Isoxazoles, pyrazoles, and isothiazoles

Isoxazole 4.1, pyrazole 4.2, and isothiazole 4.3 are the parent structures of the 1,2-azole family of heterocycles, having a nitrogen atom plus one other heteroatom in a 1,2-relationship in a five-membered ring. 

The aromatic sextet is completed by delocalisation of the lone pair from the second heteroatom, 4.4a-e. Consequently, as in pyridine, the nitrogen atoms of the 1,2-azoles have a lone pair available for protonation. However the 1,2-azoles are significantly less basic than the 1,3-azoles because of the electron-withdrawing effect of the adjacent heteroatom. Isoxazole and isothiazole are essentially non-basic heterocycles (pAas 0), and even pyrazole (pAa=2.5) is a much weaker base than the corresponding 1,3-azole imidazole (pAa=7). 

As with substituted imidazoles, substituted pyrazoles may exist as a mixture of tautomers. 5-Methyl pyrazole 4.5 and 3-methyl pyrazole 4.6 exist as a rapidly equilibrating mixture in solution. 

Although there are a few examples of naturally-occurring 1,2-azoles, many totally synthetic derivatives have found pharmaceutical application. 

Retrosynthetic disconnection of generalised 1,2-azole 4.7 gives initially 4.8 which would exist as ketone 4.9. This in turn is clearly derived from 1,3-diketone 4.10. 

---

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

Isoxazole, pyrazole and isothiazole constitute the 1,2-azole family of heterocycles that contain two hetero-atoms, one of which is a nitrogen atom. The second hetero-atom is oxygen, nitrogen or sulphur, respectively. 

They are isomeric with the 1,2-azoles isoxazole, pyrazole, and isothiazole (see Chapter 4). Their aromaticity derives from delocalisation of a lone pair from the second heteroatom, 3.4a-e. 

Electrophilic Reactions. Further studies aimed at the correlation of the reactivity of five-membered heteroaromatic rings towards electrophiles have been reported. Acid-catalysed hydrogen exchange rates were measured (n.m.r.) for isoxazole, isothiazole, and their 3- and 5-methyl derivatives. Extrapolated values for the rate constants at 100 °C and pH 0 were obtained and compared with those for other ring systems. Quantitative effects of the methyl groups reflect the relative degree of bond fixation, and indicate that the aromaticity increases in the series isoxazole, pyrazole, and isothiazole. ... 

---