1.2.5- Oxadiazoles forming 1,2,4-thiadiazoles

Chart 5 Ring systems formed by fusion of oxadiazole or thiadiazole with pyridine or pyridazine containing the... 

The ring bond order deviation from uniformity partially agreed with the order of reactivity computed on the basis of FMO energy gaps. The least aromatic was 1,2,5-oxadiazole, while 1,2,3-thiadiazole should be most aromatic (Table 36). The order of reactivity was oxadiazole, triazole, thiadiazole in all 1,2,3-, 1,2,5- and 1,3,4-series of the three heteroatom heterocycles. Except for 1,3,4-oxadiazole, the two other 1,3,4- five-membered heterocycles were predicted to be more reactive than their 1,2,3- isomers (Table 36). The prediction that 1,2,5-oxadiazole was the most reactive heterocycle as a diene for Diels-Alder reaction was unacceptable due to the fact that two C-N bonds should be formed in the course of the reaction, which usually requires an exceptionally high activation barrier. 

When the nitrogen nucleophile is replaced by a sulfur nucleophile, thiadiazoles can be formed. Thus, as shown in Scheme 7, the 5-amino-l,2,4-oxadiazole 78 gives the photolytic intermediate 79, which is intercepted by a thiourea to give intermediate 80, followed by ring closure and elimination to give the thiadiazoles 81 <1997T12629>. 

Amino-l,3,4-thiadiazol-2-yl)-l,2,5-oxadiazole-3-amine 175 was formed with a yield of more than 75% in a condensation of 3-amino 4-cyano-l,2,5-oxadiazole 174 with thiosemicarbazide in trifluoroacetic acid (Equation 30)... 

In contrast to imidazo[2,l-h][l,3,4]oxadiazoles (see Section III), im-idazo[2,l-h][l,3,4]thiadiazoles form stable salts (hydrohalides, perchlorates, picrates, picronolates). Hydrohalides are often the primary products of the cyclization reaction. 

Oxadiazoles are difficult to alkylate. However, N-methylfurazinium salts are formed on heating furazans with dimethyl sulfate (74AJC1917,95JCS(P1)1083) the reaction is approximately 7 and 62 times slower, respectively, than the corresponding methylations of 1,2,5-thiadiazole and isoxazole. The N-ethyl salts of furazan itself and 3-phenylfurazan have been prepared using triethyloxonium tetrafluoroborate (64JA1863). 

Of the various heterocycles discussed in this chapter, the pyridofuroxans show the least aromatic character. In Section 7.10.5.4, subtle differences in aromaticity between the [l,2,5]thiadiazolo[3,4-c]pyridines and the [l,2,5]oxadiazolo[3,4-c]pyridines are apparent from their dissimilar reactivity towards various reducing agents. In contrast to the former where desulfurization of the thiadiazole ring or substituent reduction occur, the latter heterocycles undergo initial reduction of the C=N bond to form the 4,5-dihydro[l,2,5]oxadiazolo[3,4-c]pyridines (120) with sodium borohydride at ambient temperature (Scheme 19). However, at 80 °C, the oxadiazole moiety is preferentially reduced... 

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). 

As for azines such as pyridine (Section 2.2.1.2.3), some azoles and their derivatives form A-oxides in which the exocyclic oxide is in conjugation with the ring. 1,2,5-Oxadiazoles, e.g., 46, commonly known as furazans, are oxidized to the A-oxides known as furoxans, e.g., 47. Derivatives of benzofuroxan 48 are well known. Since sulfur can also be oxidized, derivatives such as the 1,2,3-thiadiazole trioxide 49 are not uncommon (Figure 9). 

Oxadiazoles," 1,3,4-oxadiazoles" and 1,2,5-oxadiazoles are well known, but the 1,2,3-oxadiazole system, which calculations indicate to be unstable relative to its ring-open diazo-ketone tautomer," is known only as a benzo-fused derivative (in solution) and in mesoionic substances, known as sydnones ," which have been well investigated. Furoxans ," which are formed by the dimerisation of nitrile oxides, have also been extensively studied. 1,2,3-Thiadiazoles, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles" and... 

The reaction of diethyl 3,4-dimethylthieno[2,3-Z ]thiophene-2,5-dicarboxylate (117, R = Me, EWG = C02Et) with hydrazine hydrate afforded dihydrazide 231, which was subjected to various transformations. For example, the reactions with acetylacetone, ethyl acetoacetate or malononitrile (93BCJ2011) are accompanied by the closure of the exocyclic pyrazole ring to form the corresponding derivatives 232-234. The reaction of dihydrazide 231 with carbon disulfide in the presence of KOH followed by decomposition with dilute HCl or concentrated H2SO4 produces di(oxadiazole) (235) or di(thiadiazole) derivative (236). Condensation of di(oxadia-zolyl)thienothiophene 235 with hydrazine hydrate affords di(triazolyl)thienothio-phene 237. 

Synthesis from Acylhydrazines. The condensation of acyl hydrazines and ethyl dithioacetate in boiling ethanol furnishes 5-aryl-2-methyl-l,3,4-thiadiazoles, but 1,3,4-oxadiazoles are formed as main products in some cases. Under suitable conditions, the intermediate thioacetylacylhydrazines may be isolated. ... 

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