Formation of N-Oxides

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 two nitrogens in the pyrimidine structure are also likely candidates for enzymatic oxygenation. Indeed, the antibacterial agent 2,4-diamino-5-(3,4,5-trimethoxybenzyl) 

The relative contribution, in intact microsomal preparations, of the two monooxygenases to the formation of N-oxygenated C=N functionalities has been frequently assessed by measurements in the presence and absence of selective enzyme inhibitors or positive effectors. These observations were supplemented by studies using highly purified native or recombinant proteins in reconstituted systems. 

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N-Quaternization and the formation of N-oxides of alkaloids cause strong paramagnetic deshielding effects for the carbon atoms neighboring the nitrogen atom however the carbons located at /(-position usually become more shielded [600, 606, 634, 643],... 

Figure 34 Oxidative reactions of amines. Formation of N-oxides from oxidation of tertiary amines and formation of hydroxylamines from oxidation of primary and secondary amines.

The enzymes reductively activate dioxygen using NADPH as an electron source. One oxygen atom is then reduced to water and the other atom is transferred to a substrate, resulting in the hydroxylation of alkenes and arenes, the epoxidation of alkenes and the formation of N-oxides and S-oxides from amino and sulphur compounds. Other P-450 reactions include N-dealkylation, O-dealkylation and reductase-like dehalogenation of halocarbons. Typical P-450 reactions are summarised in Ihble 5-4. 

A good account of the earlier work on this series of compounds has been given by Bambas.1 In more recent work, attention has been directed toward three main aspects—electrophilic substitution, reactions and rearrangements of 3-amino derivatives and related compounds, and formation of N-oxides and sulfoxides. 

Fig. 6. Electrospray mass spectrum of an acetonitrile solution of [(salen)Mn]C104,p-CN-iV,iV-dimethylaniline N-oxide, and iodosobenzene, showing the formation of N-oxide ligated man-ganese(III) and oxomanganese species...

Fig. 20. Formation of N-oxide 38 by photolysis of (C59N)2 in the presence of traces of oxygen...

In continuation of their stereochemical studies of sparteine N-oxides cf. Vol. 6, p. 91), Wiewiorowski and co-workers prepared 2-phenylsparteine N-16-oxide and its perchlorate salt (6) X-ray analysis of the salt shows that there is a strong hydrogen bond between the N-16 oxygen function and the N-1 proton/ Almost exclusive formation of the N-16-oxide in the reaction of 2-phenylsparteine with hydrogen peroxide is attributed to a greater accessibility of the N-16 atom to the reagent, although this site is protonated preferentially (Scheme 1). Previous views on the formation of N-oxides of sparteine and its derivatives have thus been revised protonation affects the rate of reaction, but does not influence the site at which oxidation occurs. 

SO -HgOg added to a soln. of 2-phenyl-4-chloro-6-methylpyrimidine in acetic acid, and heated 6 hrs. at 70-80 on a water bath -> 2-phenyl-5-chloro-6-methyl-4-pyrimidone. Y 73%. - The expected formation of N-oxides did not occur. F. e. s. T. Kato, H. Yamanaka, and H. Hiranuma, Chem. Pharm. Bull. 16, 1337 (1968). 

The formation of N-oxides of tertiary amines and demethylation of secondary amines are biochemical processes which may also be involved in detoxification. In the case of A, iV-dimethylaniline, the N-oxide is considered to be the possible intermediate in its NADPH- and oxygen-dependent oxidative demethylation. The formation of this A -oxide appears to be catalyzed via a flavoprotein oxidase (509). Tertiary amine A -oxides, thus formed, are often excreted in urine. In the case of A -methyl-4-aminoazobenzene (MAB), demethylation to 4-aminoazoben-zene (AB) appears to occur via a cytochrome P-450 mediated oxidation. Since an A -methyl substituent is regarded as essential for carcinogenic activity among derivatives of AB, this oxidative demethylation would be a specific mode of detoxifying this carcinogenic aromatic amine. 

The carboxylic acids precipitate out of the reaction mixture and can be isolated by filtration. Even the hetroaromatic aldehydes like formyl pyridines, formyl quinolines and formylazaindoles can be oxidised by the above procedure to the corresponding carboxylic acids in this procedure, the formation of N-oxides is avoided. 

The oxidation of aldehydes to the corresponding carboxylic acids has been widely investigated and numerous procedures are known in aqueous and organic media [33]. Aromatic aldehydes have recently been oxidized at 0-4°C in aqueous performic acid produced by the addition of H2O2 to formic acid [34]. Generally, the carboxylic acid precipitates out of the reaction mixture and can be isolated simply by filtration. When heteroaromatic aldehydes such as formylpyridines, formylquinolines and formylazaindoles are oxidized, the formation of N-oxides is avoided. The use of cosolvents (tetrahydrofuran (THE), Af,A-dimethylformamide (DMF)) gives less satisfactory results. 

In the presence of NADPH and oxygen, hepatic microsomal enzymes convert the following substrates to the corresponding N-oxides chlorpromazine, chlor-qrclizine. imipramine. nicotinamide, guanethidine, and trimethylamine. Based on limited data, it was sug sted that the formation of N-oxides might be an intermediate step in all microsomal N-dealkylations. It is now clear that although N-oxides are formed by liver microsomes, they are not obligatory intermediates in all N-dealky-lation reactions. 

Direct formation of N-oxides of amino-aza-heterocycles can be troublesome. Welcome, therefore, is a report that m-chloroperbenzoic acid in acetone can be used as oxidizing agent without the need to protect the amino-function. " 2-Aminopyridine AT-oxide (71%), 2-aminopyrimidine N-oxide (68%), and 1-aminoisoquinoline A"-oxide (66%) are amongst the examples cited. An alternative method of synthesizing O-aryl-oxypyridinium salts has been proposed " and is illustrated in Scheme 12. The unsymmetrical diaryliodonium tetrafluoro-borate (56) suffers preferential attack at the electron-poor aryl ring, and the yields of W-aryloxy-pyridinium (57) are good when X = N02-... 

The tertiary amine groups are often metabolised by demetbylation, which leads to the formation of secondary amines which often possess antidepressant properties. As a rule of thumb, secondary amines appear to show higher selectivity for NAT whereas their parent, tertiary counterparts tend to be either less selective (mixed SERT/NAT) or display a somewhat higher selectivity for SERT. The other major transformations are based on hydroxylation followed by glucuronidation and, in some cases, formation of N-oxides. 

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