Demethylation of aromatics

The above reactions in this section have been examples of addition alone or addition followed by elimination. Ligand reactions involving nucleophilic substitution are also known and these are of the dealkylation type. Lewis acids such as aluminum chloride or tin(IV) chloride have been used for many years in the selective demethylation of aromatic methyl ethers, where chelation is involved (Scheme 27). Similar cleavage of thioethers, specially using mercury(II) salts, is commonly used to remove thioacetal functions masking ketones (equation 27).104 In some cases, reactions of metal ions with thioether ligands result in isolation of complexes of the dealkylated organic moiety (equations 28 and 29).105-107... 

Other types of P450-mediated metabolic processes are the oxidative hydroxy-lation of aliphatic compounds with labile hydrogen substituents and oxidative demethylations of aromatic methoxy groups or methylamines. 

Recently Wilson and Joule 158> studied the demethylation of a variety of quaternary ammonium acetates in aprotic solvents. Earlier Lawson and Collie 92> showed that the decomposition of solid tetramethylammonium acetate at 180—200 °C gives the methyl ester in good yield. However, the use of an aprotic solvent significantly lowers the temperature (60—140 °C) required for decomposition. This reaction is most useful for the demethylation of aromatic quaternary ammonium salts that are soluble in benzene or benzene-chloroform mixtures. Its application to aliphatic quaternary ammonium salts requires a longer time, although N,N-dimethylpiperidinium acetate was demethylated at 100 °C in xylene-... 

Studies on the mechanism of the O-demethylation of aromatic substrates catalyzed by HRP have shown that the methyl group is removed as methanol (and not as formaldehyde, as in cytochrome P450-mediated oxidations). This work has been useful in understanding the mechanism of lignin oxidation by ligninase, as some authors considered ligninase as an oxygenase, not as a peroxidase. 

Blount JF, Mohacsi E, Vane FM, Mannering GJ (1973) Isolation, X-ray analysis and synthesis of a metabolite of (-)-3-hydroxy-N-allylmorphinan. J Med Chem 16 352-355 Bogriar R, Gaal Gy, Kerekes P, Horvath G, Kovacs MT (1974) Hydroxyl group elimination in the morphine series. Org Prep Proc Int 6(6) 305-311 Brossi A, Teitel S (1970) Partial 0-demethylation of aromatic substituted 3,4-dihydroisoquino-Hnes. Helv Chim Acta 53 1779-1787... 

Scheme 1 Demethylation of aromatic ethers by BCI3 in CH2CI2...

Another important use of BCl is as a Ftiedel-Crafts catalyst ia various polymerisation, alkylation, and acylation reactions, and ia other organic syntheses (see Friedel-Crafts reaction). Examples include conversion of cyclophosphasenes to polymers (81,82) polymerisation of olefins such as ethylene (75,83—88) graft polymerisation of vinyl chloride and isobutylene (89) stereospecific polymerisation of propylene (90) copolymerisation of isobutylene and styrene (91,92), and other unsaturated aromatics with maleic anhydride (93) polymerisation of norhornene (94), butadiene (95) preparation of electrically conducting epoxy resins (96), and polymers containing B and N (97) and selective demethylation of methoxy groups ortho to OH groups (98). 

Condensation of adipic acid derivative 17 with phenylethylamine in the presence of carbo-nyldiimidazole affords the bis-adipic acid amide 18. The synthesis is completed by reduction of the carbonyl groups with diborane followed by demethylation of the aromatic methoxy groups with hydrogen bromide the afford dopexamine (19) [3]. 

Grbic-Galic D (1986) O-Demethylation, dehydroxylation, ring-reduction and cleavage of aromatic substrates by Enterobacteriaceae under anaerobic conditions. J Appl Bacteriol 61 491-497. 

In contrast, cells grown anaerobically with nitrate and vanillate were able to oxidize vanillate under both aerobic and anaerobic conditions. The cells were also able to demethylate a much wider spectrum of aromatic methoxy compounds under anaerobic conditions than under aerobic conditions (Taylor 1983). Such subtleties should be clearly appreciated and taken into consideration in evaluating the degradative potential of comparable organisms under different physiological conditions. 

The low specificity of electron-donating substrates is remarkable for laccases. These enzymes have high redox potential, making them able to oxidize a broad range of aromatic compounds (e.g. phenols, polyphenols, methoxy-substituted phenols, aromatic amines, benzenethiols) through the use of oxygen as electron acceptor. Other enzymatic reactions they catalyze include decarboxylations and demethylations [66]. 

One of numerous examples of LOX-catalyzed cooxidation reactions is the oxidation and demethylation of amino derivatives of aromatic compounds. Oxidation of such compounds as 4-aminobiphenyl, a component of tobacco smoke, phenothiazine tranquillizers, and others is supposed to be the origin of their damaging effects including reproductive toxicity. Thus, LOX-catalyzed cooxidation of phenothiazine derivatives with hydrogen peroxide resulted in the formation of cation radicals [40]. Soybean LOX and human term placenta LOX catalyzed the free radical-mediated cooxidation of 4-aminobiphenyl to toxic intermediates [41]. It has been suggested that demethylation of aminopyrine by soybean LOX is mediated by the cation radicals and neutral radicals [42]. Similarly, soybean and human term placenta LOXs catalyzed N-demethylation of phenothiazines [43] and derivatives of A,A-dimethylaniline [44] and the formation of glutathione conjugate from ethacrynic acid and p-aminophenol [45,46],... 

N-demethylation at the three N-methyl sites. In this regard, the 3-N-demethylation of caffeine to generate paraxanthine can serve as a particularly good in vivo indicator of the presence and activity of CYP1A2 (Fig. 4.7). In the case of phenacetin, CYP1A2 catalyzes N-deethylation to generate acetaminophen. Not unexpectedly, 1 A2 s selectivity toward heterocyclic aromatic substrates carries over to inhibitors of the enzyme. Furafylline (Fig. 4.7) is an example of a particularly potent 1A2 mechanism-based inhibitor. 

A different mode of reaction, however, is observed in photoreductions of nitroaromatics by aromatic tertiary amines. Irradiation of benzene solutions of N-methylated anilines and either m-chloronitrobenzene or 1-nitronaphthalene results in oxidative demethylation of the amines accompanied with reduction of the nitro compound to the corresponding arylamine 49). The authors suggest that hydrogen abstraction from the methyl group takes place as the primary chemical event. 

Highly efficient and stereoselective addition of tertiary amines to electron-deficient alkenes is used by Pete et al. for the synthesis of necine bases [26,27], The photoinduced electron transfer of tertiary amines like Af-methylpyrrolidine to aromatic ketone sensitizers yield regiospecifically only one of the possible radical species which then adds diastereospecifically to (5I )-5-menthyloxy-2-(5//)-furanone as an electron-poor alkene. For the synthesis of pyrrazolidine alkaloids in approximately 30% overall yield, the group uses a second PET step for the oxidative demethylation of the pyrrolidine. The resulting secondary amine react spontaneously to the lactam by intramolecular aminolysis of the lactone (Scheme 20) [26,27]. 

An alternative approach was used in the synthesis of the herbicide 530, where the sulfoxide 529 was converted to 530 in a single step by heating with lithium chloride in refluxing pyridine <1997TL4339>. The one-pot transformation involves sigmatropic sulfoxide elimination, lithium chloride-induced demethylation of the carbomethoxy group, decarboxylation, and a final isomerization/aromatization step <1997TL4339>. 

Dibenzothienobisbenzothiophene has been synthesized by the intramolecular cyclization of aromatic methyl sulfoxides under acid conditions followed by demethylation <1999JMC2095>. Thus, treatment of the corresponding sulfoxide with trifluoromethanesulfonic acid gives the cyclized product which is demethylated in refluxing pyridine (Equation 73). 

Two mechanisms help protect the fetus from drugs in the maternal circulation (1) The placenta itself plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it. Several different types of aromatic oxidation reactions (eg, hydroxylation, /V-dealkylation, demethylation) have been shown to occur in placental tissue. Pentobarbital is oxidized in this way. Conversely, it is possible that the metabolic capacity of the placenta may lead to creation of toxic metabolites, and the placenta may therefore augment toxicity (eg, ethanol, benzpyrenes). (2) Drugs that have crossed the placenta enter the fetal circulation via the umbilical vein. 

Demethylation of the TNT leading to the formation of 1,3,5-trini trobcnzcne (TNB) and following transformation (nitrodisplacement, reduction) leading to the target amines (Route C). Most attention has been paid to Route C as it is the most universal approach to the preparation of the substituted aromatic diamines. 

Since arucadiol and miltirone both have an aromatic "B" ring, enone 64 served as a common intermediate for both of these quinone pigments. The aromatization of 64 was readily achieved using 2,3-dicyano-5,6-dichloro-l,4-quinone (DDQ) (Equation 5.2). With substrate 65 in hand, only demethylation of the ethers was required to complete a synthesis of arucadiol (58). This transformation was accomplished in nearly quantitative yield using boron tribromide. Our synthetic arcudiol was spectrally identical with the natural material. 

Except for aromatization, the 14a-demethylation of lanosterol 64 seems to operate by the same sequence of events in order to remove the angular C(14) methyl group with concomitant introduction of the C(14) double bond to furnish 65 (Fig. 12). 

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