Electrophiles, reactions of annular nitrogens

Grimmett, M. R., Keene, B. R. T., Reactions of Annular Nitrogens of Azines with Electrophiles, 43, 127. 

Reactions of Annular Nitrogens of Azines with Electrophiles... 

Thiadiazoles undergo a facile reaction with electrophiles on the annular nitrogen atoms. In an extensive study, the quaternization of 2,5-disubstituted 1,3,4-thiadiazoles with methyl iodide was compared with quaternization in the pyridazine series. The influence of the alkyl substituents on product-distribution was less in the thiadiazole series than in the pyridazine series, probably due to the difference in geometry of the two compounds. The conditions chosen for the quaternization were such that the reaction was irreversible and the product distribution therefore kinetically controlled. Some of the results obtained are summarized in Table 13 (73ACS391). NMR data on these compounds are presented in Section 4.27.2.3.4. 

When the imidazole ring already has a substituent at C-4 or C-5 then there will be a directional effect imposed on electrophilic attack at annular nitrogen. As outlined earlier (Section 4.02.1.3) this orientation may be related to the tautomeric nature of the substrate. In spite of the inherent pitfalls in equating tautomeric nature with chemical reactivity there are examples which seem only to be explicable in terms of a major tautomer reacting, e.g. methylation of 4-nitroimidazole. Substituents at C-2 can only affect the rate of a reaction at ring nitrogen. 

In 4-ethoxyimidazoles the 5-position becomes more reactive towards electrophiles than the annular nitrogen, allowing 5-benzylation with benzyl chloride in the presence of potassium carbonate (Equation (25)). The Vilsmeier reaction gives the 5-carbaldehyde in 86% yield, and a number of unsaturated reagents also substitute at that site <88CPB1669>. 

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