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

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. R R' O 1 2 3 960 Quadrelli and Caramella 12 + 11 10 9 + 4 5 6 8 7 -HX 16 a N=O 13 b NH 2 _ X 9 N=O 7 NH 2

The Easy Approach to N-Hydroxy-N-cycloalkenylamides through Nitrosocarbonyl Ene Reactions to Cycloalkenes: Valuable Compounds for Antiviral Syntheses

“…The experiments performed with nitrosocarbonylmesitylene 7B and cycloalkenes 13a-d were conducted by adding mesitylenecarbonitrile oxide (12) to a stirred dichloromethane solution of NMO (1.2 equiv) and excess cycloalkenes 13a-d (10 equiv) at room temperature. The ene adducts 14B(a-d) were isolated in high yields (50-99%) along with small amounts of the corresponding 1,3-dipolar ).…”

“…The reactions were conducted in a simple Pyrex flask by dissolving the Wieland heterocycles 12 16 or 17 in methanol and adding 10 equivalents of the desired cycloalkene 13.…”

The 2:1 cycloadducts from [3 + 2] 1,3-dipolar cycloaddition of nitrile oxide and vinylacetic acid. Synthesis and liquid crystal behaviour

“…The attempts to prepare the bisadduct 7a by reacting 1,2,4-oxadiazole oxide 8 with dipolarophile 5 were unsuccessful. The oxadiazole oxide can be formed by the addition of one equivalent of arylnitrile oxide 4a, which was formed in situ, followed by the subsequent addition of one equivalent of oxime 3a [27]. Furthermore, we failed to prepare the corresponding 3,5-disubstituted isoxazolines 9 from the cycloaddition of the aryloxime 3a and the aryl ester derived from vinylacetic acid 5 due to the base-induced isomerisation of vinylacetic acid to crotonic acid that was observed in the esterification step [28][29][30].…”

1,2,4‐Oxadiazole 4‐Oxides as Nitrones in 1,3‐Dipolar Cycloaddition Reactions to Vinyl Ethers

“…[1] These compounds remained largely a chemical curiosity until very recently when further studies on their synthesis and reactivity widened their applications. [2] These heterocyclic N-oxides have properties that are closely related to the chemistry of nitrile oxides 2, which were actively studied in the past half century and provided the first access to disubstituted 1,2,4-oxadiazole 4-oxides carrying the same substituents (referred to herein as symmetrical). [3] The dimerization of 2 typically affords furoxans 3 in the absence of special additives.…”

“…Alternatively, under slightly different catalytic conditions (BF 3 excess or pyridine/EtOH), nitrile oxides 2 afford the six-membered dioxadiazines 4 (Scheme 1). [2] However, the more general route to 1,2,4-oxadiazole 4-oxides 1 is based on the nitrile oxide 2 cycloadditions to amidoximes 5, which afforded, through the labile adducts 6, either the symmetrical or the asymmetrical (R ϶ RЈ) disubstituted 1,2,4-oxadiazole 4-oxides 1 by combining nitrile oxides 2 with amidoximes 5 carrying the same or different substituents in benzene or methanol. [4] [a] Dipartimento di Chimica, Università degli Studi di Pavia Viale Taramelli 12, 27100 Pavia, Italy Fax: +39-0382-987323 E-mail: paolo.quadrelli@unipv.it pierluigi.caramella@unipv.it Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201101615.…”