1.2.5- Oxadiazoles forming 1,2,4-triazoles

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>. 

The same research group has shown that the 5-fluorophenyl-l,2,4-oxadiazoles 73 (Scheme 6) form the triazoles 74 as the major products in the presence of amine nucleophiles, together with varying amounts of side products 75-77, with product 76, for example, being formed by the competitive addition of the methanol solvent to the N-O-cleaved photolytic product <2005H(65)387>. The formation of quinazolin-4-ones 75 has been studied separately, and has been optimized to allow good yields as shown by the example in Equation (6) <1999JOC7028>. 

Thermal recyclization of the 3-diazenofuroxanyl unit to form the 4-nitro-l,2,3-triazole fragment has been found in noncondensed 1,2,5-oxadiazole 2-oxide derivatives (3,3 -azofuroxans) with acetamido substituents in the 4,4 -posi-tions <1999MC17>. 

The reaction of 5-aryl-3-(chloromethyl)[l,3,4]oxadiazole-2(3//)-thiones 100 with hydrazine or methylhydrazine yields the corresponding 2,3-dihydro[l,2,4]triazolo[3,4-A][l,3,4]oxadiazole derivatives 102 <1984JCED477>. By analogy, hydrazine and phenylhydrazine convert the [l,2,4]triazole-2(3//)-thiones 101 into 3,7-dihydro-2//-[l,2,4 tria-zolo[4,3-r][ 1,2,4] triazoles 103 <1992PS99, 2002JCCS1035>. Finally, the azole-2(3//)-thiones 101 react with hydroxylamine to form the 3,7-dihydro[l,2,4]triazolo[5,l-d[l,2,4]oxadiazoles 104 (Scheme 8) <1992PS99>. 

Acyl substituents at the 3- and/or 4-positions result in decreased hydrolytic stability compared with the alkyl and aryl derivatives described above. Despite this constraint most of the usual reactions of the carbonyl group are possible. Aldehydes <9ILA1211> and ketones are oxidized to the carboxylic acid, borohydride reduction affords the expected alcohols, and epoxides are formed on reaction with diazomethane. Oximes and arylhydrazones are formed with hydroxylamine and arylhydrazines, and the products may subsequently undergo monocyclic rearrangement involving the oxadiazole to give the corresponding isomeric furazans and 1,2,3-triazoles (Section 4.05.5.1.4). 

Pyrimidones (472) react with hydrazine hydrate at 130-140°C to give the 1,2,4-triazole (473) (83H(20)1243). 1,3,5-Oxadiazinium salts (475) with hydroxylamine give the 1,2,4-oxadiazoles (474) and with hydrazines form the 1,2,4-triazole derivatives (476). The substituents in these cationic species are usually aryl, restricting the appeal of these ring interconversions (65CB334,67CB3736). 

Unlike 1,2,4- and 1,3,4-oxadiazoles, the 1,2,4-triazole heterocycle has the possibility of existing in different tautomeric forms (Scheme 20). X-ray crystal analysis of the peptide-based triazole 63 showed only one tautomerJ102 Additionally, the 13C NMR spectrum for this compound indicated only one tautomeric form since the signals due to C3 and C5 appeared as sharp peaks. This is not the case for some other peptidergic triazoles (Table 5) where peaks corresponding to C3 and C5 were broad and of low intensity or not visible. Differences in tautomeric preferences have been explained by the ability of some triazole-containing peptides to form intermolecular hydrogen bonds and thus stabilize one tautomer over the other. 

In contrast to uncharged TAs, such protonated forms as perchlorates 206 easily react with hydrazines and hydroxylamine at the 2 position to give recyclization products—2-mercaptophenyl triazoles and oxadiazoles 241—which show promise for use as ligands (91KGS1220) (Scheme 94). 

Heterocycles also serve as precursors to 1,2,3-thiadiazoles (B-79MI42400). For example, mercapto-substituted triazole (36) exists in equilibrium with thiadiazole (37 equation 35), as does (38) with (39 equation 36). Isothiazoles may react to form benzothiadiazoles (equation 37). Treatment of 1,2,3-oxadiazoles with ammonium hydrogen sulfide (B-61MI42400) provides yet another route to thiadiazoles (equation 38). 

Examples adduced in Scheme 87 indicate the caution required when a nitrilimine intermediate favours the formation of a heterocycle other than triazole. The bromo derivative (179) of the semicarbazone (180) is formally analogous to (172) the nitrilimine (181) is formed even in the presence of such weak bases as sodium acetate or water and undergoes ring closure to the 1,3,4-oxadiazole (182), In anhydrous acetic acid the triazolinone (183 R = H) is formed (72JCS(P1)1918) a similar reaction occurs on treating the iV-methyl homologue of (180) with bromine in acetic acid to obtain (183 R = Me). 

Alkyl- and aryl-triazolium compounds are formed mostly by quaternization of preformed triazoles, more rarely by rearrangement of oxadiazoles proceeding through acylamidrazone intermediates. An unusual method (Scheme 136) is the addition of the alkoxydiazenium fluoroborate (312) to the Schiff base (313) to form the triazolium salt (314) through a mechanism that may involve a triazolidine intermediate (315) (69CB3176). 

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