Substituted 2-aminophenol

Recently, the substituent effect on the diazotization of substituted 2-aminophenols was studied53 in aqueous hydrochloric acid solution. When the substituent is strongly electron-withdrawing, such as a nitro group, the diazotized product deprotonates and forms a substituted 1,2-benzoquinone-l-diazide which usually precipitates. 

A 48-membered library of 2-arylbenzoxazoles has been prepared by the condensation of substituted 2-aminophenols with a series of acid chlorides. The reactions proceeded in the absence of a base in sealed tubes in an automated microwave instrument, which used sequential rather than parallel reaction processing. Comparisons to the conventional thermal conditions demonstrated the importance of the high temperatures and pressures achieved under microwave heating, which ensured that the reactions proceeded efficiently (Scheme 3.16)26. An analogous synthesis ofbenzoxazolesby the cyclocondensation reaction of 2-aminophenols with S-methylisothioamide hydroiodides on silica gel, under microwave irradiation, has also been reported (Scheme 3.16)27. 

A solution of dimethyl-2-oxoglutarate (2 10 mmol, 1.74 g) in 10 mL of dry methanol was added dropwise under stirring to a solution of the corresponding substituted 2-aminophenol (1 10 mmol) in 20 mL of dry methanol at room temperature (20"C). The reaction was almost completed after stirring for 1 h at room temperature the crystals formed were filtered off and recrystallized from methanol to obtain pure products of substituted 3-(2-oxo-2//-benzo[b][l,4] oxazin-3-yl)propanoates 3 with 40-60% yield. AU the products were characterized by elemental analyses as well as detailed spectral studies. 

The derivatives of the aminophenols have important uses both in the photographic and the pharmaceutical industries. They are also extensively employed as precursors and intermediates in the synthesis of more compHcated molecules, especially those used in the staining and dye industry. All of the major classes of dyes have representatives that incorporate substituted aminophenols these compounds produced commercially as dye intermediates have been reviewed (157). Details of the more commonly encountered derivatives of the aminophenols can be found in standard organic chemistry texts (25,158). A few examples, which have specific uses or are manufactured in large quantities, are discussed in detail in the following (see Table 6). 

Diozo Oxides. Diazo oxides are obtd irom substituted aminophenols amino-naphthols. They are also obtd from amino-phenolcarboxylic acids with the amino group either ortho or para to the hydroxyl group. 

P. Y. Chung, S. L. Highly chemoselective acylation of substituted aminophenols with... 

Hydroxylation of arylamines with persulfate ion, or Boyland-Sims oxidation, gives ortho-substituted aminophenols in good yields [29]. As with the Elbs oxidation, the procedure is also carried out in two steps - first, treatment with the oxidant to obtain an aminophenyl sulfate ester and, second, hydrolysis to obtain the final product. Primary, secondary and tertiary amines can all be used in this reaction. The ortho product is formed, except when no ortho-positions are available, which leads to para-substitution. Electrophilic attack on the ipso-carbon is believed to be the most likely mechanism, although minor radical pathways also seem to be present. 

Certain nuclear substituents ortho to a newly formed diazonium group may interact to form a cyclic structure with or without retention of the nitrogen atoms. Such is the case in the diazotization of o-phenylene-diamine in aqueous solution, the product being 1,2,3-benzotriazole (81%). If the ortho substituent is an activated methyl group, an indazole is formed. Hydroxyl groups ortho or para to the diazonium group may interact to form internal condensation products called diazo oxides. These compounds may also form in the reaction of halo- and nitro-substituted aminophenols. 

Substituted aminophenols and phenolic or anilino moieties bearing N-hetero-cycles contain two distinguished CB functional centres. Substituted BQMI 57 are formed via 4-aminophenoxyl after ROO trapping by aminophenols. For example, the aminophenolic moiety creates the active part of 2,4-bis(octylthio)-6-(3,5-di-ter -butyl-4-hydroxyanilino)-1,3,5-triazine, a very efficient AO for diene based polymers. The respective QI 173 is formed transiently and 2,6-di-fm-butyl-l, 4-benzoquinone is released by hydrolysis of 173 in the ultimate phase of its lifetime [251]. The respective QI are also formed in sacrificial transformations of 6-hydroxy- or 6-anilino-2,2,4-trimethyl-1,2-DHQ, 6- or 8-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolines or 6-hydroxycarbazole [37]. All these bifimctional heterocyclic amines are strong AO. 

Cyclohexane-1,3-diones generally, for example the parent compound, dihydroresorcinol, available from rhe hydrogenation of resorcinol, have been aromatised by various techniques including the use of mercuric acetate in the presence of secondary amines to afford yields of 3-substituted aminophenols in the range 32-79% (ref.84). 

Bis(benZoxaZol-2-yl) Derivatives. Bis(benzoxazol-2-yl) derivatives (8) (Table 3) aie prepared in most cases by treatment of dicaiboxyhc acid derivatives of the central nucleus, eg, stilbene-4,4Cdicarboxyhc acid, naphthalene-l,4-dicarboxyhc acid, thiophene-2,5-dicarboxyhc acid, etc, with 2 moles of an appropriately substituted o-aminophenol, followed by a ring-closure reaction. These compounds are suitable for the brightening of plastics and synthetic fibers. 

The aminophenols are chemically reactive, undergoing reactions involving both the aromatic amino group and the phenoHc hydroxyl moiety, as weU as substitution on the benzene ring. Oxidation leads to the formation of highly colored polymeric quinoid stmctures. 2-Aminophenol undergoes a variety of cyclization reactions. 

Condensation Reactions. Condensation of substituted ben2aldehydes with 2-aminophenol in the presence of a catalyst (aluminum, iron,... 

Aminophenols are either made by reduction of nitrophenols or by substitution. Reduction is accompHshed with iron or hydrogen in the presence of a catalyst. Catalytic reduction is the method of choice for the production of 2- and 4-aminophenol (see Amines BY reduction). Electrolytic reduction is also under industrial consideration and substitution reactions provide the major source of 3-aminophenol. 

Substitution of various groups by amino or hydroxyl functions is industrially unimportant for the production of 2- and 4-aminophenol, but this type of reaction is used for the synthesis of 2- and 4-aminophenol derivatives. However, 3-aminophenol caimot be obtained easily by reduction. It is made by the reaction of 3-aminobenzenesulfonic acid [121 -47-1] with sodium hydroxide under fusion conditions (5—6 h 240—245°C). The product is purified by vacuum distillation (25). 

An interesting preparation of substituted o-aminophenols has been developed by Birkofer and Daum (30). 2-Acylfurans (8) plus an aliphatic secondary amine presumably condense to give the eorresponding enamine (9) (not isolated), which undergoes thermal isomerization to the o-amino-phenol (10). 

Hydrogenolysis of methylenediisoxazoles have been useful in preparing substituted resorcinols and aminophenols (7). The isoxazole annelation reaction (71,89,90,91,103) is well suited to the synthesis of steroids and other complex molecules. 

N-substituted phenylhydroxylamine derivatives, e.g. N-acetyl and N-sulphonic acid, also form the para-aminophenol", but more bulky groups prevent reaction, it is thought by steric hindrance to the approach of the hydronium ion. -substituted phenylhydroxylamines, on the other hand form only the ortho product, it is thought via an intramolecular rearrangement, e.g. 

Formaldehyde aftertreatment was employed to link together pairs of amino-substituted dye molecules by a methylene bridge (10.211). The required reactivity of the sites in the dye towards formaldehyde was ensured by pairs of o- and p-directing electron-donating groups provided by resorcinol, m-phenylenediamine or 3-aminophenol. 

Substitution of two chlorines in (l,2-benzenedioxy)trichlorophosphorane by N,0 bis(trimethylsilyl)amino acids gives 34 (X = Cl) further substitution of chlorine by phenol gives 34 (X = OPh) (Scheme 22) <1998S855>. The reaction of P(NMe2)3 with 2-aminophenols generates aminophosphoranes 33 (R = H, Buc) (Equation 20) <2000HAC11>. 

A direct catalytic conversion of esters, lactones, and carboxylic acids to oxazolines was efficiently achieved by treatment with amino alcohols in the presence of the tetranuclear zinc cluster Zn4(0C0CF3)60 as catalyst, essential for condensation and cyclodehydration reactions. For example, the use of (5)-valinol allowed the easy synthesis of oxazolines 125 and 126 in satisfactory yields <06CC2711>. A one-pot direct preparation of various 2-substituted oxazolines (as well as benzoxazoles and oxadiazoles) was also performed from carboxylic acids and amino alcohols (or aminophenols or benzhydrazide) using Deoxo-Fluor reagent <06TL6497>. 

Mamyama et al.25 have obtained high-molecular-weight poly(benzoxazole)s by the low-temperature solution polycondensation of A,A 0,0 -tetrais(trimethyl-silyl)-substituted 2,2-bis(3-amino-4-hydroxyphenyl)-l,l,l,3,3,3-hexafluoro-propane (25) with aromatic diacids and subsequent thermal cyclodehydration of the resulting poly(o-hydroxy amide)s in vacuo. In this method, aromatic diamines with low nucleophilicity are activated more positively through the conversion to the /V-silylated diamines, and the nucleophilicity of the fluorine-containing bis(o-aminophenol) can be improved by silylation. 

Wang resin was purchased from Advanced ChemTech (1% DVB, 0.70mmol/g substitution, 100-200 mash, Cat. SA5009). Anhydrous tetrahydrofuran (THF), A/A-dimcthyl-formamide (DMF), methanol, dichloromethane, pyridine, 1,1 -carbonyldiimidazole (CDI), piperazine, homopiperazine, trans-1,4-diaminocyclohexane, 4-(dimethylamino)pyridine (DMAP), succinic anhydride, diglycolic anhydride, 3-methyl-glutaric anhydride, 2-aminophenol, 2-amino-p-cresol, 2-amino-4-tert-butyl phenol, /V-methylmorpholine (NMM), triphenylphosphine, diethyl azodicarboxylate (DEAD), and trifluoroacetic acid (TFA) were purchased from Aldrich Chemical Company, Inc. and used without further purification. PyBOP was purchased from Novabiochem. 

Covalent protein adducts of quinones are formed through Mchael-type addihon reachon with protein sulfhydryl groups or glutathione. Metabolic activahon of several toxins (e.g., naphthalene, pentachlorophenol, and benzene) into quinones has been shown to result in protein quinone adducts (Lin et al, 1997 Rappaport et al, 1996 Zheng et al., 1997). Conversion of substituted hydroquinones such as p-aminophenol-hydroquinone and 2-bromo-hydroquinone to their respective glutathione S-conjugates must occur to allow bioactivation into nephrotoxic metabolites (Dekant, 1993). Western blot analysis of proteins from the kidneys of rats treated with 2-bromo-hydroquinone has revealed three distinct protein adducts conjugated to quinone-thioethers (Kleiner et al, 1998). 

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