Methoxynaphthalenes bromination

SELECTIVE a-BROMINATION OF AN ARALKYL KETONE WITH PHENYLTRIMETHYLAMMONIUM TRIBROMIDE 2-BROMOACETYL-6-METHOXYNAPHTHALENE AND 2,2-DIBROMOACETYL-6-METHOXYNAPHTHALENE... 

A kinetic study9 of the mechanism of acid-catalysed chlorination of a range of substituted phenols by A-chlorobenzenesulfonamide has suggested a common mechanism for the compounds studied, with a change in rate-limiting step with the varying nature of the substituents. The formation of some novel addition products on bromination of some bicyclic aromatics has been reported.10 Bromination of 1-methoxynaphthalene... 

Naproxen was introduced to the market by Syntex in 1976 as a nonsteroidal antiinflammatory drug in an optically pure form. The original manufacturing process (Scheme 1) before product launch started from P-naphthol (1) which was brominated in methylene chloride to produce 1,6-dibromonaphthol (2). The labile bromine at the 1-position was removed with bisulfite to give 2-bromo-6-hydroxy-naphthalene that was then methylated with methyl chloride in water-isopropanol to obtain 2-bromo-6-methoxynaphthalene (3) in 85-90% yield from p-naphthol. The bromo compound was treated with magnesium followed by zinc chloride. The resultant naphthylzinc was coupled with ethyl bromopropionate to give naproxen ethyl ester that was hydrolyzed to afford the racemic acid 4. The final optically active naproxen (5) was obtained by a classic resolution process. The racemic acid 4 was treated with cinchonidine to fonn diastereomeric salts. The S -naproxen-cinchonidine salt was crystallized and then released with acid to give S -naproxen (5) in 95% of the theoretical yield (48% chemical yield) [8,9]. 

When dissolved in tetrahydrofuran, PTT (like pyridinium hydrobromide perbromide) is a source of Brf ions, the properties of which are different from those of molecular bromine. In particular, it is much less electrophilic and less reactive toward aromatic rings and double bonds. It is thus a selective hrominating reagent for ketones or ketals - when the molecule has double bonds or activated aromatic nuclei which would be attacked by bromine. The two examples of use of this reagent clearly differentiate between its reactivity from that of bromine. Reaction of bromine with 2-acetyl-6-methoxynaph-thalene (in ether solution) gives a mixture, the main constituent of which is the product resulting only from ring bromina-tion (2-acetyl-5-bromo-6-methoxynaphthalene). ... 

An interesting solution was provided by a process developed by the Zambon company. [197] Friedel-Crafts acylation of 2-methoxynaphthalene is followed by a ketaUsation with diethyl (RJl)-tartrate and a double bromination, at C-1 and in the side-chain, yielding a 92 8 mixture of diastereomers. After hydrolysis of the tartrate, the reaction mixture is heated to 90 °C in water. Thereby, under kinetic resolution and by a [l,2]-aryl migration with complete inversion at the stereogenic centre, bromonaproxen is formed, which is finally converted by reductive dehalogenation into enantiomericaUy pure (S)-naproxen. 

A novel regiospecific synthesis of islandicin was described by Glein etal. 145) (Scheme 21). Thus Fries rearrangement of l-propionyloxy-5-methoxynaphthalene followed by methylation and bromination yielded the ketone (172). Alkylation with sodium diethyl malonate followed by demethylation, ester hydrolysis and decarboxylation gave the acid (173). Elbs oxidation and sulfuric acid cyclisation of the acid yielded 1-O-methyl-islandicin (174). 

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