Oxadiazoles and Thiadiazoles

Only one divalent heteroatom can be incorporated into a simple live-membered, aromatic heterocycle. These systems are named with the non-nitrogen atom nnmbered as 1, and the positions of the nitrogen atoms shown with reference to the divalent atom. 

4-Oxadiazoles, 1,3,4-oxadiazoles and 1,2,5-oxadiazoles are well known, but the 1,2,3-oxadiazole system, which calculations indicate to be unstable relative to its ring-open diazo-ketone tautomer, is known only as a benzo-fused derivative (in solution) and in mesoionic substances, known as sydnones , which have been well investigated. Furoxans , which are formed by the dimerisation of nitrile oxides, have also been extensively studied. 1,2,3-Thiadiazoles, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles and 

As with the azoles, oxa- and thiadiazoles are very weak bases due to the inductive effects of the extra heteroatoms, although A-quatemisation reactions can be carried out. For similar reasons, electrophilic substitutions on carbon are practically unknown, apart from a few halogenations and mercurations - it is an intriguing paradox that mercurations, with what is generally thought of as a weak electrophile, are often successful in electron-poor heterocycles. Another important difference from other azoles is of course the absence of A-hydrogen, so that A-anion-mediated reactions are not available. 

All these systems are susceptible to nucleophilic attack, particularly the oxadiazoles, which often undergo ring cleavage with aqueous acid or base unless both carbon positions are substituted. Similarly, leaving groups are generally displaced easily there is substantial differential positional reactivity in both 1,2,4-oxa- and -thiadiazoles a 5-chlorine is displaced much more easily than a 3-chlorine, no doubt due to the more effective stabilisation of the intermediate anionic adduct in the former situation. 

Base-catalysed proton exchange occurs readily, but decomposition via cycloreversion or p-elimination in the anion often competes, for example a 4-aryl-1,2,3-thiadiazole is deprotonated at C-5 by carbonate 

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A/-Chloroamidines are usehil for preparation of biocidal imidazoles (106) and thiadiazolines (107). Ai-Chloroguanidines, RNHC(=NC1)NHR, serve as starting materials for synthesis of imidazoles, oxadiazoles, and thiadiazoles (108,109). 

Acyltetrazoles lose nitrogen spontaneously to give oxadiazoles, and thiadiazoles can be prepared similarly from 2-thioacyltetrazoles (Scheme 63) (77AHC(21)323). 

An ab initio theoretical study was conducted on 1,2,5-oxadiazole and 3-phenyl-l,2,5-oxadiazole to determine the molecular structures of these heterocyclic compounds. The rotational energy barrier between Ph ring and diazole nucleus was also evaluated. No considerable change of bond lengths inside the diazole nucleus was observed in the Ph-substituted heterocyclic compounds as compared to the oxadiazole and thiadiazole alone <2001MI215>. 

One procedure for the synthesis of these title ring systems appeared recently <2003S1079>. Yadav and Kapoor described that the transformation of some oxadiazole and thiadiazole derivatives bearing specially substituted methylsulfinyl side chain 131, when reacted with thionyl chloride, give ring-closed compounds 134. The reaction was carried out in pyridine under reflux conditions in 74-79% yield. As shown in Scheme 25, the authors assume that the first step is the formation of the sulfonium salt 132 which undergoes cyclization with hydrogen chloride and sulfur dioxide elimination to 133 and, finally, demethylation of this intermediate leads to the final product 134. 

Table 15.20. Preparation of triazoles, tetrazoles, oxadiazoles, and thiadiazoles.

N NMR is useful in distinguishing between isomers of heterocyclic entities, such as oxadiazoles and thiadiazoles. The 13C chemical shifts for 1,2,5- and 1,3,4-thiadiazoles are almost the same, and the XH chemical shifts for 1,2,3- and 1,2,5-thiadiazoles are identical. In contrast, the nitrogen chemical shifts are very different. Thus, in 1,2,3-thiadiazoles the N-3 resonates at —59p.p.m. and the N-2 at —33p.p.m., while in 1,2,5-thiadiazole both nitrogen atoms resonate at +35 p.p.m. Finally, in 1,3,4-thiadiazole both nitrogen atoms resonate at +10 p.p.m. (a plus value means upheld from nitromethane) (78MI42701). 14N values for other thiadiazole derivatives are presented in Table 4 (81MI42701). 

OXADIAZOLES AND THIADIAZOLES FUSED WITH AZINES INTRODUCTION 711... 

The oxadiazole and thiadiazole rings are 7r-eIectron deficient and hence do not readily react with electrophiles at nitrogen or at carbon. Electrophilic attack in the azine ring proceeds in the presence of electron-releasing substituents. 

Several 3-(5-tetrazolyl)pyridines 634 containing bulky groups on the pyridine ring were acylated in acetonitrile at elevated temperature and under microwave irradiation to afford various 3-(l,3,4-oxadiazol-2-yl)pyridines 635 in good yields (Scheme 279) <2006T1849, CHEC-III(5.06.10)444>. See also Section 3.4.3.12.4 for the preparation of oxadiazoles and thiadiazoles by the elimination of N2 from 2-acyltetrazoles and 2-thioacyltetrazoles, respectively. 

As a rule, oxadiazoles and thiadiazoles are not nitrated. Reports on the production of 2-nitro-5-amino-l,3,4-thiadiazole during the nitration of 2-amino-l,3,4-thiadiaz-ole [274] proved erroneous [275], The compound obtained in this case was 2-nit-ramino-l,3,4-thiadiazole [275], There is only a single paper on the nitration of derivatives of 1,3,4-oxa- and 1,3,4-thiadiazoles [276], 2-Dimethylamino-l,3,4-oxa-and 2-dimethylamino-l,3,4-thiadiazoles react with the nitrating mixture with the formation of 2-dimethylamino-5-nitro derivatives. Aryl-substituted oxadiazoles and thiadiazoles are nitrated in the phenyl ring [277, 278],... 

There are eight structurally isomeric oxadiazoles and thiadiazoles ... 

The introduction of a second aza group into the 5-membered rings reduces further the susceptibility to electrophilic attack. Triazoles,oxadiazoles and thiadiazoles are practically completely resistant to electrophilic substitution unless powerful electron-releasing substituents are present. No quantitative studies on the reactivities of these rings have been made. 

Very recently more comprehensive research on the solid-supported preparation of substituted oxadiazoles and thiadiazoles was reported [108], Initially, a set of ten oxadiazoles was prepared by microwave-mediated cyclization of semicarba-zides. In the presence of polymer-bound DCC the desired compounds were obtained within 1 h at 140 °C (Scheme 16.70a). To find a different pathway a set of nine polymer-bound bases was used in an optimization sequence employing sul-fonyl acid chlorides. If the reactions were performed in THF under the action of microwave irradiation for 1 h, PS-BEMP was found to be the most effective base. A set of twenty sulfonyl acid chlorides was used in this microwave procedure to afford the corresponding compounds in moderate to good yields and excellent purity... 

Finally, using the same procedure the corresponding 2-sulfonamide oxadiazoles have been prepared from 1,4-disubstituted thiosemicarbazides (Scheme 16.70b). Because of the two reactive moieties in the molecule, however, both species, the oxadiazoles and thiadiazoles, could be obtained in good yields and high purity from the cyclization step, depending on the substrate used [108]. 

Oxadiazoles and thiadiazoles contain two sp -hybridized N-atoms and an oxygen or sulfur atom, respectively from each type of heterocycle, four structural isomers are possible ... 

Fluorine-Induced Reactivity of Fluorinated Oxadiazoles and Thiadiazoles. 396... 

Abstract A literature survey of the chemistry of fluorinated oxadiazoles and thiadiazoles is presented. The core part on synthetic procedures is given by type of heterocycle and includes recent developments up to the end of 2012. Reactivity is discussed when induced by the presence of the fluorinated moiety. Selected examples of bioactive compounds and applications are illustrated. 

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