1,2,4-Oxadiazole ring synthesis

There is an extensive literature on the use of 2,1,3-benzoxadiazole 1-oxide [often called benzofuroxanie) (BFO) (462)] as a substrate for the primary synthesis of quinoxaline 1,4-dioxides and occasionally quinoxaline mono-A -oxides or even simple quinoxalines. Very few substituted derivatives of the parent substrate (462) have been employed in recent years. The general mechanism clearly involves a fission (usually amine-catalyzed) of the oxadiazole ring followed by reaction with an ancillary synthon. The following examples are divided according to the type of synthon employed. 

An interesting example of oxadiazole ring formation from formally O-C-N-N-C-O component 109 is the synthesis of tricyclic system (pyridooxadiazolpyridine) depicted in Scheme 26 <1998MI655>. 

A synthesis and physicochemical characterization, including molecular second-order nonlinear optical properties, of new push-pull-based chromophores 170 properly functionalized for polymerization and containing oxadiazole rings were reported <2002J(P2)1791>. 

The physical and chemical properties of the 1,2,4-oxadiazoles are also reviewed in this report. In particular, the stability of the ring system is discussed when only one or no substituent is present, and when the substituents contain functional groups. Attention is also particularly drawn to some novel routes of synthesis leading to the oxadiazole ring. 

Even though N-acylated amidoximes have never been isolated, their existence as intermediates in some reactions involving the formation of the oxadiazole ring cannot be excluded. Indeed, the formation of N-acyl-amidoximes is postulated in the following methods of oxadiazole synthesis. 

Some new methods for the synthesis of the oxadiazole ring have been recently published. 1,2,4-Oxadiazoles can be easily obtained in a one-pot solvent-free process starting from P-keto esters 169 and amidoximes 170. The process is likely to go through an acyl ketene intermediate <07TL2231>. 

For the first time, the 1,2,4-oxadiazole ring has been used as a bioisosteres of the ester group in the field of nucleotide chemistry for the production of inhibitors of the bacterial cell-wall synthesis like compound 171.<07JA12642>. 

LI Y, Liu J et al (2006) Stereoselective synthesis and fungicidal activities of (E)-a-(methoxyimino)-benzeneacetate derivatives containing 1,3,4-oxadiazole ring. Bioorg Med Chem Lett 16 2278-2282... 

The reaction sequence of Scheme 3 might well be classified as an imidazole synthesis from other heterocycles, but it seems more logical to treat this as a cyclization involving formation of the 1,5-bond. The enaminoketone condensation products (12) of 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl compounds are cyclized by base to imidazoles (13) in 60-80% yields." Such a reaction makes use of the well-established general attack of a nucleophilic center in the side chain on N-2 of the oxadiazole ring. Benzamidine combines with 2-amino-3-phenacyl-l,3,4-oxadiazolium bromides to produce 1-acyl-amino-2-benzimidoylamino-4-arylimidazoles. ... 

The paths to the production of compounds containing an oxadiazole ring from isatoic anhydrides are more varied. For example, the synthesis of 5-(2-aminophenyl)-3-phenyl-l,2,4-diazole in two stages was patented a mixture of phenylacetonitrile, hydroxylamine sulfate, and the salt of the dibutylamide of sulfonated oleic acid was kept with an aqueous solution of sodium carbonate at 90°C for 5 h, the anhydride 1 was added, and the reaction mixture was kept at the same temperature with 50% aqueous sodium hydroxide for 1 h [12],... 

Compound 267, containing condensed imidazole and quinazoline rings and also a 1,2,4-oxadiazole ring, was obtained by a two-stage synthesis [178]... 

Mikroyannidis, J.A., Spiliopoulos, I.K., Kasimis, T.S., Kulkarni, A.P., Jenekhe, SA, 2004. Newpoly(p-phenylene vinylene) derivatives with two oxadiazole rings per repeat unit synthesis, photophysical properties, electroluminescence, and metal ion recognition. J. Polymer Sci. Part A42, 2112-2123. 

K1Z Kizhnyaev, V.N., Pokatilov, A.F., Vereshchagin, L.I., Adamova, L.V., Safronov, A.P., and Smirnov, A.I., Synthesis and properties of caibon-chain polymers with pendant 1,3,4-oxadiazole rings, Russ. J. Appl. Chem., 79, 1167, 2006. 

Interestingly, Frizon et al. reported for the first time the synthesis and characterization of LC-based diselenides by couphng of aryl bromides with elemental selenium using a copper oxide nanopowder catalyst. These new structures, e.g., 42, which are characterized by the presence of 1,2,4-oxadiazole rings, exhibit a smectic A phase by POM and DSC, and showed weak blue fluorescence in solution (2012LC769 Figure 8). 

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