Mono N-oxides

Cerium(IV) ammonium nitrate in methanol has been used to oxidize phenazine to the mono-N-oxide (41) in good yield (75JCS(P1)1398), but no other reports on the application of this reagent to the pyrazine or quinoxaline series have appeared. 

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). 

Quinoxaline mono-N-oxides are also available by a direct synthesis from n-nitroaniline derivatives. Condensation of acetyl chloride derivatives with o-nitroaniline followed by treatment with sodium ethoxide in ethanol yields the mono-N-oxides in good yields (Scheme 20) (64JCS2666). 

Phenazine mono-N-oxides have also been prepared from nitrobenzene derivatives. Condensation of nitrobenzene with aniline using dry NaOH at 120-130 °C results in modest yields of phenazine 5-oxide, although the precise mechanism of this reaction is not well understood (57HC(ll)l) with unsymmetrical substrates it is not possible to predict which of the isomeric fV-oxides will be produced. Nitrosobenzene derivatives also function as a source of phenazine mono-fV-oxides thus, if 4-chloronitrosobenzene is treated with sulfuric acid in acetic acid at 20 °C the fV-oxide is formed (Scheme 21). 

Figure 7.3 Nakajima s chiral bipyridine N,N -dioxide 18 and the less effective mono-N-oxide derivatives 19 and 20.

Nakajima reported the use of a chiral bipyridine N,N -dioxide 18 in the desym-metrization of acyclic meso epoxides (Figure 7.3). Although the enantioselectivity was not as high as in the method developed by Fu for meso-stilbene oxide (90% ee vs. 94% ee), it was higher for the same aliphatic epoxide (74% ee vs. 50% ee) [57]. Nakajima showed that mono-N-oxide derivatives 19 and 20 were much less effective than 18 in tenns of both yield and enantioselectivity, and accordingly proposed a unique mechanism for 18 involving a hexacoordinate silicon intermediate coordinated to both N-oxides of the catalyst. 

N-Nitroamino)pyridine N-oxide, 1852 2,2 -bipyridyl 1-oxide, 3258 4-Nitropyridine /V-oxide, 1833 2,2/-Oxybis(iminomethylfuran) mono-N-oxide, 3260 Pyridine N-oxide, 1849... 

No UV data appear to have been reported for mono-N-oxides the N,N-dioxide 85 has a peak at 347 nm (log e 3.98). ... 

Qulnoxaline mono-N-oxIde, AL91 Quinoxaline 1-oxide, AL91... 

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... 

Alternatively, N-hyroxypyridine-2-thione, a versatile antibacterial and antifungal agent commercially available as Omadine, has been used. As expected, in the presence of DNA its photolysis causes SSBs (via OH), but after its photolytic consumption continuing photolysis at 350 nm caused the photooxidation of G in DNA and in dGuo (Adam et al. 1999). Apparently this effect is induced by one of its photolytic products that are largely the N,AT-dioxide, the mono-N-oxide, the disulfide and the sulfonic acid (Adam et al. 1999). 

Oxybis(iminomethylfuran) mono-N-oxide (Dehydrofurfural oxime)... 

Pyridazines are oxidized to mono-N-oxides by peroxydichloromaleic acid prepared in situ from 90% hydrogen peroxide and dichloromaleic anhydride (equation 507) [339]. 

Tirapazamine is inactivated by two-electron reduction steps catalyzed by quinone reductase, yielding first the mono-N-oxide (reaction a and compound 18). In contrast, it is activated to a cytotoxic nitroxide (16) by a one-electron reduction catalyzed by NADPH-cytochrome P450 reductase (reaction b). This delocalized radical loses one molecule of water to yield a reactive radical (reaction c and compound 17). Radical 17 can then abstract one hydrogen radical from DNA (reaction d and compound 18), leading to DNA breaks and cytotoxicity. In summary, both inactivation and activation involve reduction reactions, but cytotoxicity will depend on the relative levels of quinone reductase and CYP reductase in hypoxic cells. 

The two possible mono N-oxides of retamine, and the bis N-oxide, have been prepared by the perhydrol oxidation of retamine. In the mono iV-oxide-C (17) ring c is thought to have the boat conformation, and the molecule has a trans C-D ring-junction, since it exhibits Bohlmann bands in its i.r. spectrum. The bis A -oxide (18) also has a boat-shaped ring c and a trans c-d ring-junction, since it can be prepared by further oxidation of mono N-oxide-C. 

Quinoxaline di-iV-oxides without substituents in the pyrazine ring have been prepared by reaction of benzofuroxans with synthons of the type RCH==CHX, where R = COMe or 4-substituted benzoyl and X = ONa, or where R = H and X = NR2 or OAc. - Two cases are known of mono-N-oxide rather than di-N-oxide formation using benzofuroxan. Thus reaction with benzofuran-3(2H)ones gives 3-(o-hydroxyaryl)quinoxaline... 

---