Oxadiazoles 3-halogeno

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. 

When treated with dilute hydrochloric acid, the mercuric derivatives regenerate the starting oxadiazoles. They also react with halogen to yield the 5-halogeno-oxadiazoles. 

When electronegative substituents are present, oxadiazoles undergo nucleophilic reactions on the carbon atoms, both in position 3 or 5- The substitution of halogen, alkoxy and trichloromethyl derivatives has. been studied. 5-Halogeno-oxadiazoles react with ahphatic and aromatic primary and secondary amines, to give the corresponding amino-derivatives. With sodium hydroxide and -alcoholate, hydroxy and alkoxy oxadiazoles are obtained 25 a, 55 b). 

For example, 3-halogeno oxadiazoles are hydrolysed only when heated in alkaline solution and 3-trichloromethyl oxadiazoles react with NaOH at the level of the CCI3 group rather than on the 3-carbon of the heterocycle. 

Halogeno derivatives can be prepared from 3 i onosubstituted oxadiazoles. Direct substitution is not possible however, they are easily prepared via mercurated derivatives (see p. 837). 

Methyloxadiazole and HgClg yield a complex XLIV. S-Phenyl-oxadiazole and HgCl gives directly the substituted derivative XLV. These mercurated compounds, on treatment with a halogen, yield the desired 5-halogeno-oxadiazoles 25a). 

Amino-l,3,4-oxadiazoles (205) on treatment with cr-halogeno-ketones gave intermediate quaternary salts 206 that did not cyclize directly to imidazo[2,l-6]oxadiazoles (208) with base. Hydrolysis of 206 with aqueous potassium carbonate caused ring-opening at C-2 with subsequent closure to the imidazolone 207. These latter compounds could be cyclized to 208 with phosphorus oxychloride.204c 21 246... 

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