Oxadiazoles or thiadiazoles

Ring transformation of 2-amino-3-phenacyl-l,3,4-oxadiazolium halides with amines, liquid ammonia or heterocyclic bases gives l-acylamino-2-amino-4-arylimidazoles [57], When treated with an a-halogenoketone in ethanol 2,5-diamino-1,3,4-thiadiazolcs form salts, which react with hydrazine hydrate to give l-aminoimidazolin-2-thiones [58], 

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Unsymmetrical systems can in principle undergo cleavage in either ring. Table V shows that benzazoles are more stable than azoles (e.g., in 415, 348, and 405) and that the s-triazole ring is more stable than the oxadiazole or thiadiazole ring (e.g., in 299c, 303, and 183). 

The heteroatoms in oxadiazoles or thiadiazoles can be arranged in a [1,2,3], a [1,2,4], a [1,3,4] or a [1,2,5] manner. The azoles can be fused to a six-membered ring containing the minimum number of nitrogens in 14 different ways. The possible systems have been classified accordingly as shown in Chart 5. 

Chart 5 Ring systems formed by fusion of oxadiazole or thiadiazole with pyridine or pyridazine containing the... 

Fused ring systems can be prepared either from an azine precursor or from an oxadiazole or thiadiazole precursor. In the sections on the synthesis of these compounds, the former method is grouped under Azine approach , the latter under Azole approach . 

A third problem is the ambiguity of cyclizations leading to oxadiazoles or thiadiazoles as in Scheme 64 where oxadiazole is the minor product 58JOC1912). Conversion of the amidrazone (154) into the triazole (155 Scheme 65) takes place in basic solution, while the oxadiazole (156) is obtained in the presence of acid 69JHC965). However, dehydration of the amidrazone to triazole may take place in polyphosphoric acid. 

Compounds of the 1,3,4-oxadiazole or 1,3,4-thiadiazole series react with hydrazine or substituted hydrazines to afford 1,2,4,5-tetrazines or 4-amino-l,2,4-triazoles, depending on the reaction conditions used. 

The oxadiazole and thiadiazole rings are 7r-eIectron deficient and hence do not readily react with electrophiles at nitrogen or at carbon. Electrophilic attack in the azine ring proceeds in the presence of electron-releasing substituents. 

In addition to these classical changes, much use was made of 1,2,4-oxadiazoles or 1,2,4,-thiadiazoles as carboxylic ester surrogates in series of benzodiazepine and muscarinic receptor ligands (Fig. 13.14). For muscarinic agonists, numerous successful attempts to replace the oxadiazole ring by other heterocyclic ring... 

Oxadiazoles and thiadiazoles contain two sp -hybridized N-atoms and an oxygen or sulfur atom, respectively from each type of heterocycle, four structural isomers are possible ... 

Due to the peculiar features introduced by fluorinated moieties, the synthesis, the reactivity, and the appUcation of fluorinated oxadiazoles and thiadiazoles still are challenging research topics. Therefore, the updated synthetic guidelines reported in this chapter will represent a useful tool for both the experienced synthetic chemists and those willing to embrace the study of fluorinated azoles. For this reason, it is the authors opinion that synthetic information organized by kind of heterocycle is better approached by the reader for faster consultation. On the other hand, reactivity has been presented by focusing on the type and position of the fluorinated moiety, in the attempt to provide general concepts transferable also to other heterocycUc systems. Finally, examples of fluorinated oxadiazoles and thiadiazoles used in materials chemistry or as bioactive compounds have been briefly illustrated to suggest the potential application of newly synthesized compounds. 

In azole chemistry the total effect of the several heteroatoms in one ring approximates the superposition of their separate effects. It is found that pyrazole, imidazole and isoxazole undergo nitration and sulfonation about as readily as nitrobenzene thiazole and isothiazole react less readily ica. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration or sulfonation. Strong electron-donor substituents help the reaction. 

Morpholino-3-[4-phenyl(thiosemicarbazido)carbonyl]quinoxaline (129) gave 2-morpholino-3-(4-phenyl-5-thioxo-5,6-drhydro-4//-l,2,4-triazol-3-yl)quin-oxaline (130) (2M NaOH, reflux, 3 h 35%), 2-(5-anilino-l,3,4-thiadiazol-2-yl)-3-morpholinoquinoxaline (131, X = S) (98% H2SO4, 0°C, 1 h, then 20°C, 12 h 89%), or 2-(5-anilino-l,3,4-oxadiazol-2-yl)-3-morpholinoquinoxaline (131, X = O) (NaOH, H2O, EtOH, I/Kii dropwise, 5°C 95°C, 4 h 81%) analogs of all three products were made similarly. ... 

A number of ring systems have been converted into 1,2,4-thiadiazole derivatives. The most common include 5-imino-1,2,4-dithiazolidines, isoxazoles, oxadiazoles, and 5-imino-l,2,3,4-thiatriazolines. In general, a ring-opening reaction is followed by rotation and ring closure, or the heterocyclic ring may act as a masked 1,3-dipole which reacts with a suitable dipolarophile. 

Other 3,6-disubstituted-[l,2,4]triazolo[3,4- ][l,3,4]thiadiazoles 139 or [l,2,4]triazolo[3,4- ][l,3,4]oxadiazoles 145 were also evaluated for anticancer properties but showed little, if any, activity <2004PS1595, 2004JCCS1343>. 

The amino group of 3-amino-1,2,4-oxadiazoles shows little nucleophilic character. For example, addition to phenyl isothiocyanate to give 3-(phenylthioureido) compounds requires heating of the components without solvent at 120-130 °C or the use of polar aprotic solvents (DMSO, DMF) and long reaction times (30 days at 23°C) <77JCS(P1)1616>. 3-(Thioureido)-1,2,4-oxadiazoles undergo fast ring transformations to thiadiazoles (see Section 4.04.5.1.1). 

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