Syntheses of the Imidazole Ring System

It becomes apparent when one is faced with a synthetic problem in imidazole chemistry that there is no single, widely applicable synthetic procedure. Even the methods devised by Bredereck (Section II, A) and the reaction of a-aminoketones with cyanates or thiocyanates (Section II, F) have limitations. 

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. 

Hydrolysis (especially with bromoacetic acid)28 of the dicarboxylic esters can be followed by decarboxylation and it is possible to remove one carboxyl group at a time to prepare the imidazole-4-carboxylic acid. The decarboxylation of imidazolecarboxylic acids has been discussed by Schipper and Day.2 

The a-dicarbonyl compounds required as starting materials in the Radziszewski synthesis are often difficult to prepare. A recent method of synthesis of such compounds has been described20 using propane-1,3-dithiol to prepare a stable dithiane anion (1), which can be converted into either an a-diketone or an a-hydroxyketone. 

A further efficient synthesis of glyoxals and a-diketones involves the reaction of an a-ketonitrate ester with sodium acetate in dimethyl 

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