, good yields and variable for substitutes, which promoted us to synthesis 8-azaguanines by using aza-Wittig reaction. In this thesis, we intend to modify the structure of 8-azaguanine, which had been isolated as the natural fungicide, in order to find high selective, high efficient, environment compatible agricultural fungicide. It's an attracting work but also a challenging one. According to the literature, a famous German organic chemist, Heinrich Wamhoff and a Chinese chemist attempted to do so in 1984 and 2003 respectively, but failed. They just got the uncyclized intermediates. Based on our earlier research foundation, fortunately, after innumerable times of failures, we make it. One hundred and eleven unreported 8-azaguanine derivatives in six series have been synthesized. The structure of all these compounds were confirmed by 1H NMR, 13C NMR, IR, MS, elemental analysed and X-ray diffraction. It may be summarized as follows:Ⅱ-5: 3,6-disubstituted-5-dialkylamino-3,6-dihydro-l,2,3-triazolo[4,5-d]pyrimidin-7-one (24)Ⅲ-5:3,6-disubstituted-5-alkylamino-3,6-dihydro-l,2,3-triazolo[4,5-d]pyrimidin-7-ones (28)Ⅲ-6: 3,6-disubstituted-5-arylamino-3,6-dihydro-1,2,3-triazolo[4,5-d]pyrimidin-7-ones (9)Ⅳ-5: 3,6-disubstituted-5-alkyl (or aryl) oxy 1-3,6-dihydro-1,2,3 -triazolo [4,5-d]pyrimidin-7-one (25)Ⅴ-4: 3, 5-disubstituted-3,5-dihydro-6-arylamino-1,2,3-triazolo[4,5-d]-1,2,4-triazolo[1,5-a] pyrimidin-9-one (12)V-6: 3,5-disubstituted-3,5-dihydro-6-alkyl-1,2,3-triazolo[4,5-d]-1,2,4-triazolo[1,5-a] pyrimidin-9-one (7)Unreported intermediate(6)The reaction of 4-ethoxylcarbonyl-l,2,3-triazole-5-yl-carbodiimide with various neucleo-philes such as amine, alcohol, phenol etc. was studied. Our research indicated that the mixed solvent of ethanol and methylene chloride as well as the catalysis of sodium ethoxide is critical to the cyclizaton of guanidine.The selectivity of cyclization of the carbodiimide with primary amines was investigated also. There is a good selectivity of the cyclization according to the steric hindrance of the primary amine. When R ≠ H, Me and NH2, the reaction of carbodiimide with aliphatic primary amines give guanidine intermediate. In the presence of EtONa, it cyclized to provide only 5-alkylamino- 7-1,2,3- triazolo[4,5-d]pyrimidin-7-ones(III-5), one of the possible regioisomers. On the other hand, the reaction of carbodiimides with ammonia, methylamine or hydrazine (R=H, Me, NH2) gave directly 5-arylamino-7H-1,2,3-riazolo[4,5-d]pyrimidin-7-ones(III-6), the other of the possible regioisomers, as the single product in the absence of sodium ethoxide. A possible mechanism for the selectivity was suggested in this thesis.The reactions of the carbodiimide with alcohol and phenol were studied. The routes of alcohols are similar with that of amines while phenols are very different. When the nucleophile was phenol, the reaction took place in presence of solid potassium carbonate with heating at 45 'C, otherwise only uncyclized intermediate can be got.Further more, with the aim of enhancing the bioactivity of 8-azaguanines, we introduce a 1,2,4-triazole ring to the system by using aza-Wittig reaction again. If hydrazine monohydrate was added into the solution of carbodiimide, automatically cyclization product 6-amino-3-substituted-5-arylamino-3,6-dihydro-[l,2,3]trizaolo[4,5-d]pyrimidin-7-one was obtained with high yield. Here we got a new amino group, which can convert to the second aza-Wittig regent as the amino group in p-enamine ester does. Aza-Wittig reaction of the second iminophos-phorane with aromatic isocyanate...