Some pyrrolopyrimidine chemistry directed to the synthesis of tricyclic purine analogues

Abstract

Chemistry directed to the synthesis of the tricyclic ring system 3, a purine analogue with degenerate hydrogen-bonding potential, has been investigated and has resulted in the synthesis of several novel pyrrolo[2,3-d]pyrimidine derivatives as potential precursors. The known analogue 2-amino-7H-pyrrolo[2,3-d]pyrimidin-4-one (7-deazaguanine) is converted by the Vilsmeier reagent into 4-chloro-2-dimethylaminomethyleneamino-6-formyl-7H-pyrrolo[2,3-d]pyrimidine 10. Formylation at the α-position of the pyrrole ring was determined by the comparison of ¹³C NMR data of the corresponding alcohol and the unsubstituted derivative and is in agreement with the regiospecificity reported for the Mannich reaction of this compound. In contrast, base-catalysed hydroxymethylation of 4-chloro-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine with formaldehyde in aqueous THF occurs at the desired β-position to afford the 5-hydroxymethyl product 17. 7-Methylation of the Bu^tMe₂Si-protected alcohol 17 led to several potential precursors of the desired tricyclic structure. The 5-phthalimidooxymethyl derivatives of either 2-methylsulfanyl- or 4-chloro-7-methyl-2-methylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine with ammonia gave the aminooxymethyl derivatives but these subsequently failed to cyclise. Several approaches to cyclise 4-hydroxyamino-5-hydroxymethyl-7-methyl-2-methylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine 27 afforded the corresponding 4-amino compound as the major component. Both the experimental and modelling results show that considerable strain is associated with the formation of 3.