Heterocyclics oxadiazoles

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). 

Any heterocycle containing the OCH=CH moiety can in principle extrude the superfluous fragment and form oxirene, as illustrated for a five-membered ring in Scheme 105. Probably the most propitious AB fragment would be nitrogen, but the required 1,2,3-oxadiazole (123) is unknown (see Chapter 4.21), probably because of ready valence tautomerization to diazoethanal (Scheme 106) (this approach has been spectacularly successful with the sulfur analogue of (2) (8UA486)). The use of (123) as an oxirene precursor is thus closely linked to the important diazo ketone decompositions discussed in Section 5.05.6.3.4(f). 

Deviations of this magnitude are very unusual but can also be found for other sensitive heterocycles, such as 1,2,5-oxadiazole-2-oxides. Although the authors... 

Acylation of benzamidoxlme (144) with chloropropionyl chloride gives the 0-acylated derivative (145). Reaction of that intermediate with diethylamine serves first to cyclize the molecule to the 1,2,4-oxadiazole heterocycle subsequent displacement of the halogen on the side chain gives oxolamine (146),a drug with antltussive and spasmolytic activity. 

Heterocycle = quinoxaline, imidazole, oxadiazole, benzoxazole, benzimidazole... 

From a medicinal chemist s point of view, oxadiazoles are among the most important heterocycles as they are one of the most commonly used bioisosters for amide and ester groups [67]. As such it is hardly surprising that the two regioisomeric oxadiazole scaffolds received the most interest in the field of microwave-assisted synthesis using polymer-supported reagents. 

In 2005, a group of researchers at Abbott turned their attention to the synthesis of a different regioisomer, the 1,2,4-oxadiazoles [75]. These heterocycles are normally prepared by reaction (mediated by a couphng reagent) of a carboxyhc acid with an amidoxime, followed by based-catalyzed cychzation at high temperature (Scheme 11). 

Many other examples have been prepared (2) from the corresponding aminomethyl heterocycles using the very versatile reaction between HHTs and diaryl phosphites, as demonstrated specifically above for the 5-phenyl-l,3,4-oxadiazole system. Conversion of the 2-aminomethyl-l,3,4-oxadiazole 68 to the required HHT intermediate 69 was accomplished... 

Although benzofuroxan (Bfx) and furoxan (Fx) were first synthesized over 100 years ago, it was not until the middle of the 20th century that its relevant bioactivities were identified. Bfx s and Fx s relevant biological behaviors convert these systems in one of the most current study heterocycles in medicinal chemistry. Formally, these compounds are 1,2,5-oxadiazole hf-oxide derivatives, specifically Bfx should be named as benzo[l,2-c][l,2,5]oxadiazole 1-oxide and Fx as 1,2,5-oxadiazole 2-oxide, however, the common trivial... 

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]. 

The concept of five-membered ring heterocyclic synthesis by transformation of the initial adduct of the ADC compound and substrate is not limited to cyclization of substitution products. l,3,4-Oxadiazol-2-ones (30, Scheme 3) result from heating the initial DEAZD-dichlorocarbene adduct.72 Treatment of the Diels Alder adducts 96 with zinc in acetic acid gives pyrroles in good yield (Eq. 17).151 The reaction has been extended to the synthesis of dipyrroles from the appropriate Diels-Alder adduct (96, R = pyrrol-2-yl). 

Ring syntheses of 1,2,4-oxadiazoles from other heterocycles 282... 

The role of substituents X on the mononuclear heterocyclic rearrangement (MHR) of 20 phenylhydrazones 54 of 3-benzoyl-5-phenyl-l,2,4-oxadiazole into the triazoles 55 (Equation 2) has been investigated, allowing the influence of X on the product distribution to be evaluated and first-order rate constants and Hammett correlations to be determined <1999T12885>. 

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>. 

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