2- 1,3,4-oxadiazole

Pyrazolone derivatives were widely used in the last century, but nowadays their medicinal application has been strongly reduced due to their considerable side-effects. 

Several oxo compounds are derived from pyrazolidine, a cyclic N,N -disubstituted hydrazine. Pyrazolidin-3-ones as well as pyrazolidin-4-ones are known [459]. The anti-inflammatory phenylbutazone (1) is a substituted pyrazolidine-3,5-dione. It is prepared by C-alkylation of l,2-diphenylpyrazolidin-3,5-dione. For the industrial synthesis, cyclocondensation of 1,2-diphenylhydrazine with diethyl 2-butylmalonate is preferred  

Phenylbutazone possesses considerable C-H-acidity (pK = 4.5) it is soluble in sodium hydroxide forming the salt 2. 

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  

Some selected systems derived from these parent compounds will be discussed. 

The statements concerning the reactivity and selectivity of the reactions of azoles with electrophiles and nucleophiles can be further defined on the basis of the donor-acceptor concept [142]. 

There are eight structurally isomeric oxadiazoles and thiadiazoles  

3-Oxadiazoles are not known. Although they are formed in some reactions, they isomerize immediately to a-diazoketones. 

Sydnones, like miinchnones (see p 129), are mesoionic compounds. The synthesis of the first example, namely 3-phenylsydnone 1, was achieved by Earl and Mackney at the University of Sydney. It was carried out by cyclodehydration of A-nitroso-A-phenylglycine with acetic anhydride  

Handling compound known to possess potent biological activities in humans toxic by skin contact or inhalation. 

Preparative Method Furazan can be accessed in gram quantities by dehydration of glyoxime using succinic anhydride (eq 1).  

Functionalization of Furazan. 1,2,5-Oxadiazole belongs to the broader class of furazans that are known to possess potent biological activities. Although this class of compounds are well explored, little is known about direct functionalization of 1,2,5 oxadiazole to access its substituted congeners, which are usually synthesized from their corresponding substituted glyoxime derivatives. Neat 1,2,5-oxadiazole reacts with methyl diazoacetate in the presence of cupric stearate to form 4-methoxycarbonylmethyl 1,2,5-oxadiazole in 12% isolated yield (eq 2). It should be noted that the reaction does not proceed with the use of rhodium acetate. 

Chandra Sekhar Navuluri Universite de Montreal, Montreal, Quebec, Canada 

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In contrast to pyridine chemistry, the range of nucleophilic alkylations that can be effected on neutral azoles is quite limited. Lithium reagents can add at the 5-position of 1,2,4-oxadiazoles (Scheme 16) (70CJC2006). Benzazoles are attacked by organometallic compounds at the C=N a-position unless it is blocked. 

Oxygen-containing azoles are readily reduced, usually with ring scission. Only acyclic products have been reported from the reductions with complex metal hydrides of oxazoles (e.g. 209 210), isoxazoles (e.g. 211 212), benzoxazoles (e.g. 213 214) and benzoxazolinones (e.g. 215, 216->214). Reductions of 1,2,4-oxadiazoles always involve ring scission. Lithium aluminum hydride breaks the C—O bond in the ring Scheme 19) 76AHC(20)65>. 

Catalytic reduction of 1,2,4-oxadiazoles also breaks the N—O bond e.g. (264) gives (265). Benzofuroxan can be reduced under various conditions to benzofurazan (266), the dioxime (267) or o-phenylenediamine (268) (69AHC(10)l). Reduction by copper and hydrochloric acid produced o-nitroanilines (Scheme 30) (69AHC(lO)l). 

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. 

In comparison to N—S bond formation, O—N bond formation by essentially oxidative procedures has found few applications in the synthesis of five-membered heterocycles. The 1,2,4-oxadiazole system (278) was prepared by the action of sodium hypochlorite on A(-acylamidines (277) (76S268). The A -benzoylamidino compounds (279) were also converted into the 1,2,4-oxadiazoles (280) by the action of r-butyl hypochlorite followed by base. In both cyclizations A -chloro compounds are thought to be intermediates (76BCJ3607). 

The reaction is illustrated by the conversion of the 1,2,4-oxadiazole oxime (504) into the 3-acylamino-l,2,5-oxadiazole (505). This irreversible rearrangement occurred on heating (504) in hydrochloric acid (81AHC(29)l4l). Isoxazoles also undergo this rearrangement and these are discussed in Chapter 4.16. 

Oxadiazole, 5-ethyl-3-phenyl-dipole moment, 6, 379 (77JOC1555)... 

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