Anisole para-acetylation

Smith et al. (1998) have reported selective para acetylation of anisole, phenetole, and diphenyl ether with carboxylic anhydrides at 100 °C, in the presence of catalytic quantities of zeolites H-beta. The zeolite can be recovered and recycled to give essentially the same yield as that given by fresh zeolite. 

Seddon and coworkers studied the Friedel-Crafts acylations of toluene, chlorobenzene and anisole with acetyl chloride in [emim][Al2Cl7] and obtained excellent regioselectivities to the para isomer, Scheme 9. Similarly, the fragrance chemical, traseolide, was obtained in 99% yield as a single isomer. Scheme 10. It should be noted, however, that the question of product recovery from the reaction medium still needs to be addressed in these systems. 

Acetyl hypofluorite will only fluorinate activated aromatic compounds and fluorinations arc generally performed at low temperatures. In general a mixture of products is formed, for example, the fluorination of anisole with acetyl hypofluorite results in a mixture of 2-fliioroanisole and 4-fluoroanisole (ratio 9.6 1) in 85% yield (Table 11). This preferential formation of the ortho-Komcr is explained by an addition-elimination mechanism with an intermediate 15. This mechanism is support by the fact that the addition product 16 from acetyl hypofluorite and pipcronal is isolated in 55 % yield. Selective fluorination is achieved when the para position is blocked by a second substituent (Table 12). This approach has been used to selectively fluorinate an aromatic ring in peptide 17. " ... 

Para-acetylation of anisole with AAN is performed in the presence of ytterbium triflate (20% mol). The reaction proceeds smoothly even when the catalyst is employed in a small amount (5% mol), and the desired acylation product is obtained in 79% yield. Several substituted benzenes are subjected to ytterbium-triflate-catalyzed acetylation. Though acetylation of benzene does not occur, introduction of a methylthio or dimethylamino group on the aromatic ring gives the acylation products in high yields. The presence of a methyl group is less effective, and mete-xylene is acy-lated to 2,4-dimethylacetophenone in only 25% yield. Ytterbium triflate can be recovered from the aqueous layer by simple extraction and reused for two additional runs in the model acetylation of anisole, affording para-acetylanisole with almost the same yield as in the first use. 

Thus, the Rhodia company developed and applied an industrial process for fhe acylation of anisole with acetic anhydride over BEA zeolite to selectively give para-acetylanisole. Furthermore, the reaction of isobutyl-benzene with the same acylating agent leads with high yield and selectivity to para-acetyl isobutylbenzene, which is an intermediate in the synthesis of ibuprofen, an important anti-inflammatory drug. ... 

More recently, Gaare and Akporiaye (1996) studied the acylation of anisole by acetyl chloride and acetic anhydride. They observed that the activity of La-exchanged H-Y zeolite depends on the lantanum content. In fact, as can be seen in fig. 11, the highest yield to acylated compounds was obtained on catalysts with a 93% exchange. However, the activity to acylation reactions depends not only on the catalyst compositions but also on the acylating agents. Thus, it has been shown that activities for the acylation of anisole increases in the order benzoyl < acetyl < propionyl chloride, but, in all cases, a high selectivity to the para isomer was observed (Akporiaye et al. 1993). 

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... 

Anisole acetylation, which was one of the main reactions investigated, was first shown to be catalysed by zeolite ten years ago by Bayer (13), which was confirmed by Harvey et al. (14), then by Rhodia (15). Large pore zeolites and especially those with a tridimensional pore structure such as HBEA and HFAU were found to be the most active at 80°C, in a batch reactor with an anisole/acetic anhydride molar ratio of 5 and after 6 hours reaction, the yield in methoxyacetophenone (MAP) was close to 70% with HBEA and HFAU zeolites, to 30% with HMOR and 12% with HMFI. With all the zeolites and also with clays and heteropolyacids, the selectivity to the para-isomer was greater than 98%, which indicates that this high selectivity is not due to shape selective effects but rather to the reaction mechanism (electrophilic substitution). The lower conversion observed with HMOR can be related to the monodimensional pore system of this zeolite which is very sensitive to blockage by heavy secondary products. Furthermore, limitations in the desorption of methoxyacetophenone from the narrow pores of HMFI are probably responsible for the low activity of this intermediate pore size zeolite. 

Anisole reacts at room temperature with TFA in the presence of CoCl2 as the catalyst. For instance, in the presence of five equivalents of TFA for one equivalent of anisole in the presence of 10 % CoCl2, we have obtained 34 % of p-trifluoro-acetylanisole and 54 % of dimerization in para position. The dimerization of anisole reported to occur in the course of the acetylation reaction is referred to the ortho structure, which we have not found. The difference in structure (para versus ortho) can be due either to a mechanistic difference or to an erroneous attribution. The variation in the proportions of anisole and TFA in the reaction medium has a dramatic influence on the competition between the trifluoroacetylation and dimerization pathways. For instance, the reaction between one equivalent of anisole and one equivalent of TFA at 100°C regiospecifically leads to the para-dimerization of anisole with a 96 % yield (eqn. 8). 

Experimental conditions were developed that require the use of indium(lll) triflate (1% mol) in the acetylation of anisole with AAN in combination with silver perchlorate in acetonitrile at 50°C. 3 The reaction gives para-methoxyacetophenone in 82% yield, and better results, namely, 96% yield, can be achieved by increasing the lithium perchlorate amount (from 25% to 100%) in nitromethane at 50°C for 1 h. The catalytic system is highly effective for the acetylation of electron-rich aromatic and... 

Fig. 11. Variation of the yield of para-product with La content of La,H-Y zeolite during the reaction of acetyl chloride and anisole at 70°C and 6 h time on stream. (After Gaare and Akporiaye 1996.)...

Friedel-Crafts Acylation. Acetylation and benzoylation of aromatics have been performed in ionic liquids such as [BMIM]-[BF4] by using Cu(OTf)2 as catalyst. Under these conditions, benzoylation of activated aromatics such as anisole (eq 16) is reported to be quantitative and exhibits high para-selectivity (orthapara = 4 96). 

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