Preparation of 1,3,4-Oxadiazoles

Preparation by Ring Closure of Chains with a Preformed 1,3,4-Oxadiazole Skeleton 

Ring Closure by Means of a Condensation Reaction a. Condensation with Elimination of Water. The starting materials are mono- and diacid hydrazides, acylsemicarbazides, and related compounds. The ring closure producing the oxadiazole proceeds as in Eq. (1). The well-known conversion of JV.A -diacid hydrazides to 

5-diaryl(alkyl)-l,3,4-oxadiazoles has been described by Stolle1,3 who used dehydrating agents and also by Pellizzari4 who employed 

Pellizzari, Atti Reale Accad. Lincei [5] 8, Part I, 327 (1899). 

Grekov, Sb. Statei, Vses. Nauchn.-Issled. Inst. Khim. Reaktivov i Osobo Chistykh Khim. Veshchestv. No. 24, p. 131 (1961) see Chem. Abstr. 58, 3418 (1963). 

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Synthetic applications of tetrazoles are deoxygenation of phenols, preparation of nitrilimines and preparation of 1,3,4-oxadiazoles by the Huisgen reaction. All these have been previously... 

Introduction Preparation of 1,3,4,-oxadiazoles Intermolecular cycloadditions of 1,3,4-oxadiazoles Tandem intermolecular-[4+2]/intramolecular-[3+2] cycloadditions of 1,3,4-oxadiazoles... 

Thiadiazolidines can be obtained from aliphatic aldehydes or ketones and disubstituted hydrazine derivatives (Scheme 29). A typical preparation of a mesoionic compound consists in the reaction of 1-methylthioacylhydrazine and phosgene (Scheme 31a). Syntheses by three-bond formation are rare for example, a one-pot reaction of an aldehyde with hydrazine and sulfur. A typical ring transformation reaction is the irradiation of 1,3,4-oxadiazoles to yield 1,3,4-thiadiazoles. 

Several examples of 1,3,4-oxadiazole derivatives have been prepared and characterized for application as new materials for sensors (compound 174) <07TL7788> or fluorescent probes <07CC 1352 07JMC 1981 > or liquid crystals <07JMC4711 07T12429>. 

The preparation of a novel polystyrene-supported dehydrating agent and its application to the synthesis of 1,3,4-oxadiazoles under thermal and microwave conditions has been reported. An alternative procedure using tosyl chloride and P-BEMP has also been presented [33] (Scheme 5.16). 

Oxadiazoles and 1,2,4-oxadiazoles are heterocyclic aromatic compounds that appear in many bioactive molecules. Previous methods for the synthesis of 1,2,4-oxadiazoles include the coupling of amidoximes with carboxylic acid derivatives, aerobic C—H oxygenation of amidoximes, or a cyclization of nitrile oxides to nitriles. Telvekar and Takale developed the preparation of 1,2,4-oxadiazoles from substituted diketone derivatives through a Beckmann rearrangement process tScheme S.3S1. When treated with diphosphorus tetraiodide in dichloromethane at room temperature, dioximes 150 formed the Beckmann products, 1,2,4-oxadiazoles 151, in excellent yields. 

Bretanha et al. [118] reported tiie alternative synthesis of 1,2,4-oxadiazoles using ultrasound irradiation from tri-chloroacetoamidoxime (164) and acyl chlorides (165). The 3-trichloromethyl-5-alkyl(aryl)-l,2,4-oxadiazoles (166) have been S5mthesized in better yields (84-98%) and shorter reaction times compared to the conventional method (60-90%) which required significantly longer reaction times (20h) and toluene reflux [119]. The proposed protocol can be applied for the preparation of 1,2,4-oxadiazoles containing aryl or alkyl groups attached to their C5 side chain (Scheme 43). 

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]. 

The need for the high reaction temperature has been a major obstacle in developing the tandem cycloadditions of 1,3,4-oxadiazoles. As a consequence, chemoselectivity of such processes is poor. Successfiil activafion of the [4 + 2] step in such a tandem process using high pressure or Lewis acids is unknown. Only highly symmetrical products could be prepared until recently via double intermolecular and itner-[4 + 2]/intra-[3 + 2] variants. The chemoselectivity of a double intramolecular variant of the tandem process is not plagued by these limitations and it has been employed in the syntheses of Vinca alkaloids and their analogs. 

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). 

Finally, a series of 2-chloromethyl-5-aryl-1,3,4-oxadiazoles 82 were prepared by reaction of aromatic hydrazides 81 and a chloromethylorthofor-mate used as the solvent under microwave activation [62]. Potentially, the chloromethyl group could imdergo nucleophiUc substitution expanding the scope of this reaction (Scheme 28). 

Alkyl- and 5-aryl-2-amino-1,3,4-oxadiazoles were prepared by tosyl chloride/pyridine-mediated cyclization of thiosemicarbazides in good yields (79-99%). Interestingly, thiosemicarbazides exhibited a higher rate of cyclization than the corresponding semicarbazides. For example, 171 (X-S) was converted to oxadiazole 172 within 5 h <06JOC9548>. 

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. 

In the preparation of novel 1,3,4-oxadiazoles 56 from 1,2-diacylhydrazines 55, Brain and coworkers [29] used a highly efficient cydodehydration assisted by use of micro-waves, in THF as solvent, using polymer-supported Burgess reagent (Scheme 8.21). 

Electroluminescent phenantroline dyes containing triphenylamine and 1,3,4-oxadiazole fragments were prepared using tetrazole-oxadiazole interconversion performed in the presence of aroyl chlorides <2004TL6361>. Also, iV-tributylstannyltetrazoles treated with acetic anhydride gave oxadiazole derivatives <2002RCB357>. 

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. 

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