7- Hydroxy-2-naphthylamine

The best source of information on preparative aspects of coupling reactions is still the book of Fierz and Blangey (1952). Four examples of coupling reactions can be found in Organic Syntheses (Conant et al., 1941, and Fieser, 1943 Azo coupling with 1- and 2-naphthol Hartwell and Fieser, 1943 8-Hydroxy-l-naphthylamine-2,4-di-sulfonic acid Clarke and Kirner, 1941 A/,7V-Dimethylaniline). 

The role of N-sulfonyloxy arylamines as ultimate carcinogens appears to be limited. For N-hydroxy-2-naphthylamine, conversion by rat hepatic sulfotransferase to a N-sulfonyloxy metabolite results primarily in decomposition to 2-amino-l-naphthol and 1-sulfonyloxy-2-naphthylamine which are also major urinary metabolites and reaction with added nucleophiles is very low, which suggests an overall detoxification process (9,17). However, for 4-aminoazobenzene and N-hydroxy-AAF, which are potent hepatocarcinogens in the newborn mouse, evidence has been presented that strongly implicates their N-sulfonyloxy arylamine esters as ultimate hepatocarcinogens in this species (10,104). This includes the inhibition of arylamine-DNA adduct formation and tumorigenesis by the sulfotransferase inhibitor pentachlorophenol, the reduced tumor incidence in brachymorphic mice that are deficient in PAPS biosynthesis (10,115), and the relatively low O-acetyltransferase activity of mouse liver for N-hydroxy-4-aminoazobenzene and N-OH-AF (7,114,115). 

The exceptional reactivity of DNA for protonated N-hydroxy arylamines can be rationalized by at least two mechanisms. First, intercalation of the electrophilic intermediate between DNA bases could sterically assist in desolvation and in directing the electrophilic center of the carcinogen over the nucleophilic region of the DNA base. This seems unlikely, however, as pretreatment of DNA with cis-Pt, which decreased the DNA contour length by 50%, failed to reduce the reactivity of N-hydroxy-1-naphthylamine for the DNA (137). A second possibility involves an electrostatic attraction between the electrophile and the phosphate backbone of the DNA (77). This seems more probable since eithe j +high ionic strength or stoichiometric (to DNA-P) amounts of Mg strongly inhibit DNA adduct formation (77,137). In addition, evidence has been presented that N-hydroxy arylamine-DNA/RNA phosphotriesters may be formed which induce strand breaks (137,138) and could serve as a catalyst for desolvation and subsequent adduct formation. 

This reaction [65-67] is only rarely encountered in the benzene series but is extremely useful for appropriate derivatives of naphthalene, where the mechanism of the reaction has been investigated extensively. The reaction allows a hydroxy group to be exchanged for an amino group or vice versa. When a hydroxy group is to be converted into an amino group, the naphthol is heated under pressure with ammonium bisulphite (often produced in situ by introduction of ammonia liquor and sulphur dioxide into a sealed autoclave) at a temperature of 100-150 °C the naphthol is thereby converted into the corresponding naphthylamine. The mechanism of the reaction is outlined in Scheme 4.22. 

In the above reaction mechanisms it is noteworthy that the sulphonic acid group introduced has been shown to enter at the 3-position and not the 4-position as previously postulated. A consequence of this situation is that an attempted Bucherer reaction on a naphthol (or a naphthylamine) carrying a sulphonic acid group located meta to the hydroxy (or amino) group would require a second sulphonic acid group to be introduced at this position. Since it is impossible to locate two sulphonic acid groups on the same carbon atom, these compounds cannot undergo the transformation. 

After sulphonation to 2-naphthylamine-l,5,7-trisulphonic acid, the labile 1-sulphonic acid substituent, which has now served its purpose, is eliminated by diluting the sulphonation mixture and heating. Fusion of the resulting disulphonic acid (4.42) with sodium hydroxide replaces the more labile 5-sulphonic acid group by a hydroxy group, forming ] acid. 

What about jr-electron donor substituents on nitrosoarenes other than dimethylamino Pedley gives us the enthalpies of formation for three hydroxy derivatives the isomeric 4-nitroso-l-naphthol, 2-nitroso-l-naphthol and l-nitroso-2-naphthol, species 45-47 respectively. Of the three species, only the first cannot have an intramolecular hydrogen bond. By analogy to nitrophenols75 — there being no thermochemical data for the more related and hence relevant nitronaphthols—we expect that species 46 would be less stable than 45. After all, gaseous 2-nitrophenol is ca 20 kJ mol 1 less stable than its 4-isomer. We recall from the discussion of the isomeric naphthylamines that 1- and 2-naphthol are of almost identical stability. This suggests that species 46 and 47 should be of comparable stability. Both expectations are sorely violated by the literature results the enthalpies of formation of species 45, 46 and 47 increase in the order —20.3 4.9, —5.4 6.2 and 36.1 4.7 kJmol-1 respectively. If there is experimental error, where does the error lie ... 

Thus, sulfate conjugation and acetylation may be involved in the metabolic activation of N-hydroxy aromatic amines, glutathione conjugation may be important in the nephrotoxicity of compounds, methylation in metal toxicity, glucuronidation in the carcinogenicity of p-naphthylamine and 3, 2 -dimethyl-4-aminobiphenyl. 

Other 7- substituents that have been introduced include the dialkylamino, acetamido, hydroxy, alkoxy and alkylthio groups (B-71MI11209). Acylation of the 7-amino group by heterocycles such as cyanuric chloride and its derivatives was inevitable, as was incorporation of a 7-triazole substitution pattern by diazotization of the 7-amino group and o-coupling with 2-naphthylamine followed by triazolization (94). 

Known compounds in this class include mainly 1,3-oxazine, 1,3-thiazine, 1,3-diazine (perimidine), and to a lesser extent 1,3-dithiine and 1,3-dioxine peri-annelated derivatives. The general strategy for constructing such systems is based on heterocyclization of 8-hydroxy-, 8-mercapto-, or 8-amino-substituted 1-naphthylamines 426 (X = NR)... 

The interaction between ammonia and l-R1-3-aryl-substituted ben-zo[c]pyrylium salts 30, as well as 3,4-diaryl-substituted indeno[e l,2-]-benzo[c]pyrylium, and other substituted cations having a similar fragment is more complicated, especially in hydroxyl-containing solvents. In these cases, mixtures in different ratios are obtained that contain isoquinolines 138, 3-hydroxy-3,4-dihydroisoquinolines 137, OR-adducts 109, anhydro-bases 119, diketones 29, a-naphthylamines 140, and a-naphthols 141 (88UP2). 

Evidently, the stability of 3-hydroxy-3,4-dihydroisoquinolines 137, formed as the result of heterocyclization, is also determined by the anne-lated benzenoid ring. The lower tendency toward aromatization for these compounds, compared to monocyclic analogs, leads to the ability of 137 to react as a cyclic azomethine. The addition of a molecule of nucleophile to the C=N bond causes opening of the isoquinoline ring and formation of a new ring system (for instance, a-naphthols 141 in alkaline aqueous solutions). Such conversions occur even under conditions of the recyclization reaction of 2-benzopyrylium salts, namely, on heating 137 in alcoholic ammonia a mixture of isoquinoline 138 and a-naphthylamine 140 results (88MI1). 

In the Bechamp reaction, para orientation predominates, although small amounts of ortho isomers are formed, together with some arsinic acids (e.g., 4,4,-diaminodiphenylarsinic acid from aniline) none of the meta isomer results. If the para position is blocked, the reaction usually yields the ortho isomer in a low yield however, in the case of p-hydroxy-benzenesulfonic acid no reaction occurs.76 As might be expected, ortho 4 substitution prevails when a-naphthylamine is employed as the starting material.58... 

A route involving 1,4-dihydroxybenzene intermediates has been suggested for the oxidation of several naphthols and naphthylamines, and also hydroxy- and amino-quinolines and isoquinolines. 

Sulfotransferases (SULTs) are cytosolic phase II detoxification enzymes involved in sulfonation of various xenobiotics and endobiotics. There are also membrane-bound SULTs that are not involved in phase II metabolism but are involved in the sulfonation of proteins and polysaccharides. Substrates of cytosolic SULTs include alcohols (ethanol, 2-butanol, cholesterol, bile acids), phenols (phenol, naphthol, acetaminophen), aromatic amines and hydroxyamines (2-naphthylamine, A-hydroxy 2-naphthylamine). SULTs transfer sulfonate (S03) to a hydroxy or amino group of a substrates from the cofactor 3 -phosphoadenosine-5 -phosphosulfate (PAPS), generating highly water-soluble metabolites for elimination through the kidney and liver. 

K5. Kaneko, M., and Leadon, S. A., Production of thymine glycols in DNA by N-hydroxy-2-naphthylamine as detected by monoclonal antibody. Cancer Res. 46, 71-75 (1986). 

Groups of Class 1, when present in the 2 position, direct partly to the 1 position (in direct relation to the strength of their orienting influence), and partly to positions in the other ring, especially the 8 position, then the 6 position. Sulfonation of j3-naphthylamine gives a mixture of all four heteronuclear monosulfonic acids. The 3 position is seldom entered, and then only if the other ring bears at least one substituent. The reaction of carbon dioxide with sodium j3-naphtholate is an exception to this rule. In this case 2-hydroxy-l-naphthoic acid is formed at lower temperatures, but at higher temperatures the product is 2-hydroxy-3-naphthoic acid. 

The nitro substitution products of naphthalene are easily prepared by the action of nitric acid on the hydrocarbon. By such direct nitration the product obtained is alpha-nitro naphthalene. This is proven by the following series of reactions. Nitro-naphfhalene by reduction yields amino naphthalene, naphthylamine, which by the diazo reaction yields hydroxy naphthalene, naphthol. Now the naphthol so obtained is identical with the one resulting from the phenyl vinyl acetic acid synthesis (p. 768) and this must be the alpha compound. 

The mechanism of chronic toxicity is related, but not identical. 2NA and other aromatic amines including benzidine and 4-aminobiphenyl are potent human urinary bladder carcinogens. Apparently the AT-hydroxy-2-naphthylamine is N-glucuronide and the product is transported from the liver to the urinary bladder, where the glucuronide can be hydrolyzed liberating N-hydroxy aromatic amine. This material is... 

I joined the Miller laboratory in September, 1952, and my first project was to synthesize 1-hydroxy-2-aminonaphthalene, a suspected carcinogenic metabolite of /3-naphthylamine (a bladder carcinogen). After many attempts to synthesize... 

BON maroon. A calcium or manganese precipitated compoundof 3-hydroxy-2-naphthoic acid and 2-naphthylamine-l-sulfonic acid. 

Grech and coworkers studied 8-hydroxy-A,A-dimethyl-l-naphthylamine and suggested that the high frequency shift in dioxane compared to cyclohexane was due to formation of a bifurcated bond. This is somewhat unexpected. See also how multiple hydrogen bonding may affect equilibria (Section U.K). 

The amino group of naphthylamines can be replaced by a hydroxy group by treatment with aqueous bisulphite. The scope of the reaction is very limited. With very few exceptions, the amino group (NH2 or NHR) must be on naphthalene or phenanthrene rings. The reaction is reversible and both the forward and reverse reactions are called the Bucherer reaction. 

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