Benzotriazines, reduction

Benzotriazines. Reduction of 2-nitrophenylhydrazones 463 or similar hydrazides 466 gives 1,2-dihydro-l,2,4-benzotriazines 464 (Scheme 240). In most cases the initial dihydro compounds 464 are oxidized by air or potassium ferricyanide to the aromatic 1,2,4-benzotriazines 465 <1997J(P1)3107, 1999JHC589, CHEC-III (9.02.7.4)177>. 

The general procedure used for the synthesis of [l,2,3]triazolo[l,2-tf][l,2,4]benzotriazin-l-5(6//)-dione derivatives 506 is shown in Scheme 86. Ionic 1,3-dipolar cycloaddition of the appropriate azide 503 to ethyl phenylacetates gives l-(2-nitrophenyl)-4-aryl-5-oxo[l,2,3]triazoles 504. Catalytic reduction of these compounds affords the corresponding amines 505. Cyclocondenzation of these amines to the final tricyclic compounds 506 is performed using triphosgene in anhydrous tetrahydrofuran solution at room temperature (Scheme 86) <2005JME2936>. 

Nitrophenyl)hydrazides (468) give 1,2-dihydro-1,2,4-benzotriazines (469) with sodium amalgam in ethanol. In most cases the initial dihydro compounds (469) are oxidized by potassium ferricyanide to the aromatic 1,2,4-benzotriazines (470) (78HC(33)189). Similarly, reduction of the nitrohydrazones (471) affords 1,2,4-benzotriazines (470) (78HC(33)189, p. 666). 

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). 

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). 

Under hypoxic conditions, cellular enzymes reduce the benzotriazine di-N-oxide [(reaction (68) P450 reductase Cahill and White 1990 and NADPH may be involved Walton et al. 1992 Wang et al. 1993]. Upon microsomal reduction of tirapazamine the radical formed in reaction (68) has been identified by EPR (Lloyd et al. 1991). Using the pulse radiolysis technique, it has been shown that this radical has a pKd of 6 (Laderoute et al. 1988), and it is the protonated form that undergoes the DNA damaging reaction (Wardman et al. 2003). The rate constants of the bimolecular decay of the radical [reaction (70)] has been found to be 2.7 x 107 dm3 mol-1 s 1. The reaction with its anion is somewhat faster (8.0 x 108 dm3 mol-1 s 1), while the deprotonated radicals do not react with one another at an appreciable rate. From another set of pulse radiolysis data, a first-order process has been extracted (k = 112 s 1) that has been attributed to the water elimination reaction (72), and the tirapazamine action on DNA [reaction (74)] has been considered to be due to the resulting radical (Anderson et al. 2003). 

Walton Ml, Wolf CR, Workman P (1992) The role of cytochrome P450 and cytochrome P450 reductase in the reductive bioactivation of the novel benzotriazine di-N-oxide hypoxid cytotoxin 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233, WIN 59075) by mouse liver. Biochim Pharmacol 44 251-259... 

On the basis of both structural correlation between benzotriazine and Qx nucleus and mode of action reported for QDO, Monge et al. described at a first time 3-amino-2-cyano-substituted QDO as selective hypoxic cy-totoxins, bioreductive compounds, i.e., compounds 38-41 (Table 6) [27]. In this first approach, the best compounds were the 7-electron-withdrawing substituted derivatives. Electrochemical properties, assessed via voltammet-ric studies, showed that as the electron-withdrawing nature of the 6-(7)-substituent increases, the reduction potential becomes more positive. Compounds with reduction potential more positive are more hypoxia-cytotoxic. However, due to the poor solubility in water of these derivatives, a new generation of compounds was designed and synthesized, i.e., compounds 42-45 (Table 6) [28]. In this second generation of compounds it is possible to highlight derivatives 42 and 45 (Table 6) with excellent hypoxic potency... 

A somewhat similar result97 is obtained in the reduction of 4-methyl-l,2,3-benzotriazine-3-oxide (94) to 3-methylindazole (95) and hy-droxylamine by a four-electron reduction. At pH 4 94 gives two four-electron waves the second wave is probably caused by the reduction of the intermediate oxime (96). Both waves disappear during the electrolysis at the potential of the first wave (Scheme 11). 

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