The synthesis of heterocycles via addition–elimination reactions of 4- and 5-aminoimidazoles

Abstract

4-Aminoimidazoles 1 undergo addition–elimination reactions with the electrophilic reagents 5–12 to give exclusively N-adducts, which are useful intermediates for further synthetic transformations to novel heterocyclic systems. Diethyl ethoxymethylenemalonate 5 and 4-amino-1-benzylimidazole 1g give the adduct 13g and subsequent acid-catalysed cyclisation gives the imidazo[4,5-b]pyridine 25 and the heterocyclic mesomeric betaine 26 which undergoes 1,3-dipolar cycloaddition with di-methyl acetylenedicarboxylate to give two products 29 and 30. When the 2-alkyl-4-aminoimidazoles 1b–d are generated in situ in the presence of the reagent 5, significant products are the 5,5′-diimidazoles 15 and a mechanism for this novel transformation is proposed. 4-Amino-3-cyano-imidazo[1,5-a]pyrimidines 40 and 41 are formed by cyclisation of the N-adducts prepared using ethoxymethylenemalononitriles 6 and 7. Ethoxymethyleneurethane 9 gives the adducts 66 and cyclisation of the parent adduct 66a gives the novel imidazo[1,5-a]-1,3,5-triazin-4-one 68a, the potassium salt of which undergoes N-alkylation. The use of the reagents 10–12 leads to novel 4-aminoimidazo[1,5-a]-1,3,5-triazine derivatives 72 whose chemical reactions with both electrophilic and nucleophilic reagents are reported. 5-Aminoimidazoles 3 undergo addition–elimination reactions with the electrophilic reagents 5–12 to give N-adducts and/or C-adducts, depending upon the structure of the reagent. These stable addition–elimination products are usually obtained in good yield and are useful intermediates for further synthesis. Reaction of the amines 3 with diethyl ethoxymethylenemalonate 5 gives mainly N-adducts 17 which can be cyclised using phosphoryl chloride to give the versatile 7-chloroimidazo[4,5-b]pyridines 31. With ethoxymethylenemalononitrile 6 the amines 3 give C-adducts 42. Thermal cyclisation of these adducts 42 gives 5-amino-6-cyanoimidazo[4,5-b]pyridines 43 which are transformed into novel heterocyclic systems including the tricyclic imidazo[4′,5′:5,6]pyrido[2,3-d]pyrimidines 55. Cyclisation of the adducts obtained using ethoxymethyleneurethane 9 and the N-cyano analogues 10 and 12 provides new synthetic routes to amino-purine derivatives 86 and 87 and hypoxanthines 70. The preference of electrophilic reagents for N- or C-addition to 5-aminoimidazoles 3 is rationalised using Frontier Molecular Orbital theory.