1.2.4- Oxadiazoles electrophilic

Oxadiazole, 2,5-diaryl-electrophilic substitution, 6, 438 as fluorescent whitener, 6, 446 herbicidal activity, 6, 445... 

Oxadiazoles, 6, 365-391 aldol condensation, 6, 383 bond lengths, 6, 378 catalytic hydrogenation, 5, 75 chemotherapy, 6, 391 dipole moments, 6, 378 electron densities, 6, 378 electrophilic substitution, 6, 382 ethers... 

Access to oxadiazolopyrimidinium salts, for example, compound 93, was achieved via intramolecular electrophilic attack of the 2-nitrogen of the 1,2,4-oxadiazole 92 in the presence of HCIO4 (Equation 9). Competing reaction at N-4 also occurs and the products are often not isolated, but used as intermediates for hydrolysis, thereby producing pyrimidines <2006T1158>. 

The 1,2,4-oxadiazole ring is almost inert to electrophilic attack at carbon and there are no further examples to supplement those few important exceptions reported previously in CHEC-II(1996) <1996CHECII-(4)179>. 

The reaction of 2-chloro-4,5-dihydroimidazole 347 with hydroxylamine-O-sulfonic acid gives 2-hydroxylamino-4,5-dihydroimidazolium-O-sulfonate 348, which reacts with aldehydes and cyclic ketones to give the imidazo[l,2-f] fused 4,5-dihydro-l,2,4-oxadiazoles 350 (Scheme 58). Mechanistically, the reaction may be explained by the reaction of an imidazoline NH with the carbonyl followed by intramolecular electrophilic amination of the anionic oxygen present in the resultant intermediate 349 and elimination of the sulfate group <2003JOC4791>. 

Rutavicius and Kuodis reported several examples of electrophilic alkylations of the ring nitrogen atom in 5-(4-pyridyl)-l,3,4-oxadiazol-2-thiones (Scheme 7) sometimes, the reaction on nitrogen was accompanied by alkylation on sulfur atom. The direction of substitution depended both on the structure of the initial reactants and on the reaction conditions <2002CHE852>. 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

A series of inhibitors containing an electrophilic keto-l,3,4-oxadiazole moiety as the warhead has been reported in which the substituent at the 5-position was varied resulting in the identification of furan as the optimal prime side substituent. Exploration of P3 substituents led to the identification of 10 with a K, of 1 nM against Cat K with > 700-fold selectivity over off-target cathepsins (Cat B Ki = 730 nM Cat L Rj = 960 nM Cat S Rj = 700 nM) [54], The potency of this compound was shifted in a functional bone resorption assay (Cat K IC50= 132 nM). 

Reactions at ring atoms consist mainly of electrophilic attack at nitrogen and cycloadditions. Examples of the reaction of 2-substituted 1,3,4-oxadiazoles with bifunctional compounds at both ring nitrogen and at the substituent, leading to cyclic systems, are included in Section 4.06.5.2 irrespective of where the initial point of attack took place. A few examples of nucleophilic attack at unsubstituted carbon are described, the more common nucleophilic attack at substituted carbon being included under reactions of the appropriate substituent (Sections 4.06.7.1-7.5). 

The electrophilic substitution reactions commonly used with aromatic compotmds could not be applied to monosubstituted oxadiazoles 25a, 55 b). The hydrogen atoms in position 3 and 5 of these derivatives could not be replaced by a halogen atom or a nitro group and are also inactive towards Friedel-Craft reagents. 

Treatment of 18 with ethylenediamine afforded the desired triazolo piperazine 3 at room temperature albeit in low yields. Attempts to improve the reaction revealed that when the oxadiazole was added to two equivalents of ethylenediamine in methanol at 0 °C, a new species crystallized directly from the reaction mixture. This solid was isolated, identified as the amidine 20, and was found to convert to 3 by refiuxing in methanol for 4h (Scheme 5.11). The formation of amidine 20 was curious since it suggested that initial attack of ethylenediamine did not occur at the carbon of the oxadiazole vicinal to the trifluoromethyl group. Of the three carbons of the oxadiazole which need to react with ethylenediamine, this would easily be rationalized as the most electrophilic. In order to understand the mecha-... 

Oxadiazoles are rather inert against electrophilic attack. However, electrophilic mercuration of 5-unsubstituted oxadiazoles is possible. 5-Halooxadiazoles are prepared from the 5-mercurio compounds (Scheme 15) (64HCA838) only the 5-iodo derivatives are obtained in good yields. 

At present the only successful electrophilic agent for oxadiazoles is mercury(II) chloride173 (see also Section V, I). Chlorine in turn will displace the —HgCl group [Eq. (62)]. 

Acylation with the acylium ion in the gas phase. An unusual experiment was performed by Seldes et aL <20010MS1069>. The N2-tautomeric form of a 5-substituted tetrazole was reacted in the gas phase with an acyl ion generated as the secondary reactive chemical by ionization plasma in a mass spectrometer. It was suggested that the mechanism of this process involved the formation of an acylated tetrazole intermediate, which could not be isolated in a condensed phase, and by rearrangement with nitrogen loss afforded an oxadiazole <20010MS1069> (cf. Section 6.07.5.2.2, Equation 16). This experiment has no preparative value but provides important information on the interaction mechanism between the neutral N-unsubstituted tetrazoles and electrophilic agents in the gas phase. 

Mercury(II) chloride results in introduction of the —HgCl group at C-5 in 3-phenyl-l,2,4-oxadiazole and the group can be displaced by Cl with chlorine gas. Other electrophilic substitutions are not successful. 

The relatively low electron density at carbon, coupled with the possibility of protonation at nitrogen, makes electrophilic substitution at carbon difficult. A further problem is acid-catalyzed ring cleavage, particularly with alkyloxadiazoles. No examples of nitration or sulfonation of the oxadiazole ring have been reported and attempted brominations were unsuccessful. A low yield of 2-(2-furoyl)-5-phenyl-l,3,4-oxadiazole is obtained when 2-phenyl-l,3,4-oxadiazole is treated with 2-furoyl chloride in the presence of triethylamine (77LA159). 

Electrophilic substitution into the aryl nucleus of a 2,5-diaryl-l,3,4-oxadiazole can be carried out but such reactions are difficult with the more acid sensitive monoaryl-1,3,4-oxadiazoles. A variety of transformations of the functional group on an aryl ring in a mono-or di-aryl-1,3,4-oxadiazole have been performed (66AHC(7)183). 

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. 

Thiadiazoles like oxadiazoles are 7r-electron deficient systems. When fused to azines, electrophilic substitution on carbon is only to be expected in the presence of strongly electron-donating substituents. Thus the lactams (666) and (667) are activated for electrophilic substitution (74BCJ2813), whereas in the absence of an activating substituent the electrophile may attack an aromatic side-chain as in the case of (668) (70JOC1965). 

Arylpyrazoles mercuriate in the 4-position (54JCS2293 55JCS1205 60ZOB2931), and 3-phenyl-1,2,4-oxadiazole mercuriates in the 5-position (64HCA838), the only electrophilic substitution reported in this hetero-cylic ring. 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

Secondary ketoenamines react with electrophilic diazenes to give products which undergo rearrangement to an adduct which affords benzimidazolinones after subsequent cyclization322. In the case of tertiary a-enaminones, l,3,4-oxadiazole-2-ones, as unstable intermediates of a [4 + 2]-cycloaddition, can be obtained323 (equation 241). 

---