1.2.3- Benzotriazine hydrolysis

Treatment of 36 with nitrous acid in dilute acetic acid gives a mixture of anthranilazide (37) and 3-amino-1,2,3-benzotriazin-4(3/f)-one (10, R = NH2). When the same reaction is carried out in dilute hydrochloric acid, the sole product formed initially with one mole equivalent of nitrous acid is 10, R = NHj, but this readily reacts further to give 10, R = Diazotization of acetophenone anthranylhydrazone followed by mild acid hydrolysis is a superior route to 10, R = NHj, and gives a much purer product. l,2,3-Benzotriazine-4(3/0-thione (39, R = H) and the 3-substituted derivatives (39) are readily available by diazotization of thioanthranilamide (38, R = H) and its derivatives. ... 

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. 

Hydrolytic cleavage of condensed 1,2,3-triazine derivatives is normally a straightforward, high-jneld process which results in production of one or other of several distinct types of product. 3-Alkyl- and 3-aryl-3,4-dihydro-l,2,3-benzotriazines, for example, undergo facile hydrolysis in concentrated hydrochloric acid to give, via the diazonium compound, A(-alkyl- and W-aryl-substituted o-chlorobenzylamines (100, R = Cl). If the reaction is carried out in water or in dilute mineral acid, the corresponding -alkyl and iV-aryl-substituted o-hydroxybenzylamines (100, R = OH) are obtained. 

Hydrolysis of 3-alkyl-l,2,3-benzotriazin-4(3i/)-ones (10, R = alkyl) with cold, aqueous potassium hydroxide leads to anthranilic acid derivatives. The related 3-aryl-l,2,3-benzotriazin-4(3H)-ones (10, R = aryl) react less readily, but on treatment with hot aqueous or alcoholic potassium hydroxide are converted into 3-aryltriazenes (53, R = aryl) which, on further reaction, give anthranilic acids. ... 

Most known monocyclic 1,2,3-triazines and 1,2,3-benzotriazines are stable at room temperature. No detailed study of the stability of monocyclic 1,2,3-triazines towards water, aqueous acids or bases has been published, but one can assume from the reaction conditions used in the preparation of monocyclic 1,2,3-triazines, by oxidation of (V-aminopyrazoIes, that they are stable to water, aqueous acids or bases at room temperature, at least for a short time. Treatment of triaryl-1,2,3-triazines with aqueous hydrochloric acid at higher temperatures leads to hydrolysis of the ring and formation of 1,3-dicarbonyl compounds (Scheme 3) (60TL(13)19,76UP21800). 

A frequently used method for the preparation of 1,2,4-benzotriazines is the cyclization of formazans by treatment with sulfuric acid in acetic acid. When mixed formazans are used, both possible 1,2,4-benzotriazines 2 and 3 are formed.152 When acylformazans are used, 3-acyl-1,2,4-benzotriazines are isolated. The parent 1,2,4-benzotriazine is isolated when the formazan ester (R = C02R) is cyclized ester hydrolysis and decarboxylation also occur under these reaction conditions.153... 

Substituted l,2,3-benzotriazin-4(3 -ones, e.g. 12, in a reversal of the hydrolysis process (cf. p 438), are obtained by cyclization of the diazonium salts derived from the TV-substituted anthranilic acid amides 11 ... 

A strategy based on silver-ion mediated selective activation of a C-terminal thiolcarboxyl group initially reported by Blake [48] was modified by Aimoto et al., employing the more oxidation- and hydrolysis-resistant thioester in place of thioacid and HOBt or 3,4-dihydro-3-hydroxy-4-oxo-l,2,3-benzotriazine (HOOBt) as an additive to facilitate the formation of the activated ester (Scheme 8) [49,143]. This activated ester-based coupling requires the protection of side-chains of Lys... 

Substituted l,2,3-benzotriazin-4(3H)-ones, for example, 18, are obtained by cychza-tion of the diazonium salts 17 derived from the N-substituted anthranihc amides 16 (as a reversal of hydrolysis, cf p. 502) ... 

---