1.2.4- Oxadiazoles, formation

This oxadiazole formation involves O-acylation of the amidoxime followed by a condensation. 

R, R- = aryl, heieroaryl, alkyl Scheme 5.35 Oxadiazole formation. 

In comparison to N—S bond formation, O—N bond formation by essentially oxidative procedures has found few applications in the synthesis of five-membered heterocycles. The 1,2,4-oxadiazole system (278) was prepared by the action of sodium hypochlorite on A(-acylamidines (277) (76S268). The A -benzoylamidino compounds (279) were also converted into the 1,2,4-oxadiazoles (280) by the action of r-butyl hypochlorite followed by base. In both cyclizations A -chloro compounds are thought to be intermediates (76BCJ3607). 

The irradiation of 3-amino-5-phenyl-l,2,4-oxadiazole (98) gave the corresponding 1,3,4-oxadiazole (99) (Scheme 41) [88JCS(P1)1313 88JHC931 95FI(41)2095). The formation of 99 has been explained by assuming a RCRE mechanism. 

Oxadiazole was obtained through the first excited singlet state. When the reaction was carried out in the presence of a triplet sensitizer, 99 was not detected but the quinazolinone 100 was obtained (Scheme 41) [91JCS(P2)187]. Compound 99 cannot be obtained via the Dewar isomer. The author supposed the formation... 

A hyperbranched polymer 42 comprising oxadiazole subunits has been synthesized, but defect formation in such a structure appears to limit its use as a holeblocking material [74]. 

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

Many other miscellaneous additions of alcohols have been described. Polar addition of methanol to 2//-pyrroles264 and to azepines265 has been observed. Photoaddition of methanol to the 1,3,4-oxadiazole 320 is followed by cycloelimination of methyl benzoate (321) to give the ylid 322.266 An adduct (323) of the ylid and the 1,3,4-oxadiazole has been isolated. Photoaddition of methanol to the quaternary ammonium salt 324 results in ring expansion and the formation of the azonine 325.267... 

The formation of 5-methyl-l,2,3-oxadiazole 3-oxide 9 by the fixation of nitric oxide (NO) using propynyllithium has been investigated using ab initio (U)MP2 and DFT/(U)B3LYP methods (Scheme 1) <2005JOC5045>. 

The chemistry of 1,2,3-oxadiazoles is dominated by the sydnones, sydnonimines, and their analogs. There are many examples that employ the standard route to sydnones the method remains unsurpassed. Methods for cyclization have been described that bypass the need for mixed anhydride formation, helping to shorten the standard route (Section 5.03.9.2). 

The irradiation of 3-( -aminophenyl)-l,2,4-oxadiazoles 65 allowed the process to be extended to the formation of an internal N-N bond (Scheme 4), leading either to the indazoles 68 directly from photolytic species 66, or to the formation of benzimidazoles 69, which were formed from the carbodiimide 67, the rearrangement product of photolytic species 66 <1996JOC8397>. 

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>. 

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