Acetyl-6-METHOXYNAPHTHALENE

The reaction mixture is cooled in an ice bath and poured, with ma nual stirring, into a 600-ml. beaker containing 200 g. of crushed ice, and then treated with 100 ml. of concentrated 

The yellow distillate (ca. 40 g., m.p. 85-95°) is recrystallized from 75 ml. of methanol, cooled in an ice bath (Note 8) and filtered. The yield of white crystalline 2-acetyl-6-methoxy-naphthalene (Note 9) is 22.5-24 g. (45-48%), m.p. 106.5-108° (lit. 104r-105°).3 

The nitrobenzene may be dried by distilling the first 10% and using the residue directly, or by standing over anhydrous calcium chloride overnight and filtering. 

2-Methoxynaphthalene (Matheson Coleman and Bell), m.p. 71.5-73°, was used without further purification. 

Acetic anhydride can be used instead of acetyl chloride. However, it is then necessary to take two molecular equivalents of aluminum chloride per mole of anhydride and the amount of nitrobenzene must be increased by about 30%. About the same yield of ketone is obtained. 

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Another patent apphcation (28) describes the use of zeolite/TUD-1 with optionally a metal function for a variety of reactions. In an example, as-synthesized MCM-22 / TUD-1 was tested for acylation of 2-methoxynaphthalene with acetic anhydride to 2-acetyl-6-methoxynaphthalene at 240°C. After reaction for six hours, conversion of 2-methoxynaphthalene reached 56% with 100% selectivity to 2-acetyl-6-methoxynaphthalene. Other zeolite catalysts were similarly tested, but none were nearly as effective. 

Acetylenedicarboxylic acid, dimethyl ester, 50, 25, 36 Acetylenes, reaction with tri-methylsilyl azide, 50, 109 Acetylenic sulfonium salts, furans from, 53, 3 2-Acetylindane-l,3-dione, 52, 4 2-ACETYL-6-METHOXYNAPHTHALENE, 53, 5... 

The procedure herein described is a modification of that of Haworth and Sheldrick,3 the efficiency of which has been confirmed by many authors.4-7 2-Acetyl-6-methoxynaphthalene has also been prepared by the reaction of methylzinc iodide on 6-methoxy-2-naphthoyl chloride.8... 

Whatever the zeolite, 1-AMN is rapidly isomerized within the micropores into 2-acetyl-6-methoxynaphthalene (2-AMN). The 2-AMN/l-AMN ratios in the RM and AM mixtures are quite similar with H-FAU zeolite but smaller in RM than in AM with H-BEA and especially H-MFI (Table 2.2). This indicates limitations in the desorption of the linear 2-AMN molecules from the micropores of the latter two zeolites. In the case of H-BEA, these unexpected limitations were... 

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...

SELECTIVE SYNTHESIS OF 2-ACETYL-6-METHOXYNAPHTHALENE OVER HBEA ZEOLITE... 

Aromatic ketones are important intermediates in the production of fine chemicals and pharmaceuticals1,2. Thus, the anti-rheumatic Naproxen is produced by the Friedel-Crafts acetylation of 2-methoxynaphthalene into 2-acetyl-6-methoxynaphthalene and subsequent Willgerodt-Kindler reaction. Commercial acylation processes involve over-stoechiometric amounts of metal chlorides (e g. AICI3) as catalysts and acid chlorides as acylating agents, which results in a substantial formation of by-products and in corrosion problems. This is why the substitution of these corrosive catalysts by solid acid catalysts and of acid chlorides by anhydrides or acids is particularly desirable. 

This paper deals with the selective synthesis of 2-acetyl-6-methoxynaphthalene, precursor of Naproxen, over zeolite catalysts and especially over HBEA zeolites. As has been previously observed3 8, acetylation of 2-methoxynaphthalene occurs preferentially at the kinetically controlled 1-position with formation of l-acetyI-2-methoxynaphthalene (I). The desired isomer, 2-acetyl-6-methoxynaphthalene (II) and the minor isomer, l-acetyl-7-methoxynaphthalene (HI), are the other primary products. However, it will be shown that in presence of 2MN, isomerization of I can occur allowing a selective production of II, the desired product the effect of the operating conditions (solvent, temperature) and of the acidity and porosity of the zeolite catalyst will be presented. 

Selective Synthesis of 2-Acetyl-6-methoxynaphthalene over HBEA Zeolite... 

Over HBEA zeolites, acetylation of 2-methoxynaphthalene with acetic anhydride leads mainly to l-acetyl-2-methoxynaphthalene. However, the desired product, i.e. 2-acetyl-6-methoxynaphthalene, precursor of Naproxen is obtained at long reaction time by an intermolecular irreversible isomerization process. A very selective production of II (83%) can be obtained by acetylation of 2-methoxynaphthalene over a commercial HBEA zeolite (Si/Al = 15) at 170°C, with nitrobenzene as a solvent. With dealuminated HBEA samples (framework Si/Al ratio between 20 and 40), better results could be expected. Furthermore, preliminary experiments showed that this selective synthesis of 2-methoxynaphthalene can be carried out in a flow reactor system. 

Selective Synthesis of 2-Acetyl-6-methoxynaphthalene over HBEA Zeolite 145 E. Fromentin, J.-M. Coustard and M. Guisnet... 

The catalytic test reaction, the acylation of 2-methox)maphthalene (2MN), distinguishes between the inner and outer surfaces by means of product selectivity. Absorption experiments under the same reaction conditions show that the linear ketone product 2-acetyl-6-methoxynaphthalene (2AC) can pass through the 12-ring channels of beta whereas the other product l-acetyl-2-methoxynaphthalene (lAC) is too bulky to enter into any zeolite except Y. Once formed, lAC is unstable in the presence of acids and can deacylate to give the starting material (see reaction scheme 1). Since 1 AC can only form outside the micropore space of zeolite beta, the yield can be used as a measure of the catalytic activity on the external surface, although high yields can be expected because the 1-position is the most favoured for electrophilic attack. 

Acetylation of 2-methoxynaphthalene by acetic anhydride over HBEA zeolite gives l-acetyl-2-methoxynaphthalene, 2-acetyl-6-methoxynaphthalene and a small amount of l-acetyl-7-methoxynaphthalene (equation 45) . The l-acetyl-2-methoxynaphthalene rearranges to the other isomers under longer contact times, probably involving both intermolecular transacylation and intramolecular rearrangements (equation 46). 

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]. 

To mention some examples, benzoylation of xylenes was particularly studied because of the use of dimethylbenzophenones as UV-light stabilizers in plastics. Moreover, 2-acetyl-6-methoxynaphthalene represents the precursor to the antirheumatic Naproxen.i ortho- and para-Hydroxy-acetophenones are widely used for the synthesis of aspirin and paracetamol (4-acetamidophenol), respectively. orf/zo-Hydroxyacetophenone is also a key intermediate in the production of 4-hydroxycoumarin and warfarin, both used as anticoagulant drugs in the therapy of thrombotic diseases, and it is also employed in the synthesis of flavonones. ... 

Isomerization of 1-acetyl-2-methoxynaphthalene was investigated over HFAU, HBEA and HMFI zeolites (batch reactor, T=120°C). Due to its pore size, HMFI was inactive for isomerization while HFAU is about 3 times more active than HBEA. This can be attributed to the easier desorption of the isomers from the HFAU pores. However, the selectivity of 2-acetyl-6-methoxynaphthalene (the desired isomer) is favoured over HBEA. Analysis of the compounds retained in the zeolite pores show that the reaction occurs inside the micropores of the zeolites. Indeed, the desired isomer was found to be retained in the pores of HMFI showing that even for this zeolite, isomerization occurs in its micropores and that the desorption of the reaction products appears to be the limiting step. 

An essentially more elegant and shorter synthesis is the asymmetric hydrogenation of naphthacrylic acid, which is accessible by electrocarboxylation of 2-acetyl-6-methoxynaphthalene in an undivided cell with a sacrificial aluminium anode. [198]... 

As already underlined, the acetylation of 2-methoxynaphthalene with acetic anhydride is particularly investigated due to the use of 2-acetyl-6-methoxynaphthalene (21) as an intermediate for the synthesis of (5)-Naproxen, a nonsteroidal anti-inflammatory drug (Scheme 3.10). 

The desired product 2-acetyl-6-methoxynaphthalene (21) is obtained in 80% yield in the presence of a polar solvent such as nitrobenzene and zeolite HBEA as catalyst, because it has a more restricted pore structure that allows the preferential formation of isomo- 21 less hindered with respect to isomCTs 19 and 20 [56]. 

Following Noyori s success in using chiral P-amino alcohols as ligands with arene-ruthenium(II) precursors [66], (5)-lactic acid and mandelic acid-based P-amino alcohol ligands 46 and 47 were employed in the Ru-catalysed ATH of various ketones (4-substituted acetophenones, 2-acetyl-6-methoxynaphthalene,... 

Phenyltrimethylammonium perbromide reacts like pyridinium perbromide but is easier to prepare and more stable. It dissolves easily in tetrahydrofuran, in which these reactions are performed. It monobromi-nates selectively ketones and cyclic ketals in a-posi-tion without affecting double bonds and reactive benzene rings.—E 2-Acetyl-6-methoxynaphthalene- 2-(co-bromoacetyl)-6-methoxynaphthalene. Y 80%. 

Sb(0S02CF3)3 has been reported as Lewis catalyst for reactions requiring traces of water. Benzoylation of toluene, acylation of m-xylene, and sulfonylation of toluene were examples demonstrating its role in Friedel-Crafts reactions [26]. Also, catalytic amount of Sb(OTf)3 catalyzed the reaction of 2-methoxynaphthalene with acetic anhydride in nitromethane-lithium perchlorate to afford 2-acetyl-6-methoxynaphthalene, a well-known intermediate for the synthesis of naproxen, in a high yield [27]. 

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