Amino-5-cyanoimidazole

Synthesis of this imidazole is discussed in Section II,C,3. Its use for conversion to purines is outlined in Section VI,A. 

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Photochemical reactions of HCN tetramers in such eutectic solutions to give 4-amino-3-cyanoimidazole (Orgel, 2004)... 

The addition of nucleophiles to double and triple bond systems is often a convenient way of effecting an intramolecular ring closure. Addition to cyano groups has received considerable attention, as in addition to ring formation it provides a convenient method for the introduction of an amino group. Reaction of methyl Af-cyanodithiocarbimidate with Af-methylaminoacetonitrile resulted in displacement of methanethiol and formation of (314). Sodium ethoxide treatment in DMF converted (314) into a 4-amino-5-cyanoimidazole... 

The photocyclization of cis-diaminomaleonitrile (372) to 4-amino-5-cyanoimidazole (373) has been shown to proceed via the trans isomer 374.308 4-Amino-3-cyanopyrazole does not seem to be an intermediate in this transformation.309 Analogous cyclizations have been reported in the imidazole 373 which undergoes further photoreaction to yield the bicycle 375, and in o-aminobenzonitrile which is converted into indazole.310 This photocyclization has been extended to include enaminonitriles 376 spectroscopic evidence for the intermediacy of iminoketenimes 377 in this311 and other similar transformations312 have been reported. 

Photolysis of DAMN over a relatively long period of time produces 4-amino-5-cyanoimidazole (8) (Scheme 2). Unlike the photoreaction producing 7, which may be an intermediate to 8, this conversion is irreversible (74JA6707). 

Amino-5-cyanoimidazole can also be obtained nonphotochemically. The monocarboxamide from hydrolysis of 13 (R = H) (see Section IIl.B) undergoes Hoffmann rearrangement on treatment with chlorine and sodium hydroxide to give 8 (Scheme 2) (76JAP(K)51-1466, 1467, 1468). 

The zwitterion, or carbene, derived from 4,5-dicyano-2-diazoimidazole reacts with acetic acid to give 4,5-dicyanoimidazolin-2-one (79JOC1717). Photolysis of 4-amino-5-cyanoimidazole gives l,6-dihydroimidazo[4,5-d]imidazole (207 Scheme 109) (74JA2010). 

Oxidation of the Schiff bases (22) of diaminomaleonitrile monoamide gives 4-cyanoimidazole-5-carboxamides with a variety of 2-substituents. When diaminomaleonitrile reacts with formamidine, the condensation product (23) can form imidazoles in two ways. Direct loss of ammonia gives 4,5-dicyanoimidazole, but isomerization, followed by cycliz-ation in which HCN is eliminated, gives 4-amino-5-cyanoimidazole. With further formamidine this latter product is converted into adenine (Scheme 11) (79JOC4532). 

A further example of a similar sequence of reactions is provided by the reactions of N-cyaniminodithiocarbonic esters (55) with a-cyanoammonium salts. The initial condensation product (56) cyclizes when heated with sodium ethoxide in DMF, again giving a 4-amino-5-cyanoimidazole. Related is the reaction of (55) with the hydrochloride salt of ethyl methylaminoacetate, which gives imidazoles directly perhaps this might be classified... 

There have also been a few examples of ring expansions involving azetines. One such instance, which follows a pericyclic mechanism, is the thermolysis of 4-cyano-l-t-octyl-3-t-octylamino-2-t-octyliminoazetine (160), producing the 4-amino-5-cyanoimidazole (Scheme 89). Such azetine species have been implicated as intermediates in the photolysis of enaminonitriles to imidazoles (Section 4.08.1.1.1 Scheme 17). In strongly basic medium the azetidinone (161), which possesses a lactam group, is ring expanded to the 4H-imidazolinone (163), probably via the anionic acylic species (162 Scheme 89) <80AHC(27)241>. 

Treatment of 5-cyanoimidazole-4-acetonitrile (439 R = H) with anhydrous HBr gave 6-amino-4-bromoimidazo[4,5-c]pyridine (440 R = H, R = Br) (74JHC233). Likewise, the l-(tri-0-benzoyl-/S-D-ribofuranose) derivative of (439) gave (440 R = tri-O-benzoyl-jS-D-ribofuranose, R = Br), whereas treatment with liquid ammonia and with... 

Ferris JP, Orgel LE. Studies on prebiotic synthesis. I. Aminoma-lononitrile and 4-amino-5-cyanoimidazole. J. Am. Chem. Soc. 1966 88 3829-3831. 

There are a number of examples of photochemical transformations of DAMN which may have some synthetic applications. At first, irradiation isomerizes the cir-dinitrile to the rrani -dinitrile, which then forms 5-amino-4-cyanoimidazole (18). Both azctidine or azirine intermediates have been postulated for these cyclizations [54, 55]. Although yields are good the photolytic conditions require dilute solutions ( lO moll solutions of the enaminonitriles) and may not prove practicable for the synthesis of larger quantities of imidazoles. On a small scale, however, the method merits consideration particularly since the process works for a wide variety of enaminonitriles (Scheme 2.1.9) [56-58]. 

Similarly, 1-aralkyl analogues can be made by base-induced cyclization of iV-aralkyl formamidincs related to (24) (e.g. 5-amino-l-benzyl-4-cyanoimidazole (77%)) [33],... 

A similar reaction sequence condenses iV-cyanoiminodithiocarbamic esters (7) with a-cyanoammonium salts (e.g. sarcosine nitrile sulfate) (Scheme 2.3.2). The isothiourea product (8) readily cyclizes to give 4-amino-5-cyanoimidazoles when heated with sodium ethoxide in DMF solution. It is possible to convert the dithiocarbamic esters directly into imidazoles if they are heated in DMF solution with sarcosine ethyl ester hydrochloride or methylaminoacetophenone in the presence of triethyamine [3]. These direct cyclizations arc, however, examples of both 1,2 and 1,5 bond formation. (See also Section 3.2). 

Reaction of an imidate with aminomalonodinitrile gives a 1-substituted 5-aminoimidazole-4-nitrile in low to moderate yields (10-60%) (Scheme 4.1.4). The reactions are carried out at room temperature in an acetate buffer, and there are similarities to reactions of DAMN (see Sections 2.1.1, 2.2.1 and 3.1.1) [35], and to the synthesis of 5-amino-4-cyanoimidazole from aminomalonodinitrile and formamidine acetate [41]. The reaction with an ethyl formimidate may initially involve replacement of the ethoxy group by amino followed by ring closure. Yields are reported to be low to moderate, with ethyl A-heteroarylformimidates reacting more readily than the iV-aryl analogues. Indeed, the phenyl derivative will not react at all. 

Aminomalononitrile (readily made in 45-50% yield by reduction of the oximino compound with aluminium amalgam) condenses with formamidine acetate in ethanol to give 5-amino-4-cyanoimidazole in 35% yield [34]. 

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