Imidazole-4-carboxylates

UV, 5, 356 ... 

Imidazole-2-carboxylic acid, 4-methylr ethyl ester synthesis, 5, 474 Imidazole-4-carboxylic acid coupling, 5, 403 iodination, 5, 400 reactions... 

Imidazole-4-carboxylic acid, 5-amino-cyclization, 5, 583 decarboxylation, 5, 434—435 ethyl ester diazotization, 5, 414 synthesis, 5, 477... 

Imidazole-4-carboxylic acid, 5-methylamino-ethyl ester thermolysis, 4, 438 Imidazolecarboxylic acids decarboxylation, 5, 434—435 reactions, 5, 92, 434—435 Imidazolediazonium fluoroborates reactions, 5, 439 Imidazolediazonium salts reactions... 

Aromatic diazonium salts react easily in neutral aqueous solution with thiols such as N-acetylcysteine, forming compounds of the type Ar — N2 —S —CH2CH(NHAc) COOH. Nifontov et al. (1990) suggested that such compounds, e.g., that of 5-diazo-imidazole-4-carboxylate, function as a form of transport depot for cytotoxic diazo-carboxylate in the human body. 

The imidazole ring is a privileged structure in medicinal chemistry since it is found in the core structure of a wide range of pharmaceutically active compounds efficient methods for the preparation of substituted imidazole libraries are therefore of great interest. Recently, a rapid synthetic route to imidazole-4-carboxylic acids using Wang resin was reported by Henkel (Fig. 17) [64]. An excess aliphatic or aromatic amine was added to the commercially available Wang-resin-bound 3-Ar,M-(dimethylamino)isocyano-acrylate, and the mixture was heated in a sealed vial with microwave irradi-... 

Reduction of the carboxylic acid group passes through the intermediate aldehyde. For a number of examples in the heterocyclic series, the aldehyde becomes a major product because it is trapped as the hydrated vfc.-diol form. Examples include imidazole-2-caiboxylic acid [139], thiazole-2-carboxylic acid [140] and pyridine-4-carboxylic acid [141] reduced in dilute aqueous acid solution. Reduction of imidazole-4-carboxylic acid proceeds to the primary alcohol stage, the aldehyde intermediate is not isolated. Addition of boric acid and sodium sulphite to the electrolyte may allow the aldehyde intermediate to be trapped as a non-reducible complex, Salicylaldehyde had been obtained on a pilot plant scale in this way by... 

A solution of 3,5-dimethyl-3H-imidazole-4-carboxylic acid (7.14 mmol) and 1,1 -carbonyl-diimidazole (10.7 mmol) in 35 ml DMF was stirred 3 hours at ambient temperature and then treated with A-hydroxy-acetamidine (9.18 mmol). The mixture was stirred an additional 16 hours at 80°C, then concentrated, and the residue dissolved in 30 ml acetic acid. This mixture was stirred 2 hours at 100°C and was then reconcentrated. The residue was then treated with 50 ml saturated NaHC03 solution and extracted seven times with 30 ml CH2C12. The extracts were washed with 70 ml brine, dried using MgS04, concentrated, and the product isolated in 61% yield as a white solid, mp = 95°C. 

The Step 1 co-reagent, 3,5-dimethyl-3H-imidazole-4-carboxylic acid, was prepared according to the method of Leone-Bay (2). 

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... 

Henkel [24] used the novel 3-A, A (dhnethylamino)-isocyanoacrylate-wang resin (xxvi) for the synthesis of imidazole-4-carboxylic acids (xxvii) in a microwave reaction condition. 

Imidazolecarboxylic acids are stable, crystalline compounds which form salts with metals, and which may exist in zwitterionic forms such as (198 Scheme 106). Such zwitterionic forms have been implicated in the decarboxylation mechanisms of the compounds. The carboxyl functions exert a pronounced base-weakening effect on the parent molecules, but it is surprising that a 5-bromo substituent in imidazole-4-carboxylic acids is not subject to ready nucleophilic displacement by CN or SOs . 

Claisen rearrangement of the adduct (43) formed when a propiolate ester and an aryl aldoxime combine leads to imidazole-4-carboxylates in 61-72% yields. This reaction also proceeds by ring closure of an amidine (44 Scheme 24) (80AHC(27)241). 

To the above mercaptoester (3.0 g, 19 mmol) in ethanol (20 ml) is added a wet suspension of freshly prepared Raney nickel [26] in ethanol ( 5 g). The mixture is heated under reflux and monitored by TLC on silica (ethyl acetate). The desulfurization is complete in about 1 h. The suspension is then treated with activated charcoal, filtered (Celite) and washed with a little ethanol, and then the filtrate is rotary evaporated. Recrystallization of the residue from aqueous ethanol gives methyl imidazole-4-carboxylate (1.27g, 53%), ra.p. 149°C. 

Such hydroxyimidazoles or oxides are capable of complete reduction to the unoxygenated imidazoles, while the 1-hydroxyimidazole 3-oxides can also be partically reduced with, for example, NaBUi [53], or completely deoxygenated with Raney nickel [52, 54], Although most cyclizations of a-ketooximes lead to A -oxygenated imidazoles, there are exceptions. When an o(-oximino-)6-dicarbonyl compound is refluxed with benzylamine in a suitable solvent (c.g. DMSO, acetonitrile, toluene), 4-acylimidazoles (11) are formed in moderate to good yields. The reaction is readily adapted to the synthesis of imidazole-4-carboxylates and -amides (Scheme 4.1.7)... 

Usually decarboxylation is accomplished by heating the acids above their melting points, often in the presence of a copper-chromium catalyst. Imidazole-4,5-dicarboxylic acid can be monodecarboxylated by heating its monoanilide imidazole- and benzimidazole-2-carboxylic acids decarboxylate very readily indeed, so readily that the carboxyl function makes a useful blocking group in metallation procedures (see Scheme 7.2.1) [3-5]. A potentially useful method of preparation of imidazole-4-carboxylic acid derivatives heats the 4,5-dicarboxylic acid (2) with acetic anhydride to form (1), which is essentially an azolide and very prone to nucleophilic attack which cleaves the nitrogen-carbonyl bond (Scheme 8.3.1). With methanol the methyl ester (3) is formed with hydrazines the 4-hydrazides (4) result [6]. 

Specific preparation of each of the above isomers should theoretically be possible by methylation of imidazole-4-carboxylic acid in neutral and basic media. Methylation yields, however, are unlikely to be high, and the separation... 

Imidazole-4-carboxylates have been made from amidines derived from or-ainino acids (see Section 2.2.1 and Table 2.2.1), by Claisen rearrangement of the adduct formed when an arylamidoxime reacts with a propiolate ester (see Section 2.2.1 and Scheme 2.2.6), from a-aminocarbonyls with cyanates or thiocyanates (see Section 4.1 and Table 4.1.1), from a-oximino- 6-dicarbonyl compounds heated with an aUcylamine (see Section 4.1 and Scheme 4.1.7), and by anionic cycloaddition of an alkyl isocyanoacetate to diethoxyacetonitrile (see Section 4.2 and Scheme 4.2.11 see also Scheme 4.2.12). A further useful approach is to use an appropriate tricarbonyl compound with an aldehyde and a source of ammonia (see Chapter and Scheme 5.1.1). Irradiation of 1-alkenyltetrazoles bearing an ester substituent may have applications (see Section 6.1.2.3). 

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