1.2.4- Triazolo pyrimidines, hydrolysis

Heating solutions of the 3-(5-formamidoimidazol-4-yl)-l,2,4-triazoles 79 eaused their intramoleeular eyelodehydration to the l,2,4-triazolo[l,5-cjpyrimidines 80. Tire starting eompounds 79 were obtained by aeid- or base-eatalyzed pyrimidine ring hydrolysis of the l,2,4-triazolo[4,3-c]pyrim-idines 78 (65JOC3601) (Seheme 26). 

Heating the 8-amino-7-chloro-2-oxo-l,2,4-triazolo[l,5-c]pyrimidine 189 with hydrochloric acid caused hydrolysis of the chloro group yielding the 2,7-dioxo derivative 190 (68JOC530) (Scheme 72). 

Oxidation of benzotriazoles and other fused triazoles by potassium permanganate is a well-established route to lif-triazole 4,5-dicarboxylic acid derivatives. Many of the triazolo[d]pyrimidines, synthesized as purine analogs, can be degraded to monocyclic triazoles by acidic or basic hydrolysis (in other triazolopyriraidines, however, the triazole ring is cleaved preferentially ), e.g. Scheme 24. 

Treatment of the phenacyliminium salt 114, derived from 5,7-dimethyl[l,2,4]-triazolo[l,5-fl]pyrimidine 113 and phenacyl bromide, with 2 equiv of triethylamine gives rise to the 2-iminooxazoline 118 by way of the in situ generated intermediary A -ylides 115. Acidic hydrolysis affords the 3-(2-pyrimidinyl)-2(3//)-oxazolone... 

Muehlstaedt et al. reported an unusual ring transformation in which the thermodynamically more stable 7-amino-6-cyano-l,2,4-triazolo[l,5-a]-pyrimidine (67) underwent an acid-catalyzed retro-Dimroth rearrangement to the thermodynamically less stable 7-amino-6-carboxamido-l,2,4-tria-zolo[4,3-a]pyrimidine (115) (70JPR254). The structure of this product was confirmed by comparison with authentic material obtained (70JPR254) from the acid hydrolysis of the known 7-amino-6-cyano-l,2,4-triazolo[4,3-a]pyrimidine (66) (Scheme 48). 

Hydrolysis of 2-phenyl-[l. 2.3]triazolo[4,5-d]pyrimidine-5,7-dione N-oxides 463 in basic solution gives rise to 4-amino- and 4-ureido-2-phenyl-l,2,3-triazole-5-carboxylic acid 1-oxides 464, as well as their hydrazides and methylamide (2005JGU636) (Scheme 134). 

The aldehyde from the hydrolysis of 25 proved to be difficult to isolate but could be converted directly to the hydrazone 26, whose oxidation with lead tetraacetate gave the l,2,3-triazolo[l,5-c]pyrimidine 27 (78JHC1041). 

Hydrolysis of the N-alkyl derivatives of l,2,3-triazolo[4,5-d]pyrimidines 47-51 to give N-alkyl-4-aminotriazole derivatives 52-56, respectively, took place with dilute acid or base at room temperature [57JOC707 65JOC2488 69JCS(C)2379 74JCS(P1)2030 77JCS(P1)1819] (Scheme 10). 

Reaction of the 3-substituted l,2,3-triazolo[4,5-d]pyrimidines (183) with one equivalent of a Grignard reagent in THF afforded the dihydro compounds 185 after hydrolysis of the intermediates 184. Aromatization of 185 by oxidation with potassium ferricyanide (79CPB3176) or with 2,3-dichloro-4,5-dicyanobenzoquinone (DDQ) (89CPB1731) gave the 3-substituted 7-alkyltriazolopyrimidines 186. Replacement of the methylsul-... 

These isomers (XLVIII) are formed as side-products during the cycUzation reaction or when the 2,3-dihydro-l,2,4-triazolo[4,3-a]pyri-midine-3-thiones (XLVII) are heated either in water or water-pyridine mixtures. These isomerisations are probably proceeded by the hydrolysis of the (XLVII) first formed. The hydrolysis likely yields either the Schiff s base of 5-amino-2l4-l,2,4-triazoline-3-thione (XLIXa) or 5-amino-zl4-l,2,4-triazoline-3-thione (XLIXb) and the corresponding -dicarbonyl compound. These substances can now cyclize again either on the Nj or the nitrogen atom. This re-cyclization however will occur most readily on the more nucleophile nitrogen atom of the hydrazino function (Nj). Similar conversion reactions are known and have been studied in detail for the non-thioxo substituted l,2,4-triazolo[4,3-a] pyrimidines 3, 317, 318, 319, 383). 

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