Quinoline ring oxidation

Ni et al. [143] investigated the profile of the major metabolites of primaquine produced by in vitro liver microsomal metabolism, with silica gel thin-layer and high performance liquid chromatography analysis. Results indicated that the liver microsomal metabolism could simultaneously produce both 5-hydroxyprimaquine (quinoline ring oxidation product) and carboxyprimaquine (side-chain oxidative deamination product). However, the quantitative comparative study of microsomal metabolism showed that the production of 5-hydroxyprimaquine was far much higher than that of carboxyprimaquine. 

The photochemical ring enlargement of quinoline 1-oxides provides 3,1-benzoxazepines 1 (see Houben-Weyl, Vol.4/5b, p 12971T).24... 

Quinoline N-oxide is brominated in the 3- and 6-positions on treatment with bromine in acetic anhydride, the mechanism probably involving an addition process in the hetero ring (65YZ62). 

The photolysis of quinoline AT-oxides in protic media mainly leads to carbostyrils (Scheme 120) (63ACS1461) while in aprotic media ring expansion and contraction products are obtained (69ACS2149, 71TL1311). Isoquinoline TV-oxides behave similarly (Scheme 120)... 

Methoxy-8-hydroxylaminoquinoline, an N-hydroxylated metabolite of primaquine (Fig. 7.46), is directly toxic, causing hemolysis and methemoglobinemia in rats. However, there are several pathways of metabolism for primaquine and several potential toxic metabolites. Thus, hydroxylation of primaquine at the 5-position of the quinoline ring also forms redox-active derivatives able to cause oxidative stress within normal and G6PD-deficient human red cells as well as rat erythrocytes (Fig. 7.46). 

The intramolecular cyclization of a nitro group with a triple bond has been extended to the synthesis of six- and seven-membered ring compounds analogous to isatogens. Thus, the reaction of the acetylene group with the nitro group in 39 yields 2-phenyl-3-oxobenzo[prepared from the corresponding biphenyl derivative.19... 

In other compounds, reaction can occur in both rings. Under such circumstances the orientation can depend on the conditions frequently reaction in the benzene ring involves the cationic species, whereas that in the pyridine ring involves the free base. Thus, the temperature dependent nitration of quinoline 1-oxide (578) reflects the decrease in intrinsic acidity as the temperature rises, which in turn increases the available amount of free base species. 

Quinoline 1-oxides can be rearranged photochemically into indoles (103 — 104 — 105) or N-hydroxyindoles (106 — 107). Cinnolines are reductively ring-contracted into indoles (Section 3.2.1.6.9.ii). 

Table 6 Indoles by Photochemical Ring Contraction of Quinoline N-Oxides...

AT-Benzoyl-2-hydroxy-2,3-dihydroindoles (192) are additional products resulting from the photolysis of 2-phenylquinoline 1-oxide (193) and its derivatives in ethanol solution.162 These dihydroindoles are also formed by the solvolysis of the corresponding benz[d]-l,3-oxazepines (194) with aqueous ethanol at room temperature, and are therefore interpreted as arising in this way in the photolysis. Quinoline 1-oxide itself undergoes ring contraction166 to IV-formyl-2-hydroxy-2,3-dihydroindole on irradiation in a protonic solvent. 

Small amounts of the benzopyridines quinoline and isoquinoline are excreted as their N-oxides (41) by guinea-pigs and are also formed by guinea-pig and rabbit hepatic microsomes15,28. Moreover, the antimalarial agent chloroquine affords an N-oxide as a metabolite of the quinoline ring system104. 

The decreasing reactivity of the most familiar aromatic heterocyclic compounds with nucleophilic reagents may be illustrated by the following sequence quinoxaline > acridine > phenanthridine > isoquinoline > quinoline > pyridine. Acridine is alkylated in the 4-position, phenanthridine and quinoxaline in the a-position, isoquinoline in the 1-position, and quinoline and pyridine in the 2- or 4-positions. Weaker nucleophilic reagents seem to enter the 4-position of the pyridine and quinoline rings. If the addition occurs readily and in good yield, the intermediate dihydro derivative may sometimes be isolated otherwise, the product of the subsequent oxidation results. In synthetic work the dihydro derivative is usually directly oxidized. 

In the oxidative amination of quinoline, using potassium amide in liquid ammonia and permanganate as oxidant, it was found that the site of ami-nation is strongly depending on temperature. When the amination is carried out at — 65 °C 2-aminoquinoline is isolated (52%) 4-aminoquinoline is formed (with some 2-aminoquinoline) when the amination is performed at room temperature. By NMR spectroscopy it was unequivocally observed that at — 65 °C addition of the amide ion occurs at position 2 of the quinoline ring, yielding the a-adduct 2-amino-1,2-dihydroquinolinide, which under the conditions of the reaction remained stable. When warming up the solution this C-2 adduct irreversibly converts into the... 

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