Methylation of a phenol

Occasionally we have found iron contaminants in aromatic steroids that have not been adequately purified. The methylation of a phenolic steroid with methyl sulfate and alkali is often carried out just prior to a Birch reduction and iron in the tap water precipitates with the steroid during the... 

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). 

Methylations. Example (2) illustrates the inactivation of the catecholamine norepinephrine by methylation of a phenolic OH group (see p. 334). 

However, the possibility that the methylation of a phenolic hydroxy group in deacetylisoipecoside (186) takes place prior to lactamization in A. lamarckii cannot be ruled out. This leads to the proposal (21) of alternative plausible pathways to 50-52, protoemetinol (34), and demethylprotoemeti-nols (35 and 36), as outlined in Scheme 2. 

Methylation of a phenolic -OH group in (S)-3 -hydroxy-JV-methyl-coclaurine by SAM gives (S)-reticuline through the usual Sn2 pathway, and epimerization of the chirality center forms (i )-reticuline. The epimerization is a two-step process, the first an oxidation of the tertiary amine to an intermediate iminium ion and the second a hydride reduction of the iminium ion. The mechanism of the oxidation step is not yet known, but the reduction of the iminium ion requires NADPH as cofactor (Figure 25.11). 

Anthiylmethyl ethers, formed from the sodium salt of a phenol and 9-anthryl-methyl chloride in DMF, can be cleaved with CH3SNa (DMF, 25°, 20 min, 85-99% yield). They are also cleaved by CF3CO2H/CH2CI2 (0°, 10 min, 100% yield) they are stable to CF3C02H/dioxane (25°, 1 h). ... 

In an early synthesis a methyl carbonate, prepared by reaction of a phenol with methyl chloroformate, was cleaved selectively in the presence of a phenyl ester. ... 

The three alkaloids concerned, morphine, codeine and thebaine, all behave as tertiary bases. Morphine contains two hydroxyl groups of which one is phenolic and the other a secondary alcohol group. On methylation of the phenolic hydroxyl codeine results. On oxidation, codeine is transformed into codeinone by conversion of the secondary alcohol group into a carbonyl group, and when thebaine is boiled with A-sulphuric acid for a few minutes, it is hydrolysed into codeinone and methyl sulphate, and in other ways thebaine has been shown to contain two methoxyl groups. That the relationship between the three alkaloids is close may be illustrated by the following slightly extended formula —... 

The stereoisomeric pair, morphine and a-womorphine, on methylation of the phenolic hydroxyl at C, give rise to codeine and isocodeine respectively, and similarly and y-i omorphines produce [Pg.250]

The Simmons-Smith reaction has been used as the basis of a method for the indirect a methylation of a ketone. The ketone (illustrated for cyclohexanone) is first converted to an enol ether, an enamine (16-12) or silyl enol ether (12-22) and cyclopropanation via the Simmons-Smith reaction is followed by hydrolysis to give a methylated ketone. A related procedure using diethylzinc and diiodomethane allows ketones to be chain extended by one carbon. In another variation, phenols can be ortho methylated in one laboratory step, by treatment with Et2Zn and... 

Neilson AH, A-S Allard, P-A Hynning, M Remberger, L Landner (1983) Bacterial methylation of chlorinated phenols and guiaiacols formation of veratroles from gnaiacols and high molecular weight chlorinated lignin. Appl Environ Microbiol 45 774-7S3. 

Neilson AH, C Lindgren, P-A Hynning, M Remberger (1988) Methylation of halogenated phenols and thiophenols by cell extracts of Gram-positive and Gram-negative bacteria. Appl Environ Microbiol 54 524-530. 

Synthetic routes that access appropriately substituted thienobenzazepines are also quite important for medicinal chemistry stracture activity relationship studies, and many involve similar bond connectivity strategies. One notable example employs the use of conunercially available 4-methyl-3-nitrophenol (Scheme 6.3). Methylation of the phenol followed by bromination, hydrolysis, and oxidation of the benzylic alcohol afforded aldehyde 9 in quantitative yield. Treatment of this aldehyde with 5-lithio-2-methylthiophene provided, after dehydroxylation, nitro intermediate A in good overall yield. Reduction of the nitro functionality and treatment with phosgene presented the corresponding isocyanide which upon cychzation using aluminum trichloride in a Friedel-Crafts fashion afforded the... 

As is also illustrated in Scheme 6.23, the optically enriched amino nitriles can be converted to the corresponding a-amino esters through a four-step sequence (74—> 75). Unlike the aforementioned imine alkylations with alkylzinc reagents, methylation of the phenolic OH is required, since the corresponding o-methoxy aniline is less reactive and affords significantly lower enantioselectivities similar observations are made when aniline is used. 

Experiments.—To an ice-cooled solution of 2-3 g. of a phenol (phenol, cresol, /3-naphthol, salicylaldehyde, quinol) in a little ether, acetone, or methyl alcohol, the diazomethane solution prepared as described above is added in small portions until evolution of gas no longer takes place and the solution is coloured faintly yellow. 

Hutchins and Fife, 1973. The reference reaction is the attack of the anion of a phenol of pX, 9.0 on phenyl N-methyl-N-phenylcarbamate under the same conditions f 18 times slower than B.3.1... 

TABLE 4.4 The 0-Methylation of Different Phenols (ArOH) with DMC in a CSTR"... 

Figure 14. Time on stream dependence of (a) phenol conversion, and (b) orthoalkyl phenol selectivity on Cu0.5Co0.5Fe204 at optimum reaction conditions, described earlier. Different alkylation is indicated by the name of the alkylation agent in the left panel. 2,6-xylenol selectivity is given for methylation with MeOH/DMC.

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