1.2.3- Benzotriazine oxides, synthesis

The two main approaches to iV-oxides of 1,2,4-triazines are (a) iV-oxidation (Section 6.11.5.4), and (b) ring synthesis by closure to an oxime group (Scheme 78). See also Equation (25). Other methods can be applied to 1,2,4-benzotriazine oxides, including the rather spectacular trioxide synthesis (Equation (60)). 

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). 

Reduction of 2-nitrophenyloxaloamidrazonates (733) with iron and hydrochloric acid was used for the synthesis of 1,2-dihydro-1,2,4-benzotriazine-3-carboxylates (734), which can be oxidized to the fully aromatic compounds (735) (56G484). 

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). 

Catalytic reduction of the 2-nitrophenyIhydrazones (745) and subsequent air oxidation of the tetrahydro-l,2,4-benzotriazines (746) which are formed is used for the synthesis of 3,4-dihydro-1,2,4-benzotriazines (747) (80FES715). In another cyclization of an o-nitro group, which somewhat resembles others (e.g. 736 —> 737) described earlier, treatment of l,l-dialkyl-2-(2-nitrophenyl)hydrazines (748) with acids affords 2-alkyl-1,2,4-benzotriazinium salts (749) (77JCS(P1)478). The 2-nitrophenylbromohydrazone (750) with sodium ethoxide and ethyl cyanoacetate forms 6-bromo-3-phenyl-l,2,4-benzotriazine (751) a mechanism for this interesting transformation, in which the cyanoacetate plays no part, has been proposed (79JHC33). 

Hydroxyquinazolin-4-ones (62), which are tautomers of 4-hydroxyquin-azoline 3-oxides (see also 3, Section II,A), were useful catalysts for peptide synthesis when dicyclohexylcarbodiimide was used. They decreased the amount of racemization of a-amino acids during formation of the peptide bond. They are not, however as effective as 3-hydroxy-l,2,3-benzotriazin-4-one. 

Four methods have been published for the introduction of hydrogen into the 1,2,4-triazine ring, i.e. reduction of halo-1,2,4-triazines, oxidation of hydrazino-l,2,4-triazines, treatment of sul-fonylhydrazino-l,2,4-triazines with base, and decarboxylation of 1,2,4-triazinecarboxylic acids. Decarboxylation of l,2,4-triazine-3-carboxylic acid has been used for the synthesis of the parent 1,2,4-triazine (l) 2 120 this method was also used for the synthesis of other 1,2,4-triazines.270 l,2,4-Benzotriazine-3-carboxylic acid was decarboxylated to give the parent 1,2,4-ben-zotriazine (2).151 271... 

The most appropriate technical synthesis of triazoxide [60], as described in Scheme 21.5, starts with phosgenation of 2-nitro-4-chloroaniline, followed by am-monolysis of the isocyanate. Cyclization of the formed arylurea occurs by treatment with aqueous sodium hydroxide to obtain the sodium salt of 3-hydroxy-7-chloro-l,2,4-benzotriazine-l-oxide. After acidification, the hydroxy group can be converted into the corresponding imidazolyl derivative after being transformed into the chloro compound with thionyl chloride. 

Also the synthesis of fluorinated 1,2,4-benzotriazines illustrates the advantage of the oxidative reaction, as the key step in modification of fluorinated nitroben-zenes with guanidine followed by annelation of the 1,2,4-triazine ring (Scheme 58) [181],... 

An ethanolic soln. of l-morpholino-6-oximinocyclohexene refluxed 2 hrs. with hydrazine hydrate, cyclohexanone added, and refluxed overnight -> 2,3,5,6,7,8-hexahydro-l,2,4-benzotriazine 4-oxide deriv. Y 62%. F. e. s. R. H. Fischer and H. M. Weitz, Synthesis 1975, 794. 

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