Phenol, methylation reactions

Methyl Orange.--The first point to notice in this reaction is that the diazonium salt forms no diazoamino-compotind with the dimethylanilinc, but at once pioduces an azo-compound. This is always the case with tertiary amines, some secondary amines like diphenyl.amine and the phenols. The reaction may be regarded as typical of the formation of all azo-colounng m.atters. At least two substances are requisite in this process on the one hand. an aromatic compound containing an amino-groujD in the nucleus, and, on the other, a base or phenol... 

However, heterocycles containing thiophenols have not been reported. It has been observed that the thiophe-nolate ion undergoes nucleophilic attack by the halo/ nitro compounds more easily than the phenolate ion in displacement reactions [37-39]. The experimental result shows that the reactivity of 3-nitro-N-phenyl-phthali-mide with 4-methyl-thiophenolate (reaction 1) is 100 times faster than that of 4-methyl phenolate [40] (reaction 2) ... 

The results obtained indicate that in the reaction between phenol and methanol, formaldehyde is the trae methylating agent when basic catalysts are used. This indicates that the type of transformation occurring with methanol is the factor that mainly differentiates performances in phenol methylation when catalyzed by either basic or acid catalysts. The catalyst plays its role in the generation of the methylating species the nature of the latter then determines the type of phenolic products obtained. 

The literature on basic- and acid-catalyzed alkylation of phenol and of its derivatives is wide [1,2], since this class of reactions finds industrial application for the synthesis of several intermediates 2-methylphenol as a monomer for the synthesis of epoxy cresol novolac resin 2,5-dimethylphenol as an intermediate for the synthesis of antiseptics, dyes and antioxidants 2,6-dimethylphenol used for the manufacture of polyphenylenoxide resins, and 2,3,6-trimethylphenol as a starting material for the synthesis of vitamin E. The nature of the products obtained in phenol methylation is affected by the surface characteristics of the catalyst, since catalysts having acid features address the electrophilic substitution in the ortho and para positions with respect to the hydroxy group (steric effects in confined environments may however affect the ortho/para-C-alkylation ratio), while with basic catalysts the ortho positions become the... 

The final coal product in the MeOH/KOH experiments was 20%-25% soluble in the methanol. When the methanol was removed, the resultant product was a room temperature liquid with the properties described in Table V. Apparently the polymethylphenol fraction is formed by the cleavage of phenolic ethers and subsequent methyla-tion by the CO that is present in the reaction mixture as a result of methanol decomposition. The methylation reaction has been observed before for similar systems (3). 

Phenol methylation to 2,6-xylenol has been widely studied for the past few deeades owing to the room for improvisation from the viewpoint of product selectivity. Generally during phenol methylation to 2,6-xylenol, occurs via sequential methylation of phenol to o-cresol to 2,6-xylenol, various reaction parameters mediate the selectivity between the two. For instance, when the reaetants stoichiometry of methanol to phenol molar ratio > 2, and significant residence time of o-cresol may favor 2,6-xylenol selectivity. However, excess methanol is often used, sinee some amount of methanol tend to undergo oxidation into various reformate produets [71] under vapor phase condition. Similarly, reaction temperature, catalyst acid-base property, and space velocity of the reaetant are the parameters that govern the selectivity to 2,6-xylenol. 

Cu-Mn mixed-oxide binary spinel catalysts (CuxMn3 x04, where x = 0, 0.25, 0.5, 0.75 and 1) prepared through co-precipitation method exhibit phenol methylation activity imder vapor phase conditions [75]. All of the catalysts, irrespective of the compositions, produced only C-methylated phenols. However, a total ortho selectivity of 100% with 2,6-xylenol selectivity of 74% was observed over x = 0.25 compositions at 400°C. This composition was found to be relatively stable under reaction conditions compared with the other compositions studied. The catalysts with high copper content suffered severe reduction under methylation conditions whereas, catalysts with low copper content had a hausmannite phase (Mu304) that sustained... 

The interaction of adsorbed reactants (phenol and methanol adsorbed separately and coadsorbed) and possible reaction products of phenol methylation with the Cul-xCoxFe204 system has been studied at temperatures between lOOoC and 350oC and probed by in situ FTIR spectroscopy. The spectra of adsorbed methanol, phenol and methylated products on catalyst surface, at lOOoC, did not possess much changes compared to the spectra of pure components that indicated the molecular adsorption of species on catalyst surface. The remarkable changes in the spectra occur, above 100°C due to the chemisorption of substrates, were observed and correlated with the observed reaction trend. 

The coenzyme tetrahydrofolate (THF) is the main agent by which Ci fragments are transferred in the metabolism. THF can bind this type of group in various oxidation states and pass it on (see p. 108). In addition, there is activated methyl, in the form of S-adenosyl methionine (SAM). SAM is involved in many methylation reactions—e. g., in creatine synthesis (see p. 336), the conversion of norepinephrine into epinephrine (see p. 352), the inactivation of norepinephrine by methylation of a phenolic OH group (see p. 316), and in the formation of the active form of the cytostatic drug 6-mercaptopurine (see p. 402). 

Lithiation of dibenzofuran with butyllithium and mercuration both occur at the 4-position. Thallation occurs at the 2-position, however (57IZV1391). The mercury and thallium derivatives serve as a source of the iodo compounds by reaction with iodine. Bromodibenzofurans undergo bromine/lithium exchange with butyllithium and the derived lithio compounds may be converted into phenols by reaction with molecular oxygen in the presence of a Grignard reagent, into amines by reaction with O-methylhydroxylamine, into sulfinic acids by reaction with sulfur dioxide, into carboxylic acids by reaction with carbon dioxide and into methyl derivatives by reaction with methyl sulfate (Scheme 100). This last reaction... 

In the presence of trace amounts of water, the tetrameric p,2-oxo complex (182) in 1,2-dimethoxyethane is transformed into a p, -oxo tetrameric complex (183 equation 254), characterized by an X-ray structure.574 In contrast, (182) 572,575 is inactive towards the oxidation of phenols. The reaction of N,N,N, AT -tetramethyl-l,3-propanediamine (TMP) with CuCl, C02 and dioxygen results in the quantitative formation of the /z-carbonato complex (184 equation 255).s76 This compound acts as an initiator for the oxidative coupling of phenols by 02. 6 Such jz-carbonato complexes, also prepared from the reaction of Cu(BPI)CO with 02 [BPI = 1,3 bis(2-(4-methyl-pyridyl)imino)isoindoline],577 are presumably involved as reactive intermediates in the oxidative carbonylation of methanol to dimethyl carbonate (see below).578 Upon reaction with methanol, the tetrameric complex (182 L = Py X = Cl) produces the bis(/z-methoxo) complex (185 equation 256), which has been characterized by an X-ray structure,579 and is reactive for the oxidatiye cleavage of pyrocatechol to muconic acid derivatives.580,581... 

A convenient method for the introduction of a formyl group, specifically in the ortho position of a phenol, involves reaction with tin(iv) chloride in the presence of tributylamine followed by treatment with paraformaldehyde.46 It is applicable to phenols with other electron-donating or -withdrawing substituents, and is illustrated by the conversion of p-cresol into 5-methyl-2-hydroxybenzaldehyde (Expt 6.112). The reaction is thought to proceed via two successive six-membered coordinated tin complexes. 

C-Methylation also features in the biosynthesis of usnic acid (Figure 3.41), an antibacterial metabolite found in many lichens, e.g. Usnea and Clado-nia species, which are symbiotic combinations of alga and fungus. However, the principal structural modification encountered involves phenolic oxidative coupling (see page 28). Two molecules of methylphloracetophenone are incorporated, and these are known to derive from a pre-aromatization methylation reaction and not by... 

The methyl group on SAM behaves as an electrophilic +CII3 positively charged carbocation that is attracted to electron-rich nucleophilic O, N, and S atoms on a xenobiotic compound methylation of carbon is rare. Therefore, the kinds of compounds commonly methylated include amines, heterocyclic nitrogen compounds, phenols, and compounds containing the -SH group. A typical methylation reaction is that of nicotine ... 

Phenolic methyl ethers were usually prepared by treatment of the alkaloid with dimethyl sulfate and sodium hydroxide or with diazomethane 17). In the first case a side reaction was N-methylation or even cleavage of the lactone (3). In decodine (6) the C-17 OH group was methylated on treatment with ethereal diazomethane. The hindered C-21 OH group was alkylated with methanolic CH2N2 (77). 

Phenylenediamine and 2-aminophenol initially give N-arylimidoyl fluoride. Elimination of hydrogen fluoride from the product and further intramolecular nucleophilic cyclization lead to perfluoroalkyl derivatives of benzimidazole and benzoxazole, respectively. In the case of 2-aminothio-phenol, the reaction occurs at the sulfur atom and forms a carbanion. If RF is fluorine, then the carbanion is destabilized by the interaction of the lone electron pairs of fluorine with the center, and the stabilization reactions occur with participation of the proton. If, however, RF is the trifluoro-methyl group, the negative charge is stabilized by it. The fluoride ion is eliminated with further intramolecular nucleophilic cyclization. 

During a synthesis of quinone imine precursors to the Dynemicins, Myers and co-workers100 encountered problems with the lability of the dimethyl acetal function in 56,1 [Scheme 1.56] whilst removing the robust phenolic methyl group using sodium ethanethiolate in hot DMF, However prior conversion of the free hydroxy function in the substrate to the magnesium salt 56.2 by reaction with ethylmagnesium bromide afforded protection for the dimethylacetal under the strenuous conditions of nucleophilic demethylation. 

The p-anisyloxymethyl group520 (abbreviated AOM) played an important role in the synthesis of Calicheamicinone reported by Clive and co-workers.521 Its removal from the sensitive multifunctional substrate 285 1 [Scheme 4.285] was accomplished with CAN in a mixture of pyridine, methanol and water. The excellent yield (89%) attests to the mildness of the conditions. Attempts to apply the same conditions to the deprotection of an AOM group from 286 1 [Scheme 4.286]522 failed but the deprotection was successful if it was conducted in the presence of 2,6-pyridinedicarboxylic acid N-oxide — conditions previously used to convert a phenol methyl ether to a quinone.523 AOM ethers undergo easy reductive cleavage to the corresponding methyl ethers with borane in toluene — a reaction that could have synthetic value when simple O-methylation procedures fail. 

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