Methoxyphenyl demethylation

Synthesis (Cavalla and White (Wyeth), 1969 1969 Bradley 1980 Kleemann et al. 1999) By condensation of 2-(m-methoxyphenyl)butyronitrile with ethyl 4-iodobutyrate by means of NaNH2 in liquid NH3 to give ethyl 5-cyano-5-(m-methoxyphenyl)heptanoate, which is cyclized by hydrogenation with H2 over Raney Ni in cyclohexane to yield 6-ethyl-6-(m-methoxyphenyl)hexahydro-2H-azepin-2-one this ketone is reduced with LiAIH4 in THF to 3-ethyl-3-(m-methoxyphenyl)hexahydro-IH-azepine, which in turn, is reductively methylated with HCHO, H2 and Pd/C in ethanol to give 1-methyl-3-ethyl-3-(m-methoxyphenyl)-hexahydro-1H-azepine, and finally demethylated by refluxing with 80% HBr to yield a racemic mixture of the final product. 

An important extension of this method has made it possible to synthesize polycyclic benzofurans under the influence of various demethylating and dehydrating media.335 For such ring closures, pyridine hydrochloride is especially suitable thus coumestan has been synthesized from 4-hydroxy-3-(2-methoxyphenyl)coumarin.8 4,7-Di hydroxy-3-(2,4-dimethoxyphenyl)coumarin gives coumestol with aniline hydrochloride 336 other polymethoxycoumestans have been obtained with pyridine hydrochloride or with HBr (or HI) and acetic acid.337-339... 

The resulting solution was filtered through animal charcoal and, after addition of 2 liters of methanol, it was debenzylated by hydrogenation at 60°C over palladinized charcoal as a catalyst. After removal of the catalyst by filtration, the filtrate was concentrated by evaporation, whereupon the hydrochloride of l-p-methoxyphenyl-2-(p-3, 5 -dihydroxyphenyl-p-oxo)-ethylamino-propane (MP 244°C) crystallized out. For the purpose of demethylation, the 350 grams of the hydrochloride thus produced were refluxed for 2 hours with 3.5 liters of aqueous 48% hydrobromic acid. Upon cooling of the reaction solution, 320 grams of l-p-hydroxyphenyl-2-(p-3, 5 -dihydroxyphenyl-p-oxo)-ethylamino-propanehydrobromide (MP 220°C) crystallized out. 

The synthesis of bufotenine itself followed closely upon the proof of its structure. Hoshino and Shimodaira reduced the ethyl ester of 5-ethoxy-indole-3-acetic acid by the Bouveault-Blanc procedure to the corresponding primary alcohol, which was treated with phosphorus tribromide and then dimethylamine, to give the ethyl ether of bufotenine, which was demethylated with aluminum chloride (130). In a later synthesis, 2,5-dimethoxybenzyl cyanide (XXIII) was alkylated by Eisleb s method with dimethylaminoethyl chloride in the presence of sodamide to give l-(2,5-dimethoxyphenyl)-3-dimethylaminopropyl cyanide (XXIV), which was then hydrogenated over Haney nickel to yield 2-(2,5-di-methoxyphenyl)-4-dimethylaminobutylamine (XXV R = Me). De-methylation of this with hydrobromic acid, followed by oxidation of the product (XXV R = H) with potassium ferricyanide yielded bufotenine (XIX) via the related quinone (109). 

Disposition in the Body. Incompletely absorbed after oral administration bioavailability about 70%. Metabolised by N-demethylation to the active metabolite, phenobarbitone, and by p-hydroxylation. Over a period of 10 days, less than 2% of a dose is excreted in the urine as unchanged drug, about 30 to 35% is excreted as p-hydroxymethylphenobarbitone both free and conjugated, and up to 10% may be excreted as phenobarbitone. Small amounts of p-hydroxyphenobarbitone, 5-ethyl-5-(4-hy-droxy-3-methoxyphenyl)barbituric acid, and 5-ethyl-5-(4-hy-droxy-3-methoxyphenyl)-l-niethylbarbituric acid have also been detected in the urine. 

Diastereoselective [2+2] photocycloaddition of a polymer-supported cyclic chiral enone with ethylene has been reported (Scheme 12.33) [43]. The auxiliary was derived from (-)-8-(p-methoxyphenyl) menthol (87). Protection of the secondary alcohol and demethylation were carried out to give (-)-8-(p-hydroxyphenyl)menthyl acetate (88). An alkyl linker was introduced and finally loaded to poly (ethylene glycol) grafted Wang resin. Deprotection of the alcohol functionality was followed by esterification with cyclohexen-3-one-l-carboxylic acid to provide the chiral enone 89. The photochemical reaction with ethylene was performed by irradiating with light (k > 280 nm). Trifluoroacetic acid (TFA) or aqueous hydrolysis with... 

The treatment of saturated enolisable aldehydes and ketones with acids is known to result in aldol condensation [1]. In the case of arylethanoid derivatives, this treatment results concomitantly in aldol condensation followed by cyclisation and aromatisation. Furthermore, when the acid used is known to promote the demethylation of methoxyphenyl derivatives into phenols, this reaction appears to lead to a great structural diversity of biologically active natural and synthetic polyphenols. In this review, I will focus on the reaction of arylpropanoid and arylethanoid derivatives with acids, mainly boron tribromide but also simple protic acids. The former allows, in a one-pot procedure, aldol condensation, cyclisation, aromatisation and demethylation. The latter may be used... 

Bis-O-hydroxyphenyl) ether is synthesized as follows 5 Bis-(/ -methoxyphenyl) ether (24 g) is boiled for 4 h with 48 % aqueous hydrobromic acid (60 ml) and acetic anhydride (30 ml) (previously mixed with caution) and the whole is then poured into warm water (300 ml). On cooling, the bis(hydroxyphenyl) ether crystallizes in colorless leaflets (19.7 g, 93 %), m.p. 160-161°. Demethylation by A1C13 gives much resinous by-products. 

Another alternative approach primarily intended for the synthesis of 3-alkylphenols consisted in the reaction of (i) alkylmagnesiumbromides with 3-methoxybenzamide to afford the corresponding 3-methoxyphenyl n-alkylketone which was reduced (ii) by the Clemmensen method to the n-alkyl-3-methoxybenzene, demethylation of which with aluminium chloride was considered to give the 3-n-alkylphenol (ref. 15). 

The presence of electron-withdrawing groups positioned on an aromatic nucleus bonded directly to phosphorus can be a source of instability in the phosphorus-carbon bond. This situation is found particularly in (4-nitrophenyl)phosphonic acids. (2-Methoxy-4-nitrophenyl)phosphonic acid can be demethylated in 40% HBr, but cleavage of the carbon-phosphorus bond becomes more pronounced in a reaction with 48% HBr moreover, hydrogenation of the same acid over Raney nickel yields the expected (4-amino-2-methoxyphenyl)phosphonic acid, but a similar reduction of (2-hydroxy-4-nitrophenyl)-phosphonic ac id results in the separation of 3-aminophenol. These and other, similar, reactions have been surveyed by Freedman and Doak ". ... 

Obtained (by-product) by Fries rearrangement of phenyl cyclohexanecarboxylate with aluminium chloride at 120° for 2 h (1%) [1412]. - Preparation by demethylation of 4-methoxyphenyl cyclohexyl ketone (SM) by treatment with boron Iribrotnide in methylene chloride (76%). SM was obtained by Friede-Crafts acylation of anisole with cyclohexanecaiboxylic add chloride [1416]. 

Obtained by demethylation of l-[4-(3-chloro-propoxy)-3-methoxyphenyl]elhanone in concentrated sulfiiric acid at 65° fw 23 h (22%) [3207]. 

Also obtained by demethylation of 2-methoxyphenyl benzyl ketone (oil, b.p. gg, 130-140°),... 

Preparation by demethylation of 2-(4-bro-mophenyl)-l-(4-methoxyphenyl)etha-none with 48% hydrobromic acid in refluxing acetic acid for 7 h (89%) [5409], (82%) [5410]. 

Also, using sodium tetraphenylethene in THF, Tashiro et al. prepared disubsti-tuted [2.2]metacyclophanes in 1981 via intermolecular ring closure of the dimeric buildingblockl,2-bis[5-terr-butyl-3-(iodomethyl)-2-methoxyphenyl]-ethane[15]. As a side product of intramolecular reaction, they obtained a methoxy-substituted tetra-tert-butyl-[24]metacyclophane in 34% yield. Demethylation with BBrs gave 7. 

A genetically-engineered strain of Saccharopolyspora erythraea has been used to produce 2-nor-erythromycins. A mutant strain of S. fradiae generates tylosin analogues in which the mycinose sugar unit is converted to 2-demethoxy, 2-demethoxy-4-epi, and 2-0-demethyl derivatives. 4 -0-(4-methoxyphenyl)-acetyl-tylosin has... 

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