Di-N-oxides

Many pyrazine and quinoxaline syntheses yield mono- or di-N-oxides (76H(4)769). The condensation of a-aminooximes with 1,2-diketones results in the direct formation of pyrazine mono-N-oxides. The a-aminooximes themselves are not easily prepared but 2-amino-2-deoxy sugars readily form the oximes, which have been condensed with glyoxal to yield the pyrazine 4-oxides (Scheme 18) (72JOC2635, 80JOC1693). 

The reaction of isobenzofuroxan (131) with the morpholine enamine of cyclohexanone results in a 1,4 cycloaddition to form quinoxaline-di-N-oxide 132 (777). Quinone dibenzenesulfonimide has been found to undergo... 

Nucleophilic chlorination of 1,5-naphthyridine mono- and di-N-oxides yields 2-chloro- and 2,6-dichloro-naphthyridines via electrophilic catalysis of the reaction of intermediates such as 430 with chloride ion. An interesting example of electrophilic catalysis is the... 

Reactions of 2-nitrosopyridine with nitrile oxides afford, depending on structure of the latter, either l,2,4-triazolo[l,5-a]pyridine 1,3-di-N-oxides (370) or the corresponding 1.2.4-triazolo, 5-a Ipyridine 3-oxides (371) (419). 

Dioximes are known to generate isoxazoles and related compounds when oxidized with IBTA. However, these reactions are of limited use because of formation of side products. For example, oxidation of dioximes of /B-diketones 159 gives rise to a mixture of 3,5-disubstituted oxazoles 160 and pyrazole-di-N-oxides 161 (82MI1). In another case, oxidation of dioximes 162 affords a mixture of the isomeric dihydroisoxazolo-isoxazoles 163 and pyridazine dioxides 164 (76S837 79JOC3524 82MI1). 

There are few examples of the preparations of heterocyclic compounds containing two or more heteroatoms which involve cyclization with formation of a bond between two heteroatoms. The best known instances of this type of reaction, all of which are [6 + 0] reactions, are the preparations of benzocinnolines as outlined in equations (l)-(4). A similar type of approach to that outlined in equation (4) has been used for the direct preparation of the di-N-oxide (2) from the dioxime (1 equation 5). The naphthotriazine betaine (4) is obtained as one of the products of the thermal decomposition of the azidoazo compound (3 equation 6). 1,2-Dithiins and their dibenzo derivatives have been prepared by oxidation of appropriate dithiols and related starting materials as outlined in equation (7). All of these reactions are, however, somewhat specialized and there has been essentially no systematic study of the preparation of six-membered heterocycles via formation of a bond between two heteroatoms. 

Use of Caro s acid does result in di-N-oxidation of 2,3-dichloropyrazine and 2,3-dichloroquinoxaline, but it is of interest to note that other heterocycles such as pyridine... 

Quinol inol-5-sulfoni c acid, A086 Quinone, AG08 Quinone oxime, AG49 Quinonimine, AG37 Quinoxaline, AL88 Quinoxaline di-N-oxide, AL94 Quinoxaline 1,4-dioxide, AL9 ... 

Oral administration of 42 to rats resulted in extensive reduction to trimethoprim106. The 1,4-di-N-oxide olaquindox (49), a substance used as a growth promotor in cattle breeding, pig husbandry and poultry farming, has been shown to be converted to a limited extent to the 4-mono-N-oxide in rats164, and compound 46 was readily reduced to N,N-diallylmelamine both in vivo and in vitro109. The anerobic reduction, in the presence of xanthine oxidase, of a series of purine N-oxides, such as adenine 1-N-oxide or guanine... 

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... 

The quinoxaline di-N-oxides, carbadox and olaquindox, are used as growth promoters in pigs. As both of these compounds are rapidly metabolised... 

Fig. 9 Chloroquine (I), desethyl-(II) and dides-ethylchloroquine (III). Side-chain N-oxide (IV), di-N-oxide (V), and 7-chloro-4-aminoquinoline (VI). IV and V, polar metabolites II and III, relatively nonpolar metabolites. (17).

Isobenzimidazoles and their mono and di-N-oxides show no tendency to react in a Diels-Alder fashion with tetracyanoethylene or a wide range of other dienophiles. However, with DMAD in cold benzene, the di-iV-oxide 421 gave a 1 2 adduct (422) whose structure was assigned on the basis of X-ray data.227... 

The only reported synthesis of this system is the synthesis of 3a,4,7,7a-tetrahydro-l,2-benzisoxazol-3-yl dimer by the reaction of 1,4-cyclohexadiene with cyanogen di-N-oxide (equation 64) (65LA(687)19l). 

Initial nucleophilic attack and ring opening are involved in the conversion of benzofuroxans into quinoxaline di-N-oxides by treatment with imines, enamines, carbonyl compounds, and active methylene compounds (the Beirut reaction, also see Section 3.4.1.10.1) a representative example is shown in Scheme 197 <2003EJM791, 2005H(65) 1589, CHEC-III(8.03.10)313>. 

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