Semicarbazones 1.3.4- oxadiazoles

Formyl-oxadiazoles present all the properties of aldehydes they reduce ammonical silver nitrate, form Schiff bases, oximes, hydrazones, semicarbazones and give dichloromethyl derivatives when treated with PClg. 

Early work of Stolle58 had indicated that oxidations of benzal-benzhydrazone (21) (also as the silver salt), usually by free halogen, give 2,5-diphenyl-l,3,4-oxadiazole.57 Apart from this, it has been almost exclusively the semicarbazones of aldehydes and of various a-keto acids that have been converted into 5-substituted 2-amino-1,3,4-oxadiazoles in this way.48... 

Examples adduced in Scheme 87 indicate the caution required when a nitrilimine intermediate favours the formation of a heterocycle other than triazole. The bromo derivative (179) of the semicarbazone (180) is formally analogous to (172) the nitrilimine (181) is formed even in the presence of such weak bases as sodium acetate or water and undergoes ring closure to the 1,3,4-oxadiazole (182), In anhydrous acetic acid the triazolinone (183 R = H) is formed (72JCS(P1)1918) a similar reaction occurs on treating the iV-methyl homologue of (180) with bromine in acetic acid to obtain (183 R = Me). 

Anodic oxidation of azomethine, hydrazone, oxime, formazane, and semicarbazone structures has been used to initiate the intramolecular cyclization [119] under formation of heterocycles like triazoles [126,127], oxadiazoles [128,129], triazolinones [129], benzoxa-zoles [130,131], benzimidazoles [130,131], pyrazoles [132], indazoles [133], furoxanes [134], and tetrazolium salts [135] (see Chapter 18). Some of these reactions can be performed advantageously by indirect electrolysis using tris(4-bromophenyl)amin or 2,3-dihydro-2,2-dimethylphenothiazine-6(l/7)-one as mediators [119,136]. Two examples are given in Eqs. (19) and (20). 

Anodic addition of an oxygen function to a C = N or C = C double bond may be exemplified by the oxidative cyclization of aryl semicarbazones to 1,3,4-oxadiazoles in acetonitrile-acetic acid containing H2SO4 or, under strictly anhydrous conditions (in the presence of acetic anhydride), to triazolinones [40]. Other examples are the anodic oxidation of benzaldehyde-2-hydroxyanil to 2-phenyl-1,3-benzoxazole derivatives [41] and the indirect oxidation of 2-hydroxychalcones to flavonoids using tris(4-bromophenyl)amine in MeOH-CH2Cl2 as mediator [42] ... 

Indirect oxidation with tris-(4-bromophenyl)amine or 2,3-dihydro-2,2-dimethylphe-nothiazine-6(l/7)-one transforms formazane to tetrazolium, semicarbazones to 2-amino-1,3,4-oxadiazoles, benzaldehyde 2-pyridylhydrazones to 5-triazolo[4,3-a]pyridinium compounds, and phenyl 2-pyridyl ketone phenylhydrazone to 1/7-1,2,3-triazolo[3,4-a]-pyridi-nium compounds [123]. 

Oxidative cyclization of the semicarbazone 737 with lead tetraacetate gave the carbocyclic analog 738 of 1,3,4-oxadiazole C-nucleosides (75TL985 76CJC861) (Scheme 198). 

Bromine I sodium acetate 1,3,4-Oxadiazoles from semicarbazones O... 

The preparation, properties and reactivity of 1,3,4-oxadiazoles have been extensively reviewed [173]. The 1,3,4,-oxadiazole most commonly used for the cycloadditions is 2,5-bis(trifluoromethyl)-l,3,4-oxadiazole. Its properties, preparation, and reactivity have also been reviewed [174]. The most commonly used procedure for the synthesis of this and other 1,3,4-oxadiazoles involves dehydration of N,N -diacyUiydrazides using agents such as perfluoroalkyl anhydrides [175], P2O5 [176], BF3 EtjO [177], or SO3 [178] (Scheme 16.85a). Unsymmetrically substituted 1,3,4-oxadiazoles also can be prepared by this route [179]. Alternatively, they may be prepared by oxidation of semicarbazones [180]. For example, an early procedure for the synthesis of 2-amino-5-aIkoxycarbonyl-l,3,4-oxadiazoles involves thebromination of semicarbazones followed by cyclization (Scheme 16.85b). Subsequently, a milder procedure was introduced that involves the preparation of unsymmetrical diacyUiydrazines followed by dehydration with tosyl chloride (Scheme 16.85c) [172]. Sulfonyl groups also activate 1,3,4-oxadiazoles and the preparation of 2-ethylsulfonyl-5-trifluoromethyl-l,3,4-oxadiazole has been described [181]. 

---