6-Acyl-2-methoxynaphthalenes

Acyl-2-methoxynaphthalenes have been prepared in a large-scale procedure which is dependent on the reversible acylatton of 2-methoxynaphthalene to give the thermodynamic product (ref. 125). 

In a similar scheme, acylation of 2-methoxynaphthalene gives ketone, 15. This is then converted to the acetic acid by the Wilgerodt reaction. Esterification, alkylation of the carbanion (sodium hydride methyl iodide), and finally saponification affords naproxen (17). The intense current effort on nonsteroid antiinflammatory agents and acrylacetic acids in particular make... 

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. 

Friedel-Crafts acylation is widely used for the production of aromatic ketones applied as intermediates in both fine chemicals and pharmaceutical industries. The reaction is carried out by using conventional homogenous catalysts, which represents significant technical and environmental problems. The present work reports the results obtained in the Friedel-Crafts acylation of aromatic substrates (anisole and 2-methoxynaphthalene) catalyzed by Beta zeolite obtained by crystallization of silanized seeds. This material exhibits hierarchical porosity and enhanced textural properties. For the anisole acylation, the catalytic activity over the conventional Beta zeolite is slightly higher than with the modified Beta material, probably due to the relatively small size of this substrate and the weaker acidity of the last sample. However, the opposite occurred in the acylation of a bulky substrate (2-methoxynaphthalene), with the modified Beta showing a higher conversion. This result is interpreted due to the presence of a hierarchical porosity in this material, which favors the accessibility to the active sites. 

In contrast, the opposite result was observed when these materials were used in the acylation of a bulky substrate (2-methoxynaphthalene, 2-MN). In this case, l-acetyl-2-metoxynaphthalene (1-A,2-MN) and 6-acetyl-2-metoxynaphthalene (6-A,2-MN) are the main reaction products (Scheme 2). The latter is an intermediate for the preparation of Naproxen (antiinflammatory drug) and, therefore, the most interesting product. Initially, 2-MN acylation leads to 1-A,2-MN (the kinetically controlled product). However, at long times, the selectivity to 6-A,2-MN usually increases due to two secondary reactions transacylation of 1-A,2-MN with a molecule of 2-MN and protodeacylation of 1-A,2-MN yielding 2-MN [7],... 

The Beta material prepared by seed silanization show interesting catalytic properties in aromatic acylation reaction, especially when using a bulky substrate, such as 2-methoxynaphthalene. The superior activity and selectivity exhibited by this sample has been related to the presence of a hierarchical porosity, which decreases the steric and diffusional hindrances, favoring the accessibility to the active sites and allowing the occurrence of the transacylation reaction. 

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. 

In this reaction, nitrobenzene as solvent has an important function because it causes acylation to occur predominantly at the 6-position, whereas l-acetyl-2-methoxynaphthalene is the principal product when carbon disulfide is used. The main feature of this procedure is the particular attention given to temperature control in order to obtain reliable results. It has been observed that the ratio of 6-acetylated to 1-acetylated nerolin is dependent on the temperature, the lower temperatures favoring 1 -acetylation. Below 0° the yield of 6-acetylated product is only 3-10%. At higher temperatures the 6-acetylated product predominates, but an increased amount of tarry material is formed. 

Amorphous and mesostructured Zr02 solid catalysts impregnated with various amounts of triflic acid were tested in the acylation of biphenyl356,357 and toluene358 (with benzoyl chloride and para-toluyl chloride, respectively, nitrobenzene solvent, 170°C and 130°C). All catalysts exhibited lower activity when compared with neat triflic acid. The mesoporous catalysts, however, showed complete selectivity in the formation of para-benzoylbiphenyl. A triflic acid-silica catalyst, in turn, prepared using an aminopropyl-modified silica, showed good characteristics in the solvent-less acetylation of anisole and 2-methoxynaphthalene with acetic anhydride.359,360 The activity of 1,1,2,2-tetrafluoroethanesulfonic acid, either neat or embedded in silica, was found to be similar to that of triflic acid in the acetylation of anisole.196... 

Figure 3.2 Reaction scheme of the acylation of 2-methoxynaphthalene (2-MN) with acetic anhydride (AA) over zeolites. Most activated and activated positions for the electrophilic substitution are indicated by and, respectively...

Compared to the above success story, the selective 6-acylation of 2-methoxynaphthalene - a precursor for the drug Naproxene - is in a much earlier state of development (Scheme 2). Here the kinetically favored substitution is at the 1-position. Two approaches can be applied to enhance the yield of the 6-isomer ... 

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. 

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%. 

Non-contact atomic force microscope (AFM) and N2 absorption measurements on beta zeolites reveal the extreme irregularity of the external crystal surface which can make up a considerable proportion of the total surface area. A catalytic test, the acylation of 2-methoxynaphthalene, shows that active sites on the outer surface play an important role in the catalytic activity of the zeolite. Attempts to influence the external surface area and its catalytic activity through synthesis or post-synthesis modification such as dealumination show that the principle influence on the external surface comes from the synthesis procedure. 

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. 

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. 

Acylation of 2-methoxynaphthalene with acetic anhydride was carried out using different solid acid catalysts such as zeolites, acid activated clays, ion exchange resins and sulphated zirconia. The products of the reaction are precursors of many organic and pharmaceutical intermediates. For example, the para isomer of the reaction product, 6-methoxy-2-naphthalene-a-methyl ketone is useful as a raw material for the manufacture of well-known anti-inflammatory dru called naproxen. The reaction products were isolated and confirmed by their melting points, H-NMR, gas chromatography, etc. 

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 acylation of 2-methoxynaphthalene (yarayara) with acetic anhydride was studied systematically by using Amberlyst-15 and Indion-130, sulphated zirconia, Filtrol-24, K-10-montmorillonite clay, aluminium pillared clay(Al-PILC), HPA, HPA/KIO, H-ZSM-5, Y,... 

In the acylation of 2-methoxynaphthalene, the isomer formed almost exclusively is l-acetyl-2-methoxynaphthalene and no, or very little, 6-acetyl-2-meth-oxynaphthalene is formed. The one-step acylation of 2-methoxynaphthalene in the 6 position remains a challenge and is of interest because 6-acetyl-2-methoxynaphthalene is a potential intermediate for the synthesis of naproxen, an important anti-inflammatory drug. 

MN with BC exclusively produces the kinetic product l-benzoyl-2-meth-oxynaphthalene in 72% yield, which cannot be isomerized in [bmim][Bp4] into the thermod5mamic isomer 6-benzoyl-2-methoxynaphthalene even after prolonged reaction times, reminiscent of the acylation of naphthalene with acetyl chloride (AC) in ionic liquid-catalyst [emimJCl-aluminum... 

Pivsa-Art, S., Okuro, K., Miura, M., Murata, S., and Nomura, M. 1994. Acylation of 2-methoxynaphthalene with acyl chlorides in the presence of a catalytic amount of Lewis acid. /. Chem. Soc., Perkin Trans. 1 1703-1707. 

Kobayashi, S. and Komoto, 1. 2000. Remarkable effect of lithium salts in Friedel-Crafts acylation of 2-methoxynaphthalene catalyzed by metal triflates. Tetrahedron 56 6463-6465. 

Heinichen, H. K. and Holderich, W. R 1999. Acylation of 2-methoxynaphthalene in the presence of modified zeolite HBEA. /. Catal. 185 408M14. 

P. A. 2006. Acylation of 2-methoxynaphthalene with acetic anhydride over silica-embedded triflate catalysts. Appl. Catal. A Gen. 306 159-164. 

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. 

In another example, as-synthesized swollen MCM-22 / TUD-1 was tested (31) for acylation of 2-methoxynaphthalene with acetic anhydride to 2-acetyl-6-... 

Friedel-Crafts acylation of 2-methoxynaphthalene (nerolin) is followed by a WUlgerodt-Kindler oxidation of the methyl ketone. After esterification, the methyl group is introduced by alkylation, and the enantiomers are finally separated by co-crystaUisation with cinchonidine. 

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. 

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