One- or Two-Step Synthesis of C-8 and N-9 Substituted Purines

Abstract

A novel and original strategy to obtain rapidly a large diversity of C-8 and N-9 substituted purines was developed. The present procedure describes annulation reactions in one or two steps starting from 5-aminoimidazole-4-carbonitriles 1-8 in moderate to good yields. 8,9-Disubstituted-6,9-dihydro-1H-purin-6-ones 9-14, 6-amino-8,9-disubstituted-3,9-dihydro-2H-purin-2-ones 15-20, 8,9-disubstituted-3,9-dihydro-2H-purin-2,6-diamines 21-24 and 6-imino-1-phenyl-8,9-disubstituted-6,9-dihydro-1H-purin-2-(3H)-ones 25-26 were synthesized in one step using formic acid, urea, guanidine carbonate, and phenylisocyanate, respectively, whereas 8,9-disubstituted-9H-purin-6-amines 27-31 and 6-imino-8,9-disubstituted-6,9-dihydro-1H-purin-1-amines 32-33 were obtained in two steps using formamide and hydrazine, respectively.

A Three‐Way Regioselective Synthesis of Amino Acid Decorated Imidazole, Purine and Pyrimidine Derivatives by Multicomponent Chemistry Starting from Prebiotic Diaminomaleonitrile

“…[34,35] In order to generalize the procedure, the reaction was repeated under the optimal experimental conditions (MeCN at 25 °C for 15 h) using the methyl esters of alanine 3 b, valine 3 c, serine 3 d, phenylalanine 3 e, and tyrosine 3 f. Amino-acid decorated imidazoles 4 b-4 f were isolated as the only recovered products from acceptable to high yield (Table 1, entries 6-10). In accordance with data previously reported for the multicomponent synthesis of imidazole derivatives bearing simple alkyl and aryl amine side-chains, [1,36] compounds 4 a-4 f were obtained by the concerted electrophile/nucleophile-oriented condensation of DAMN with 2 and 3 a-3 f to yield the intermediate I (not isolated), followed by ring-aromatization and internal displacement of a methanol molecule (Scheme 1 DAMN pathway, Supporting Information, section 1). As a general trend, the yield of compounds 4 a-4 f increased in the presence of aliphatic amino acids, imidazole 4 d being isolated in the highest yield (Table 1, entries 9-10 versus 3,6-8).…”

Aminomalononitrile inspired prebiotic chemistry as a novel multicomponent tool for the synthesis of imidazole and purine derivatives with anti-influenza A virus activity

“…The possible formation of bis-imidazole derivatives by reaction of compounds 4a–f with trimethyl orthoformate was not observed under our experimental conditions. 28 On the other hand, the low value of the mass balance was probably due to the competitive self-oligomerization of AMN to HCN polymers. 32 As a general trend, the yield of the reaction products decreased by increasing the structural complexity of the α-amino acid side-chain ( Table 1 , entry 1 vs. entries 2–3), with the only exception of aromatic derivatives phenyl alanine and tyrosine ( Table 1 , entries 5–6).…”

“…The beneficial effect of the aromatic moiety in the annulation of AMN with simple amine has been previously reported. 28 Compounds 4a–f were successively de-protected (NaOH 1 M for 18 h at 25 °C) 33 to afford the corresponding amino imidazole carbonitriles (AIC) 5a–f ( Scheme 1 , Pathway B) ( Table 1 , entries 7–12).…”

“… 25–27 In addition, imidazoles are synthons in the preparation of bioactive purines by annulation with compounds as simple as urea, guanidine, formic acid and NH 2 CHO. 28 Here we report that AMN inspired multicomponent prebiotic chemistry yields amino imidazole carbonitrile derivatives decorated with different α-amino acid side-chains. The reaction involves the microwave-assisted condensation between aminomalononitrile para -toluenesulfonate salt (AMNS), α-amino acids and trimethyl orthoacetate (TOA).…”

Synthesis of 4,7,9-Trihydroxy[1]benzofuro[3,2-d]pyrimidine-6-carboxamide: Evaluation of Cytotoxicity and Inhibition of Protein Kinase C (CaPkc1)

“…Cyclization using sodium hydride furnished benzofuran ring bearing the amino group at position 3 and ester function at position 2 [15]. Tricyclic pyrimidine derivative 6 was synthesized from benzofuran precursor 5 [16]. From compound 6, attempts for the conversion of nitrile to carboxamide remained unsuccessful [13,[17][18][19].…”