1.3- Azoles relative reactivity

The above relative rates of deuterium exchange at the 2-positions of benzo[b]furan and benzo[6]thiophene were confirmed by Attanasi et al. [79PS(5)305], who also found benzo[b]selenophene to be less reactive than benzo]b]thiophene, the relative exchange rates for different heteroatoms being Se (1.0), O (2), S (7). However, in the corresponding benzo-azoles, the relative reactivities at the 2-positions for different heteroatoms were S (1.0), Se (4), O (20) [79PS(5)305]. Possible reasons for these latter differences are considered in Section 2.C. 

The oxygen-substituted 1,3-azoles exist in their carbonyl tautomeric forms. The bromination of thiazol-2-one, at C-5, is a nice demonstration of relative reactivity here the double bond carries both sulfur and nitrogen, and it is the latter, i.e. the enamide rather than the enethiol ester character, that dictates the site of electrophilic attack. ... 

NMR data for 4-methyloxazole have been compared with those of 4-methylthiazole the data clearly show that the ring protons in each are shielded. In a comprehensive study of a range of oxazoles. Brown and Ghosh also reported NMR data but based a discussion of resonance stabilization on pK and UV spectral data (69JCS(B)270). The weak basicity of oxazole (pX a 0.8) relative to 1-methylimidazole (pK 7.44) and thiazole (pK 2.44) demonstrates that delocalization of the oxygen lone pair, which would have a base-strengthening effect on the nitrogen atom, is not extensive. It must be concluded that not only the experimental measurement but also the very definition of aromaticity in the azole series is as yet poorly quantified. Nevertheless, its importance in the interpretation of reactivity is enormous. 

The order of reactivity of the individual positions in 1,2-type and 1,3-type azole N-oxides can be predicted by comparison of the relative stability of the intermediate adducts similar to the analyses presented in Schemes 6 and 7. The total sequence including alkylation and final dealkylation constitutes a nucleophilic displacement of a leaving group in an azole /V-oxide, which can be run in a telescoped protocol. 

The order of reactivity for the reaction sites of azole compounds in electrophilic reactions is known to be 5 >4> 2 [18]. Thus arylation at the relatively electron-rich 5-position may be regarded as similar to that of pyrroles, furans, and thiophenes (Scheme 1). In contrast, the reaction at the 2-position may be regarded as proceeding differently [3], Although the precise mechanism is still unclear, it may involve base-assisted deprotonative palladation with the ArPd(II) species (path d in Scheme 2). Insertion of the C=N double bond into the Ar-Pd bond is also a possi-... 

The 2-position in azoles with 1,3-heteroatoms should be more reactive than the 5-position of azoles with 1,2-heteroatoms, but for reactions of the free base this turns out not to be the case because of the adjacent lone pair effect illustrated by the relative reaction rates in Scheme 7.3. Thus the 2-position of thiazole is 7 times less reactive than the 5-position of isothiazole. The same reasoning accounts for the 3-position of isothiazole being less reactive than the 4-position of thiazole. The former should be the more reactive since the electron-withdrawing effect of nitrogen should be greater across the bond of higher order, and the fact that it is not more reactive suggests that the effect of the adjacent lone pair is more severe across the shorter C-3—N bond in isothiazole. For reaction of the azol-... 

Much of the work on nitration of azoles has concerned the phenyl derivatives. These substitute in the phenyl ring at positions that depend on the reaction conditions and the relationship of the phenyl ring to the heteroatoms. Preferential nitration in the phenyl ring does not necessarily mean that the azole is intrinsically less reactive than benzene, because the phenyl ring may be strongly activated by one of the heteroatoms whereas the azole is relatively weakly activated by the phenyl group. The combination of bond-order effects and relationship to the heteroatom means that the preferred sites of substitution are as shown by arrows in structures 7.37-7.42. The effect of protonation is discussed later. 

The second possibility requires the assumption that the lone pair on nitrogen (but not the sulfur d orbitals) has a smaller space requirement than a C—H bond. Consequently, when the probe is adjacent to nitrogen, the empty p orbitals in the carbocation in the transition state are better able to overlap with the p orbitals in the azole ring, and the reactivity will be enhanced. One must also assume that this is relatively unimportant in pyrolysis, which is reasonable since less charge is developed in the transition state. A parallel discrepancy in reactivity adjacent to nitrogen is evident in pyridine chemistry, in which the results tend to support the former interpretation this is discussed further in Chapter 9. 

Application of these principles permits prediction of the relative positional reactivities of the azoles as shown in Scheme 7.15. For X = NH(R) the orders 8 > 9 and 11 > 12 may be reversed. 

Few examples are reported in the literature regarding the reactivity of fluorinated 1,2,5-oxadiazoles. As for many azoles, the nucleophilic substimtion of a fluorine atom is relatively easy and provided high yields. Huorofurazans A react with bisfuraza-nopyrazine dianion 194 yielding a disubstituted compound 195 (73 %) containing two tris (furazanyl)-amino moieties [98], The same reaction performed on fluoro-derivative B gave compound 196 (85 %), the precursor of macrocycle 197 synthesised by oxidative cyclization with dibromoisocyanurate (DBI) (Scheme 50). 

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