1- //-Imidazole-2-carboxylic acid, decarboxylation

Amino-5-imidazole carboxylic acid (38) has been synthesized from 4-nitro-5-imidazole carboxylic acid by catalytic hydrogenation and shown [56JBC(218)175] to spontaneously decarboxylate at low pH to give 4-aminoimidazole (39). 

Five approaches to the synthesis of 5-amino-4-unsubstituted imidazoles (96) have been described and are summarized in Scheme 9. These are (a) reduction of 5-nitroimidazoles (97), (b) hydrolysis of carbamates and amides (98), (c) decarboxylation of imidazole carboxylic acids (99), (,d) ring transformations of 5-aminothiazoles (100), and (e) cyclisation of nitrile derivatives (101). 

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]. 

Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position (80AHC(27)241). Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. These reactions have been reviewed (74AHC(i6)123) the mechanism involves an intermediate cr-complex. 

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... 

For quantitative work, it is necessary to estimate the concentration of 5-amino-l-(P-D-ribofuranosyl)imidazole in aqueous solution. It seems that the only available method is the Bratton-Marshall assay, which was originally developed for the estimation of arylamines in biological fluids. The principle of the method is the spectrometric estimation of a salmon-pink colored dyestuff obtained by diazotation in situ, followed by coupling with /V-( 1 -naphthyl)ethyl-enediamine.65 The only remaining problem then is to know the molar extinction of this dye because pure samples of AIRs are not available. A value of 16800 at 520 nM was obtained for the dyes prepared from a model compound, 5-amino-l-cyclohexylimidazole-4-carboxylic acid (54), which is crystalline. A comparable molar extinction can be expected for the dye prepared from imidazole 55, if the carboxyl group does not exert too much influence on the chromophore. Actually, its influence is perceptible even with the naked eye, the dyestuff prepared from 53 having a somewhat different, wine-red color, with max>520 nM. The molar extinction for 55 is 17400 at 500 nM. When the decarboxylation of 54 was conducted under mild acidic conditions (pH 4.8, 50°C, 1 hour), estimation of 5-aminoimidazole 55 by the Bratton-Marshall method led to the conclusion that the reaction was almost quantitative.66 Similar conditions for the final decarboxylation were adopted in the preparation of samples of AIRs labeled with stable isotopes.58... 

The only problem for the matrix-isolation of 21 consisted in the non-availability of a reasonable diazo precursor molecule suited for this technique. But since we already had experience with the preparation of 2,3-dihydrothiazol-2-ylidene46 (see below) by photofragmentation of thiazole-2-carboxylic acid we tried the same method with imidazole-2-carboxylic acid (20). Indeed, irradiation of 20 with a wavelength of 254 nm leads to decarboxylation and the formation of a complex between carbene 21 and CO2. This is shown by the observation that the experimental IR spectrum fits only with the calculated spectrum of complex 21-CC>2 (calculated stabilization energy relative to its fragments 4.3 kcal mol-1). The type of fixation of CO2 to 21 is indicated in the formula S-21 C02. 

The oxazole (232) heated with formamide gave the imidazole (233) oxazolium cations undergo similar conversions. Primary amines convert oxazole-4-carboxylic acids (234) at 150°C into imidazoles (235) with accompanying decarboxylation (53CB88) (see CHEC 4.07 and 4.18). 

The dihydrothiazol-2-ylidene (4) was generated by photolysis of matrix-isolated thiazol-2-carboxylic acid.12 Calculations suggested that the barrier to isomerization to thiazole is about 42.3 kcal mol 1 and that the carbene resembles the related imidazol-2-ylidene in structure. An ab initio study of hydroxyoxiranone predicted that the decarboxylation of the zwitterion (5) to form hydroxycarbene (6) would be favourable in vacuo but not in water.13 A theoretical study showed that dihalosulfenes (X2C=S02) are best viewed as dihalocarbenc-SO complexes with a carbon-sulfur bond order of approximately zero.14 hi a study directed at the elusive thionformic acid (7), tandem mass spectrometric methods were applied to isomeric ethyl thioformates.15 The results suggest that the radical cations generated have the carbene structure [(HS)C(OH)]+ ... 

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 nucleophilic radicals formed by the silver-catalyzed, oxidative decarboxylation of carboxylic acids by peroxydisulfate ions attack protonated imidazoles mainly at the 2-... 

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 . 

Decarboxylation can be achieved by heating the acids above their melting points, often in the presence of a copper-chromium oxide catalyst, and it is possible to remove one group at a time from imidazole-4,5-dicarboxylic acid by heating the monoanilide. Studies of the kinetics of decarboxylation of 5-aminoimidazole-4-carboxylic acids implicate a first-order decarboxylation of both the acid and the zwitterion the anion is stable and not... 

Radical substitution reactions include alkylations and arylations in the main. Nucleophilic radicals produced by the silver-catalyzed oxidative decarboxylation of carboxylic acids (by peroxydisulfate ion) attack proton-ated azoles at the most electron-deficient sites.Thus, imidazole and 1-alkylimidazoles are methylated exclusively at C-2 in rather low yields. The use of isopropyl and t-butyl radicals gives improved yields, but benzyl and acyl radicals tend to dimerize rather than substitute the... 

---