Reactivity of neutral azoles

Replacing a CH group of benzene with a nitrogen atom gives pyridine (1) replacing a CH = CH group of benzene with NH, O or S gives pyrrole, furan or thiophene (3), respectively. 

The carbon atoms of azole rings can be attacked by nucleophilic (Section 3.4.1.6), electrophilic (Section 3.4.1.4) and free radical reagents (Section 3.4.1.9.2). Some system, for example the thiazole, imidazole and pyrazole nuclei, show a high degree of aromatic character and usually revert to type if the aromatic sextet is involved in a reaction. Others such as the isoxazole and oxazole nuclei are less aromatic, and hence more prone to addition reactions. 

Electron donation from pyrrole-like nitrogen, or to a lesser extent from analogous sulfur or oxygen atoms, helps electrophilic attack at azole carbon atoms, but as the number of heteroatoms in the ring increases, the tendency toward electrophilic attack at both C and N decreases rapidly. 

Reactivity of Five-membered Rings with Two or More Heteroatoms 

All neutral azoles possess a positively charged azohum counterpart. In addition, as discussed in Chapter 2.4, certain olylium species exist which have no neutral counterparts, for example dithiolylium salts. 

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Reactivity of neutral azoles Azolium salts Azole anions... 

As previously noted, the most reactive site of neutral fully conjugated l,4-(oxa/thia)-2-azoles is the sp2 ring carbon atom of the exocyclic double bond. A detailed account of all reported data has been given in CHEC-II(1996) <1996CHEC-II(4)510>. An outline of all these reactions is given in Scheme 5. 

Pyrazole and indazole anions, in a manner similar to other azole anions, show the expected inversion of reactivity when compared with the cations. They are more reactive towards electrophiles, both at the nitrogen and carbon atoms, and less reactive towards nucleophiles than the corresponding neutral molecules. For practical purposes most of the N -alkylated pyrazoles and indazoles are prepared from the corresponding anions. 

The general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should be consulted as some of the conclusions reported therein are germane to this discussion. Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation, etc.). Pyrazole cations, formed in strong acidic media, show a pronounced deactivation (nitration, sulfonation, Friedel-Crafts reactions, etc.). For the same reasons quaternary pyrazolium salts normally do not react with electrophiles. 

The C-H/C-X coupling between electron-rich or -neutral heteroarenes such as indoles, thiazoles, furans, and 1,3-azoles with aryl hahdes have been described frequently in the literature (see earlier discussion). However, the couphng of electron-deficient heteroarenes such as pyridines has remained Hmited due to their low reactivity toward electrophilic metalation as well as CMD processes. Furthermore, 2-metallaazines are generally unstable and incompatible with the reaction conditions, although examples of such cross-coupling reactions (C-M/C-X coupling) exist. 

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