5-Amino-l,2,4-triazine 4-oxides

The increase in thermodynamic stability of 85 is achieved by easy ring opening (01H127). This knowledge allows one to control the regioselectivity of the oxidative amination of the 6-aryl-l,2,4-triazine 4-oxides 53, obtaining either (i) the 5-amino-1,2,4-triazine 4-oxides 56 in the reaction of 53 with amines at low temperature in the presence of the oxidant or (ii) the 3-amino-l,2,4-triazine 4-oxides 88, provided the reaction is carried out in two steps (addition and oxidation) at room temperature or higher. 

Another pathway for the aromatization of the cr -adducts was found in the reactions of 3-pyrrolidino-l,2,4-triazine 4-oxide 81 with amines. Thus the treatment of 1,2,4-triazine 4-oxide 81 with ammonia leads to 5-amino-1,2,4-triazine 4-oxides 54—products of the telesubstitution reaction. In this case the cr -adduct 82 formed by the addition of ammonia at position 5 of the heterocycle undergoes a [l,5]sigmatropic shift resulting in 3,4-dihydro-1,2,4-triazine 83, which loses a molecule of pyrrolidine to yield the product 54. This mechanism was supported by the isolation of the key intermediates for the first time in such reactions—the products of the sigmatropic shift in the open-chain tautomeric form of tiiazahexa-triene 84. The structure of the latter was established by NMR spectroscopy and X-ray analysis. In spite of its open-chain character, 84 can be easily aromatized by refluxing in ethanol to form the same product 54 (99TL6099). 

Only pyrazine and its benzo derivatives are easily converted into di-A-oxides, although di-A-oxides have been reported, for example, in the pyridazine, pyrimidine, and cinnoline series. Oxidation of 3-amino-l,2,4-triazine 2-oxide with H2O2 in polyphosphoric acid at 24C affords 3-amino-l,2,4-triazine 2,4-dioxide 90. However, 3-amino-l,2,4-... 

Aminopyridine A-oxides can be diazotized and the diazonium salts 757 undergo coupling. These diazonium salts are resonance stabilized. Amino groups in pyridazine A-oxides can also be diazotized and the diazonium group further replaced by other functionality. Nitrosation of 3-amino-l,2,4-triazine 2-oxides and subsequent thermolysis of the diazonium tetrafluoroborate salts affords 3-fluoro-l,2,4-triazine 2-oxides. 

Interestingly, the reaction of 3-pyrrolidino-l, 2,4-triazine 4-oxide with ammonia has been established to give 5-amino-l,2,4-triazine 4-oxide, due to the te/e-substitution process with elimination of pyrrolidine (Scheme 25) [51 ]. As for the mechanism of this amino-dehydrogenation reaction, a sigmatropic shift of hydrogen has been postulated, substantiated by registration of the key intermediates. 

The amino-imino tautomerism in 3-amino-l,2,4-triazine 2-oxides 1 was suggested as the reason for the oxidation of 3-amino-1,2,4-triazines 2, predominantly atN(2) (77JOC546). 

Reactions of 3-hydrazino-l,2,4-triazine 1-oxide 31 or 3-hydrazinopyrido [2,3-c]-l,2,4-triazine 1-oxide 32 with diethoxymethyl acetate or triethyl orthoformate proceed as cyclization reactions at the N(4) atom and the amino group to form the corresponding pyrazolo[3,4-c]-l,2,4-triazine 6-oxides 33 and 34 (74MI, 80JOC5421, 80MI). 

Deoxygenative autoaromatization was reported to occur in the reaction of 3-amino-1,2,4-triazine 2-oxides 42 with alcohols in the presence of HCl or acetyl chloride. In this case the intermediate cr -adducts undergo elimination of water or acetic acid, resulting in 6-alkoxy-3-amino-l,2,4-triazines 75 (77JOC3498). 1,2,4-Triazine 1-oxides do not react with alcohols under these conditions (77JOC3498). 

The treatment of 3-amino-1,2,4-triazine 2-oxides 1 or 3-amino-1,2,4-benzotri-azine 1-oxides 29 with nitrous acid proceeds as a diazotization reaction, but the diazo compounds have never been isolated owing to the easy displacement of the di-azo group with nucleophiles. Thus the reaction of 3-amino-1,2,4-triazine 2-oxides 1 with sodium nitrite in hydrochloric or hydrobromic acids leads to the corresponding 3-halogen-1,2,4-tiiazine 2-oxides 119 or 3-bromo-l,2,4-benzotriazine 1-oxides 120 (77JOC546, 82JOC3886). 

The reaction of 3-amino-1,2,4-triazine 1-oxide 1 with methyl iodide in the presence of sodium bicarbonate leads to the methylation of the amino group to afford 3-methylamino-l,2,4-tiiazine 1-oxide 123. This iV-oxide 123, under neutral conditions in the presence of Mel, undergoes methyl group migration to the N(2) atom of the 1,2,4-triazine ring, yielding 3-imino-2-methyl-1,2,4-triazine 1-oxide 124. The same product 124 was obtained by direct methylation of compound 1 under neutral conditions (84TL1677). 

Diese Aminierung ist auch fur l,2,4-Triazin-4-oxide beschrieben3 die Aminierungspro-dukte (z. B. 5-Amino-3-methyhhio-l,2,4-triazin-4-oxid) werden in einer zweiten Stufe mit Phosphor(III)-chlorid zu den 1,2,4-Triazinen (z.B. 5-Amino-3-methylthio-l,2,4-triazin) deoxygeniert. 

Diaminoimidazoles (741) and 1,2-diaminobenzimidazoles (743) can be oxidized by manganese dioxide or lead tetraacetate to give a useful synthesis of 3-amino-l,2,4-triazines (742) and -benzotriazines (744) (76SC457, 76TL903, 77JOC542, 78JOC2693). 

Oxidation of 3-amino-l,2,4-triazine (39) with peracetic acid led to 3-amino-1,2,4-triazin-5-one (233) (79JHC555) while oxidation with permanganate gave the 3,5-dione (234) (79JHC1649). When 3-amino-5,6-dimethyl-l,2,4-triazine (235) was treated in basic or acidic medium with potassium permanganate the only isolated product was the 3-amino-6-methyl-... 

Oxidation of methyl ketone guanylhydrazones (686) with selenium dioxide affords the corresponding monosubstituted glyoxal derivatives (687) which cyclize to the 5-unsubstituted 3-amino-l,2,4-triazines (473) <78HC(33)189, p.360). We have already noted the cyclization of bis(alkylidene)- or bis(arylidene)-acetone guanylhydrazones (475) in the synthesis of 6-(vinyl-substituted) 3-amino-l,2,4-triazines (477) (Section 2.19.4.1.1). 

Methyl-,242 3-phenyl-,450 or 3-amino-l,2,4-benzotriazine 1-oxide or -2-oxide afford benzo-triazoles 4 when treated with sodium hydroxide377 The same reaction is observed for pyrido-[2,3-e]-l,2,4-triazin-3-amine or pyrido[4,3-e]-l,2,4-triazin-3-amine 1-oxide in sodium hydroxide affording the corresponding products in 77 and 40% yield, respectively.370 379... 

Chloro(bromo)-3-amino-l,2,4-triazines 76 were obtained by the reaction of the 3-amino-1,2,4-triazine 2-oxides 42 with HCl or HBr (78JOC2514). 

Fluoro-l,2,4-triazin-2-oxides 26 were obtained through diazotization of the corresponding amino derivatives 24 followed by thermolysis of the resulting diazonium tetrafluoroborates 25 (Scheme 14). It should be noted the salts 25 have been isolated first as rather stable heterocyclic diazonium species [22]. 

In contrast to the above situation with respect to oxidation of the ring nitrogen atoms of 1,2,3-triazines, oxidation of derivatives of 3-amino-l,2,3-benzotriazin-4-(3/0-one (101a) has proved to be of considerable interest and has been investigated in some detail by Rees and his colleagues. Treatment of 101a with lead tetraacetate at 80° has been shown to give benzyne in very low yield, but at room... 

Irradiation of 1,2,4-triazine 4-oxides (124) led to the deoxygenated products, and also, when position 5 was unsubstituted, to 1,2,4-triazoles (364) (76LA153). 4-Amino-l,2,4-triazin-5-ones (365) are photochemically deaminated. This has been demonstrated, in particular, with the 6-r-butyl-3-methylthio compound (8) which is used as a herbicide... 

Oxidation of 1,2-diaminobenzimidazole, leading to the formation in high yield of 3-aminobenzo-l,2,4-triazine 838, is thought to proceed through recyclization of an intermediate nitrene 836 (possibly via diazene intermediate 837) as evidenced by the formation of amine 838, with a high efficiency on the thermolysis of l-amino-2-azidobenzimidazole 835. The reaction works well also for other A -amino—azidoimidazoles and 4-amino-3-azido-l,2,4-triazoles. 

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