8-Azapurines 1,2,3-triazoles from

For more than half a century, every preparation of an 8-azapurine began from a pyrimidine intermediate. The possibilities of 1,2,3-triazoles as starting materials were first realized in a burst of publications in 1956-1960. - In large measure, this new activity sprang from Hoover and... 

Aminotriazoles which are appropriately substituted at the C(5)-position are important intermediates for the synthesis of 8-azapurines. These reactions have been reviewed <86AHC(39)ll7>. The pharmaceutically useful acyclonucleosides bearing 1,2,3-triazolines and 8-azapurines have been synthesized <888879). 4,5-Diaminotriazoles react with 1,2-dicarbonyl reagents to give 1,2,3-triazolo[4,5- )]pyrazines. 4,5-Diamino-2-phenyltriazole and sulfur monochloride afford the triazolo[4,5-c][l,2,5]thiadiazole (855) <86AHC(40)129>. The synthesis of triazolopyridines from triazoles has been described in a review <83AHC(34)79>. For further applications of substituted triazoles in preparations of complex heterocycles, see Section 4.01.4. 

A general reaction for preparing 6-amino-8-azapurines from 5-cyano-4-(dimethyl-aminomethylene)amino-l,2,3-triazoles has been reported (B-78MI41104). When the triazole... 

The first of the 8-azapurines, 1,3-dimethyl-8-azapurin-2,6-dione (1), was made at the start of this century by Wilhelm Traube, who cyclized the corresponding 4,5-diaminopyrimidine with nitrous acid. Similar syntheses from pyrimidines, although excluding any possibility of placing an alkyl substituent in the 7 or 8 position, dominated the field until 1968 when appropriately substituted triazoles were introduced to overcome these limitations. These two approaches to the preparation of 8-azapurines, from pyrimidines or from triazoles, are expanded in Sections IV,A and B, respectively. 

Quantum mechanical calculations of molcular orbitals have been performed on five examples (8-azapurine, -hypoxanthine, -guanine, -adenine, and -xanthine) by two methods (a) a semiempirical approximation, which included contributions from the a electrons of the skeleton, and (b) the CNDO approximation, which included contributions from all the valence electrons of the molecule. The results were tabulated in parallel for each of the three possible positions of the triazole proton. In all 15 entries, the highest occupied and the lowest unoccupied molecular orbitals were calculated and also the dipole moment, the molecular energy, and the UV absorption maxima (the last-named showed only a modest agreement with experimental results). It was concluded that both types of calculation indicated that relative stabilities for the three tautomers (in each of the five sets) should decrease in the order HN-9, HN-7, and HN-8, and that the HN-8 tautomers should be 85 to 125 kJ (20-30 kcal) per mol less stable than the other two. However, it had to be admitted that, in all sets of three isomers examined experimentally, the HN-8 member has never been found inferior in stability. ... 

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. ... 

The acetates of acetamidine and benzamidine were condensed with 4-aminotriazole-S-carboxamide (73a) and its 7- and 8-methyl derivatives to give 2-metoyl- and 2-phenyl-8-azapurin-6-ones, respectively, in 80-90% yield, after refluxing for 4 - 8 h in butanol, hexanol, or octanol (toe choice of solvent determined toe optimal yield in each case). The reaction with tri-chlOFoacetamidine terminated at, e.g., (a-amino-i ) )9-trichloroethyliden-amino) 1,2,3-triazole (84) (from 73a). These intermediates were cyclized to 2-trichlorometoyl-8-azapurin-6-ones, in excellent yields, by stirring with 0.5 N potassium hydroxide (24°C, 5 h). This reaction gave only poor yields with 73b,c. 

To obtain 2-amino-l,6-dihydro-8-azapurine, 96 (and its 2-methyl and 3-benzyl analogs) were refluxed with cyanogen bromide in methanol (4 h), giving 40-75% yields of the correspondingly alkylated products. 4-Amino-5-ethoxycarbonylaminomethyl-l,2,3-triazole (99) (from 96 and ethyl chloroformate), when refluxed in butanolic sodium butoxide (1 h), produced 7-methyl-l,6-dihydro-8-azapurin-2-one the 8-methyl and 9-ben-zyl analogs were made similarly (76-92% yield). ... 

The parent, 8-azapurine, has been made only by nitrosation of 4,5-di-aminopyrimidine, which is an item of commerce. - - The 7- and 8-alkyl derivatives of 8-azapurine, whether with or without further substituents, require 1,2,3-triazole starting materials (Section IV,B), of which the best source is Hoover and Day s historic condensation of benzyl azide with ethyl cyanoacetate or (better) cyanoacetamide. An 8-aralkyl group has been introduced similarly. In favorable cases, an 8-aryl group can be derived from the action of a benzenediazonium chloride on a pyrimidine that bears enough electron-releasing substituents to activate the 5 position (the Benson synthesis Section IV,A). 

The preparation of 2-substituted 8-azapurines, unsubstituted in the triazole ring, from pyrimidines is described in ref. 48, and from triazoles (via 1,6-dihydro-8-azapurines) in Section 1V,B,3. 8-Azapurines with strongly electron-attracting groups in either the 2 or the 6 position are unknown and may turn out to be unstable. 

Azapurines undergo ring fission to give many kinds of 1,2,3-triazoles, often in excellent yields. At first sight, it may not seem rewarding to prepare triazoles in this way, particularly when the azapurine itself has to be made from a triazole. However, in practice, this approach has often furnished triazoles with patterns of substitution that would be laborious, or even impossible, to prepare by any other known method. 

Thiourea has been used similarly to prepare, at 175°C (3 hr) up to 205°C (20 min), good yields of annelated 2-thioxopyrimidin-4-ones such as 8-methyl-2-thioxo-8-azapurin-6-one (156) from 4-amino-1,2,3-triazole-5-car-boxamides (see 20),254 as well as pyrazolo[4,3-d]- and pyrazolo[3,4-d]pyri-midinediones from the appropriate aminopyrazolecarboxamides (see 15) 24,221 and thieno[2,3-d]pyrimidine-2,4-diones (see 12) from 2-amino-thiophene-3-carboxamide.25 5... 

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