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In contrast to the N(3)-selectivity in N-alkylation, N-oxidation of 7-benzyladenine (17) with m-chloroperoxybenzoic acid in MeOH has been found to give 7-benzyladenine 1-oxide (18) in 76% yield. Alternatively, the same N-oxide (18) has been synthesized in 81% yield from 1-benzyl-4-(ethoxymethyleneamino)imidazole-5-carbonitrile(19) and hydroxylamine. Treatment of 1-benzyl-4-(hydroxyamino)imidazole-5-carbonitrile (24), obtained in 63% yield from the corresponding 4-nitro drivative (20) by catalytic hydrogenation (Pt/H2), with formamidine acetate in boiling EtOH furnished 7-benzyladenine 3-oxyde (23) in 78% yield. A UV spectroscopic approach indicated that the neutral species of 18 exists in H2O in the N(1)-oxide form rather than the N(1)-OH form (27).

Oxidation of 1-benzyladenine (12) with m-chloroperoxybenzoic acid in MeOH or in MeOH-0.5 M phosphate buffer (pH 6.6) has been found to afford 1-benzyladenine 7-oxide (13) as the main product. Nonreductive debenzylation of 13 gave adenine 7-oxide (14) in 63% yield. The structure of 13 was unequivocally established by an X-ray crystallographic analysis.

Methylation of adenine 3-oxide (8a) with MeI in AcNMe2 afforded 3-emthoxyadenine (9a) in 44% yield. This compound (9a) underwent hydroxide-ion attack at the 2-position to give 2-hydroxyadenine (isoguanine) (10a) in 38% yield. A parallel reaction sequence starting from N6-benzyladenine 3-oxide (8c) and proceeding through N6-benzyl-3-methoxyadenine (9c) provided N6-benzyl-2-hydroxyadenine (10c) in 29% overall yield, together with a small amount of N6-benzyladenine (11c).

An alternative synthesis of N6, 3, 9-trimethyl-8-oxoadenine (caissarone) (7b) has been accomplished by regio-selective methylation of N6, 3-dimethyl-8-oxoadenine (9-demethylcaissarone) (5b), which was obtained by N(7)-oxidation of N6, 3-dimethyladenine (2b) with m-chloroperoxybenzoic acid followed by O-methylation with MeI and subsequent treatment with aqueous NaOH. The UV spectral data for the dimethylated 8-oxoadenine 5b and eight of its regioisomers, among with the O8, 9-dimethyl isomer 9 was prepared for the first time in the present work, are summarized.

The synthesis of 8-methylguanine 7-oxide (3) was accomplished via a "phenacylamine route", which started from condensation of alpha-(4-methoxybenzylamino)propiophenone (6), prepared by coupling of alpha-bromopropiophenone (4) and 4-methoxybenzylamine (5), with 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone (7) and proceeded through cyclization of the resulting phenacylaminopyrimidinone (8) and removal of the 4-methoxybenzyl group. The N-oxide 3 and its 9-arylmethyl derivatives 9 and 11 showed only very weak antileukemic activity and no antimicrobial activity.

1-Alkoxy-9-alkyladenines (VIIIa, b, c) have been found to undergo alkylation mainly at the N6-position when treated with alkyl halide in N, N-dimethylacetamide. The structure of the resulting N6-alkylated derivatives (IXa, b, c) has been established by comparison with authentic IXa (X=I, ClO4) and by catalytic hydrogenolysis of IXb, c (X=ClO4) to N4, 9-dialkyladenines (XIb, c). In the case of the benzyl analog (IXc : X=ClO4), removal of the benzyloxy group at the 1-position has also been effected stepwise through the 1-oxide (Xc).

L'etude est faite sur des derives benzyloxy-1 et benzyloxy-1 substitues de methyl-9 adenine protonee ou non

Treatment of 1-alkoxyadenine (I) with reactive alkyl halides (R2X) in N, N-dimethylacetamide yielded the 9-alkylated salts (II) in good yields. However, an alkyl halide (R2X) less reactive than that (R1X) whose alkyl group was the same as in I reacted with I to give a mixture of at most four possible 1-alkoxy-9-alkyladenine salts (II, IV, V, and VII), two 9-alkyladenine 1-oxides (III and VI), and, possibly, a more reactive alkyl halide (R1X). The intricate pattern of formation of products was due to O→N (9) alkyl migration during the reaction, and a plausible mechanism is presented. A clear O→N (9) benzyl migration was demonstrated by the reaction of 1-benzyloxyadenine (I: R1=C6H5CH2) with 0.1 equivalent of benzyl bromide to give 0.58 equivalent of 9-benzyladenine 1-oxide (VI: R1=C6H5CH2).

Alkylation of adenosine 1-oxide (I) and its 2', 3'-O-isopropylidene derivative (V) with alkyl halides in N, N-dimethylacetamide furnished the corresponding 1-alkoxy derivatives (IIa-f). The free bases, obtained from IIa-f, readily underwent rearrangement to give the isomeric N6-alkoxy derivatives (IVa-f) when heated in water. Treatment of 1-benzyloxyadenosine perchlorate (IIc : X=ClO4) with water at pH 9.5 and 39-41°for 4 hr afforded the ring-opened intermediate (IIIc)(79% yield), which was recyclized in hot water (pH 7) to IVc. In alternative synthesis of IVa, b, c, condensation of 6-chloro-6-β-D-ribofuranosylpurine (VIa) with the appropriate alkoxyamines proceeded smoothly. Removal of the isopropylidene group from IVe under acid conditions or exchange amination of adenosine with ethoxyamine at pH 5 also yielded N-ethoxyadenosine (IVb).

The Dimroth rearrangement of 1-alkoxy-9-alkyladenines (Ia,b,c,d) to 6-alkoxyamino-9-alkylpurines (IIa, b, c, d) was readily effected by treating the free bases (I) with boiling water. On the other hand, treatment of the 1-alkoxy derivatives (Ia, b, c) with water at a lower temperature produced N′-alkoxy-1-alkyl-5-formamidoimidazole-4-carboxamidines (IVa, b, c), the intermediates in the Dimroth rearrangements, in good yields. When heated in water, IVa, b,c were recyclized to the rearranged products (IIa, b, c) with formation of a trace of the reversion products (Ia, b,c). The reaction of I with hot aqueous alkali afforded N′-alkoxy-1-alkyl-5-aminoimidazole-4-carboxamidine (III), the deformylated product of IV, and a small amount of the rearranged product (II). Treatment of IVc with alkali also gave IIIc and a small amount of IIc, whereas the reaction with acid resulted in the rapid reversion to Ic.

Racemic 1'-methylzeatin [(±)-2] has been synthesized from (±)-alanine [(±)-3] through a 9-step route proceeding via the intermediates (±)-4-(±)-11. In the tobacco callus bioassay, (±)-2 exhibited a strong cytokinin activity at 0.04- 1μM concentration, a range between the optimum concentrations of both enantiomers (1'R)-2 and (1'S)-2.