Oxidative arylamines

Some reagents are milder and less powerful oxidants and have been used to oxidize arylamines to the corresponding nitroso compounds. These include 30 % hydrogen peroxide in acetic acid, ° aqueous solutions of potassium permanganate, and alkaline hypochlorite amongst others. The hypochlorite oxidation of arylamines containing o-nitro substiffients is reported to yield benzofuroxans. For a discussion of the synthesis of aromatic nitroso compounds the readers are directed to a review by Boyer. ... 

Palladium(II) salts apparently oxidize arylamines to arylpalladium salts since alkenes are arylated by reaction with only an aromatic amine and a palladium salt. However, yields are generally low.100 Much better yields are obtained if /-butyl nitrite is added and, of course, this forms the diazonium salt in situ. This not only saves a step but some diazonium salts which are too unstable to be isolated may be used as well. The reactions are carried out in the presence of acetic or chloroacetic acid with 5-10% bis(di-benzylideneacetone)palladium as catalyst (equation 41).101... 

Azoxy compounds can also be obtained by oxidizing arylamines with peroxy compounds. Aniline is oxidized to azoxybenzene by hydrogen peroxide in acetonitrile-methanol at 50°, the yield being 62% 373 and 3,3 -dinitroazoxybenzene is obtained in 79% yield from m-nitroaniline and per-oxyacetic acid in glacial acetic acid.318... 

Only a few intermolecular oxidative arylamination reactions in the heterocyclic series have so far been reported. 5-AzacinnoUne, 1,2,4-triazines, 3-nitropyridines, and heterocyclic quinones are among those compounds which react with anilines or hetarylamines in the presence of a strong base. In fact, in order to perform these reactions metal salts of arylamides are needed as nucleophiles. For instance, interaction of 5-azacinnoline with arylamines in the presence of potassium hydroxide demands 20 days to complete the process with crucial access to air oxygen (Scheme 36) [89]. 

Direct nitration of aniline and other arylamines fails because oxidation leads to the formation of dark colored tars As a solution to this problem it is standaid practice to first protect the ammo group by acylation with either acetyl chloride or acetic anhydride... 

In the ketone method, the central carbon atom is derived from phosgene (qv). A diarylketone is prepared from phosgene and a tertiary arylamine and then condenses with another mole of a tertiary arylamine (same or different) in the presence of phosphoms oxychloride or zinc chloride. The dye is produced directly without an oxidation step. Thus, ethyl violet [2390-59-2] Cl Basic Violet 4 (15), is prepared from 4,4 -bis(diethylamino)benzophenone with diethylaruline in the presence of phosphoms oxychloride. This reaction is very useful for the preparation of unsymmetrical dyes. Condensation of 4,4 -bis(dimethylamino)benzophenone [90-94-8] (Michler s ketone) with AJ-phenjl-l-naphthylamine gives the Victoria Blue B [2580-56-5] Cl Basic Blue 26, which is used for coloring paper and producing ballpoint pen pastes and inks. 

Diphenylmethane Base Method. In this method, the central carbon atom is derived from formaldehyde, which condenses with two moles of an arylamine to give a substituted diphenylmethane derivative. The methane base is oxidized with lead dioxide or manganese dioxide to the benzhydrol derivative. The reactive hydrols condense fairly easily with arylamines, sulfonated arylamines, and sulfonated naphthalenes. The resulting leuco base is oxidized in the presence of acid (Fig. 4). 

In a variation of this method, isolation of the ben2hydrol derivative is not required. The methane base undergoes oxidative condensation in the presence of acid with the same or a different arylamine direcdy to the dye. New fuchsine [3248-91 -7] Cl Basic Violet 2 (16), is prepared by condensation of two moles of o-toluidine with formaldehyde in nitrobenzene in the presence of iron salts to give the corresponding substituted diphenylmethane base. This base is also not isolated, but undergoes an oxidative condensation with another mole of o-toluidine to produce the dye. 

Kinetic mles of oxidation of MDASA and TPASA by periodate ions in the weak-acidic medium at the presence of mthenium (VI), iridium (IV), rhodium (III) and their mixtures are investigated by spectrophotometric method. The influence of high temperature treatment with mineral acids of catalysts, concentration of reactants, interfering ions, temperature and ionic strength of solutions on the rate of reactions was investigated. Optimal conditions of indicator reactions, rate constants and energy of activation for arylamine oxidation reactions at the presence of individual catalysts are determined. 

The synthesis can be conducted both in solution and without solvents. The reaction in solvent (e.g., methanol, ethanol, dioxane, dimethylformamide) is recommended for volatile 1,3-diynes and amines in this case the pyrroles are purer and the yield is higher. With disubstituted diacetylenes, ammonia and primary alkyl- and arylamines produce 1,2,3-trisubstituted pyrroles under the same conditions (65CB98 71MI1). Since disubstituted diacetylenes are readily obtained by oxidative coupling of acetylenes (98MI2), this reaction provides a preparative route to a wide range of pyrroles. 

Lee J, M Simurdiak, H Zhao (2005) Reconstitution and characterization of aminopyrrolnitrin oxygenase, a Rieske iV-oxygenase that catalyzes unusual arylamine oxidation. J Biol Chem 280 36719-36727. 

Tricarbonyl(cyclohexadienyl)iron cations react with a variety of nucleophiles to give substituted tricarbonyl(cyclohexadienyl)iron complexes88 with arylamines, N- or C-alkylation can occur depending on the nature of aryl ring substituents. Deligation of C-alkylated arylamines can be achieved by either ferric chloride, which gives the free arylamine, or by iodine in the latter case, cyclization with concomitant oxidation occurs, and carbazoles are produced in moderate yield (Scheme 52).89... 

The Clauson-Kaas pyrrole synthesis was adapted to a soluble polyglycerol (PG) support <060L403>. Electrochemical oxidation of furan 33 in the presence of methanol followed by hydrogenation gave 2,5-dimethoxytetrahydrofuran 34. Cyclocondensation with primary arylamines gave A-arylpyrroles 35. Removal from the PG support was then accomplished by treatment of 35 with LiOH which gave 2-pyrrolepropanoic acids 36. 

N-Hydroxy arylamines readily form glucuronide conjugates, but in contrast to the N-hydroxy arylamides, these are N-glucuronides which are unreactive and stable at neutral pH. The N-glucuronides are readily transported to the lumens of the urinary bladder and intestine where they can be hydrolyzed to the free N-hydroxy arylamines by mildly acidic urine or by intestinal bacterial 3-glucuronidases (13,14). Non-enzymatic activation of N-hydroxy arylamines can occur in an acidic environment by protonation (15,16) of the N-hydroxy group (VIII) as well as by air oxidation (reviewed in 17) to a nitrosoarene (IX). 

Alternative metabolic pathways involve ring-oxidation and peroxidation of arylamines. Although ring-oxidation is generally considered a detoxification reaction, an electrophilic iminoquinone (X) can be formed by a secondary oxidation of the aminophenol metabolite (18,19). Lastly, reactive imines (XI) can be formed from the primary arylamines by peroxidase-catalyzed reactions that involve free radical intermediates (reviewed in 20). 

Only a limited number of activation pathways appear to be available to N-methyl arylamines. Following enzymatic N-hydroxyla-tion to secondary N-hydroxy arylamines (21,22), these compounds are converted into reactive electrophiles through enzymatic esterification (9) to N-sulfonyloxy-N-methyl arylamines (XII) or by further oxidation to N-arylnitrones (XIII). 

The formation of 0-seryl or 0-prolyl esters (Figure 1) of certain N-hydroxy arylamines has been inferred from the observations that highly reactive intermediates can be generated in vitro by incubation with ATP, serine or proline, and the corresponding aminoacyl tRNA synthetases (11,12,119). For example, activation of N-hydroxy-4-aminoquinoline-l-oxide (119,120), N-hydroxy-4-aminoazobenzene (11) and N-hydroxy-Trp-P-2 (121) to nucleic acid-bound products was demonstrated using seryl-tRNA synthetase from yeast or rat ascites hepatoma cells. More recently, hepatic cytosolic prolyl-, but not seryl-, tRNA synthetase was shown to activate N-hydroxy-Trp-P-2 (12) however, no activation was detectable for the N-hydroxy metabolites of AF, 3,2 -dimethyl-4-aminobiphenyl, or N -acetylbenzidine (122). 

The identification of C8-guanyl and N6-adenyl adducts of 4-aminoquinoline-l-oxide (102,103) in DNA modified by the metaboli-cally-generated 0-seryl ester and the similarity of the adduct profile with that obtained on reaction of DNA with N-acetoxy-4-araino-quinoline-l-oxide suggest an electrophilic reaction mechanism similar to that for the N-acetoxy or N-sulfonyloxy arylamines (Figures 4 and 5). However, N-seryloxy or N-prolyloxy arylamines have not been synthesized and the decomposition products of the esters generated in vitro have not yet been studied. 

Nitrosoarenes are readily formed by the oxidation of primary N-hydroxy arylamines and several mechanisms appear to be involved. These include 1) the metal-catalyzed oxidation/reduction to nitrosoarenes, azoxyarenes and arylamines (144) 2) the 02-dependent, metal-catalyzed oxidation to nitrosoarenes (145) 3) the 02-dependent, hemoglobin-mediated co-oxidation to nitrosoarenes and methe-moglobin (146) and 4) the 0 2-dependent conversion of N-hydroxy arylamines to nitrosoarenes, nitrosophenols and nitroarenes (147,148). Each of these processes can involve intermediate nitroxide radicals, superoxide anion radicals, hydrogen peroxide and hydroxyl radicals, all of which have been observed in model systems (149,151). Although these radicals are electrophilic and have been suggested to result in DNA damage (151,152), a causal relationship has not yet been established. Nitrosoarenes, on the other hand, are readily formed in in vitro metabolic incubations (2,153) and have been shown to react covalently with lipids (154), proteins (28,155) and GSH (17,156-159). Nitrosoarenes are also readily reduced to N-hydroxy arylamines by ascorbic acid (17,160) and by reduced pyridine nucleotides (9,161). 

Although several N-methyl-substituted arylamines have been shown to be carcinogenic (184-186), metabolic activation pathways have been investigated primarily for the hepatocarcinogenic aminoazo dyes, N-methyl-4-aminoazobenzene (MAB) and its 3 -methyl derivative (9,21, 22,187,188). N-Hydroxy-N-methyl arylamines are generally regarded as proximate carcinogenic metabolites (22,187,189) and have been shown to be converted to electrophilic N-sulfonyloxy derivatives by hepatic sulfotransferases (9,187) or to reactive N-arylnitrones by air oxidation (21). 

N-sulfonyloxy arylamines (vide supra) and is supported by mechanistic studies using the analogous N-sulfonyloxy esters of purine N-oxides (201,202). 

N-AryInitrones (XIII) formed by oxidation of N-hydroxy-N-methyl arylamines, show high reactivity toward carbon-carbon and carbon-nitrogen double bonds in non-aqueous media (21,203) (Figure 10). Under physiological conditions, however, it appears that N-arylnitrones exist as protonated salts that readily hydrolyze to formaldehyde and a primary N-hydroxy arylamine and efforts to detect N-arylnitrone addition products in cellular lipid, protein or nucleic acids have not been successful (204). Nitroxide radicals derived from N-hydroxy-MAB have also been suggested as reactive intermediates (150), but their direct covalent reaction with nucleic acids has been excluded (21). 

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