1.2.4- Oxadiazoles substituent reactivity

Substituents cannot directly conjugate with /3-pyridine-like nitrogen atoms. Azole substituents which are not a or y to a pyridine-like nitrogen react as they would on a benzene ring. Conjugation with an a-pyridine-like nitrogen is much more effective across a formal double bond thus the 5-methyl group in 3,5-dimethyl-l,2,4-oxadiazole (323) is by far the more reactive. 

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. 

Irradiation of 1,2,4-oxadiazoles 205 bearing fluorinated substituents in the 3- or 5-positions in the presence of an amine delivered the corresponding 1,2,4-triazoles 206a-e and 207a-e via a photochemical rearrangement. Several other competing reactions served to divert some of the reactive intermediates and, hence, yields of the fluorinated triazoles were modest (Equation 64 and Table 44) <2005H(65)387>. 

Numerous transformations of functional groups attached to 1,2,3-oxadiazoles have been reported in the last 10 years. The reactivity of substituents attached to ring carbon atoms was thoroughly discussed in CHEC(1984) and CHEC-11(1996). 

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. 

Of the various heterocycles discussed in this chapter, the pyridofuroxans show the least aromatic character. In Section 7.10.5.4, subtle differences in aromaticity between the [l,2,5]thiadiazolo[3,4-c]pyridines and the [l,2,5]oxadiazolo[3,4-c]pyridines are apparent from their dissimilar reactivity towards various reducing agents. In contrast to the former where desulfurization of the thiadiazole ring or substituent reduction occur, the latter heterocycles undergo initial reduction of the C=N bond to form the 4,5-dihydro[l,2,5]oxadiazolo[3,4-c]pyridines (120) with sodium borohydride at ambient temperature (Scheme 19). However, at 80 °C, the oxadiazole moiety is preferentially reduced... 

BSF1149) and a plot of the tt densities against the log rates of pyrolysis of l-(thiazolyl)ethyl acetates is linear. The reactivity order for 1,2,5-diazoles from ir-density measurements is oxadiazole > selenadia-zole > thiadiazole (73CHE1331) the effects of substituents in 1,2,4-tri-azole have also been calculated (71CHE377). 

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... 

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. 

The examples previously presented have featured ANRORC reactions on 6-membered rings. More recently, ANRORC-type rearrangements have been observed in dieir five-membered counterparts, although most examples feature oxadiazoles with bidentate nucleophiles. Spinelli has shown that oxadiazoles with perfluoro-substituents (46) undergo reaction with hydroxylamine to form oxadiazoles (47) with a net reversal in substitution pattern. A perfluoro-group is required at the 5-position for reactivity, as the product 3-perfluoro-oxadiazole (47) is inert to the reaction conditions (preventing reversibility). Hydrazine also efficiently reacts with oxadiazoles to form 1,2,4-triazines. 

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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