1.3.4- Oxadiazoles acylhydrazones

The 1,3,4-oxadiazole 113 is formed from the azo compound 112 by the action of triphenylphosphine <96SL652>. A general synthesis of 1,3.4-oxadiazolines consists in boiling an acylhydrazone with an acid anhydride (e.g., Scheme 18) <95JHC1647>. 2-Alkoxy-2-amino-l,3,4-oxadiazolines are sources of alkoxy(amino)carbenes the spiro compound 114, for instance, decomposes in boiling benzene to nitrogen, acetone and the carbene 115, which was trapped as the phenyl ether 116 in the presence of phenol <96JA4214>. 

The second most popular method of oxadiazole preparation starts from acylhydrazones 110, which undergo cyclization usually under the action of oxidizing agents (Br2, PhN02, HgO, iodobenzene diacetate). Also, the use of acetic anhydride can lead to cyclization of compound 110. The cyclization can be supported by microwave irradiation. In particular cases, heating is sufficient to accomplish the reaction. 

Oxidative cyclization of acylhydrazones 110a, derived from aldehydes or ketones, with the use of lead tetraacetate (LTA) has been developed into a useful route to several disubstituted and tetrasubstituted oxadiazole derivatives 122, being a convenient source of relatively stable carbenes, like N(0)C , S(0)C , 0(0)C , or S(S)C <2000J(P1)2161 >. Some representative recent examples of the syntheses are collected in Table 2. 

Table 2 Representative examples of the synthesis of oxadiazole derivatives 122 from acylhydrazones 110a...

In a related study, it has been shown that several aldehyde N-acylhydra-zones undergo oxidative cyclization with IBD in methanolic sodium acetate to give 2,5-disubstituted 1,3,4-oxadiazoles (Eq. 32). The oxidation of ketone N-acylhydrazones by IBD in methanol or ethanol affords the corresponding 2-alkoxy-A -l,3,4-oxadiazolines in excellent yields (Eq. 33), while oxidative cyclization of acetone 4-phenylsemicarbazone provides 2-(A -phenylimino)-A -l,3,4-oxadiazoline in 93% yield (Eq. 34) (93JOC3381). 

Nonoxidative cyclization of acylhydrazones in acetic anhydride yields 4-acetyloxadiazolines, as in the conversion of hydrazone (96f R = 2-benzthiazolyl) into oxadiazoline (90b) <89MI 406-03). Hydrazones derived from tetra-O-acetyl-D-arabinose cyclized (Ac20/ZnCl2) to oxadiazoles pos-... 

R CONHNHCOR (ii) the formation of oxadiazoles by oxidation of acylhydrazones RCH=NNHCOR, and (iii) the formation of oxadiazolinones, oxadiazolinethiones, and amino-oxadiazoles by the action on hydrazides RCONHNH2 of phosgene, carbon disulfide (or thiophos-gene), and cyanogen bromide respectively. 

Substituted acylhydrazones (95), formally derivatives of 1,2-diacylhydrazines (75), also cyclize to oxadiazoles (76), with loss of HX. Imidol ethers (95a R2 = H), prepared from acylhydrazines R1CONHNH2 and ortho esters HC(OR)3, cyclize on heating to monosub-stituted oxadiazoles (76 R1 = H). This reaction is an important synthesis of monosubstituted... 

Silver salts of acylhydrazones (99) yield 4-acetyloxadiazolines (104) on treatment with acetyl chloride. With benzoyl chloride the corresponding 4-benzoyl-A2-oxadiazolines are produced (67T1379). Aldazines (RCH=N)2 react with LTA to form A2-oxadiazolines (104 R1 = R3 = R, R2 = H), which, on prolonged reaction time, lose acetic acid to give 2,5-disubstituted 1,3,4-oxadiazoles (67JOC3318). 

The reaction of isonicotinic acid hydrazide and corresponding benzaldehyde under microwave conditions gave the heterocyclyl acylhydrazones (xxi). The oxidation of xxi with iodobenzene diacetate (IBD) gave the heterocyclyl-1,3,4-oxadiazoles (xxii) in a solid state [29]. 

An efficient one pot synthesis of unsymmetric 2,5-disubstituted-1,3,4-oxadiazoles has been developed by Pore et al. [39]. The target oxadiazoles were formed by the oxidation of acylhydrazones using trichloroisocyanuric acid (TCCA) at an ambient temperature. 

A new method for the synthesis of 1,1-dialkyldiazomethanes (2.101) has been developed by Warkentin s group (Majchrzak et al., 1989). A-Acylhydrazones of ketones (2.99) are oxidized with lead tetraacetate to 2,5-dihydro-l,3,4-oxadiazoles (2.100). This intermediate undergoes a photolytic cleavage if irradiated with UV light (300 nm) at room temperature in benzene (2-45). 

Oxadiazoles from acylhydrazones Oxidative ring closure... 

A mixture of benzoylhydrazine and 2 eqs. benzoic acid heated at 240° for 6 h - 2,5-diphenyl-1,3,4-oxadiazole. Y 51%. Reduced yields were obtained from reactants in equimolar amount, while heating at lower temp. (150 ) gave intermediate diacyl-hydrazines the method is simple, work-up is easy, and starting materials readily available. F.e., also from N-acylhydrazones by KMn04 oxidation, s. P.S.N. Reddy, P.P. Reddy, Indian J. Chem. 26B, 890-1 (1987). 

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