Azoles alkyl-, deprotonation

It can be assumed that the azoles are deprotonated by the interfacial exchange mechanism, but it is noteworthy that it has been suggested that the rate of alkylation of indole under liquiddiquid two-phase conditions decreases with an increase in the concentration of the sodium hydroxide [8]. The choice of catalyst appears to have little effect on the reaction rate or on the overall yields of alkylated azole. Benzyltriethylammonium chloride, Aliquat, and tetra-n-butylammonium hydrogen sulphate or bromide have all been used at ca. 1-10% molar equivalents (relative to the concentration of the azole) for alkylation reactions, but N-arylation of indole with an activated aryl halide requires a stoichiometric amount of the catalyst [8]. 

Azole iV-oxides, iV-imides and iV-ylides are formally betaines derived from iV-hydroxy-, iV-amino- and iV-alkyl-azolium compounds. Whereas iV-oxides (Section 4.02.3.12.6) are usually stable as such, in most cases theiV-imides (Section 4.02.3.12.5) andiV-ylides (Section 4.02.3.12.3) are found as salts which deprotonate readily only if the exocyclic nitrogen or carbon atom carries strongly electron-withdrawing groups. 

Similarly, alkyl groups at the C2 positions (but not the C4 or C5 positions) can be deprotonated giving carbanions 3.39a,b which can also be quenched with electrophiles to afford 1,3-azoles 3.40. 

Imidazole alkylations can be carried out under a variety of reaction conditions. For conventional iV-alkylations which are unlikely to be complicated in terms of regiochemistry, it is preferable to alkylate the imidazole anion (an Se2cB process). Such reactions are faster, higher yielding and less prone to azole salt formation than those in neutral conditions. The anion is generated best by the use of sodium in ethanol or liquid ammonia, with sodium or potassium hydroxide or carbonate, or by use of sodium hydride in dry DMF [3]. Addition of the alkylating agent to the deprotonated substrate completes the reaction. 

The benzo-1,3- and -1,2-azoles do not undergo electrophilic substitution on the hetero-ring some examples of electrophilic halogenations are known in the benzene ring. These bicyclic systems are slightly weaker bases than the azoles, but react easily with alkyl halides to give salts. N-Deprotonation of indazoles or benzimidazoles allows substitution on nitrogen. 

The rapid deuteration of purine at C-8 in neutral water at 100 °C probably involves 8-deprotonation of a concentration of purinium cation to give a transient ylide (cf. 1,3-azole 2-H-exchange, 24.1.2.1). 9-Alkylated purines undergo a quite rapid exchange in basic solution involving direct deprotonation of the free heterocycle. 

Protons on alkyl groups at the 1,3-azole 2-positions are sufficiently acidic for strong base deprotonation,and are more acidic than methyl groups at other positions even the assistance of an or/Ao-related carboxylate is usually insufficient to overcome the intrinsic tendency for 2-methyl-lithiation, though an adjacent tertiary amide can do this. The side-chain metallated derivatives can be utilised in reactions with electrophiles. The presence of a 5-nitro group allows much milder, base-catalysed condensations to occur. The condensation at the 2-methyl of thiazoles proceeds in organic acid solution. ... 

Compared with imidazol-2-yUdenes less attention has been paid to N,X-heterocychc carbenes pC = 0, S), mainly due to the instabihty of the free ligands which easily undergo dimerization processes.A probably better alternative would be to force the tautomerization of the coordinated azole ligand upon a deprotonation/protonation (or alkylation) sequence as that described earlier for N-alkyihmidazole Hgands. This method is illustrated in Scheme 36 for Mn(azole)(CO)3(bipy) (azole = oxazole, thiazole) complexes to afford the corresponding Prior to this work,... 

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