1.2.3- Benzotriazines reactions

Pyrrolo[2,1 -c][l, 4]benzodiazepines synthesis, 7, 614 Pyrrolo[l, 6]benzodiazocines synthesis, 7, 515 Pyrrolo[3,4-c]benzopyrazoles reactions, 6, 1034 Pyrrolobenzothiazoles synthesis, 4, 785 Pyrrolo[l, 2-c]benzotriazines synthesis, 4, 240 Pyrrolo[3,4-c]cinnolines synthesis, 4, 240... 

The reaction of the sodium salts of pyrido[2,3-e]-l,2,4-triazin-3(4//)-one 1-oxide 22 (Y = N) or l,2,4-benzotriazin-3(4//)-one 1-oxide 23 with acetobro-moglucose results in tetra-(9-acetyl derivatives of /3-D-glucopyranosides 24, 25 deacetylation of 25 gives nucleosides 26 (82JHC497). 

Reactions of compounds 23 with 2-chloromethoxyethyl acetate lead to N-alkylation products 27, which are hydrolyzed to form4-(2-hydroxyethoxymethyl)-1,2,4-benzotriazine 28 (82JHC497). 

The reaction of 3-morpholino-l,2,4-benzotiiazine 4-oxide 38 with zinc in hydrochloric acid afforded 3-morpholino-l,2,4-benzotriazine 39 (78USP4091098). 

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). 

Treatment of l-morpholino-6-iminocyclohexene with hydrazine hydrate in the presence of ketones leads to 2,3,5,6,7,8-hexahydro-l,2,4-benzotriazine 4-oxides 156. In the absence of carbonyl compounds, this reaction affords the spirobicyclo compound 157 (75S794). 

The reaction of benzofurazan iV-oxide with diethylamine affords 3-methyl-1,2,4-benzotriazine 4-oxide 160 (79T681, 82T1793). 

In some cases, the position of the N-oxidation depends on the temperature. The reaction of 3-phenyl-1,2,4-benzotiiazine 172 with peracetic acid affords 3-phenyl-l,2,4-benzotriazine 1-oxide 173 at 50°C and 2-oxide 174 at room temperature (57JCS3186). Only the 1-oxide 175 was obtained by the oxidation of 3-unsubstituted 1,2,4-benzotriazine 176. The oxidation of 3-methyl-1,2,4-benzo-triazine 176 (R = Me) under the same conditions results in a mixture of 3-methyl-l,2,4-benzotriazine 1-oxide 175 and 2-oxide 177 in 25 and 10% yields, respectively. 

Benzannulated azocines can be prepared starting from 4-phenyl-l,2.3-benzotriazine (16), flash-vacuum pyrolysis of which leads to 2-phenylbenzazete (17) (cf. Houben-Weyl. Vol. E16c, p 939), which is stable until about 40 °C and easily enters into cycloaddition reactions with dienes. With tetraphenylcyclopentadienone, a nonisolable adduct is formed which, by loss of carbon monoxide, gives an azabicyclo[4.2.0]octatriene derivative that isomerizes to the 1 -benzazocine 18.22... 

Photolytic nitrogen elimination from 8f/-quinazolino[3,2-c][l,2,3]benzotriazin-8-one (1) leads to two intermediates, only one of which can be isolated. When the reaction is performed in the presence of nucleophiles, both intermediates react, via ring enlargement, to provide di-benzo[l,5]diazocines.43 In addition to morpholine and methanol, other alcohols or water can be used as the nucleophile. 

Cyclization of pyrazole 220 (R = NH2), obtained from the reaction of 2-nitophenylhydrazine with 219 and subsequent hydrogenation, gave (81USP4260751) pyrazolo[l,2-al[l,2,4]benzotriazines 221, a useful antiinflammatory agent (Scheme 49). 

In warm mineral acid, formazans (195) rearrange to a benzotriazine (196) eliminating an amine (Scheme 29).8,26 27 334 338 339 H owever, when R is methyl, phenylazo, or oxalyl, the main product is the phenazine 197 along with a trace amount of the benzotriazine.340 The mechanism of this reaction is not well understood.341 345... 

As noted above, a convenient pathway to cinno-lines consists of intramolecular condensation of a diazonium group with a ketonic methyl group, or alternately with a double bond. The analogous reaction with an amide nitrogen leads to 1,2,3-benzotriazines, such as 198. Reaction of isatoic anhydride with N-aminomorpholine affords the hydrazide 196 then, treatment with nitrous acid yields initially the diazonium salt (197). Under the reaction conditions... 

Reaction of triazenes 112 with -BuLi and subsequent treatment with di-fer/-butyl dicarbonate afforded the tricycles 113 as single diastereomers. The analogs of 112 with two alkyl substituents on the N atom (when N atom is not incorporated in a ring) gave diastereomeric mixtures of the corresponding benzotriazines under the same conditions (Equation 12) <2002AGE484>. 

Lead tetraacetate oxidation of 3-substituted 1- and 2-aminoindazoles 6 and 7, has been shown by Rees to result in rapid and almost quantitative conversion into 4-substituted 1,2,3-benzotriazines (8, R = Me, OMe, Ph). 1,2,3-Benzotriazine (8, R = H) was prepared similarly, and for the first time, by carefully controlled oxidation of either 1- or 2-aminoindazole (6, 7, R = H). These remarkable ring expansion reactions, which apparently proceed via the formation of intermediate nitrenes, appear to be a direct and logical extension of original work by Bamberger and Goldberger in 1898 on the oxidative ring expansion of... 

There are two general ring syntheses available for the preparation of 3-substituted l,2,3-benzotriazin-4(3//)-ones, namely, (i) diazotization of anthranilamide and its derivatives and (ii) cyclization of 1-alkyl- or 1-aryl-3-(o-carbalkoxy)triazenes, and both reactions have been studied in considerable detail. 3-Substituted l,2,3-benzotriazin-4(3//)-ones have also been obtained by alkylation and acylation of l,2,3-benzotriazin-4-one these last reactions are discussed separately (see Section II, C, 3). 

Diazotization of anthranilamide and its derivatives is the most common and widely exploited reaction for the preparation of 1,2,3-benzo-triazine derivatives. The reasons for this are 3-fold (i) many nuclear substituted anthranilic acid derivatives are readily available (ii) the diazotization reactions generally proceed smoothly and in high yield, and the product triazinones are usually very stable and easily handled and (iii) many 3-substituted l,2,3-benzotriazin-4(3i/)-ones have been found to possess a wide range of pronounced pharmacological activity, while others undergo a number of very interesting chemical transformations, and hence a very large number of these compounds have been prepared. 

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. ... 

Reaction of the benzyne precursor (54) with triphenylphosphine arylimides (55) has been shown to give 3-aryl-1,2,3-benzotriazin-4(3/0-ones in poor (< 20%) yield and, while of mechanistic interest, these reactions are of no synthetic significance. Another surprising reaction was reported recently by Moriconi and Shimakawa, who found that... 

For many years it was believed that anthraniionitrile did not react with either ammonia or hydrazine to give the corresponding amidines, and consequently, 4-amino- (56, R = H) and 4-hydrazino-1,2,3-benzotriazine (56, R = NHj) were first prepared by reaction of 4-methylthio-l,2,3-benzotriazine with ammonia and hydrazine, respectively. In general, alkylamines react readily with 1,2,3-benzotriazine-4(3 -thione (39, R = H) to give the corresponding 4-amino 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. 

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. 

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. ... 

The reactions of 3-amino-l,2,3-benzotriazin-4(3//)-one and a number of its derivatives (lOla-g) under both acidic and basic media have been investigated in some detail by Gibson and Green. Earlier work by Heller and his colleagues had apparently established that treatment of lOla-e with hot aqueous sodium hydroxide solution gave o-azido-benzoic acid (102), and Gibson and Green showed that lOlf behaved similarly. The benzylidenamino derivative 10 Ig, however, was reported by Heller to yield benzaldehyde o-carboxyphenylhydrazone (103) under basic conditions, and benzimidazolone (104) under acidic conditions. 

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... 

As mentioned above, condensed 1,2,3-triazine derivatives can be arylated by treatment with nitro-activated aryl halides. The only other report of direct arylation of the 1,2,3-triazine system is due to McKillop and Kobylecki, who studied the reaction of l,2,3-benzotriazin-4-one (10, R = H) with diaryliodonium salts in the presence of base. Treatment of 10, R = H, with diphenyl- and di-p-bromophenyliodonium chloride results in exclusive arylation at N2 and gives the corresponding triazinium betaines (77, R = Ph, p-BrCjH4) in good yield. When di-p-tolyliodonium chloride is used, a mixture of the Nj-, Nj-, and 0-arylated... 

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