6-Bromo-2-methoxynaphthalene

To a dry flask containing 8 gm (0.329 atom) of magnesium turnings, 150 ml of dry ether, and a crystal of iodine is added dropwise a solution of 50 gm (0.212 mole) of 2-bromo-6-methoxynaphthalene in 150 ml of dry benzene. The reaction mixture is refluxed on a water bath and 2 ml of ethyl bromide is added every hour for 5 hr. After this time, most of the magnesium has reacted, the flask is cooled, and a solution of 37 gm (0.328 mole) of 1-methyl-2-piperidone in 100 ml of ether is added dropwise. After the addition, the reaction mixture is refluxed for 3 hr, cooled, decomposed with dilute hydrochloric acid, the solid hydrochloride of the product, after filtration, reacts with warm aqueous sodium hydroxide, is extracted with ether, dried, and distilled to afford 11.0 gm (20.6%), b.p. 175°C (2.0 mm). 

Bromo-6-methoxynaphthalene Ethyl bromoisobutyrate Potassium bisulfate Sodium hydroxide... 

A first step involves the preparation of 2-cyano-6-methoxynaphthalene (cyanonerolin). 90 g of 2-bromo-6-methoxynaphthalene are heated with 60 g of cuprous cyanide in a metal bath at 240° to 250°C stirring for one hour. At the instant when the cuprous cyanide begins to react and dissolves, the mass turns brown, liquefies and heats up strongly. The molten mass is poured onto a cold surface, is pulverized and sifted. This powder is treated with dilute ammonia (1 liter of water to 300 cc of commercial ammonia solution). The solution is filtered on a Buchner filter and the precipitate that remains on the filter is washed with dilute ammonia and then with water. 

A mixture consisting of 2-bromo-6-methoxynaphthalene (20 mmol), 4-carboxyox-ybenzene boronic acid (20 mmol), and 40 ml of 1-propanol were mixed at ambient... 

Friedel-Crafts acylation. Posner el al. have developed a remarkably efficient route to the methyl ether of the steroid 11-oxoequilenin (5) from 2-methyl-2-cyclopentenone (1). jS-Addition of the organocoppermagnesium reagent 2 to 1 followed by a-alkylation with ethyl iodoacetate proceeds stereospecifically to give the secosteroid 3 in 94% yield. The final step requires an intramolecular Friedel-Crafts acylation, a reaction that has proved troublesome in previous syntheses of steroids via 9,11-secosteroids. And indeed attempts to cyclize the free acid corresponding to 3 with HF proceeded in yields of 10%. However, cyclization of the ketal acid 4 gives stereochemically pure 5 in 75% yield based on recovered secosteroid. The overall yield from 2-bromo-6-methoxynaphthalene is 52%. 

C11H9BrO 2-bromo-6-methoxynaphthalene 5111-65-9 25.00 1.4473 2 21668 C11H10O3 7-methoxy-4-methylcoumarin 2555-28-4 25.00 1.1909 2... 

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]. 

Bromo-6-methoxynaphthalene has been transformed in 91% yield to 2-hydroxy-6-methoxynaphthalene by conversion in tetrahydrofuran to the Grignard reagent. This solution wasgradually added to 2-tert-butylperoxy-1,3,2-dioxaborolane, reacted at ambient temperature for 16 hours, refluxed for 3 hours and worked up by acidic treatment to afford the product (ref.197). 

Another biphasic Heck reaction was described by Beller et al. [25]. The medium consisted of xylene and ethylene glycol. The catalyst was a palladium complex with a carbohydrate-substituted triphenylphosphine (9 and 10). Aryl bromide (15 mmol), styrene (22.5 mmol), and NaOAc (16.5 mmol) were suspended in 10 mL of xylene and 10 mL of ethylene glycol. The catalyst precursor (Pd(OAc)2) and ligand (Pd/ ligand ratio 1 3) were added and the mixture was heated to 130 °C for 20 h. Both ligands A and B showed better results than the TPPTS ligand (cf Section 2.2.3.2) in the case of activated aryl bromides (for instance, p-nitrobromobenzene). However, for deactivated aryl bromides (for instance, 2-bromo-6-methoxynaphthalene) TPPTS proved to generate a more stable and thus more productive catalyst system. 

An example of an industrial Heck reaction of an aryl bromide is the announced synthesis of Naproxen by Albermarle. Toward that end, 2-bromo-6-methoxynaphthalene is reacted with ethylene in the presence of a homogeneous palladium catalyst. Apparently, as a ligand a sterically hindered basic phosphine is used. Known Pd-catalyzed hydro-carboxylation of 2-methoxy-6-vinylnaphthalene and subsequent resolution give access to Naproxen (Scheme 3). In addition, it was shown that Ketoprofen can be produced by a similar reaction sequence. 

Other examples for which homogeneously catalyzed Heck reactions have been exploited toward an industrial production include the preparation of the fragrance Lihal developed by Givaudan, the synthesis of the nonsteroidal anti-inflammatory drug Nabumeton by Hoechst-Celanese, ° and the synthesis of the sunscreen agent 2-ethylhexyl p-methoxy-cinnamate (EHMC) by Hoechst AG and other companies (Scheme 6). Noteworthy, Nabumeton is obtained in one step via coupling and domino isomerization reaction of 2-bromo-6-methoxynaphthalene with 3-buten-2-ol. ° ... 

NSAIDs), is produced by the Albemarle Corporation by a Heck reaction of 2-bromo-6-methoxynaphthalene with ethylene, followed by carbonylation of the product [623]. Monomers for coatings are produced by a Heck couphng on 2-bromobenzocyclobutene [624]. A key step in the production of Montelukast sodium (Singulair), a leukotriene receptor antagonist for the treatment of asthma in children and adults, also makes use of the Heck reaction by way of coupling an allyl alcohol with methyl 2-iodobenzoate to give a (2-arylethyl) alkyl ketone. 

The following operations must be conducted as rapidly as possible since the flask will be open briefly to the atmosphere Close the stopcock on the gas manifold, which maintains an inert atmosphere in the 250-mL flask. Now, working quickly, stop the stirrer, remove the inert gas needle from the manifold and the vent needle from the rubber septum. Remove the rubber septum from the flask and insert a powder funnel. Pour the 2-bromo-6-methoxynaphthalene as quickly as possible into the 250-mL flask. If some of the bromo compound adheres to the funnel, tap it a few times to dislodge as much as possible, and remove the funnel. Ignore any remaining solid in the funnel. Add the catalyst from the weighing paper directly into the opened flask. Immediately, reattach the rubber septum to the flask and insert the needle from the manifold and the exit needle into the septum. Open the stopcock on the gas manifold to reestablish an inert atmosphere in the flask. Start the stirrer again, and continue to flush the flask with inert gas for 15 to 30 minutes. ... 

Remove the inert gas needle and vent needle from the rubber septum after 15 to 30 minutes, but do not remove the rubber septum. Store the round-bottom flask on a cork ring in a place in the laboratory recommended by your instructor. Allow the reaction to proceed for at least 24 hours or until the next laboratory period. During that time the solution becomes cloudy (formation of lithium bromide), and the mixture retains a yellow color. Be sure to maintain anhydrous conditions during this time period. The mechanism for the reaction of the lithium enolate with the 2-bromo-6-methoxynaphthalene is shown in eqs 4,5, and 6. 

Purchased from Alfa-Aesar, 2-bromo-6-methoxynaphthalene, AAA19450-18. 

The organic layer contains small amoimts of imreacted 2-bromo-6-methoxynaphthalene, 2-methoxynaphthalene, dicydohexylamine, and a very small amount of unhydrolyzed terf-butyl ester of naproxen. 

Weight of the racemic naproxen, and percentage yield based on the 2-bromo-6-methoxynaphthalene. 

A. Carbocyclic - A few new methods are available to prepare the steroidal skeleton. For tne most part, these involve variations of the previously reported methods for the total synthesis of steroids. Racemic equilenin is prepared stereo-specifically starting with 2-bromo-6-methoxynaphthalene and the i "butyl enol ether of 2-methyl-l,3-cyclopentanedione. Estrone was prepared from the cheap natural product eugenol the key intermediate m-methoxyallylbenzene. Progress toward the total synthesis of terpenes, specifically the pentacyclic triterpene alnusenone, is reported. The synthesis of B-nor, B-nor-D-homo, or normal steroids by the use ot an electrophilic reagent on a bicyclic enamine is recorded. In addition, a bicyclic intermediate can be converted into a D-homo-8g-methyl-B-norestrane. ... 

The third route for the preparation of steroids with the initial formation of the 00—Ci4 bond proceeds through cycloalkenylnaphthalenes, the diene condensation of which with maleic anhydride enables the and 0 2 atoms to be introduced with the formation of ring C (Table 7). Cycloalkenylnaphthalenes (300 R = H, Me n =1,2) are readily obtained by the Grignard reaction between 2-bromo-6-methoxynaphthalene and the corresponding cyclic ketones, with subsequent dehydration of the tertiary alcohols formed [393-395]. Their prolonged fusion with maleic anhydride enables high yields of the adducts to be obtained (Scheme 29) [396-398]. 

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