1.2.4- Oxadiazoles 3 acyl- from

Rice and Nuss report that the Argopore MB-CHO polymer-supported amidoximes 282 (readily available from the nitrile 281), shown in Scheme 46, can be acylated with acid chlorides in the presence of excess pyridine to give the O-acylamidoximes 283. Cyclization was carried out with TBAF in THF at ambient temperature, to give the polymer-supported 1,2,4-oxadiazoles 284. Release of the 1,2,4-oxadiazoles 285 from the polymer support was achieved by treatment with 95% trifluoroacetic acid <2001BML753>. 

The synthesis of 3-carboxyalkyl oxadiazoles, starting from acyl-aminomalonic acid monoesters has been described p. 8l6 33a). 

Oxadiazoles can also be prepared from amides via acylamidines, ° or via the cycloaddition of nitrile oxides to nitriles, as illustrated. "" 3-Alkylamino-l,2,4-oxadiazoles result from the reaction of N-acyl-l-benzotriazolyl-l-carboximidamides with hydroxylamine. " ... 

Besides acyl chloride, acetic anhydride and benzoyl anhydride were used as the acylating agents under microwave irradiation. In addition, 2-anilino-5-aryl(hetaryl)-1,3,4-oxadiazoles 11 from 5-substituted tetrazoles 12... 

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). 

A mixture of 3-hydroxy-4-phenylfurazan and 1,2,4-oxadiazole 243 was prepared from a-phenyl-a-hydroximino hydroxamic acid by acylation and subsequent treatment with 15% aqueous NaOH (Scheme 164) (25G201). The reaction of tetraacetate 244 with sodium acetate hydrate in glacial acetic acid at 70°C gives 3,4-dihydroxyfurazan (9%) (92URP1752734). a-Hydroximino ester 245 reacts with hydroxylamine to form furazan 246 in 25% yield (Scheme 164) (79JHC689). 

Scheme 9 Synthesis of 1,3,4-oxadiazoles from acyl hydrazines and isocyanates...

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. 

The cyclization of the five-atom component O-acylated amidoximes 204 leads to 1,2,4-oxadiazoles via C-N bond formation as shown in Scheme 30. The requisite O-acylated amidoximes 204 are accessed via the reaction of an amidoxime with an activated carboxylic acid or a carboxylic acid derivative. Often the O-acylated amidoxime 204 is not isolated and the cyclization is either spontaneous or occurs in a one-pot process, and these approaches are dealt with in Section 5.04.9.1.2 as syntheses from a one-atom component and a four-atom component. In this section, only those methods in which the O-acylated amidoxime 204 is isolated and cyclized in a separate step are dealt with. 

In a similar approach (Equation 53), the use of a resin-bound nitrile allowed access to the corresponding resin-bound amidoximes 274, which could be converted into 1,2,4-oxadiazoles 275 via acylation with either an appropriate acid halide/ anhydride in the presence of a base or a carboxylic acid in the presence of a coupling reagent followed by cyclization, where the latter step was performed by heating in pyridine or diglyme and could be accelerated by the use of a microwave oven. Cleavage from the resin was easily achieved by the use of TFA in dichloromethane <2000BML1431>. 

Each of the routes discussed thus far in this section are reliant upon amidoxime-based methods. In a change from this paradigm, Makara etal. produced the polymer-supported benzotriazoles 294 and converted them easily into the iV-acyl-177-benzotriazole 1-carboximidamides 295. Cyclization with hydroxylamine gave the supported 3-amino-l,2,4-oxadia-zoles 296 which were cleaved with TFA to give the free 3-amino-l,2,4-oxadiazoles 297 (Scheme 49) <2002TL5043>. 

A one-pot synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from acids and acyl hydrazides has recently been reported. The method involves an activation of an acid with carbonyl diimidazole followed by the addition of benzoyl hydrazide and then the addition of CBr4 and Ph3P. Under the conditions, the dehydration proceeds smoothly to provide the desired oxadiazoles in high yields <2006TL4827>. 

Heterocyclic ring systems are also used to connect two anthraquinone groups. Typical examples include Cl Vat Red 10 (6.106), which is an oxazole derivative obtained from 2-amino-3-hydroxyanthraquinone and the appropriate acyl chloride, the similar thiazole derivative Cl Vat Blue 31 (6.107) and the oxadiazole derivative Cl Vat Blue 64 (6.108). 

One principal access to 1,2,4-oxadiazoles consists of N—O bond formation by electrocyclic ring closure of nitrenoids N—CR —N—CR =0. For instance, heating acyl isocyanates (159) with trimethylsilyl azide alfords high yields of 1,2,4-oxadiazoles (Scheme 68) <79JCS(P1)185,80JOC5130). Similarly, elimination of HCl from A -chloroamidines (160) (Scheme 69) <84BCJ1I6> and ther-... 

The synthesis of 2-acylpyridazin-3(2//)-ones has been discussed in Section 8.01.5.5.3. These compounds have been used as mild acylating reagents for amines <2002S733>. Symmetrical and unsymmetrical 1,3,4-oxadiazoles were also synthesized starting from these 2-acyl(or aroyl)pyridazin-3(2//)-ones <2003S560>. 

It must be pointed out that the "amide process allows the preparation of oxadiazole containing acylable group in the substituent. For example, 3-phenyl-5-hydroxy methyl oxadiazole has been obtained in 55% yields from benzamidoxime formate and glycolamide. 

Amino-oxadiazoles have been prepared from oxyguanidine. The yields do not exceed 10% 2,121) (s. p. 815). They have also been prepared from ethyl a-amino-a-isonitroso-acetate, which condenses with acylating agents to form 3-carboethoxy-oxadiazoles. 

Anilino-oxadiazoles have been prepared from acyl isothioureas and hydroxylamine 125) see p. 816). 

Acylation of A-hydroxy-2-phenylbutyramidine (112-1) with 3-chloropropionyl chloride in the absence of an added base proceeds as might be expected to give the product (112-2) from acylation on the more basic nitrogen. Heating this compound leads to the formation of the oxadiazole (112-3) almost certainly via the enol tautomer of the amide. Displacement of the terminal chlorine with diethylamine leads to the tertiary amine and thus proxazole (112-4) [123], a compound that is said to exhibit antispasmodic activity. 

A related series of 5-substituted-2-amino-oxadiazole compounds have also been prepared in a one-pot procedure using a microwave-assisted cyclisation procedure (Scheme 6.26)164. Rapid preparation of the pre-requisite ureas from the mono acyl hydrazines and various isocyanates (or the isothiocyanate) was easily achieved by simple mixing. The resulting products were then cyclo dehydrated by one of the two procedures either by the addition of polymer-supported DMAP and tosyl chloride or alternatively with an immobilised carbodiimide and catalytic sulphonic acid. Purity in most cases was excellent after only filtration through a small plug of silica but an SCX-2 cartridge (sulphonic acid functionalised - catch and release) could be used in the cases where reactions required additional purification. 

Sydnones 78 (R1 = Ph, Ar or 3-pyridyl, R3 = H or Me) are obtained from the nitrosoamino acids 77 and acetic anhydride under ultrasound (94MI153). Three examples of the formation of oxadiazoles by microwave irradiation are from O-acyl amide oximes 79 in the presence of aluminium oxide, from amide oximes 80 and isoprop-enyl acetate in the presence of KSF-clay and from N,N -diacylhydrazines 81 and thionyl chloride (95SC1451). 

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. 

A solid phase synthesis of substituted 3-alkylamino-l,2,4-oxadiazoles has been developed. The synthesis started from TV-acyl-1 //-bcnzotriazole-1 -carboximidamides 228. Treatment with hydroxylamine afforded the oxadiazole skeleton 229 in high yield <02TL5043>. 

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