4-Aminoimidazole-5-carbonitrile

Studies in prebiotic synthesis. IV, The conversion of 4-aminoimidazole-5-carbonitrile derivatives to purines. J. Mol. Biol, 38, 121-8. 

Ferris and Antonucci73 have reported a photochemical synthesis of imidazo[4,5-d]imidazole (80) from 4-aminoimidazole-5-carbonitrile (78), which has attracted interest since 78, and its photochemical precursor diaminomaleonitrile (77) have been proposed74 as key intermediates in the prebiotic chemical evolution of purines. Mechanistic studies7311 suggest that the fused pyrazole 79 may be an intermediate. 

All the carbon atoms of the purine ring were supposedly provided by HCN molecules through a complex step-by-step condensation process. In particular, oligomers of HCN, such as the HCN-trimer aminomaleonitrile (AMN) and the HCN-tetramer diaminomaleonitrile (DAMN), were found to be intermediates in this transformation (Scheme 1) [43,44]. In accordance with the present-day biosynthesis of purines in the cell, two 4,5-di-substituted imidazole derivatives, 4-aminoimidazole-5-carbonitrile (AICN) and 4-aminoimidazole-5-carboxamide (AICA) were successively formed from AMN and DAMN by chemical or, most probably, photochemical reactions [45-47]. Finally, a ring-closure process of AICA and HCN yielded adenine 1. 

The photolysis of enaminonitriles provides a convenient and direct one-step synthesis of imidazoles. l,6-Dihydroimidazo[4,5-d]imidazole was prepared by the photochemical rearrangement of 3-aminopyrazole-4-carbonitrile (76JOC19) and by photolysis of 4-aminoimidazole-5-carbonitrile (74JA2014) (equation 71). The precise nature of the reaction intermediates (if any) formed on irradiation of enaminonitriles remains to be determined. However, the direct photochemical inversion of the nitrile to isocyanide is a possibility. 

Several 1-substituted 7-alkyI-2-sulfanylpurines, e.g. 7, can be synthesized by the reaction of 1 -alkyl-4-aminoimidazole-5-carbonitriles with isothiocyanates. ... 

An alternative route to purines is via the self-condensation of dilute solution (>0.01 M) of HCN at pH 9 to a tetramer of HCN. Photolysis of the HCN tetramer yields 4-aminoimidazole-5-carbonitrile (9,10), This aminoimidazole reacts with HCN to generate adenine. Other purine bases are also formed by the reaction of the aminoimidazole carbonitrile with other one or two carbon compounds (5). 

The mechanism and sequential steps of the overall reaction were presumed to occur by the base-catalyzed oligomerization of HCN, first to a dimer, and then to a trimer (amino-malonodinitrile) followed by the condensation of this trimer with formamidine to 4-aminoimidazole-5-carbonitrile (AICN) or the corresponding amidine (AICAI). The eyclization into adenine is completed by condensation of either AICN or AICAI with formamidine. Guanine and xanthine are formed by condensation of AICA with urea. ... 

Fig. 4.5 The adenine synthesis can be varied to give other purine derivatives. Structures I-IX are those of I aminomalonitrile, II HCN tetramer, III aminoimidazole-carbonitrile, IV 4-aminoimidazole-5-carboxamide, V adenine, VI diaminopurine, VII xanthine, VIII guanine and IX hypo xanthine (Sanchez et al., 1966a)... 

In addition to the reactions of diaminomaleonitrile shown in Scheme 11 there are also some examples of photochemical transformations which lead to imidazole products. The initial reaction isomerizes the cw-dinitrile to the trans form which then forms a 5-aminoimidazole-4-carbonitrile via the iminoazetine (34). There are a number of related reactions, although the photochemical isomerization of enaminonitriles (35) probably involves an azirine intermediate (Scheme 17) (8UOC2872). 

Substituted 4(5)-aminoimidazole-5(4)-carbonitriles are versatile starting materials for the synthesis of purine ring systems. The combination of an electrophilie cyano group proximate to a nucleophilic amino function results in a one-step addition-cyclization reaction of electrophiles to give purine analogs. Triethyl orthoformate is widely used for the preparation of adenine and adenine derivatives without a substituent at C2. 

Nucleobase anion glycosylation of 6-substituted purines yields the jV -nucleosides as the main products. The situation changes if 5-aminoimidazole-4-carbonitrile instead of a purine is used as a precursor, then 4-amino-l-(ribofuranosyl)imidazole-5-carbonitrile (AICN-riboside) is formed as the main product and the N3 regioisomer as a minor component. For this reason imidazole nucleosides are very useful intermediates, especially for the synthesis of N7 glycosylated purines,... 

The reaction of appropriate alkyl and phenyl isocyanates with protected 5-aminoimidazole-4-carbonitrile nucleoside, followed by cyclization and deprotection, provides direct access to 1-alkyl and 1-phenyl derivatives of isoguanosine 3. ... 

The isomeric 5-aminoimidazole-4-carbonitrile 2 -deoxyribofuranosides have been condensed with diethoxymethyl acetate in the synthesis of 2 -deoxyadenosine and its N7 glycosylated isomer 6. " ... 

Like other heterocyclic iV-oxides, imidazole 3-oxides 1063 react with AC2O to give the corresponding imidazolones 1064 and 1065 (Scheme 257). TMSCN transforms 1063 into imidazole 2-carbonitriles 1066, whereas alkyl thiones convert 1063 to 1067 <2000HCA728, 1998HCA1585, 2002AGE2290>. The 2-aminoimidazoles 1068, formed from the reactions with either isocyanate or isothiocyanate, react further with isocyanates to form ureas but are inert toward thiourea formation. In contrast to nonaromatic imidazole A -oxides (nitrones), oxides 1063 react with DMAD to form butanedioates 1069, rather than the (putative) [3-1-2] adduct <2000T5405>. 

Biosynthetically, purines are built up via formation of the imidazole ring first, from glycine and formate, and thence to hypoxanthine and then the other natural purines. In the laboratory, most imidazole-based purine syntheses start with 5-aminoimidazole-4-carboxylic acid, particularly its amide (known by the acronym AICA), which as well as its riboside, is commercially available from biological sources. The use of 5-aminoimidazole-4-carbonitrile in this approach results in the formation of 6-amino-purines, as in a synthesis of adenine itself." ... 

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