Oxadiazole rings

In the 1,2,4-thiadiazole ring the electron density at the 5-position is markedly lower than at the 3-position, and this affects substituent reactions. 5-Halogeno derivatives, for example, approach the reactivity of 4-halogenopyrimidines. The 1,2,4-oxadiazole ring shows a similar difference between the 3- and 5-positions. 

The 1,2,4-oxadiazole ring is almost inert to electrophilic attack at carbon and there are no further examples to supplement those few important exceptions reported previously in CHEC-II(1996) <1996CHECII-(4)179>. 

Standard transformations at the a-carbon, as discussed in CHEC-II(1996) <1996CHEC-II(4)179>, proceed without incident. Selected recent examples (Scheme 19 Equation 22) include the conversion of the esters 153 into the hydrazides 154 and thence into the methylene carbohydrazides 155 <2005HC029>, a process that has been shown by the same workers to apply to other aldehydes (benzaldehyde, 4-A Ar-dimethylaminobenzaldehyde, furfuralde-hyde, or thiophene 2-carboxaldehyde) with equal success <1999FES747>, and the conversion of the ester 156 into amide 157 <2005NN1919>, a process that demonstrates the robustness of the 1,2,4-oxadiazole ring. 

The main group of methods for the preparation of a 1,2,4-oxadiazole ring is based on cyclization of amidoxime derivatives in the presence of acylating agents °. A surprisingly easy cyclization of O-benzoyl-/ -piperidinopropioamidoxime 247 to oxadiazole 248 in DMSO at room temperature was described (equation 107) . 3-(3-Aryl-1,2,4-oxadiazol-5-yl)propionic acids 250 were obtained by the reaction of amidoximes 249 with succinic anhydride under microwave irradiation or conventional heating (equation 108) °°. 

Oxadiazoles owe their importance mainly to their biological activities. A basic idea behind many developments is that the 1,2,4-oxadiazole ring is a hydrolysis resisting bioisosteric replacement for an ester functionality <90JMC1128,91JMC140,91QSAR109>. 

Oxadiazol-Ring verhalt sich hier wie ein elektronenziehender Rest am Aren und lenkt die Nitro-Gruppe in die 3-Position45. Disubstituierte Aryl-1,2,4-oxadiazole besitzen keine ba-sischen Eigenschaften und sind daher nicht mit Perchlorsiiure in Eisessig titrierbar57. 

Wie die meisten Azole bilden auch 1,2,4-Oxadiazole mit Metall-Salzen (z. B. vom Zink, Kupfer, Kobalt, Palladium, Platin) stabile Komplexe37, in denen die Koordination vom Metall zum 4-N-Atom des 1,2,4-Oxadiazol-Ringes besteht38 ... 

Bei dieser Aufbauvariante des 1,2,4-Oxadiazol-Ringes stellt die Komponente O—C — N-C den Teil eines Acyl-isocyanates dar, das mit Azido-trimethyl-silan als N-Lieferant formal das Het-aren bildet. 

Im allgemeinen treten Alkylierungen von Pyridyl-l,2,4-oxadiazolen am N-Atom des Pyridin-Ringes ein und nicht am 1,2,4-Oxadiazol-Ring (S. 505)75. 

Die 5-standige Trichlonnethyl-Gruppe am 1,2,4-Oxadiazol-Ring laBt sich durch Amine, Hydrazine und Guanidine substituieren. Entweder arbeitet man in einem Losungsmittel wie Ethanol oder Acetonitril oder durch einfaches Erwarmen beider Komponenten. 

Wie bereits erwahnt (S. 496), ist eine direkte Nitrierung am 1,2,4-Oxadiazol-Ring nicht moglich. Bei Aryl-1,2,4-oxadiazolen verhalt sich der 1,2,4-Oxadiazol-Rest wie eine elektronenziehende Gruppe und lenkt die Nitro-Gruppe daher in die meta-Position des Arens110. 

Unter Erhalt des 1,2,4-Oxadiazol-Rings ist es moglich, mit Dinatriumdichromat in Eisessig/ Schwefelsaure die Methyl-Gruppe am Phenyl-Rest in 5-(2-Methyl-phenyl)-3-phenyl-l, 2,4-oxa-diazol zur Carbonsaure aufzuoxidieren [5-(2-Carboxy-phenyl)-3-phenyl-l, 2,4-oxadiazol 68% Schmp. 148-150c]55. 

Glaxo scientists have reported on a new series of H3 antagonists that contain a 1,2,4-oxadiazole ring as a bioisostere equivalent of the isothiourea functionality of... 

The rearrangement is the transformation of one of the acetamidofuroxan cycles into the 1,2,4-oxadiazole ring with the cleavage of the 0(1)-N(5) bond of the furoxan and the formation of a nitromethylene fragment [558] (Scheme 104). 

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>. 

Replacement of the methyl ester moiety of the muscarinic partial agonist arecoline (16) by the putative nonclassical bioisosteric 1,2,4-oxadiazole ring system (18), where R = un-... 

The 1,2,4-oxadiazole ring system of quis-qualic acid (19), an agonist at a subpopulation... 

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