4-Imidazolecarboxylates

Scheme 7.37 Polymer-bound synthesis of 1-substituted 4-imidazolecarboxylates.

The well-known application of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine as a diene in inverse electron demand Diels-Alder cyclizations was adapted for the synthesis of purines <1999JA5833>. The unstable, electron-rich dienophile 5-amino-l-benzylimidazole was generated in situ by decarboxylation of 5-amino-l-benzyl-4-imidazolecarboxylic acid under mildly acidic conditions (Scheme 54). Collapse of the Diels-Alder adduct by retro-Diels-Alder reaction and elimination of ethyl cyanoformate, followed by aromatization by loss of ammonia, led to the purine products. The reactions proceeded at room temperature if left for sufficient periods (e.g., 25 °C, 7 days, 50% yield) but were generally more efficient at higher temperatures (80-100 °C, 2-24 h). The inverse electron demand Diels-Alder cyclization of unsubstituted 1,3,5-triazine was also successful. This synthesis had the advantage of constructing the simple purine heterocycle directly in the presence of both protected and unprotected furanose substituents (also see Volume 8). 

To address the purification issue, which frequently is a bottle-neck in the fast microwave chemistry, a solid-phase catch and release methodology was utilized in a two-component, two-step synthesis of l-alkyl-4-imidazolecarboxylates [45]. In the first step, a collection of isonitriles 25 was immobilized onto a solid support by the reaction with the commercially available N-mclhyl aminomethylated polystyrene 26. Subsequent treatment with various amines brought about simultaneous derivatization and release of the desired imidazoles 27 back into solution. Significantly, only derivatized material was released from the resin, thus ensuring high purity of the desired product. Both steps of the reaction were substantially accelerated by microwave dielectric heating, resulting in the overall reaction time reduction from 60 hours to 70 minutes (Scheme 18). 

Scheme 18 Solid-phase synthesis of l-alkyl-4-imidazolecarboxylates using catch and release methodology...

In some cases the nitration is accompanied by oxidation of the side groups [122, 123], Thus, for example, depending on the conditions, 4(5)-hydroxym-ethylimidazole is converted by the action of the sulfuric-nitric acid mixture into the corresponding aldehyde [124-126], into 4(5)-imidazolecarboxylic acid [124, 125], or into 4(5)-nitro-5(4)-imidazolecarboxylic acid [122, 123] (Scheme 11). 

Reaction of 5-amino-l -benzyl-4-imidazolecarboxylic acid 495 with 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine 496 at 80 °C in DMF led to 9-benzyl-2,6-bis(ethoxycarbonyl)purine 501 in 83% yield. Presumably, 5-amino-l-benzyM-imidazole 497 is generated siVu from the acid and is highly reactive for the cycloaddition. The cycloadduct 498 then spontaneously undergoes retro Diels-Alder reaction with the loss of ethyl cyanoformate 499 followed by the loss of ammonia and aromatization to produce the purine in a regioselective manner (Scheme 114) <1999JA5833, 2005JOC998>. 

Reaction between ethyl 3-A, A -dimethylamino-2-isocyanoacrylate 1192 and a primary amine affords l-alkyl-4-imidazolecarboxylates 1193 in good yields. The process is applicable to unhindered alkylamine substrates (R-NH2), including those containing reactive functionalities such as alcohols and secondary and tertiary amines <20020L4133>. Solid-phase bound 3-iV2V-dimethylamino-2-isocyanoacrylate 1194 undergoes the same cyclization under microwave conditions (Scheme 293) <2004TL2219>. 

Nonactivated esters are reduced only slowly if at all in strongly acidic medium at a lead cathode [45], whereas alkyl benzoates are reduced to a mixture of benzyl alcohol and alkyl benzyl ether [45,46], and alkyl 4-imidazolecarboxylates similarly are reduced to a mixture of the corresponding alcohol and ether [76]. Phenyl and benzyl benzoate give predominantly esters [23,34], as do also ethyl o-chloro- and m-bromobenzoate [46]. 

Representative procedure 2-Amino-4(5)-cyano-5(4)-imidazolecarboxylic acid (0.510 g, 3 mmol), anhydrous lithium chloride (0.5 g), pyridine (2 ml,... 

Phosphoribosyl-5-amino-4- imidazolecarboxylate carboi lyase Phosphoribosyl aminoimidazole carboxylase... 

Updated Entry replacing M-02077 3-Methyl-4-imidazolecarboxylic acid [41806-40-0]... 

AB monomers, based on cyanoimidazoles, were prepared by selective alcoholoysis of one of the nitrile groups and alkylation of the 1-nitrogen. This was accomplished in the following manner. Ethyl 2-amino-4(5)-cyano-5(4)-imidazolecarboxylate (2), prepared by Japanese workers,7 was alkylated by deprotonation of the 1-hydrogen. 

In most other reactions the azolecarboxylic acids and their derivatives behave as expected (cf. Scheme 52) (37CB2309), although some acid chlorides can be obtained only as hydrochlorides. Thus imidazolecarboxylic acids show the normal reactions they can be converted into hydrazides, acid halides, amides and esters, and reduced by lithium aluminum hydride to alcohols (70AHC(12)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show the normal range of reactions. 

Imidazole-5-carboxamide, l-methyl-4-nitro-mass spectra, 5, 359 Imidazole-4-carboxanilide, 1-methyl-synthesis, 5, 435 Imidazolecarboxylic acid, vinyl-polymers, 1, 281 Imidazole-2-carboxylic acid chlorination, 5, 398 mass spectra, 5, 360 synthesis, 5, 474... 

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... 

If in the ester synthesis CDI is introduced in excess and benzene is used as solvent without any base, treatment of the reaction mixture after the first step with Sephadex LH-20 is recommended in order to remove the abundant CDI and thereby eliminate possible reactive by-products such as imidazolecarboxylates (ImCOOR).[10]... 

In a reaction of CDI with 2 -0,3 -Af-bis(benzyloxycarbonyl)-jV-desmethyl-6-0-methylerythromycin A the corresponding imidazolecarboxylate (K2C03, THF, 36% yield) was formed, which yielded in a further reaction with C6H5CH2OH the 4 -benzyl-oxycarbonic ester of this erythromycin A analogue in 40% yield.12413... 

AK3-Imidazo[l, 2-a]pyridinyl)aminomethylenemalonates (638) were cyclized by heating in boiling Dowtherm A for 40 min to give dipyridof 1,2-a 3, 2 -e(]imidazolecarboxylates (639) in 46-76% yields (81JHC1565). 

Crosslinked polymers of vinyl-substituted imidazolecarboxylic acids have been studied as chelating resins for heavy metal ions (78MI11101). For example, polymer (75) displays stabilities and capacities in the order Cu2+ > Ni2+ > Cd2+ > Zn2+ > Mg2+ which is similar to that observed with other amino acid chelating resins. The unusual feature of the polymer, however, is that exceptionally strong complexing abilities are maintained even in strongly acidic media. Polymer (75) also displayed potential utility for the removal of mercury(II) ions from aqueous media. 

Since the electrophile is introduced adjacent to the NH protective group, substantial steric hindrance may be encountered in the following reaction steps. In case of the dimethylsulfamoyl protected imidazole-5-carboxaldehyde, a rapid isomerisation to the 4-substituted product can be induced catalytically by traces of triethylamine or by mere standing at RT for several days42. The effect of steric hindrance by the protective group was also observed in the reduction of ethyl dimethylsulfamoyl-imidazolecarboxylate with DIBAH. The 5-isomer could not be reduced, whereas the 4-isomer is reduced easily to the imidazole carboxaldehyde under the standard conditions49. 

The electrochemical reduction of imidazolecarboxylates gives a mixture (about 1 1) of ethers and alcohols when strongly acidic electrolytes are used 532) ... 

Dimethoxy-3,6-dimethylpyrazine (182) gave 6,8-dimethoxy-l,4-dimethyl-2,3-dioxa-5,7-diazabicyclo[2.2.2]octa-5,7-diene (183) (hv, 02 J, CH2C12, methylene blue, h %), and thence methyl 5-methoxy-2,4-dimethyl-l-imidazolecarboxylate (184) or its isomer (Ph3P, THF—H20, 20°C, 5 days 47% mechanism suggested).165... 

The oxidation of the hydroxymethyl group probably takes place more readily than nitration of the ring [124-127], However, the entry of a nitro group into the imidazole ring without oxidation of the hydroxymethyl group has been reported [107, 110]. Imidazolecarboxylic acids are not nitrated, and their nitro derivatives are therefore obtained by different methods. Nevertheless, the 4- and 5-mononitro-substituted compounds were isolated with the 4,5-dinitro derivative as impurity during the nitration of ethyl l-methylimidazole-2-carboxylate with a mixture of 100% nitric and sulfuric acids at 95°C [128],... 

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... 

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 . 

Heteroarylamines, for example 1195, react with (dimethylamino)propenoate 1196 to yield an imidazolecarboxylate 1199. The imidazole ring is formed via the intermediate diaminoalkenoate 1197, which undergoes an intramolecular Michael addition followed by a retro-aldol-like reaction (Scheme 294) <1998JHC1527>. Similarly, 4-dimethyl-amino-2-aza-l,3-dienes 1200, serving as y-dielectrophiles, condense with amines or hydrazines neat at 70 °C to form A -substituted imidazole-4-carboxylates 1201 in 60-75% yields (Scheme 294) <1999TL8097>. 

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