Naphthalene, 2-acetyl-6-methoxy

Gore et al.426 have used chloroform as a solvent for acetylation catalysed by aluminium chloride and at 45-55 °C find that a 2-methoxy substituent in naphthalene increases the reactivity of the 1 position 1.72 times, of the 6 position 3.8 times, and of the 8 position, 0.9 times the former and latter of these results indicate a considerable steric effect. Likewise, a 2-bromo substituent caused the reactivity of the 6 and 8 positions to be 0.63 and 0.58 times that of the corresponding positions in the unsubstituted compound. At 20-25 °C the relative reactivities of some polycyclics were as follows427 1-naphthyl, 1.0 3-phenanthryl 0.64 9-phenanthryl, 0.02 1-phenanthryl, 0.29 2-naphthyl, 0.28 2-phenanthryl, 0.12 4-phenanthryl, 0.0085. Some of these results seem to be due to steric hindrance, and the large difference in reactivity of naphthalene and biphenyl seems erroneous. 

Compound 1 is completely hydrogenated to the saturated ketone, 4-(6-methoxy-2-naphthyl)-3-butan-2-one. Compound 2 is hydrogenated in high ytield (90%) to the saturated ketone, 2-acetyl-5,8-dimethoxy-tetrahydro-naphthalene, which can be obtained in the pure form by fractional crystallization from chloroform. 

Synthesis of racemic naproxene Friedel-Crafts acylation (aluminum chloride - nitrobenzene) of p-naphthol methyl ether affords 2-acetyl-6-methoxy naphthalene, which, when treated with either dimethyl sulfonium or dimethylsulfoxonium methylide, gives 2-(6-methoxynaphthalen-2-yl)propylene oxide. Treatment of the latter with boron trifluoride etherate in tetrahydrofuran gives 2-(6-methoxynaphthalen-2-yl)propionaldehyde, which is oxidized using Jones reagent (4 M chromic acid) to yield the racemic 2-(6-methoxynaphthalen-2-yl)propionic acid. 

C. 2-Bromoacetyl-6-methoxynaphthalene. To a solution of 1 g. (0.005 mole) of 2-acetyl-6-methoxynaphthalene2 in 10 ml. of anhydrous tetrahydrofuran3 (Note 7) contained in a 125-ml. Erlenmeyer flask is added 1.88 g. (0.005 mole) of PTT in small portions. About 10 minutes is required for this operation. A white precipitate forms immediately and the solution becomes pale yellow. After 20 minutes, 50 ml. of cold water is added, and the crystalline precipitate (Note 8) is filtered and washed with 10 ml. of water. The crude, white 2-bromoacetyl-6-methoxy-naphthalene (ca. 1.3 g., m.p. 100-105°) is recrystallized from 32 ml. of cyclohexane to give 1.1 g. (79%) of crystalline product, m.p. 107-109° (lit. 107-1080)4 (Notes 9 and 10). 

Figure 3.4 Acetylation at 393 K of 2-methoxynaphthalene with acetic anhydride over HBEA-15 zeolite. Total yield in acetyl-methoxynaphthalene (x) and yields in l-acetyl-2-methoxynaphthalene >), 2-acetyl-6-methoxynaphthalene ( ) and l-acetyl-7-methoxy-naphthalene (a). Reprinted from Journal of Molecular Catalysis A Chemical, Vol. 159, Fromentin et al., Acetylation of 2-methoxynaphthalene with acetic anhydride over a HBFA zeolite, pp. 377-388, Copyright (2000), with permission from Elsevier...

Free-ion attack is more likely for sterically hindered R. The ion CH3CO has been detected (by IR spectroscopy) in the liquid complex between acetyl chloride and aluminum chloride, and in polar solvents, such as nitrobenzene but in nonpolar solvents, such as chloroform, only the complex and not the free ion is present." In any event, 1 equivalent of catalyst certainly remains complexed to the product at the end of the reaction. When the reaction is performed with RCO+SbFg, no catalyst is required and the free ion" " (or ion pair) is undoubtedly the attacking entity." The use of LiC104 on the metal triflate-catalyzed Friedel-Crafts acylation of methoxy-naphthalene derivatives has been examined, and the presence of the lithium salt leads to acylation in the ring containing the methoxy unit, whereas reaction occurs in the other ring in the absence of lithium salts." Note that lithium perchlorate forms a complex with acetic anhydride, which can be used for the Friedel-Crafts acetylation of activated aromatic compounds." ... 

The reaction was carried out at 100°C with sulpholane as solvent and acetic anhydride as acylating agent [9]. The results conversion of 2MN and the ratio of the two ketone products, l-acetyl-2-methoxynaphthalene (lAC) over 2-acetyl-6-methoxy-naphthalene (2AC), are given in Table 2. The selectivity for the two products was better than 95% in all cases. 

We have carried out reactions with other substrates, in particular [3-methoxy-naphthalene. The reaction is remarkably facile and leads to 1-trifluoroacetyl 2-methoxynaphthalene as the only reaction product, in 68 % yield (eqn. 11). In this case, the most reactive position is position 1 (the position para with respect to the methoxy group is now blocked). Reactivity in position 6 has been observed in a limited number of cases, for the acetylation, especially when zeolites are used (ref. 33). 

The acylation of 2-substituted naphthalenes usually occurs at l-(a-) position [2]. But there are some exceptions where it can give rise to different kind of isomers by changing the reaction conditions [9]. 2-Methoxy naphthalene (2-MON) has been shown to be acetylated mostly either in l-(a)-position to yield l-acetyl-2-methoxynaphthalene or at 6-(P)-position to yield 2-acetyl-6-methoxynaphthalene depending on the catalyst and solvent systems used [10]. The a-isomer is rep)orted in most of the cases. But in the case of AICI3 catedysed acylation of 2-MON in presence of certain solvents, especially nitro compounds, a solvated nitro complex is formed by which acylation at the P-position is preferred [3]. 

The effect of solvent was tested by conducting the reaction in presence of nitrobenzene (Ph-N02), dichloroethane (DCE) and carbon disulphide (CS2). The volume of the solvents was kept constant (25ml). 2-MON and acetic anhydride were taken under otherwise similar conditions. DCE and PI1NO2 offer practically the same conversions (Fig.8). The selectivity also remains the same towards the ortho product (l-acetyl-2-methoxy naphthalene). In the absence of solvents, the conversions were much lower. 

Mordenite etc. Dodecatungstophosphoric acid (DTPA) and the ion exchange resin catalysts showed maximum activities. Clay based catalysts and sulphated zirconia showed a moderate activity. Zeolites did not demonstrate any activity to the reaction due to pore size restriction. A 100% selectivity towards the ortho product (l-acetyl-2-methoxy naphthalene) was observed for almost all the reactions for all the catalysts. The para product (2-methoxy-6-acetyl naphthalene) was formed when the aluminium chloride was used as a homogeneous catalyst with nitrobenzene as the solvent. The reaction product was isolated and conformed by the melting point, FT-IR, H-NMR, etc. The reaction is intraparticle diffusion limited. A different catalyst would be required to get p-product selectively. 

Moreau, R, Finiels, A., Meric, R, and Fajula, F. 2003. Acetylation of 2-methoxy-naphthalene in the presence of Beta zeolites influence of reaction conditions and textural properties of the catalysts. Catal. Lett. 85 199-203. 

Acetyl-6-methoxy-naphthalene may be prepared by the acylation of 6-methoxynaphthalene. The resulting product is then subjected to a series of reactions, namely Wilgerodt-Kindler reaction, esterification, alkylation and hydrolysis ultimately yields /)Z-Naproxen. Resolution of the resulting racemic mixture is caused through precipitation of the more potent /)-enantiomer as the cinchonidine salt. 

Naproxen is prepared (13) by the acylation of 6 substituted naphthalenes by AcCI forming the 2-acetyl derivative, which is further converted to 2-naphthyl acetic acid. Esterification and alkylation of 2-naphthyl acetic acid in the prescence of H2SO4, MeOH, NaH, Mel and with NaOH gave after hydrolysis the naphthyl propionic acid. Resolution of 2-(6-methoxy-2-naphthyl) propionic (Naproxen) was readily achieved by crystallization of the cinchonidine salt. 

Acetyl naphthalene 24 on photoirradiation undergoes [4 + 2]-cycloaddition reaction with chiral electron acceptor alkene, (5)-(2-methoxy methyl-1-... 

Naproxen, [(S)-6-methoxy ex -methyl 2-naphthalene acetic acid] is a non steroidal anti-inflammatory (NSAID), indicated for the treatment of rheumatoid, osteo and juvenile arthritis, as well as ankylosing spondylitis [16]. It is very useful for the relief of mild and moderate pain. Naproxen has also caused kidney problems and has sometimes caused blood pressure increases, especially for older people [17]. In the amperometric method, mercury [18] and Pt [19] have been used as the electrode materials of choice. However, mercury electrodes have some limitations as they are toxic and there is rapid deterioration of the electrode response. Conversely, the use of Pt electrodes shows high background current in the CV resulting in low S/B ratio with the addition of analyte and the linear dynamic range of concentrations is also very narrow. During the course of the synthesis of naproxen, other conditions such as pH, light and temperature may favor the formation of impurities such as 2-acetyl-6-methoxy naphthalene (AMN) (Scheme 1) in addition to naproxen, and it is very important to detect this compound precisely in both raw materials and final products. 

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