3- Amino-l,2,4-benzotriazine 1-oxides

Treatment of l,2,4-benzotriazin-3-one 1-oxide (131) with sodium hydroxide afforded benzotriazole (132a). Similarly, 3-amino-l,2,4-benzotriazine 1-oxide (133) with a base gave benzotriazole or 1 -acetylbenzotriazole (132b) while 3-amino-1,2,4-benzotriazine 2-oxide (134) was converted into benzotriazole and benzotriazole-1-carboxamine (132c) (62JOC185). 

The product of methylation of l,2,4-benzotriazin-3-one 1-oxide (210) with methyl iodide was identified as 4-methyl-1,2,4-benzotriazin-3-one 1-oxide (211) (59JOC813). Like the amines in the monocyclic series mentioned above, 3-amino-l,2,4-benzotriazine 1-oxides (133) are acylated on the amino group (54JA3551). 

Only a few examples of the formation of 1,2,4-triazines by this fragment combination have been published, all cases being 1,2,4-benzotriazine syntheses. 2-Nitroaniline reacts with cyanamides to give 2-nitrophenylguanidines (601) which cyclize under basic conditions to 3-amino-l,2,4-benzotriazine 1-oxides (602) <78HC(33)189, p.699). With benzoyl isothiocyanate it affords Ar-(2-nitrophenyl)-N -benzoylthiourea (603), which cyclizes to l,2,4-benzotriazine-3-thione 1-oxide (604) (80MI21900).. 

Treatment of 2-nitrophenylcarboximidamides with base affords 1,2,4-benzotriazine 1-oxides.15 5a c Similar treatment of the 2-nitrophenylureas, thioureas and guanidines leads to the 3-hydroxy-, 3-sulfanyl- and 3-amino-l,2,4-benzotriazine 1-oxides or their tautomers.155a c... 

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... 

As far as 1,2,4-benzotriazines are concerned, the sites of protonation of 3-amino-l,2,4-benzotriazine 1,4-dioxide (tirapazamine), and its metabolites, including 3-amino-l,2,4-benzotriazine 1-oxide, 3-amino-l,2,4-benzotriazine 4-oxide, 3-amino-l,2,4-benzotriazine, and 3-amino-l,2,4-benzotriazine 2-oxide, have been studied <2001JOC107, 2003JAM881>. Protonation of tirapazamine in both gas and liquid phases was shown to occur exclusively at the oxygen in the 4-position <2003JAM881>. 

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). 

Anderson, R.F., Shinde, S.S., Hay, M.P., Gamage, S.A. and Denny, W.A. (2003) Activation of 3-amino-l,2,4-benzotriazine 1,4-dioxide antitumor agents to oxidizing species following their one-electron reduction. Journal of the American Chemical Society, 125, 748-756. 

The condensation of 3-amino-1,2,4-benzotriazine 1-oxides 29 with a-halo-carbonyl compounds results in imidazo[2,l-c]-l,2,4-benzotiiazine 1-oxides 30 (82JHC61, 86MI). 

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). 

Benzotriazines (442) and their 1-oxides have been subjected to nucleophilic displacements. 3-Chloro-l,2,4-benzotriazine is readily converted into the hydrazino analog (95°, 2 min, 50% yield). The amine exchange of 3-amino-7-chloro- to 3-benzylamino-7-chloro-... 

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... 

Triazines are oxidized by peroxy acids yielding 1- or 3-oxides. 3-Amino-l,2,3-benzotriazin-4(3//)-ones 5 are dehydrogenated at the amino group by lead tetraacetate. The intermediate nitrenes 6 are stabilized by eliminating a molecule of N2 yielding 3//-indazolones 7. Alternatively, by loss of two molecules of N2, they form benzocyclopropenones 8 which are confirmed by trapping [13] ... 

Mit dem Dinatriumsalz von Cyanamid wird 3-Amino-1,2,4-benzotriazin-l,4-bis-oxid (81 %)320 gebildet, mit Cyan-acetamid hingegen 2-Aminocarbony -l-hydroxy-benzimidazol-3-oxid (78%)321 [analog reagieren 1-Nitro-alkane322-324 und (3-Oxo-alkyl)-sulfone]325 ... 

Benzotriazinium betaines (13) and (26) are stable toward acids. They are slightly basic compounds and form salts with acids which are easily hydrolyzed. The corresponding 1-oxides (33) behave similarly, being, for instance, souble in concentrated hydrochloric acid from which they are reprecipitated on dilution with water (27JCS323). 4-Amino-l,2,3-benzotriazines (38) and 4-imino-1,2,3-benzotriazines (39) behave as masked diazonium compounds (40) and the products of acidic treatment of these compounds are best explained as reaction products of the diazonium salts (78HC(33)78>. Treatment of 1,2,3-benzotriazine... 

The same methods used for 1,2,4-benzotriazines have,also been applied to the synthesis of naphtho-l,2,4-triazines. l-Amino-2-arylazonaphthalenes (663) with phosgene yield naphtho[l,2-e][l,2,4]-triazin-2-ones (664) (05MI21900), and the isomeric 2-amino-l-arylazonaphthalenes (665) with phosgene or isocyanates similarly gave naphtho[2,l-c]-[l,2,4]triazin-3-ones (666) <78HC(33)189, p.732). 3-Iminonaphtho[2,1 -e][ 1,2,4]triazines (667, 668) were obtained when (665) reacted with cyanogen bromide (08MI21900) or with isothiocyanates and mercury(II) oxide (Scheme 24). 

---