Typical Reactivity of 1,3- and 1,2-azoles

Many of the lessons to be learnt apply to both 1,3- and 1,2-azoles, though the direct linking of the two heteroatoms in the latter has a substantial inductive influence, altering properties in degree. The 1,2-azoles tend to be less nucleophilic and less basic at the imine nitrogen than their 1,3-isomers. That such electrophilic additions occur, again illustrates that the imine nitrogen lone-pair is not involved in the aromatic sextet of electrons. 

Electrophilic substitution in the azoles is intermediate in facility between pyridine on the one hand and pyrroles, thiophene and furans on the other the presence of the electron-withdrawing imine unit has an effect on the five-membered aromatic heterocycles just as it does when incorporated into a six-membered aromatic framework, i.e. the comparison is like that between benzene and pyridine (chapter 4). The order of reactivity - pyrrole furan thiophene - is echoed in the azoles, though the presence of the basic nitrogen complicates such comparisons. The regiochemistry 

The converse of electrophilic substitution following the five-membered pattern, is that nucleophilic substitution of halogen follows the pyridine pattern i.e. it is much faster at the 2-position of 1,3-azoles and at the 3-position of 1,2-azoles, than at other ring positions. Resonance contributors to the intermediates for such substitutions make the reason for this plain the imine nitrogen can act as an electron sink for attack only at these positions. 

The utility of palladium(0)-catalysed processes (see section 2.7 for a detailed discussion) for the construction of azoles has been extensively developed one simple example is shown below. 

Lithiation is regioselective for the 2-position in the 1,3-azoles and for the 5-position in the 1,2-azoles. The facility with which 1,3-diazoliuni cations form ylides (carbenes) by 2-deprotonation is at the heart of the biological activity of thiamine pyrophosphate. 

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