Demethylation of a phenolic ether

Demethylation of a phenolic ether by hydriodic acid, 22, 91 Desiccator, vacuum, dumb-bell type, 23,105... 

The demethylation of aspidospermine by an Actinomycetes culture appears to be the first report of the demethylation of a phenolic ether in the alkaloid series by a... 

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

Methylating agents for phenolic groups are a) diazomethane (the reaction time varies from minutes to 24 hours), b) dimethyl sulphate (DMS) - potassium carbonate in acetone or dimethylformamide (DMF) and c) methyl iodide - potassium carbonate in acetone. For demethylation of a methyl ether group ortho to a methyl ester group boron tribromide is used, while demethylation of a methyl ether para to a methyl ester group is carried out with boron trichloride (see Scheme 8). 

Strong protic acids cleave phenolic methyl ethers. Thus hydrogen bromide accomplished the same double demethylation as that depicted in Scheme 4.104.189 The final step in a Merck synthesis of the potent dopamine agonist (A,R)-4-pro-pyl-9-hydroxy naphthoxazine (106 2), a phenolic ether deprotection was accomplished on a large scale using methanesulfonic acid in the presence of methionine as the nucleophile [Scheme 4.106]. 190 191... 

Demethylation. The last step in a synthesis of N-methyl-3,4-dihydroxyphenyl-alanine from vanillin and creatinine is demethylation of the phenolic monomethyl ether formulated." A mixture of the ether, red phosphorus, 60 ml. of constantboiling hydriodic acid, and 60 ml. of acetic anhydride is refluxed for 3 hrs. 

In a number of cases, however, enzymatic reactions do not take place specifically with respect to either enantiomer. One example of this is the demethylation of the methyl ether of racemic 8-aza-D-homoestradiol (291), which forms the racemic free phenol (292) [120] (Scheme 42). Another example is the racemic 18-norsteroid (294). Only the natural enantiomer of this compound reacts with an enzyme isolated from the bacterium Pseudomonas testosteroni, 3)3,17i3-hydroxysteroid dehydrogenase, forming the optically active 17-ketone (293). At the same time, both enantiomers of compound (294) react with another enzyme from the same source,... 

Dealkylation of certain ethers occurs when they are treated with a titanium halide. This reaction has been applied to the removal of protective groups from alcohols and phenols [655,656]. Demethylation of the permethylated tetraphenol shown in Eq. (291) with TiBc4 could be performed stepwise. The second demethylation occurred specifically at the position indicated to give the bis-phenol with C2 symmetry and a chiral plane (Eq. 291) [657]. 

---