Purines. XLIX. Synthesis and proton nuclear magnetic resonance study of 3,7-dialkylxanthines and 1,3,7-trialkylxanthines

Article abstract of DOI:10.1248/cpb.39.2855

A general synthetic route to 3,7-dialkylxanthines (type 9) from 3,7-dialkyladenines (6) [hence from 3- or 7-alkyladenines (11 or 10)] has been established. The route started with ethoxycarbonylation of 1-alkyl-4-(alkylamino)1H-imidazole-5-carboxamides (7), readily obtainable from 6 by alkaline hydrolysis, and proceeded through cyclization of the resulting carbamates (8) under alkaline conditions. Alkylation of 9 with alkyl halide in N,N-dimethylformamide in the presence of anhydrous K₂CO₃ extended the above synthetic route to the 1,3,7-trialkylxanthine level (type 14). Hydrogenolytic deb nzylation of 3-benzyl-1,7-dimethylxanthine (16), prepared by following this general synthetic route, furnished paraxanthine (26) in fair yield. Conversion of 26 into 3-(4-hydroxy-3-nitrobenzyl)-1,7-dimethylxanthine (24), isomeric with the bryozoan purine phidolopin (2), was effected through aralkylation with 4-(methoxymethoxy)-3-nitrobenzyl bromide (28) followed by O-deprotection. On the basis of proton nuclear magnetic resonance data for the 3,7-dialkylxanthines (3 and 9b-i) and 1,3,7-trialkylxanthines (5 and 14-22) thus prepared, reliable criteria for distinguishing signals of N-alkyl substituents at various positions are put forward.