Triazoles from Pyrimidine Derivatives

For the preparation of triazolopyrimidines three main types of synthesis are in use. The first of these proceeds from a pyrimidine derivative (especially the 4,5-diamino derivatives) and closes the triazole ring. The second method proceeds, on the contrary, from derivatives of u-triazole to close the pyrimidine ring. The third method finally is one which yields the derivatives through substitution or replacement of substituents in compounds prepared by one of the first-named procedures. 

Table 24 [1,2,4]triazolo[4,3-a]pyrimidine derivatives synthesized from 3-amino[1,2,4]triazoles... 

Amino-1,2,4-triazolo[l,5-a]pyrimidine derivatives (115) were prepared from 3,5-dihalo-l,2,4-triazoles (111) by amination followed by reaction with acrylic or crotonic ester (113) and then amination without the isolation of 112 and 114 [87T2497 88JAP(K)63/267782] (Scheme 22). 

The third group of EBI s are the pyrimidine derivatives nuari-mol, fenarimol, and triarimol (Figure 6). All of these compounds are closely related chemically. The commonality they have with the triazoles and imidazoles is the nitrogen heteroatom in the 3-position from the central carbon. The fourth most interesting group of EBI s are the morpholines which are represented by just two compounds, tridemorph and fenpropimorph (Figure 7). 

Another synthesis of u-triazolo[4,5-d]p5nrimidines described first by Benson et and by Hartzel and Benson also involves closing the triazole ring. It proceeds from a derivative of 4-aminopyrimidine (166), and making use of the aromatic character of the 5-position in the pyrimidine nucleus produces 4-amino-5-arylazo derivatives (167) by coupling with benzenediazonium chloride. These derivatives under-... 

A combination of the preceding type of synthesis and of cyclization of 4-amino-5-arylazopyrimidine can be seen in the novel procedure of Richter and Taylor. Proceeding from phenylazomalonamide-amidine hydrochloride (180), they actually close both rings in this synthesis. The pyrimidine ring (183) is closed by formamide, the triazole (181) one by oxidative cyclization in the presence of cupric sulfate. Both possible sequences of cyclization were used. The synthetic possibilities of this procedure follow from the combination of the two parts. The synthesis was used for 7-substituted 2-phenyl-l,2,3-triazolo[4,5-d]-pyrimidines (184, 185). An analogous procedure was employed to prepare the 7-amino derivatives (188) from phenylazomalondiamidine (186). 

A nucleophilic attack of morpholine on the pyrimidine ring in l,2,3-triazolo[l,5- ]pyrimidinium salts 1203 leads to unstable intermediates 1204. Spontaneous opening of the pyrimidine ring results in formation of 1,2,3-triazole derivatives 1205 that are isolated in 80-85% yield. A similar nucleophilic attack of the hydroxide anion (from aq. K2CO3) on dimethoxy derivative 1203 provides transition species 1206 that opens to intermediate 1207, and finally tautomerizes to ester 1208, isolated in 87% yield (Scheme 200) <2003T4297>. 

Spickett and Wright investigated the reactions of 4-substituted 3-amino-1,2,4-triazoles and EMME in acetic acid for 24-48 hr [67JCS(C)503]. Generally, they obtained [l,2,4]triazolo[l,5-a]pyrimidine-7-ones (1124) in 38-56% yields. In the case of the benzyl derivative (R = CH2Ph), the isomeric triazolo[l, 5-a]pyrimidin-5-one (1125) was also isolated from the mother liquor, in 5% yield. From the 4-ethyl and 4-phenethyl derivatives (R = Et, CH2CH2Ph), l-(l,2,4-triazol-3-yl)pyridin-2-ones (1126) were also obtained in 1-2% yields. 

Most syntheses of TPs start either from a 1,2,4-triazole derivative or from a pyrimidine residue and need annulation of a second heterocyclic ring. Preferably 5-amino-1,2,4-triazoles (AT) and 2-hydrazinopyrimidines (HP), respectively, are used as starting synthons. 

Schiff bases (112) derived from 4-chlorobenzaldehyde and 1-substituted-5-amino-3-methylthio-l,2,4-triazoles (111) underwent cyclization with phe-noxyacetyl chloride or dichloroacetic acid in the presence of phosphoryl chloride and dimethylformamide to give the 7-(4-chlorophenyl)-fram-6,7-dihydro-3-methylthio-6-phenoxy-l-substituted-l,2,4-triazolo[4,3-a]pyrimidin-5-one 113 and l-substituted-6-chloro-7-(4-chlorophenyl)-3-methylthio 1,2,4-triazolo[4,3-a]pyrimidin-5-one 114, respectively (88JHC173) (Scheme 47). 

As part of their study on aza-transfer reactions, Tisler and co-work-ers289 290 reacted 2-hydrazino-4-oxo-4//-pyrido[l,2-u]pyrimidine with various diazo derivatives and obtained 2-azido- and 2-amino-4-oxo-4/f-pyrido[l,2-u]pyrimidines. From 2-azido-4-oxo-4/f-pyrido[l,2-u]pyrimi-dines various derivatives of 2-(l,2,3-triazol-l-yl)-4-oxo-4//-pyrido[1.2- ]-pyrimidine (221) were prepared by reaction with acetylene,287 1,3-dioxo compounds,166 ordiethylamine.291 For further ring transformation reactions of the 2-azido-4-oxo-4//-pyrido[l,2- ]pyrimidine (102), see Section lll.C.lO. 

Methods of this type are best considered as reactions of the fused ring-systems in question (see Chapter 4.15). The example illustrated in Scheme 91 is of potential interest in pharmacology (75T1363, cf. 74CPB1938). The conversion of the 1-aminoadenosine (192) into the imidazolyltriazole (193) amounts to triazole formation from an amidrazone intermediate and a formyl group derived from the pyrimidine moiety. 

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). 

Nucleoside Pyrophosphates. - The synthesis of 8-aryl-3-P-o-ribofuranosylimiazo[2,l-i]purine 5 -phosphates (122) from AMP or ATP has been described. To access these fluorescent nucleotide derivatives, a combination of Kornblum oxidation reaction and imidazole formation was employed. For this conversion, the appropriate adenosine phosphate, present in its free acid form, was treated with p-nitro-acetophenone in DMSO in the presence of DBU. Treatment of a 5-(chloroethyl)-4-(triazole-l-yl)pyrimidine-nucleoside with benzylhydrazine offered the 6,6-bicyclic pyrimido-pyradazin-7-one, the precursor to (123). This triphosphate was used as a substrate for DNA polymerases. ... 

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