Fused Heterocyclic Systems with an s-Triazine Ring. 34. Development of a Practical Approach for the Synthesis of 5-Aza-isoguanines

Abstract

Purine isosteres present excellent opportunities in drug design and development. Using isosteres of natural purines as scaffolds for the construction of new therapeutic agents has been a valid strategy of medicinal chemistry. Inspired by the similarity to isoguanine, we attempted to develop a practical method for the preparation of 5-aza-isoguanines. Several synthetic approaches were explored to establish a robust general protocol for the preparation of these compounds. The significant difference in the reactivity of the C-5 and C-7 electrophilic centers of 1,2,4-triazolo[1,5-a][1,3,5]triazines (5-azapurines) towards nucleophiles was demonstrated. The most practical and general method for the preparation of 5-aza-isoguanines involved a regioselective reaction of ethoxycarbonyl isothiocyanate with a 5-aminotriazole. The intramolecular ring closure of the resulted product followed by the S-methylation afforded 7-methylthio-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-one, which could be effectively aminated with various amines. The resulted 5-aza-isoguanines resemble a known purine nucleoside phosphorylase inhibitor and could be interesting for further investigations as potential anticancer agents.

Bicyclic 5-6 Systems With One Bridgehead (Ring Junction) Nitrogen Atom: Four Extra Heteroatoms 2:2

“…98 These works, dealing with the construction of polyheterocyclic compounds, go little beyond the scope of this chapter and will not be described in any further details. <Scheme 48 A one-pot sequential multi-components reaction between thiosemicarbazides 269, carboxylic acids 270 and substituted 3-(2-bromoacetyl)coumarins 271 has been developed. This convenient procedure was performed under solvent-free conditions delivering the bicyclic systems 272 in high yields (Scheme 52).…”

“…Alternatively, 7-thiomethyl derivative 324c was obtained from methyl carbamodithioate 326 through the elimination of hydrogen sulfide. 48 Finally, the use of guanidine 315 furnished 5-amino-7-trichloromethyl triazolotriazines 327 in excellent yield (Scheme 69). [46][47]…”

“…Subsequent elimination of chloroform would afford intermediate 330, which would undergo intramolecular cyclocondensation giving rise to 319 (Scheme 70). [46][47][48]…”