Radziszewski Reactions Imidazole Synthesis

2 Modifled Radziszewski Reactions Efficient Tool for the Synthesis of Substituted Imidazoles 

The imidazole moiety is very important in heterocyclic chemistry [10]. It is present in numerous natural products and also in many synthetic compounds. There are imidazole-based drugs such as ketoconazole 13 (antifungal properties) and losartan 14 (a drug against hypertension) (Fig. 12.1) 

Among other reported methods, Radziszewski reaction has demonstrated to be an efficient tool for the synthesis of substituted imidazoles. Regioselectivity in this kind of reaction is a very difficult task however, playing with the 

Multicomponent Reactions Concepts and Applications for Design and Synthesis, First Edition. Edited by Raquel R Herrera and Eugenia Marquds-L6pez. 2015 John Wiley Sons, Inc. Published 2015 by John Wiley Sons, Inc. 

SCHEME 12.2 General mechanistic hypothesis for Radziszewski reaction. 

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Scheme 4 Model reaction of the imidazole synthesis via the modified Radziszewski method to afford tetrasubstituted imidazoles [16]...

This reaction has been extended by Weidenhagen through the condensation of Qf-acetoacetone, cupric acetate, and aqueous ammonia to afford imidazoles in yields up to 60%. " This method is thus known as the Weidenhagen modification or Weidenhagen Synthesis. In addition, the Radziszewski reaction has been further modified to proceed in acetic acid by the use of ammonium acetate or ammonium carbonate as the source of ammonia to give imidazoles of markedly improved yields,and this protocol has been recently carried out under microwave irradiation. Furthermore, it has been reported that the reaction of an amidine with an of-halo ketone also readily yields imidazoles. 

In general, Radziszewski reaction is the synthesis of an imidazole derivative 4 by the condensation of an a-dicarbonyl compound 1 (e.g., glyoxal, pyruvaldehyde, porphyrin-2,3-diones, and benzil), an aldehyde 2, and two equivalents of dry ammonia in alcohol. Interestingly, the replacement of one equivalent of ammonia with a primary amine 3 results in the formation of 1-substituted imidazoles 4 (Scheme 12.1). 

A considerable number of methods base on the Radziszewski reaction employing heterogeneous catalytic systems have come out, allowing the synthesis of 2,4,5-tri-substituted imidazoles in a very efficient way, in terms of yields and time reactions. The authors proclaimed simplicity of the operations and environmental friendliness as additional advantages of the methods. In many cases, the reactions are carried out under solvent-free conditions, and in some cases, it is possible to perform them at room temperature. Some selected examples are those using as catalysts... 

Weidenhagen Synthesis The Weidenhagen synthesis of imidazoles is a modification of the Radziszewski reaction [65] and was first pubhshed in 1935 [66]. In this... 

For the synthesis of tetrasubstituted imidazoles via a one-pot modified Radziszewski reaction carried out by means of a continuous flow process, through a priori imine formation, see C. Maton, N. De Vos, B. I. Roman, E. Vanecht, N. R. Brooks,... 

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. 

In the reaction of a-diketones with formamide and formaldehyde at 180°-200°C, no a-hydroxyketones can be detected during the reaction,65 and hence formaldehyde cannot be acting as a reducing agent. It seems then that imidazole formation must be due to generation of ammonia from formamide and subsequent reaction between the diketone, ammonia, and formaldehyde. The advantage of this method over the older Radziszewski synthesis lies in the reduced decomposition of the diketone with consequent reduction in side, reactions which normally produce mixtures of imidazoles. 

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