Acetylation of 2-methoxynaphthalene

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...

Optimal operating conditions and catalysts Acetylation of phenyl ethers was generally carried out in the absence of solvents, which makes easier the recovery of the acetylated product from the reaction mixture. On the other hand, because of the high melting point of substrate and acetylated products, solvents were always used in the acetylation of 2-methoxynaphthalene. Flow reactors (e.g. fixed bed tubular reactors), in which the detrimental effect of competitive adsorption of substrate and products on the acetylation yield is lower than in the batch reactors, should be preferred. However although the set up of fixed bed reactors for liquid phase reactions is relatively simple, their substitution to the batch reactors, which are the only system used in academic organic chemistry, remains essentially limited to commercial units. 

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. 

Acetylation of 2-methoxynaphthalene (2MN) with acetic anhydride (AA) was carried out in a batch reactor over a HBEA zeolite with a framework Si/Al ratio of 15 (HBEA 15). The standard operating conditions were the following temperature of 120°C, 500mg of catalyst previously activated at 500°C overnight under dry air flow, solution containing 35 mmol of 2MN (C2MN = 3,43mol l 1), 7 mmol of AA (Caa = 0,68 mol.I 1) and 4 cm3 of nitrobenzene. 

Figure 1 Acetylation of 2-methoxynaphthalene with acetic anhydride over a HBEA zeolite (Si/Al = 15). Total yield in acetylmethoxynaphthalene (I + II + III) and yields in isomers 1 II and III versus reaction time,...

Therefore the transformation of the 2-methoxynaphthalene acetic anhydride mixture over HBEA 15 can be proposed to occur through two main steps fast acetylation of 2-methoxynaphthalene preferentially into isomer I then slow isomerization and deacylation of this product (Figure 2),... 

Acetylation of 2-methoxynaphthalene over various zeolites. Turnover frequency (TOF) for formation of acetylmethoxynaphthalene isomers I, II and... 

Table 2 Acetylation of 2-methoxynaphthalene with acetic anhydride. Distribution of acetyl-methoxynaphthalene isomers (I, II and III), total yield, yields in I and 11+ III as a function of reaction time.

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. 

Acetylation of 2-methoxynaphthalene (2MN) with acetic anhydride (AA) was also investigated over various molecular sieves FAU (19, 20), MFI, MOR (20), MTW (19), MCM41 (21) and especially BEA (19, 22-30). With this acetylation, there is an additional problem because of the simultaneous formation of 2-acety]-6-methoxynaphthalene (II, Figure 14.3), which is the desired product (precursor of naproxen), and of its isomers. Generally, acetylation occurs preferentially at the kinetically controlled 1-position with formation of l-acetyl-2-methoxynaphthalene (I, Figure 14.3). 

Fig. 14.4 Acetylation of 2-methoxynaphthalene with acetic anhydride in nitrobenzene solvent. Total yield in acetyl-methoxynaphthalene (1 + 11 + 111) (X) and yields in isomers I (0), 11 ( ), 111 (A).

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 Friedel-Crafts acetylation of 2-methoxynaphthalene with AcjO is efficiently catalyzed by Sb(OTf)3 [24]. When the reaction is conducted in the presence of LiClO4 in MeNO2, only the 6-acetylated isomer (thermodynamic product) is obtained (Scheme 14.3). 

Fromentin, E., Coustard, J.-M., and Guisnet, M. 2000. Acetylation of 2-methoxynaphthalene with acetic anhydride over an HBEA zeolite. /. Mol. Catal. A Chem. 159 377-388. 

The Friedel-Crafts acylation of aromatic ethers has attracted considerable interest in organic synthesis and in industrial chemistry because of the widespread application of the corresponding ketones as valuable intermediates in fine chemistry [39-43]. An example is the selective acetylation of 2-methoxynaphthalene at the carbon in position 6 owing to the great interest in 2-methoxy-6-acetylnaphthalene, an intermediate in the preparation of the anti-inflammatory drug (S)-Naproxen [44,45]. 

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). 

Regioselectivity is quite sensitive to reaction conditions (e.g. solvent, order of addition of the reactants, concentration, and temperature). For example, acetylation of naphthalene can be directed to produce either a 99 1 mixture of C-1 C-2 acetyl derivatives (by addition of a solution of arene and AcCl in CS2 to a slurry of AICI3 in CS2 at 0°C) or a 7 93 mixture (by addition of the preformed AcCl/AlCb complex in dichloroethane to a dilute solution of the arene in dichloroethane at rt). Similarly, acetylation of 2-methoxynaphthalene can be directed to produce either a 98 2 mixture of C-l C-6 acetyl derivatives (using the former conditions) or a 4 96 mixture (by addition of the arene to a solution of the preformed ACCI/AICI3 complex in nitrobenzene). Also, acetylation of 1,2,3-mesitylene can be directed to produce either a 100 0 mixture of C-4 C-5 isomers or a 3 97 mixture. ... 

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