To 1.3,4-oxadiazoles

Carboxylic acid hydiazides are prepared from aqueous hydrazine and tfie carboxylic acid, ester, amide, anhydride, or halide. The reaction usually goes poody with the free acid. Esters are generally satisfactory. Acyl halides are particularly reactive, even at room temperature, and form the diacyl derivatives (22), which easily undergo thermal dehydration to 1,3,4-oxadiazoles (23). Diesters give dihydtazides (24) and polyesters such as polyacrylates yield a polyhydrazide (25). The chemistry of carboxyhc hydrazides has been reviewed (83,84). 

In the context of preparing potential inhibitors of histone deacetylase, Vasudevan and a team from Abbott have described the cyclization of 1,2-diacylhydrazides to 1,3,4-oxadiazoles with Burgess reagent under microwave conditions (150 °C, 15 min) (Scheme 6.224 a) [232], A different approach was chosen by Natero and coworkers, who prepared 2-chloromethyl-l,3,4-oxadiazoles by treatment of acyl hydrazides with 1-chloro-2,2,2-trimethoxyethane (Scheme 6.224b) [401]. Here, the reagent was used as solvent and the mixture was heated by microwave irradiation at 160 °C for 5 min. 

Dipolar cycloaddition of diazomethane to aldehydes can successfully be used for the preparation of tetrahy-drooxadiazole derivatives. Photochemical interconversion of 3-acylamino-l,2,5-oxadiazole derivatives leads to 1,3,4-oxadiazoles, though the method suffers from lack of selectivity. Many reports concentrate only on the synthesis and applications of new 1,3,4-oxadiazoles substituted with a wide variety of groups without introducing much of new chemistry. 

With phenyllithium, the iminophosphoranes of benzoic acid hydrazides 157 can be deprotonated, as shown in Scheme 62.0-Acylation of the amide-enolates 158 affords intermediates 159, which are in turn cyclized by an aza-Wittig reaction to 1,3,4-oxadiazoles 160 (68JA5626). 

UV irradiation of 3-amino-1,2,4-oxadiazoles (52) (R = NHR) leads to 1,3,4-oxadiazoles (54) and/or to open-chain compounds like (56) (Scheme 19) <88JCS(P1)1313>. A ring-contraction-ring-... 

No important new general routes to 1,3,4-oxadiazoles have been reported since the mid-1980s. The major routes (as emphasized in both CHEC-I, and in the preceding two sections, 4.06.9.1 and 4.06.9.2) are (i) the formation of oxadiazoles by cyclodehydration of diacylhydrazines... 

Joshi, S. and Karnik, A.V., Facile conversion of acyldiithiocarbazinate salts to 1,3,4-oxadiazole derivatives under microwave irradiation, Synth. Commun., 2002, 32, 111-114. 

PS-PPI13. A combination of PS-PPI13 and CCI3CN not only facilitated the formation of intermediate 1,2-diacylhydrazides by in situ conversion of carboxylic acids to acid chlorides, but also assisted subsequent cyclization to 1,3,4-oxadiazoles. The workup comprised simple filtration of the resin and evaporation of solvents, followed by flash chromatography. The cyclocondensation occurred within 20 min when heated in acetonitrile by microwaves in a sealed vial at 150 °C (68 °C above the boiling point) [92] (Scheme 32). 

Most 1,3,4-oxadiazoles are best obtained by synthesis from acylic precursors. Such reactions are mainly one-bond or two-bond cyclizations. For convenience, cyclizations of intermediates formed from two reactants are classed as one-bond cyclizations if the intermediate can be isolated. A few minor routes to 1,3,4-oxadiazoles which are described in the reviews listed earlier (Section 4.23.1) are omitted from this section and no references are given for reactions covered by these reviews. 

Other routes to 1,3,4-oxadiazoles from five-membered heterocycles include ozonolysis of pyrazoles and rearrangement of hydantoins in the presence of hypohalite. 

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] ... 

Glutaminyl cyclase (hQC) represents a new potential target for the treatment of AD, since inhibition of hQC prevents the formation of the Ap3(pE)-40,42-species. Novel molecules containing benzimidazole as the metal binding group connected to 1,3,4-oxadiazole as the central scaffold were identified. Benzimidazolyl-1,3,4-thiadiazoles and -1,2,3-triazoles display inhibitory potency in the nano-molar range [557]. 

Rearrangement of 5-substituted (aryl or akyl) tetrazoles to 1,3,4-oxadiazoles by acylation. 

Rearrangement ofPyrazoles and Hydantoins to 1,3,4-Oxadiazoles 2-Methyl-4-aryl-l,3,4-oxadiazolin-5-one (30) is obtained by the... 

Figure 10. The AMI computed transition state structures for ethylene, ethylene, and cyclopropene addition to 1,3,4-oxadiazole.

Considering other therapeutic targets, the inhibition of glycogen synthase kinase 3 (GSK-3) leads to AD-related neuroprotective effects, such as a decrease of P-amyloid production, and a reduction in tau hyperphosphorylation (2012MI381029). The oxadiazoles 94 (Figure 33) exert moderate inhibition of GSK-3 (IC50 350—710 nM), but show a lower effect with respect to 1,3,4-oxadiazole derivatives. 

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