Fluorinated 1,2,4-triazoles

The first synthesis of ring-fluorinated 1,2,4-triazoles was reported in 1973. Reaction of 3(5)-nitrotriazoles with liquid HF at 150°C produces the corresponding 3(5)-fluoro-1,2,4-triazole in good yield (Fig. 3.83). Although an efficient process, the reaction conditions make routine application problematic. 

FIGURE 3.84 Synthesis of fluorinated 1,2,4-triazoles by halogen exchange. 

Fluorinated triazole derivatives have been prepared by a somewhat deceptive route that starts with imine perfluoro(5-aza-4-nonene) 140 reaction of 140 with aromatic hydrazines gives 1,2,4-triazoles 141a-g in good yields (Equation 44 and Table 27) <2001RJ01621, 2001ZOR1693>. 

Irradiation of 1,2,4-oxadiazoles 205 bearing fluorinated substituents in the 3- or 5-positions in the presence of an amine delivered the corresponding 1,2,4-triazoles 206a-e and 207a-e via a photochemical rearrangement. Several other competing reactions served to divert some of the reactive intermediates and, hence, yields of the fluorinated triazoles were modest (Equation 64 and Table 44) <2005H(65)387>. 

Saperconazole is an experimental, water-insoluble, lipophilic, fluorinated triazole. Its structure resembles that of itraconazole and it has a long half-life. It has a broad antifungal spectrum, including Cryptococcus Species and Aspergillus species. In early studies in cases of compassionate use, only a few adverse effects were described, including hepatotoxicity (1,2), and its adverse effects were expected to resemble those of itraconazole (3). However, the manufacturers stopped developing it because of concerns about toxicity. 

FIGURE 3.93 Synthesis of fluorinated triazole-containing reversed nucleosides by cycloaddition. 

Scheme 53 The ANRORC reactivity in the synthesis of fluorinated triazoles 209 and triazines 211...

Keywords Fluorine Triazole Tetrazoles Heterocycle Synthesis Application Biological activity... 

Nucleophilic substitution of the fluorine atom in 2-fluorobenzonitrile 30 by 1,2,4-triazole gave a 10 1 mixture of 2-[l,2,4]-triazol-l-yl benzonitrile 31 and the corresponding 4-isomer 32 in crude yield of 66% (Equation 6) <2004JME2995>. 

Table 42 Reaction of fluorinated 1,2,4-oxadiazoles with hydrazine to give 1,2,4-triazole derivatives...

The fluorinated 1,2,4-oxadiazoles 70 (Scheme 5) gave, as the major heterocyclic components, the triazoles 71 and 1,3,4-oxadiazoles 72, with the product formed being dependent upon the nature of ZH. Methanol in the presence of TEA, for example, gave an approximately 1 1 mixture of the appropriate 1,3,4-oxadiazole 72 and the triazole 71 (Z = OMe), whereas methanol in the presence of a nucleophilic primary amine gave the triazoles 71 (Z = NHMe, NH2, NHPr, etc.) together with compound 72 <2004JOC4108, 2004JFC165>. 

When R2 substituent is flourocontaining alkyl group, the transformation 17 18 becomes hindered and its proceeding requires some special methods. For example, in [48] Biginelli-like cyclocondensations based on three-component treatment of 3-amino-l,2,4-triazole or 5-aminotetrazole with aldehydes and fluorinated 1,3-dicarbonyl compounds were investigated. It was shown that the reaction can directly lead to dihydroazolopyrimidines 20, but in the most cases intermediate tetrahydroderivatives 19 were obtained (Scheme 10). To carry out dehydration reaction, refluxing of tetrahydroderivatives 19 in toluene in the presence of p-TSA with removal of the liberated water by azeotropic distillation was used. The same situation was observed for the linear reaction proceeding via the formation of unsaturated esters 21. 

---