Imidazole dicarbonyl, reaction with acids

The reactions of amidines or guanidines with a-functionalized carbonyl compounds continue to be utilized for the synthesis of imidazoles. Thus, the mixed anhydride of acetic and chloroacetic acids reacts with symmetrical diarylguanidines to give l-aryl-2-arylaminoimidazolin-4-ones, and there is competitive formation of imidazoles and pyrimidines in the reaction of benzamidine with 3-bromobenzo-4-pyrones (18). Imidazoles are minor products, but are favored in nonpolar solvents. The use of a-dicarbonyl compounds with guanidine gives 2-amino-4-hydroxy-4-methyl-4//-imid-azoles, which give excellent yields of 2-aminoimidazoles on catalytic hydrogenation. " ... 

Non-volatile imidazoles that result from amino acids in reactions with a-dicarbonyl compounds, aldehydes and ammonia are betaines. The basic member of the homologous series of these imidazoles is 3-carboxymethyl-l-imidazoHum ethanoate, which arises as the main product in the reaction of glycine with glyoxal and ammonia (8-171). 

This benzilic acid type of rearrangement is the result of the action of alkali on the dicarbonyl compound, and is accelerated by calcium ions. The formation of saccharinic acids by the action of aqueous alkali on sugars is very well known 82,84,92 however, if ammonia is present, very little8 or no production of saccharinic acid has been reported. The reaction of the intermediate carbonyl compounds with ammonia is faster than the benzilic acid type of rearrangement to give saccharinic acid, and, hence, substituted imidazoles are formed, as illustrated in Scheme 9. 

Many of the classical methods grew out of the earliest synthesis of imidazole, which was achieved in 1858 by Debus [1] when he allowed glyoxal, formaldehyde and ammonia to react together. Although the earliest modifications of this method used a-diketones or a-ketoaldehydes as substrates [2, by the 1930s it was well established that a-hydroxycarbonyl compounds could serve equally well, provided that a mild oxidizer (e.g. ammoniacal copper(ll) acetate, citrate or sulfate) was incorporated [3. A further improvement was to use ammonium acetate in acetic acid as the nitrogen source. All of these early methods have deficiencies. There are problems associated with the synthesis of a wide range of a-hydroxyketones or a-dicarbonyls, yields are invariably rather poor, and more often than not mixtures of products are formed. There are, nevertheless, still applications to the preparation of simple 4-alkyl-, 4,5-dialkyl(diaryl)- and 2,4,5-trialkyl(triaryl)imidazoles. For example, pymvaldehyde can be converted quite conveniently into 4-methylimidazole or 2,4-dimethylimidazole. However, reversed aldol reactions of pyruvaldehyde in ammoniacal solution lead to other imidazoles (e.g. 2-acetyl-4-methylimidazole) as minor products [4]. Such... 

In the uncondensed imidazoles the standard method reacts an a-aminocarbonyl compound with a thiocyanate (see Section 4.1 and Table 4.1.1). If a 2-alkylthioimidazole is required directly, one can combine an N-alkyT or A -arylcarbonimidodithioate in refluxing acetic acid with the aminocarbonyl substrate (see Section 4.1 and Scheme 4.1.3). Alternatively, reaction between thiourea and a two-carbon synthon (ot-hydroxy-, a-halogeno-, a-dicarbonyl) leads to imidazoline-2-thiones (see Section 4.3). In sulfuric acid, 3-butynylthiourea cyclizes to 4,5-dimethylimidazolin-2-thione (see Section 2.2.1). 1-Substituted 2-methylthioimidazoles can be made, albeit in rather poor yields, from appropriately substituted 2-azabutadienes (see Section 3.2 and Scheme 3.2.3), and 2-arylthioimidazoles are available in moderate yields from benzyl isocyanides and arylsulfenyl chlorides (see Section 4.2 and Scheme 4.2.12). Ring transformations of 5-amino-2-alkylaminothiazoles and 2-acylamino-5-aminothiazoles may have occasional applications (see Section 6.1.2.7). The ease with which a thiol group or imidazole or benzimidazole can be alkylated, in comparison with the annular nitrogens, usually makes it more convenient to prepare alkylthioimidazoles from the thiols (or thiones). 

This reaction is a variation of the conditions reported by Debus in which a dicarbonyl is reacted with an amine salt and an aldehyde in the presence of an acid or Lewis acid. If an A -substituted imidazole is desired, then an amine can be used. Recent Lewis acids that have been used are ZrCU or InCL. ... 

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. 

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