2- Alkyl-4 -aminoimidazoles, reaction with

If cyanamide is used in place of isocyanate or thiocyanate, the cycloaddition reaction with an a-aminocarbonyl compound gives a 2-aminoimidazole (80AHC(27)24l). Alkylation of the sulfur atom of ethyl 2-thiooxamate gives products (85) which contain nucleophilic... 

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>. 

An unusual observation was noted when ethanolic solutions of 2-alkyl-4(5)-aminoimidazoles (25 R = alkyl) were allowed to react with diethyl ethoxymethylenemalonate (62 R = H) [92JCS(P1)2789]. In addition to anticipated products (70), which were obtained in low yield ( 10%), the diimidazole derivatives (33 R = alkyl) were formed in ca.30% yield. The mechanism of formation of the diimidazole products (33) has been interpreted in terms of a reaction between the aminoimidazole (25) and its nitroimidazole precursor (27) during the reduction process. In particular, a soft-soft interaction between the highest occupied molecular orbital (HOMO) of the aminoimidazole (25) and the lowest unoccupied molecular orbital (LUMO) of the nitroimidazole (27) is favorable and probably leads to an intermediate, which on tautomerism, elimination of water, and further reduction, gives the observed products (33). The reactions of amino-imidazoles with hard and soft electrophiles is further discussed in Section VI,C. 

Alkyl iV-cyanoalkylimidates (60) react with primary amines to form 1-substituted 5-aminoimidazoles. This reaction has been applied to the synthesis of 5-aminoimidazole nucleosides (Scheme 32). The reaction appears to be quite general for a wide variety of such imidates with not only primary alkyl- and aryl-amines, but also hydrazines (not 1,2-disubstituted hydrazines) and semicarbazides. Hydrazines lead to 1-aminoimidazole products thus 1,5-diaminoimidazole (61) can be prepared from hydrazine and N-cyanomethylformimidate (80AHC(27)24l, 66RCR122,80JCS(Pl)23i0). 

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. ... 

Useful precursors for the preparation of substituted hypoxanthine derivatives are alkyl 4(5)-aminoimidazole-5(4)-carboxylates. Thus, reaction of ethyl 4-amino-l-arylimida7ole-5-carb-oxylates with thioamides in the presence of a catalytic amount of formic acid gives 2-substituted 7-arylhypoxanthines, e.g. formation of l. °... 

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 major strategies leading to uncondensed imidazoles revolve around reactions of amines, ammonia or hydrazines with suitable acylamides, Af-alkenylamides, 2-azabutadicnes and Af-cyanoalkyl- or A -w-acylimidates. Alkyl Af-cyanoalkylimidates (1) are converted by primary amines into 1-substituted 5-aminoimidazoles (2) (Scheme 3.2.1) [1, 2]. With hydrazines, 1,5-diaminoimidazolcs are formed [3-5]. The reaction is quite general for... 

Analogous to the TOSMIC reactions is the cyclocondensation of an isothiourea with the enolate of ethyl isocyanoacetate (12) to give an alkyl 5-aminoimidazole-4-carboxylate (13). This regioselective synthesis provides... 

Biological oxidation of a 2-aminoimidazole gives poor yields (<38%), and none at all with l-alkyl-2-aminoimidazoles. Nor will oxidation with peroxy-trifluoroacetic acid work It is, however, satisfactory for the oxidation of 4-aminoiniidazoles (which are usually rather unstable compounds). ITie most common way of making 2-nitroi midazoles is from the diazonium fluoro-borates subjected to the Gattermann reaction (see Section 7.3). Yields vary from 20 to 50% [6, 7], and again are dependent on the availability of the 2-aminoimidazoles (see Section 8.2.2). 

The alternative 5-amino-1-substituted imidazoles are usually made by reactions between primary amines and alkyl 7/-cyanoalkylimidates (see Section 3.2). Other possibilities include ring closure of formylglycineamidines by heating them alone or with phosphoryl chloride (yields are usually low) (see Section 2.1.1), cyclization of or-cyanoalkylcyanamides (to form 5-amino-2-bromoimidazoles) (see Section 2.2), alkylation of arylamino-methylene cyanamides or cyanoimidothiocarbanates with or-halogenocarbonyl compounds (gives 4-acyl-5-aminoimidazoles) (see Section 2.3), and cycliza-tions of DAMN with amidrazones (to 1,5-diaminoimidazoles) (see Section 2.2.1). 

---