Oxidation of p-substituted phenols

In flavin-dependent monooxygenases, a flavin-oxygen intermediate reacts with the substrate, also producing water in a second step, and requiring cofactors for regeneration of the flavin moiety. The unusual flavoprotein vanillyl-alcohol oxidase (EC 1.1.3.38), in which the flavin moiety is covalently bound, catalyzes the oxidation of p-substituted phenols as well as deamination, hydroxylation and dehydrogenation reactions [10]. 

Oxidation of p-substituted phenols with f-BuOOH catalyzed by heteropoly acids such as H3PMoi2O40-nH2O (283) and H4SiWi2O40-nH2O has been carried out ". When 2,6-di(ferf-butyl)-4-methylphenol (69) was stirred with 80% f-BuOOH in the presence of 283 in AcOH (30 °C, 3 h), it afforded 2,6-di(terr-butyl)-4-(terr-butylperoxy)-4-methyl-2,5-cyclohexadienone (284) and 2,6-di(terf-butyl)-p-benzoquinone (74) in 62 and 13%... 

SCHEME 62. Ruthenium catalyzed oxidation of p-substituted phenols with i-BuOOH... 

SCHEME 76. PhI(OCOCF3)2-promoted oxidation of p-substituted phenols and silyl ethers... 

SCHEME 80. Oxidation of p-substituted phenols with PhI(OAc)2 in different solvents... 

It is of pedagogical value to discuss the first two supercritical fluid-enzyme catalysis papers that appeared within two months of each other (Randolph et al., 1985 Hammond et al., 1985). Randolph studied the hydrolysis of the disodium salt of p-nitrophenyl phosphoric acid reacting to p-nitrophenol. Hammond studied the catalytic oxidation of p-substituted phenols to first, orthocatecholic compounds and in series to o-quinone compounds, which very quickly polymerize by chemical, not enzymatic, mechanisms to form o-quinoid polymers. The product recovered is a poly(o-quinone). 

Figure 4. Flow reactor for the oxidation of p-substituted phenols using polyphenol oxidase.

A similar catalytic oxidation of p-substituted phenols bearing an alkyl or aryl group in the para position affords the corresponding p-quinols. In particular, the reaction of p-substituted phenols 54 with a catalytic amount of 4-iodophenoxyacetic acid and Oxone (4 equiv) at room temperature in an aqueous tetrahydrofuran or 1,4-dioxane solution gave p-quinols 55 in generally high yields (Scheme 4.28) [55,57]. 

Oxidation with tert-Butyl Hydroperoxide (TBHP) While catalytic amounts of CuCl resulted in poor yields of TMBQ with Oj as oxidant, the use of TBHP allowed for up to 80% yield with only 1.5wt% of CuCl and 2.8wt% of NH OH—HCl cocatalyst under ambient conditions [135]. The Ru-catalyzed oxidation of p-substituted phenols with TBHP gave corresponding (terf-butyldioxy) cyclohexadienones that can be converted to 2-substitutedp-BQ in the presence of a Lewis acid [136]. 

Earlier work on the Co(salen)-catalyzed 02 oxidation of p-substituted phenols to p-benzoquinones has been extended to include substrates that serve as models for lignin phenolic subunits. Lignin is a renewable source of carbon and its oxidation to p-benzoquinone derivatives would allow conversion to useful intermediates. Certain p-substituted phenolics can be oxidized to p-benzoquinones with dioxygen using the Co(salen) complexes A and B in Figure 4 as catalysts ". ... 

The oxidative transformation of phenols is of importance with respect to the biological and synthetic aspects. However, the oxidation of phenols generally lacks selectivity because of coupUng reactions caused by phenoxyl radicals [94], and selective oxidation of phenols is limited to phenols bearing bulky substituents at the 2- and 6-po-sitions [95]. Using ruthenium catalysts, a biomimetic and selective oxidation of phenols can be performed. Thus, the oxidation of p-substituted phenols bearing no sub-... 

Kita and Tohma found that exposure of p-substituted phenol ethers to [bis(tri-fluoroacetoxy)iodo]benzene 12 in the presence of some nucleophiles in polar, less nucleophilic solvents results in direct nucleophilic aromatic substitution [Eq. (84)] [156]. Involvement of a single-electron transfer (SET) from phenol ethers to A3-iodane 12 generating arene cation radicals was suggested by the detailed UV-vis and ESR studies. SET was involved in the oxidative biaryl coupling of phenol ethers by 12 in the presence of BF3-Et20 [157]. 

Oxidation of a number of p-substituted phenols to the corresponding o-benzoquinones was first performed by Kazandjian and Klibanov, using mushroom polyphenol oxidase and a quantitative conversion was achieved in CHCI3 as a solvent. Other hydrophobic solvents such as methylene chloride, carbon tetrachloride, benzene, toluene, hexane and butyl acetate can be used, whereas the enzyme is inactive in more hydrophilic solvents such as ether, acetone, ethyl acetate, acetonitrile and other solvents. In addition, an immobilized enzyme on glass powder or beads is more efficient than a free enzyme. 

SCHEME 75. Oxidative fluorination of p-substituted phenols withbis(trifluoroacetoxy)benzenes and synthesis of hydroindolenones... 

Oxidative functionalization. p-Substituted phenols are oxidized and trapped by various nucleophiles. For example, reaction carried out in the presence of MeCN furnishes... 

Processes involving a single-electron transfer (SET) step and cation-radical intermediates can occur in the reactions of X - or X -iodanes with electron-rich organic substrates in polar, non-nucleophilic solvents. Kita and coworkers first found that the reactions of p-substituted phenol ethers 29 with [bis(trifluoroacetoxy)iodo]benzene in the presence of some nucleophiles in fluoroalcohol solvents afford products of nucleophilic aromatic substitution 31 via a SET mechanism (Scheme 1.5) [212,213]. On the basis of detailed UV and ESR spectroscopic measurements, it was confirmed that this process involves the generation of cation-radicals 30 produced by SET oxidation through the charge-transfer complex of phenyl ethers with the hypervalent iodine reagent [213,214],... 

The oxidation of various substituted phenols 227 with [bis(trifluoroacetoxy)iodo]benzene in aqueous acetonitrile affords p-quinols 228 in moderate to good yields (Scheme 3.93) [293]. Even higher yields of p-quinols are obtained when trimethylsilyl ethers of phenols are used as starting material. In particular, it was shown that the oxidation of trimethylsilyl ethers 229 affords p-quinols 230 in greatly improved yields due to the minimization of oligomer side-product formation compared to the oxidation of free phenol [294]. 

The oxidation of o-substituted phenols with lead tetra-acetate in the presence of aP-unsaturated acids leads to the formation of o- and p-quinol esters of the acids since only the former can undergo internal [4 + 2] cycloaddition, thermal reaction... 

Zhu XP, Ni JR, Li HN, Jiang Y, Xing X, Borthwick A (2010) Effects of ultrasound on electrochemical oxidation mechanisms of p-substituted phenols at BDD and Pb02 anodes. Electrochim Acta 55 5569-5575... 

Alkylphenol Oxidation. 1,4-Quinone methides can be obtained by the reaction of p-alkylphenols with Ag20. These reactive compounds may undergo subsequent transformations, for example, a Lewis acid promoted cyclization (eq 5). 1,2-Quinone methides can also be formed by Ag20 oxidation of appropriately substituted phenols eqs 6 and 7). ... 

Reaction of these antibiotics with chlorine mostly generated chlorinated and OH-substituted by-products [86, 87]. Unlike fluroquinolones, whose quinolone ring is left mostly intact, disinfection with CIO2 may diminish the antibiotic capacity of tetracyclines because it leads to cleavage of the tetracyclines ring system [86,88]. On the other hand, oxidation of p-lactam antibiotics such as penicillin, amoxicillin, and cefadroxil with CIO2 leads to the formation of hydroquinone and a wide range of substituted phenols [89]. 

Consistent with the results of this study is the outcome of the oxidation of 4-X-substituted phenols by use of PINO, generated from HPI with Pb(OAc)4 at 25 °C in MeCN containing 1% AcOH . The reactivity (fcn) of PINO towards phenolic O—H bonds (BDE 85-90 kcal moC ) was about one order of magnitude higher than that measured towards the C—H bond of benzyl alcohols (cf. Table 4). A p value of —3.1 was obtained from plotting log kn vs. for this reaction, where removal of H-atom from the phenolic O—H bond (which is weaker than the O—H bond of aliphatic or benzyl alcohols) induces an oxidative phenolic coupling with the PINO moiety. In view of the low redox potential of the substituted phenols (in the 0.8-1.1 V/NHE range), and of the substantial value of the kinetic isotope effect = 3.1-3.7 measured, ... 

Figure 9 shows plots of Hammett fr+ values versus E j2 for the 8-p-X-Ph-dG adducts. In Fig. 9A, the OH (—0.92 ) fr+ value was used and the regression deviated from linearity. However, Fig. 9B shows that the regression is improved to almost unity when the O (2.30 ) fr+ value is used. These results suggested that the oxidation of 8-p-PhOH-dG may be coupled with phenol deprotonation. As shown in Scheme 12, resonance structures for the radical cation of 8-p-PhOH-dG create a p-substituted phenol radical cation, which possess negative pAa values (pifa for phenol radical cation ). Phenolic radical cations undergo deprotonation rapidly in the presence of water (0.6-6 x to yield neutral phenolic radicals. In the anhydrous DMF solvent used for electrochemical measurements, an N-7 adduct atom or adventitious water in the solvent could serve as base to facilitate phenolic radical production. 

Intramolecular oxidative cyclizations in the appropriately substituted phenols and phenol ethers provide a powerful tool for the construction of various practically important polycyclic systems. Especially interesting and synthetically useful is the oxidation of the p-substituted phenols 12 with [bis(acyloxy)iodo]-arenes in the presence of an appropriate external or internal nucleophile (Nu) leading to the respective spiro dienones 15 according to Scheme 6. It is assumed that this reaction proceeds via concerted addition-elimination in the intermediate product 13, or via phenoxenium ions 14 [18 - 21]. The recently reported lack of chirality induction in the phenolic oxidation in the presence of dibenzoyltar-taric acid supports the hypothesis that of mechanism proceeding via phenoxenium ions 14 [18]. The o-substituted phenols can be oxidized similarly with the formation of the respective 2,4-cyclohexadienone derivatives. 

On the other hand, PIFA-induced oxidation of p-methoxy-substituted phenols (15) in the presence of electron-rich styrene derivatives (16) resulted in new carbon-carbon bond formation via an intermolecular 1,3-cycloaddition to afford frazzs-dihydrobenzofurans (17) stereoselectively [35,36] [Eq. (4)]. A formal synthesis of neolignans such as kadsurenone (18) and denudatin B (19) was achieved by this methodology. 

Alkylrhenium trioxide-catalyzed oxidations of hydroxy-substituted arenes (i.e. phenol or naphthol derivatives, discussed as intermediates on the way to the corresponding quinones [9]) by 85 % aqueous hydrogen peroxide (diluted in AcOH) affords the corresponding p-quinones in fair to high yields [10]. Control experiments without rhenium catalysts yielded very slow oxidations (less than 10 % conversion). Furthermore, under the conditions of the H202/CH3Re03/Ac0H oxidation, the quinones formed are quite stable thus hydroxy-substituted p-quinones are not derived from overoxidation of the p-quinones. 

In the case of the rhenium-catalyzed oxidation of methoxy- and hydroxy-substituted substrates, there is some complementary work concerning the general mechanism of the arene oxidation [10b, 11]. Since the major products in the oxidation of such arenes or phenols are the quinones, the formation of intermediary epoxides seems to be a predominant reaction step. When p-substituted phenols such as 2,6-di( -butyl)-4-methylphenol are treated with the MTO/H2O2 oxidant and acetic acid as solvent, the formation of hydroxydienones is observed. This is also reported for the oxidation using dimethyldioxirane as oxidant [20]. Since an arene oxide intermediate was postulated for the dioxirane oxidation, a similar mechanism is plausible here [11], e. g., for the oxidation of l,2,3-trimethoxy-5-methylbenzene (Scheme 3) or 2,6-di(f-butyl)-4-methyl-phenol. 

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