Purine Nucleoside Analogues. 11. An Alternative Synthesis of N- and O-Alkyl Derivatives of 9- and 7-[(2-Acetoxyethoxy)methyl]-N2-acetylguanine

Abstract

Alkylations of 9- and 7-[(2-acetoxyethoxy)methyl]-N2-acetylguanine with alkyl halogenides in the presence of base have been investigated affording a new route to the preparation of 1,N2-dimethyl- as well as O6-benzyl-9(7)-alkoxyalkylguanines. 1H NMR spectra revealed that the 1,N2-dimethyl derivatives exist as mixtures of two conformers at room temperature due to the restricted rotation about the C2-N2 bond. These findings agreed with conformational calculations.

The Determinative Influence of the O6-(Diphenylcarbamoyl) Group on the Exocyclic Nitrogen Benzylation in 2-Amino-6-oxopurine Derivatives

“…Such a shift was characteristic also for 9-[(2-acetoxyethoxy)methyl]-2-[acetyl(benzyl)amino]-6benzyloxy-9H-purine and its 8-bromo counterpart synthe-sized previously. 8 However, a similar shift was not observed in the spectrum of 2-[acetyl(2-bromobenzyl)amino]-1,9-dihydro-6H-purin-6-one 12. The chemical shifts of NH group (d =10.79 and 10.69) as well as of N 9 -CH 2 and N 7 -CH 2 group proton singlets at d = 5.04 and 5.06, respectively, in the spectra of derivatives 7a,b corresponded with the established pattern of proton chemical shifts in the structurally close 6-(diphenycarbamoyloxy)-2-(isobutyrylamino)-9(or -7)-[(methoxycarbonyl)methyl)purine.…”

“…7 The formation of the N 2 ,O 6 -dimethylated or the N 2 ,O 6 -dibenzylated products together with the mono-O 6 -substituted products observed during the methylation and benzylation of the certain 2-(acetylamino)-6-oxopurine derivatives also suggested the directive influence of the 6-methoxy and 6-benzyloxy functions on the second methyl or benzyl group attachment site. 8 We have not found literature references to the benzylation of 2-aminopurine derivatives containing the 6-(diphenylcarbamoyloxy) moiety with benzyl halides, but the alkylation of such compounds usually produces the corresponding N 9 -alkylated products, sometimes contaminated with the corresponding N 7 -alkylated regioisomer. 4 At the same time, the formation of a small amount (<3%) of the N 2 ,N 9 -disubstituted product was detected during the ribosylation of silylated 2-(acetylamino)-6-(diphenylcarbamoyloxy)purine.…”

A Convenient Method for the Modification of 8-Bromoguanine via Its N9-Tetrahydrofuranyl Derivative

“…Position 1 was excluded as the tosylation site in product 14 on the basis of the established fact that the presence of a substituent at position 1 in 2-acetylamino-6-oxopurines causes significant shift of the signal arising from the protons of the acetylamino function. 19 Such changes were not observed in the spectrum of 14. The benzyl group in compound 16 was characterized by a multiplet at d = ~7.2 ppm and by a two-proton singlet at d = 5.37 ppm.…”

“…The chemical shift of the exocyclic NH-group proton singlet (d = ~10 ppm) in 3, 4, 8 and 9 supported their structures as O 6 ,N 2 -disubstituted purine derivatives rather than N 1 -substituted. 19 The spectra of compounds 11 and 12 contained doublets (d = 9.3 and 11.1 ppm) characteristic of the formamidine group. It is known that some monosubstituted formamides can exist in solution as cis and trans isomers, due to the restricted rotation of the single C-N bond.…”