8-Methyl-6-methylamino-8-azapurine

Methylation of 7-amino-l,2,3-triazolo[4,5-d]pyrimidine (8-azaadenine) (140) with dimethyl sulfate afforded the N-3 and N-9 methylated isomers 141 and 142, respectively, which upon further methylation with methyl iodide or benzenesulfonic acid methyl ester gave 3,7- and l,9-dimethyl-8-azaadeninium salts 144 and 145, respectively. Thermal decomposition of the dimethyl derivatives led to a transmethylation to give 6-methylamino-9-methyl-8-azapurine (143), whose methylation afforded 1- and 7-methyl-6-methylamino-9-methyl-8-azapurinium salts 146 and 147 (80ZOR2204) (Scheme 28). 

Other points of interest, illustrated in Table III, are the hydration of the cation of 2-amino-8-azapurine and the spectra of some 1,6- hydro-azapu-rines. The spectra of substituted l,6-dihydro-6-imino-l-methyl-8-azapu-rines (15) are similar to those of the isomeric 6-methylamino-8-azapurines to which they are readily converted, but only the latter show coupling (5 Hz) between protons of HNCH3... 

Methylation of 8-azaadenine (6-amino-8-azapurine) with dimethyl sulfate in aqueous alkali gave a mixture of 3- and 9-methyl-8-azaadenine. The same starting material, with iodomethane in dimethylformamide (100°C, 1 h), gave 3,7-dimethyl-8-azaadeninium iodide in 75% yield. 9-Methyl-8-azaadenine similarly produced l,9-dimethyl-8-azaadeninium iodide. Finally, 9-methyl-6-methylamino-8-azapurine, similarly treated, gave a mixture of the 1- and 7-methylated derivatives. 

Methylamino-8-azapurine uniquely followed a more complex path. A simultaneous Dimroth rearrangement to 6-amino-9-methyl-8-azapurine (Section C,2) allowed two isomeric amidinotriazoles to be formed, one from each 8-azapurine. 6-Amino-8-azapurine, when set aside in cupric chloride solution, produced the following complex tetrachlorobis-2-[(4-amino-5-carboxamidinium)-l,2,3-triazole]copper +, the structure of which was verified by single-crystal X-ray work. ... 

In the 8-azapurine series, methylamine acetate (but not the traditionally used free amine) quantitatively changed 6-imino-1,7-dimethyl-1,6-dihydro-8-azapurine (55) to 7-methyl-6-methylamino-8-azapurine (56) (65 °C, 2 h). The 1,8- and 1,9-dimethyl isomers and also the 9-benzyl-1-methyl analog... 

Dimethylaminomethylenamino-l-methyl-5-carbonitrile (89), obtained by the action of dmethylformamide and phosphoryl chloride on 4-amino-l-methyltriazole-5-cartoxamide, furnished 6-amino-7-methyl-8-azapurine (87% yield) when refluxed with aqueous ammonium acetate (4 equiv) for 10 min. Ammonium chloride could not replace the acetate. The 2-methyl isomer of 89 reacted similarly but the 3-methyl isomer (a much weaker base) reacted only slightly lowering the pH to increase its ionization only accelerated hydrolysis of the amidino group. Methylamine acetate solution gave, with the nitrile 89,7-methyl-6-methylamino-8-azapurine (81% yield), and butylamine acetate acted similarly (75% yield). ... 

Steric hindrance was encountered in applying this reaction to the synthesis of 1- and 3-methyl-8-azapurines. Thus, 4-amino-3-benzyl-5-methylamino-methyl-l,2,3-triazole reacted so slowly with formamidine acetate in boiling butanol that the amidine underwent destruction this situation was remedied by feeding in new supplies of the amidine every 2 hr, giving an excellent yield of 9-benzyl-l,6-dihydro-l-methyl-8-azapurine.63... 

Under these conditions, the even less reactive 5-aminomethyl-3-benzyl-4-methylamino-l,2,3-triazole gave some of the 5-formamidomethyl analog, but no 9-benzyl-3,6-dihydro-3-methyl-8-azapurine (69). An attempt to cyclize this formyl derivative by heating at 200°C caused it to undergo a Dimroth retrogression to 4-benzylamino-5-formamidomethyl-3-methyl-1,2,3-triazole other attempts to close the ring also failed.64... 

The further isomerization of the imine 108 to l-methyl-4-methylamino-pyrazolo[3,4-d]pyrimidine (109a) occurred slowly in the presence of methyl-amine. This change, at least in the 8-azapurine series,138 can be greatly accelerated by boiling in ethanolic methylamine acetate for 2 hr. When the reagent is not a primary amine but ammonia, no barrier exists to instant prototropy, which gives 109b. 

Urea has been used successfully to convert 4-aminoimidazole-5-car-boxamide (and its derivatives) to purine-2,6-diones (see 19)124>202 2-amino-,250,251 2-methylamino-,252 and 2-anilinobenzamides253 to quinazo-line-2,4-diones (see 1) 3-aminopyrazolo-4-carboxamide118 and 4-aminopy-razole-3-carboxamide221 to the related pyrazolopyrimidinediones (see 16 and 17) and 4-amino-1- and 4-amino-2-methyl-l,2,3-triazole-5-carboxa-mides to 8-azapurine-2,6-diones (see 21).254... 

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