1.2.4- Triazines covalent hydration

Hydrolysis of condensed 1,2,3-triazines results in cleavage of the heterocycUc ring and is in many respects an unexceptional and fully predictable type of reaction. The relative ease with which ring fission takes place, and the products formed, depend almost entirely on the nature of the substituents at the 3- and 4-positions and on the reaction conditions employed. Moreover, hydrolysis under basic conditions normally leads to fission of the N,—C4 bond whereas under acidic conditions most 1,2,3-benzotriazine derivatives behave as masked diazonium compounds, and hydrolysis proceeds with fission of the Nj— N3 bond and transient formation of a diazonium compound, from which the observed products are ultimately derived. Hydrolysis of certain derivatives probably also involves covalent hydration as the key step. 

Benzotriazine (8, R = H), for example, can be isolated as a reasonably stable, colorless crystalline solid, but it reacts rapidly in solution with water to give o-aminobenzaldehyde, presumably by initial covalent hydration to give 98, which decomposes to o-aminobenzaldehyde via the triazene 99. Reaction of 8, R = H, with other nucleophiles also occurs readily, while 4-substituted 1,2,3-benzo-triazines react similarly but more slowly, as expected, owing to a combination of steric and electronic effects. 

The structures of 5-azacytosine and related compounds are of interest because of their biological importance (see Section 2.20.5.6). l-Methyl-5-azacytosine exists in the amino-oxo form (23). 5-Azauracil (l,3,5-triazine-2,4-dione) is of particular interest. IR spectra indicate that it exists in the dioxo form in the solid, but H NMR studies have been interpreted to show that it exists in the monoenolic form in solution. The spectra showed a non-exchange-able sharp singlet at 8.18 8 (H, 24) (760MR(8)224). Derivatives of 5-azacytosine and 5-azauracil are covalently hydrated. Thus 5-azauridine exists entirely in the crystal form as (25) (76MI22000, p.l39>. 

Dihydro-2iT-thiazolo[2,3-c][l,2,4]triazine-3,4-dione rearranges in dilute base to give an unstable acid which decarboxylates on acidification of the sodium salt to give 5,6-dihydrothiazolo[2,3-c]-s-triazole (equation 68) (81CB1200). Kinetic evidence has been put forward in favor of covalently hydrated intermediates in the acid-catalyzed rearrangement of triazolo[4,3-a]pyrazines to 1H-imidazo[2,1 -c]-s-triazoles. The intermediate triazole has been isolated and characterized (equation 69) (72JCS(P2)4). 

While it is clear that 1,3,5-triazine can be covalently hydrated, no evidence of deuterium exchange has been presented (75JOU2691), and this follows because each position is ortho and para to nitrogen, which produces strong ( M, -1) electron withdrawal at these sites. 

In NaOD-D20 (or with added DMSO) 1,2,4-triazine and its 5- or 6-methyl and 5-phenyl derivatives exchange H-3 for deuterium with an opposite reactivity order to that observed under acid catalysis (vide supra) (73T2495). The observation that the 5-phenyl derivative reacts 15 times faster than the unsubstituted parent (Table 10.4 comparison was made in D,0-DMS0 because of solubility problems) clearly indicates that the carbanion mechanism operates in basic media rather than a process involving covalent hydration. 

Not surprisingly, C4 in 1,2,3-benzotriazines 8 is very electrophilic and easily undergoes covalent hydration across the N3-C4 bond to give, ultimately, 2-aminophenyl ketones 9.10,82 4-Phenyl-1,2,3-benzotriazine (8, R = Ph) reacted with hydrazine to form the hydrazone of 2-amino-diphenyl ketone (9, R = Ph).82 Surprisingly, the pyrido[3,2-[Pg.562]

The ester 5 reacts with thiosemicarbazide to yield the thiazole 6, the thiadiazine 8, or the corresponding carboxylic acids, depending on the acidity of the medium, but no triazine is obtained. The covalent hydrate 7 is an intermediate in the formation of 8. Acetylation of the thiazole 6 leads to unidentified thiadiazines or pyrazoles <96KGS1266 97CA(126)89345>. 

The pH-dependent NMR spectrum of [Ru(bipy)2(py)2] salts has been shown not to involve the formation of covalent hydrates. The reaction of 2,4,6-tris(2-pyridyl)-l,3,5-triazine (46) with aqueous copper(I) salts results in a metal-promoted hydrolysis to yield complexes of 2-pyridinecarboxamide and (47). A number of metal complexes have been characterized structurally from these reactions. 

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