Radziszewski reactions Debus

The imidazole ring is often found in biologically active molecules and is as such important in medicinal chemistry [16]. An interesting route for the production of substituted imidazoles is the Debus-Radziszewski reaction. This is a three-component reaction of a diketone, an amine and an aldehyde to form trisubstituted imidazoles (Scheme 3). 

One of the popular and widely used methods for the synthesis of 2-trifluoromethylimidazole involves the Radziszewski reaction (Debus-Radziszewski reaction) [2a]. Following the Davidson s modifications (using ammonium acetate in acetic acid instead of ammonia in alcohol) [13a], Lombardino and Wiseman prepared a series of 2-trifluoromethylimidazoles via the condensation of a-dicarbonyl compounds and trifluoroacetaldehyde ethyl hemiacetal (Scheme 4) [13b]. The reaction presumably proceeds via the formation of a diimide intermediate that subsequently undergoes condensation with the aldehyde to afford the final product. An anhydrous condition is highly recommended for better yields of imidazoles. 

Reactions of this type include the major early methods used by Debus,22 Radziszewski,23 Weidenhagen,24 and Maquenne.25 All these suffer from deficiencies such as difficulty of synthesis of starting materials, low yields, and, more often than not, from the formation of mixtures of products which require tedious separation. Among recent modifications26 27 of the Maquenne method is the preparation of dialkyl 4,5-imidazole dicarboxylates in yields of 45-65 % by treatment of a dialkyltartrate dinitrate with either an aliphatic aldehyde or a formaldehyde precursor, in the presence of ammonium ions at pH 3.5-6.5. 

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