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Methylation of N′-benzyloxy-5-formamido-1-β-D-ribofuranosylimidazole-4-carboxamidine (1) followed by hydrogenolysis of the N′-benzyloxy group and cyclization gave the hitherto unknown 3-methyladenosine (4), which was easily hydrolysed to 3-methyladenine (6) in 0·1 N aq. HCl and to the imidazole ribosides (3) and (5) under basic conditions.

Ethylation of N6-methoxy-3-methyladenine (5) with EtI in AcNMe2 gave the 1-ethylated product 8 (X=I) (21% yield) and the N6-ethylated product 11 (X=ClO4) (33%). The N6-benzyloxy analogue 6, prepared from 3-methyl-6-methylthiopurine (4) and benzyloxyamine, was similarly methylated to produce the 1-methylated product 9 (X=Cl) (34%) as well as the N6-methylated product 12 (X=Cl) (35%). Reduction of N6-methoxy-1, 3-dimethyladeninium iodide (7 : X=I) with NaBH4 afforded the 1, 2-dihydro derivative 14 (92% yield), which reverted to 7 (X=I) on dehydrogenation with I2 in EtOH. On hydrogenation with Raney Ni and H2, 7 (X=I) furnished 14 (26% yield) and the N6-demethoxy derivative 15·HI (17%), while 14 gave 15 on similar reduction. Dehydrogenation of 15 with 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) in CHCl3 yielded a crude solid presumed to be the 1, 3-dimethyladeninium salt (18), which readily rearranged into N6, 3-dimethyladenine (16) through the monocycle 17. It has been found that hydrolysis of 7 (X=ClO4) to give the imidazole 13 in H2O at pH 7.72 and 25°C proceeds ca. 270 times as fast as that of the 3, 9-dimethyl analogue 19 to give the monocycle 20.

3,9-Dimethyl- and 3-methyl-9-ethyl-adenine have been synthesized from N′-alkoxy-1-alkyl-5-formamidoimidazole-4-carboxamidine (II) by reduction with LiAIH4 followed by cyclisation with ethyl orthoformate and removal of the alkoxy-group by catalytic hydrogenolysis.

Methylation of N′-benzyloxy-1-(2-deoxy-β-D-ribofuranosyl)-5-formamidoimidazole-4-carboxamidine (2a) followed by hydrogenolysis of the N′-benzyloxy-group and cyclization produced the hitherto unknown 3-methyl-2′-deoxyadenosine (5a), which was readily hydrolysed to 3-methyladenine (6) in H2)O at pH ⩽7·0 and to (6) and the imidazole-(2-deoxy)riboside (4a) at pH 8·98.

Methylation of N6-methoxyadenine (3) with an excess of Mel in AcNMe2 at 40°C was found to give the 3-methylated product 8 (17% yield), 9-methylated product 4 (2%), N6, 9-dimethylated product 5 (9%), 7, 9-dimethylated product 6 (27%). 3, 7-dimethylated product 7 (10%), and N6, 3-dimethylated product 9 (11%). Similar treatment of N6-benzyloxyadenine (12) with Mel also afforded a mixture of several products, from which the 7, 9-dimethylated product 13 (X=1) was isolated in 30% yield. Similar methylation of N6-methyladenine (17), prepared in 65% yield from 1-methyladenine (16) by a Dimroth-type rearrangement. gave the 3-methylated product 18 (82% yield), 9-methylated product 20 (1.3%), 3, 7-dimethylated product 19 (1.8%), and 1, 9-dimethylated product 21 (0.3%). On methylation under similar reaction conditions, 18 furnished the 9-methylated product 22 (15% yield) as well as the 7-methylated product 19 (29%), and 20 produced 22 (17%) and 21 (11%). The probable pathways to the six methylated products from 3 and those to the four methylated products from 17 are discussed.

The effect of the N6-methoxy group on regioselectivity in methylation of all five possible isomers of N-methyladenine has been investigated. The methoxyl group attached to all these isomers orients methylation to a considerable extent to nitrogen(s) in the same pyrimidine or imidazole moiety that the original N-methyl group is attached to. On the basis of the results of the present methylation study, 7,9-dimethyladeninium perchlorate has been synthesized from 7- or 9-methyl-N6-methoxyadenine.

A detailed account is given of the final step of the general 7-alkalation procedure for adenine (1), which consists of the preferential benzylation at the 3-position of 1, regioselective alkylation of the resulting 3-benzyladenine (2) to give 7-alkyl-3-benzyladenine salts (3a-c), and debenzylation of 3a-c leading to 7-alkyladenines (4a-c). Debenzylation of 3a-c (X=Cl or ClO4) has been achieved by hydrogenolysis using hydrogen and Pd-C catalyst at atmospheric pressure, producing 7-alkyladenines (4a-c) in 38-74% yields. The use of the allyl or γ, γ-dimethylallyl group at the 3-position instead of the benzyl group for the synthesis of 7-methyladenine (4a) by this procedure has no practical value. Alternatively, the salts 3a-c (X=Br, ClO4, or I) have been debenzylated efficiently by treatment with conc. H2SO4 in the presence of toluene at room temperature for 3-6h or at 60°C for 0.5-2h, giving 4a-c in 73-93% yields.