Benzotriazines, nucleophilic substitution

The usual nucleophilic substitution of substituents directly bound to the heterocyclic ring was observed for monocyclic and condensed 1,2,3-triazines. These reactions may be accompanied by a ring opening of the 1.2,3-triazine ring after the nucleophilic attack at the 4-position. 1,2,3-Benzotriazines and monocyclic 1,2,3-triazines seem to be less stable than 1,2,3-triazines condensed with heterocycles. 

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. 

From the above discussion it is evident that alkylation of 1,2,3-benzotriazin-4-one results almost entirely in substitution at Nj and/or Nj, and that alkylation on oxygen is at most a minor reaction. Alkylation of l,2,3-benzotriazine-4(3//)-thione (39, R = H), on the other hand, leads to predominant or exclusive substitution on sulfur, presumably as a result of the greater nucleophilicity of sulfur compared to oxygen. This difference in reactivity between the oxygen (10, R = H) and sulfur (39, R = H) compounds has been elegantly demonstrated by Murray and Vaughan. Treatment of the sodium salt of 10, R = H, with phenacyl bromide gives the Nj-substituted derivative 127, which, on... 

There are a number of important reactions in this category and all of them involve at least one heteroatom functioning as a nucleophile and another as an electrophile. Diazo-tization of a variety of ortho-substituted anilines for instance, followed by intramolecular nucleophilic trapping of the corresponding diazonium salts by either nitrogen or carbon nucleophiles, is the basis of a series of very important syntheses of 1,2,3-benzotriazine and cinnoline derivatives, and this general approach has been widely exploited for the preparation of polycyclic systems. Representative examples are given in equations (51)—(54). 

Benzotriazine, and especially its conjugate acid, reacts very easily with nucleophiles such as water or acetic acid to give derivatives of 2-aminobenzaldehyde (75JCS(P1)31,71CC828). 4-Alkyl- or 4-aryl-substituted 1,2,3-benzotriazines are more stable towards attack of water or acids. 2-Aminobenzophenone (100%) is obtained when 4-phenyl-1,2,3-benzotriazine is heated under reflux for 10 min in 10% aqueous ethanol containing concentrated sulfuric acid (75JCS(Pl)3l>. 

Other auxiliary nucleophiles can be used in combination with DCC. The most important ones include 7-aza-l,2,3-benzotriazol-l-ol (7, HOAt)f l and 3-hydroxy-l,2,3-benzotriazin-4(3//)-one (8, HODhbt) which will be described in the section concerning the fragment condensation (Section 4.3.2.2). The use of isolated 3-hydroxy-l,2,3-benzotriazin-4(3//)-ones (8, HODhbt)f l will be discussed under active esters, (Section 4.3.3.1.5). The use of HOAt in peptide chemistry has been discussed by Carpino.f It decreases the time course of coupling reactions, reduces the loss of chiral integrity, and provides a visual indication, yellow to colorless, of the reaction endpoint in solution. HOAt was shown to be a superior coupling additive in both solutiont and solid-phase synthesesf when compared with HOBt. HOAt can be used as a direct substitute for HOBt. Furthermore, HOAt like HOBt is compatible with a variety of activation methods. The performance of HOAt derivatives was compared... 

A recently reported synthesis of 3-amino-l,2,4-benzotriazines is also based on the [3+3] combination of fragments (Scheme 124) <2006RCB1243>. The feature of this approach is that in 3-fluoro-substituted nitrobenzenes, nucleophilic displacement of hydrogen at C-2 or C-6 by the action of guanidine takes place, followed by intramolecular cyclization into the isomeric 3-amino-l,2,4-benzotriazines (Scheme 124) <2006RCB1243>. 

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