Synthesis and Synthetic Applications of 1,2,4-Oxadiazole-4-Oxides

Paolo Quadrelli; Pierluigi Caramella

doi:10.2174/138527207781058745

Abstract

The first 1,2,4-oxadiazole-4-oxide was prepared by Wieland a century ago, but this compound remained largely a chemical curiosity until very recently. 1,2,4-Oxadiazole-4-oxides are a family of heterocycles closely related to the chemistry of nitrile oxides which were actively studied in the past half century and provided the basic knowledge on 1,2,4-oxadiazole-4-oxides. The dimerizations of nitrile oxides under acidic or basic conditions were thoroughly studied by different research groups, and offer the more common entries to the symmetrical substituted 1,2,4-oxadiazole-4-oxides. A more general route to symmetrical and unsymmetrical substituted 1,2,4-oxadiazole-4-oxides is based on the nitrile oxide cycloadditions to amidoximes. A variety of other 1,2,4-oxadiazole-4-oxides forming reactions are also known in the literature. Many of these reactions were neither fully exploited nor mechanistically understood since they require unusual starting reagents, often difficult to prepare, or take place affording complex mixtures of products. Some of these methods still await for improved procedures and proper mechanistic attention to be of general use and will be reviewed shortly. The chemistry of 1,2,4-oxadiazole-4-oxides is related to the fragility of the heterocyclic ring, which undergoes thermal or photochemical cycloreversion to nitriles and nitrosocarbonyl intermediates. Trapping of the nitrosocarbonyls takes place easily with dienes and enes, affording a variety of hetero Diels-Alder and ene adducts, which attract great interest because of their useful synthetic elaboration toward many natural products of potential pharmaceutical applications. The high efficiency of the photochemical cleavage of 1,2,4-oxadiazole-4-oxides at room temperature or well below affords the softest entry to the nitrosocarbonyls and allows for the study of their chemistry under convenient and simple experimental conditions. The photochemical cleavage have been applied successfully to Solid Phase chemistry, allowing for a safe and environmental friendly methodology for the synthesis of important intermediates. This report is comprehensive of the synthesis and synthetic applications of the 1,2,4-oxadiazole-4-oxides.

Keywords: Beckmann formulation, nitrile oxides, Dimerization, Cycloaddition, biscycloadducts, HCl catalyzed methods

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