Reactivity of the 1,3,4-Oxadiazoles

The direct introduction of functional groups into the oxadiazole nucleus is possible in only a few cases. The protonation of the nuclear nitrogen in acidic media reduces extremely strongly the possibility of electrophilic attack.119 Thus no nitrations or sulfonations of unsubstituted oxadiazoles are known in the literature. Halogenation also has not so far been described although in this case the deactivating effect of the oxadiazole nucleus is not so important.47,61 

The introduction of other functional groups into the oxadiazole nucleus by nucleophilic substitution of substituted 1,3,4-oxadiazoles is also difficult (cf. Section III,B). The few known examples proceed with low yield.1 Thus 2-phenyl-5-amino-l,3,4-oxadiazole is obtained by ammonolysis of 2-phenyl-5-methanesulfonyl-l,3,4-oxadiazole [Eq. (9)]-96 

Katritzky and J. M. Lagowski, Heterocyclic Chemistry, p. 220. Methuen, London (Wiley, New York), 1960. 

Alkylation of 2-amino-l,3,4-oxadiazoles in neutral medium, according to previous observations, always occurs primarily at the ring nitrogen.122 

2-imino-3-methyl-5-phenyl-l,3,4-oxadiazoline is obtained from the methylation of 2-amino-5-phenyl-l,3,4-oxadiazole with methyl iodide.61,63 Only in a sealed tube with an excess of methyl iodide is 2-methylimino-3-methyl-5-phenyl-1,3,4-oxadiazoline formed.63 The structure of the alkylated product was confirmed by its nonidentity with 2-methylamino-5-phenyl-l,3,4-oxadiazole or 2-dimethylamino-5-phenyl-l,3,4-oxadiazole which were synthesized by an independent route. 

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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]. 

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 1,2,4-thiadiazole ring the electron density at the 5-position is markedly lower than at the 3-position, and this affects substituent reactions. 5-Halogeno derivatives, for example, approach the reactivity of 4-halogenopyrimidines. The 1,2,4-oxadiazole ring shows a similar difference between the 3- and 5-positions. 

The research on 1,3,4-oxadiazole in 2006-07 has brought main progress in applications of the oxadiazole moieties in optoelectronics. In other fields of the oxadiazole chemistry, for example, concerning reactivity of ring atoms or reactivity of substituents attached to ring atoms, the progress was small or not at all. 

In analogy to the reactivity described above, 1,2,4-oxadiazoles have also been used as photochemical precursors of 1,2,4-thiadiazoles. When 5-amino-3-phenyl-l,2,4-oxa-diazole 116 is irradiated at 254nm in methanol, in the presence of a sulfur nucleophile such as thioureas, significant yields of thiadiazoles 121 were obtained, most likely through the open-chain species 120 (Scheme 12.33) [73],... 

The following pages will be devoted mainly to the syntheses, the reactivity, the physical properties, and the uses of 1,3,4-oxadiazoles. 

Dihydrotetrazines (340), which can easily be oxidized to 1,2,4,5-tetrazines, can be formed by dimerization of thiohydrazides (337) or amidrazones (338). The ring closure of hydrazidines (339) in a [5 + 1] fashion proceeds well with activated carboxylic acid derivatives such as imidates (341), orthocarboxylates (342) or dithiocarboxylates (343). The [4 + 2] procedure is found in the transformation of 1,3,4-oxadiazoles (346) or 1,4-dichloroazines (345) with hydrazine. Finally diazoalkanes (344) can be dimerized in a [3 - - 3] manner under the influence of a base the dimerization of diazoacetic ester is an early example, leading to 3,6-tetrazinedicarboxylate (48), which is frequently used in (4 -I- 2) cycloaddition reactions with inverse electron demand. Nitrile imines, reactive intermediates which are formed from many precursors, can dimerize in a [3 -I- 3] fashion to form 1,3,4,6-tetrasubstituted 1,4-dihydrotetrazines. These reactions are summarized in Scheme 57. 

The ring bond order deviation from uniformity partially agreed with the order of reactivity computed on the basis of FMO energy gaps. The least aromatic was 1,2,5-oxadiazole, while 1,2,3-thiadiazole should be most aromatic (Table 36). The order of reactivity was oxadiazole, triazole, thiadiazole in all 1,2,3-, 1,2,5- and 1,3,4-series of the three heteroatom heterocycles. Except for 1,3,4-oxadiazole, the two other 1,3,4- five-membered heterocycles were predicted to be more reactive than their 1,2,3- isomers (Table 36). The prediction that 1,2,5-oxadiazole was the most reactive heterocycle as a diene for Diels-Alder reaction was unacceptable due to the fact that two C-N bonds should be formed in the course of the reaction, which usually requires an exceptionally high activation barrier. 

Because these transition state structures are symmetric, all previously used approaches for determining relative reactivity of the heterocycles should be applicable in these cases. The cycloaddition is a HOMO dienophile and LUMO heterocycle (diene) controlled cycloaddition reaction with exceptionally low demand for orbital energy changes in reactants to achieve the electronic contribution present in the transition state structure (Table 41). There is no doubt that 1,3,4-oxadiazole is the most reactive of all five-membered heterocycles with three heteroatoms. However, the question remains as to whether this heterocycle is more reactive than, for instance, furan or even cyclopentadiene. To answer this question, the deviation of bond order uniformity in the six-membered ring being formed was computed (Table 42). The bond order uniformity selected 1,3,4-... 

The reaction barrier firmly supported our previous finding that 1,3,4-oxadiazole should react with highly reactive dienophiles. In fact, it was predicted that the reaction between 1,3,4-oxadiazole and cyclopropene should be possible under moderate reaction conditions (room temperature). For reactions with dienophiles of low reactivity such as ethylene, forceful reaction conditions or even activation of the diene or dienophile are required. Both 1,3,4-triazole and 1,3,4-thiadiazole were predicted to have activation barriers that were 6 kcal/mol and correspond to comparable reactivities. In all cycloaddition reactions with cyclopropene as a dienophile, an exo cycloadduct is predicted to be a major or exclusive product, which is in agreement with some of our previous studies of cycloaddition reactions with furan as a diene and cyclopropene as a dienophile. 

As mentioned above, the cycloaddition reaction with 1,3,4-oxadiazole is predicted to be LUMO diene (heterocycle) controlled. That definitely suggests that with electron-withdrawing substituents in the two and five positions of the heterocycle ring, the heterocycle should become more reactive as a diene for Diels-Alder reactions. To study the usefulness of 1,3,4-oxadiazole and its derivatives as dienes for the Diels-Alder reaction, we are presenting the results of our theoretical study of the cyclopropene addition to 2,5-di(trifluoromethyl)-l,3,4-oxadiazole. The AMI computed FMO energy gap for this reaction pair was only 8.00266 eV in comparison to 9.64149 eV FMO energy gap between LUMO of 1,3,4-oxadiazole and HOMO of cyclopropene. Therefore, the computed activation barrier for the cyclopropene addition to 2,5-bis(trifluoromethyl)-1,3,4-oxadiazole should be very... 

As determined on the basis of the FMO energies, the addition of cyclooctyne to substituted 1,3,4-oxadiazoles is easier than the addition of acetylene. Nevertheless, computed activation barriers (AM 1 semiempirical method) were too high (33.6 kcal/mol for 2,5-dimethyl-1,3,4-oxadiazole and 27.7 kcal/mol for bis(trifluoromethyl)-1,3,4-oxadiazole). Considering the fact that the AMI computational method tends to compute activation barriers that are almost the same for distinctively different reactive homologues of the same series and having established a correlation between AMI computed and B3LYP computed energies, it is possible to estimate the activation barrier for the cyclooctyne addition to 2,5-bis(trifluoromethyl)-1,3,4-oxadiazole. Our best estimate was around 20 kcal/mol. 

The steroidal oc/ -unsaturated nitriles (424) and (425), chosen to test the reactivity of the olefinic bond to 1,3-dipolar addition of a nitrile oxide, were found to react instead at the cyano-group. Benzonitrile oxide, generated in situ from benzhydroxamoyl chloride, gave the 1,2,4-oxadiazoles (426) and (427). ... 

The Diels-Alder reactivity of 1,3,4-oxadiazoles as dienes was investigated with AMI semiempirical and hybrid density-functional methods. The validity and usefulness of the inertia principle for the qualitative evaluation of reactivity in Diels-Alder reactions is presented. The reactivity of 1,1-dimenthene to Diels-Alder cycloaddition is poor as a result of the difficulty of the diene adopting a planar conformation. The Diels-Alder transition states of dienes having conjugating substituents at C(2) or C(3) have been investigated to determine the reason for the unexpected high diene reactivity. Differences in rates of Diels-Alder reactions have been used as experimental indicators of synchronous or asynchronous transition states when non-symmetrical diene 2-(trimethylsilyloxy)cyclohexa-l,3-diene reacts with symmetrical ethylenic dienophiles. ... 

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