Demethylation hydrogen bromide

This tetrahydro-derivative, on demethylation by boiling in acetic acid containing hydrogen bromide, yields 6-acetyltetrahydro-a-morphimethine, m.p. 240-2° (vac.), which is hydrolysed by boiling normal soda solution to tetrahydro-a-morphimethine (II. MeO HO), m.p. 206-8° vac.) B. HCl, m.p. 243-9° vac ), — 29-6° (HjO) (Mosettig... 

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]. 

Pyridinium salt 422, prepared from nicotinaldehyde, was alkylated with dimethyl sodiomalonate and subsequently cyclized with hydrogen bromide to triester 423. Lithium iodide-induced demethylation, followed by decarboxylation... 

The above methyloctane is demethylated as follows. Mix 40 g of the above product with 100 ml of 48% hydrogen bromide and 320 ml of glacial acetic acid. Heat under reflux for 4 hours, and pour onto ice. Add portions of 10 N sodium hydroxide to the mixture until you get a pH of 4 to 5, then extract with ether. The ether extracts are combined, and extracted with three 150 ml portions of 2 N NaOH. These extracts are combined and acidified with acetic acid, which is then extracted with ether. Dry the combined ether extracts with MgSC 4 and evaporate under reduced pressure (vacuum) to remove the ether. Distill the residue, collecting the fraction boiling at 158-160° at 0.1 mm vacuo to get 20 g of dimetbyl-heptyl resorcinol. Tins demetbylation may be used on olivetol dimethyl ether to demethylate. 

Dopamine As a medicinal agent, dopamine, 2-(3,4-dihydroxyphenyl)-ethylamine (11.3.1), is synthesized by demethylation of 2-(3,4-dimethoxyphenyl)ethylamine (19.4.3) using hydrogen bromide [49-51]. 

Demethylation of the stilbene (2-5) by means of hydrogen bromide in acetic acid leads to DES (2-8) [2]. 

A new method for the demethylation of codeine to morphine, previously a capricious reaction, has been reported, the product being obtained in good yield. Demethylation by boron tribromide in chloroform gives 90—91%150 and by potassium t-butoxide in propanethiol gives 80% morphine.151 A patent describes an improved method for the preparation of codeinone from thebaine, by adding the alkaloid to anhydrous hydrogen bromide in solution in methylene chloride and dibutyl ether at -20 °C, in the presence of small quantities of iodine, followed by hydrolysis with aqueous sodium bicarbonate. The claimed yields of codeinone are 95% crude and 90% after purification.152 Codeinohe is an intermediate in the conversion of thebaine into codeine. An overall yield of 85% of codeine from thebaine, without purification of any of the intermediates, has been claimed for an... 

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... 

Prepared by Robinson condensation of 2,3,5-trimethoxytetrahydro-furan 88, 49) (available from furan), the ketone XXIX gave with subsequent reduction the 6-methoxytropan-3a-ol (XXXII) (see Section III,B) which, in turn, was demethylated by aqueous hydrogen bromide (90%) to (+ )-tropan-3a,6j8-diol (XXXI). As a condensing agent, p-toluenesulfonic anhydride gave good yields of 3a,6a-oxido-tropane (XLVI). 

Dihydro-i/< -codeinone is obtained in 40 per cent, yield by the Oppenauer oxidation of dihydroallo-with phosphorus pentachloride gives 8-chloro- and 1 8-dichlorodihydrocodide, which are also produced in the same way from dihydro-i/ -codeine-A thionyl chloride effects chlorination in the aromatic nucleus only. With phosphorus tribromide it apparently suffers replacement of the hydroxyl group by bromine, loss of hydrogen bromide, and demethylation, as the product is desoxymorphine-D [240] (see Chap. VIII). 

Boron tribromide in methylene chloride or benzene is recommended for demethylation of polymethoxybenzophenones, where use of hydrogen bromide in acetic acid is often accompanied by cyclodehydration of the resulting poly-hydroxybenzophenones to give xanthones. However, unexpected difficulties were encountered in the case of 2,2, 3, 6-tetramethoxybenzophenone (1), where the major product (76% yield) was the monomethyl ether (2), the desired tetra-... 

The incorporation of two aryl bridgeheads, both linked in turn through the 2,6-substitution of a pyridine nucleus has provided an intermediate which has been converted to a crown ether. Thus, 2,6-bis(2, 6 -dimethoxyphenyl)pyridine after demethylation with boron tribromide or hydrogen bromide in 65% yield was reacted in dimethylsulphoxide containing potassium carbonate with the a,o)-diiodo derivative of triethylene glycol to afford a crown ether system in 22% yield (ref. 199). 

In a similar way, 2,3-dimethoxybenzaldehyde with HO-protected 6-chlorohexan-1-ol and lithium afforded after acidic treatment 1,2-dimethoxy-3-(7-hydroxy-heptyl)benzene. Demethylation and bromide formation with boron tribromide gave 1,2-dihydroxy-3-(7-bromohepty0benzene which interacted with lithium-1-octyne in tetrahydrofuran containing hexamethylphosphoric triamide to give after selective catalytic hydrogenation, (15 1)-urushiol (ref. 138). In a different approach this has been synthesised in moderate yield from 2,3-dimethoxyphenyllithium and 1,7-dibromheptane as shown in the following scheme (ref. 139)... 

Anethole on treatment with hydrogen bromide undergoes Markownikoff s addition to yield anethole hydrobromide. The resulting product in the presenee of sodamide and liquid ammonia gives an intermediate produet which on subsequent demethylation followed by isomerization in alkali yields the official compound. 

Bromination of the latter produced a transient dibromide that underwent cycliza-tion to the desired 8-(A, A -dimethyl)aza-2-bromobicyclo[3.2.1]octane hydrobromide (i.e., tropane nucleus). Base treatment effected dehydrohalogenation and then A -demethylation and subsequent addition of hydrogen bromide (and neutralization) afforded the corresponding (presumed) mdo-3-bromide. Strikingly, sulfuric acid treatment of the bromide was apparently required to replace the bromine with (after basification) a hydroxyl group, and it is reported iJiat the wrong isomer (hydroxyl exo) resulted ... 

A similar differential reactivity is observed at the 2-position of pyrogallol trimethyl ethers and it forms the basis of the preparation of syringic acid (32) from trimethylgallic acid (31) by controlled demethylation in sulphuric acid [47] and of the derivative (34) from podophyllotoxin (33) by the action of hydrogen bromide [48]. 

Preparation by demethylation of 3,4-dichloro-5-methoxy-propiophenone (m.p. 85°) with 30% hydrogen bromide in acetic acid at reflux for 48 h (88%) [6386]. 

Reflux 6.9 g triphenylphosphine and 6.6 g lauryl bromide (or equimolar amount of homolog) in 40 ml xylene for 60 hours. Remove solvent and wash residue with 5X20 ml ether (by decanting) to get 11 g lauryl triphenylphosphonium bromide (I). To a stirred suspension of 5.6 g (0.011M)(I) in 50 ml ether add 0.01M butyllithium solution (see Organic Reactions 8,258(1954) for preparation). Stir Vz hour at room temperature and slowly add 1.66 g 3,5-dimethoxybenzaldehyde (preparation given elsewhere here) in 10 ml ether over Vi hour. After 15 hours, filter, wash filtrate with water and dry, evaporate in vacuum. Dilute residue with pentane, filter and remove solvent. Dissolve the residual oil in 25 ml ethyl acetate and hydrogenate over O.lg Adams catalyst at one atmosphere and room temperature for 2 hours. Filter and evaporate in vacuum to get the 5-alkylresorcinol dimethyl ether which can be reciystallized from pentane and demethylated as described elsewhere here. 

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