Demethylation reactions

Scheme 5.1-4 Two examples of aryl demethylation reactions followed by cyclization.

The results for the hydrolysis of chlorobenzene, o-chlorotoluene and p-chloroanisole in presence of cuprous oxide at different temperatures (Fig. 14) show a good selectivity for the reaction of the chlorobenzene. But, the p-chloroanisole is also transformed by a secondary demethylation reaction into the corresponding p-chlorophenolate. 

The deesterification reaction, or more precisely the demethylation reaction, was followed by measuring the amount of methanol liberated (Fig. 2). 

Londry KL, PM Fedorak (1993) Use of fluorinated compounds to detect aromatic metabolites from m-cresol in a methanogenic consortium evidence for a demethylation reaction. Appl Environ Microbiol 59 2229-2238. 

Berman MH, AC Frazer (1992) Importance of tetrahydrofolate and ATP in the anaerobic O-demethylation reaction for phenylmethylethers. Appl Environ Microbiol 58 925-931. 

A study of sequential Arbuzov-type demethylation reactions of the platinum(II)-phosphite complex [Pt P(OMe)3 4]2+, in which the phosphite ligands are converted to phosphonates, has been described.285 Many of the products of the reaction were characterized by NMR spectroscopy and X-ray crystallography.286 The X-ray structures are the first reported for trialkylphosphite complexes of platinum(II). 

The above syntheses are demethylation reactions induced by concentrated H2SO4, followed by substitution of hydrogenosulphate for chloride from NH4CI. 

Microbial transformations of ellipticine (15) and 9-methoxyellipticine (16) were reported by Chien and Rosazza (143, 144). Of 211 cultures screened for their abilities to transform 9-methoxyellipticine (16), several, including Botrytis alii (NRRL 2502), Cunninghamella echinulata (NRRL 1386), C. echinulata (NRRL 3655), and Penicillium brevi-compactum (ATCC 10418), achieved O-demethylation of 16 in good yield (Scheme 9). P. brevi-compactum was used to prepare 9-hydroxyellipticine (22) from the methoxylated precursor, and 150 mg of product was obtained from 400 mg of starting material (37% yield). The structure of the metabolite was confirmed by direct comparison with authentic 9-hydroxyellipticine (143). O-Demethylation is a common microbial metabolic transformation with 16 and many other alkaloids (143). Meunier et al. have also demonstrated that peroxidases catalyze the O-demethylation reaction with 9-methoxyellipticine (145). 

SAQ 8.26 The following table contains the rate constant k for the demethylation reaction of /V-methyl pyridinium bromide by aqueous sodium hydroxide as a function of temperature ... 

Miwa GT, Walsh JS, Kedderis GL, et al. The use of intramolecular isotope effects to distinguish between deprotonation and hydrogen atom abstraction mechanisms in cytochrome P-450- and peroxidase-catalyzed N-demethylation reactions. J Biol Chem 1983 258(23) 14445-14449. 

Table II summarizes the results together with the detailed experimental conditions. As is evident, metabolic activities were detectable in these 3 aquatic species, but the rate was far lower as compared with mammalian hepatic enzume preparations, and the oxidative activities in snail were particularly low although the possibility was not ruled out of the presence of inhibitors of mixed-function oxidases in the fractions. The O-demethylation reaction proceeds extremely slowly in the enzyme preparation of aquatic animals, at less than one hundredth that of mammals.

Ethylmorphine and benzphetamine are N-demethylated specifically by rodent cytochrome(s) P-450 (as opposed to cytochrome(s) P] -450) in the rat phenobarbital and the polyhalogenated biphenyls induce these demethylation reactions. However, it is clear that no such stimulation occurred in the rainbow trout (Table II). 

The presence of metal may catalyze demethylation and can occur to some extent in catalysts where the metal function is under-passivated, as by incomplete sulfiding. This would convert valuable xylenes to toluene. The demethylation reaction is usually a small contributor to xylene loss. Metal also catalyzes aromatics saturation reactions. While this is a major and necessary function to facilitate EB isomerization, any aromatics saturation is undesirable for the process in which xylene isomerization and EB dealkylation are combined. Naphthenes can also be ring-opened and cracked, leading to light gas by-products. The zeolitic portion of the catalyst participates in the naphthene cracking reactions. Cracked by-products can be more prevalent over smaller pore zeolite catalysts. 

Demethylation reactions proceed equally well using dry M-pentane or dry methylene chloride as the solvent for both the ether and the boron tribromide methylene chloride, having by far the more powerful solvent action, is to be preferred. 

Extension of studies on the occurrence of these liquid ammonia-induced demethylation reactions in other pyrimidinium salts has revealed that also 1,2-dimethylpyrimidinium iodide (74RTC114), 1,4,6-trimethylpyrimidinium iodide (74RTC114), 1,2,4,6-tetramethylpyrimidinium iodide (74RTC114), and l-methyl-4-phenylpyrimidinium iodide (82RTC367) are also easily... 

The enzyme is the principal participant in N-demethylation reactions where the substrate is a tertiary amine. The list of substrates includes erythromycin, ethylmor-phine, lidocaine, diltiazem, tamoxifen, toremifene, verapamil, cocaine, amiodarone, alfentanil and terfenadine. Carbon atoms in the allylic and benzylic positions, such as those present in quinidine, steroids and cyclosporin A, are also particularly prone to oxidation by CYP3A4, a range of substrates is illustrated in Figure 7.10. 

Figure 5. Outline of the Sterol 14 Demethylation Reaction Sequence (9).

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