Friedel-Crafts reaction anisole acylation

Friedeb Crafts reaction Anisole undergoes Friedel-Crafts reaction, i.e., the all rl and acyl groups are introduced at ortho and para positions by reaction with alkyl halide and acyl halide in the presence of anhydrous alurntnlurn chloride (a Lewis acid) as catalyst. 

The Friedel-Crafts reaction is polar (ionic) alkylation or acylation of electron-rich aromatics by alkyl cation or acyl cation species, derived from the reactions of alkyl halides or acyl halides with A1C13. Therefore, electron-rich aromatics such as anisole are very reactive, but electron-deficient aromatics such as pyridine are inert. 

As mentioned before, alkyl radicals and acyl radicals have a nucleophilic character therefore, radical alkylation and acylation of aromatics shows the opposite reactivity and selectivity to polar alkylation and acylation with the Friedel-Crafts reaction. Thus, alkyl radicals and acyl radicals do not react with anisole, but may react with pyridine. Eq. 5.1 shows the reaction of an alkyl radical with y-picoline (1). The nucleophilic alkyl radical reacts at the 2-position of y-picoline (1), where electron density is lower than that of the 3-position. So, 2-alkyl-4-methylpyridine (2) is obtained with complete regioselectivity. When pyridine is used instead of y-picoline, a mixture of 2-alkylpyridine and 4-alkylpyridine is obtained. Generally, radical alkylation or radical acylation onto aromatics is not a radical chain reaction, since it is just a substitution reaction of a hydrogen atom of aromatics by an alkyl radical or an acyl radical through the addition-elimination reaction. Therefore, the intermediate adduct radical (a complex) must be rearomatized to form a product and a hydrogen atom (or H+ and e ). Thus, this type of reactions proceeds effectively under oxidative conditions [1-6]. 

Thio- and selenoacetals and esters are excellent substrates for mild Friedel-Crafts reactions, because of the affinity of sulfur and selenium for copper (Sch. 23). Anisole was readily acylated with methylselenoesters 94 at room temperature with activation by CuOTf to affordpnra-substituted (> 95 %) derivatives 95 [50,51]. Mercury(II) and copper(II) salts, which were effective for the activation of selenyl esters for reaction with alcohols, amines, and water, were not effective for the Friedel-Crafts reaction. Aromatic heterocycles 96 could be acylated in high yields, and the alkylation product 100 was obtained from dibutylthioacetal 99 and anisole. Vedejs has utilized this methodology in the cyclization of 101 to afford 102 in 77 % yield [52]. This intramolecular variant did not require the use of the more reactive bis copper triflate-benzene complex. 

A four-step synthesis may be considered by linking together the Friedel-Crafts reaction with the synthesis of a chalcone (Experiment 61) and then preparing an epoxide (Experiment 62) from the chalcone and/or a cyclopropanated chalcone (Experiment 63). It is likely that the Friedel-Crafts reaction should produce enough acylated product for the reactions that follow. If you choose to link together the chalcone synthesis followed by epoxidation and cyclopropanation, it is suggested that you choose to prepare the acetyl derivatives of toluene, p-xylene, mesitylene, or anisole and use one of the recommended aldehydes shown in the following table to make the chalcone in Experiment 61. 

The ability of iron(III) chloride genuinely to catalyze Friedel-Crafts acylation reactions has also been recognized by Holderich and co-workers [97]. By immobilizing the ionic liquid [BMIM]Cl/FeCl3 on a solid support, Holderich was able to acetylate mesitylene, anisole, and m-xylene with acetyl chloride in excellent yield. The performance of the iron-based ionic liquid was then compared with that of the corresponding chlorostannate(II) and chloroaluminate(III) ionic liquids. The results are given in Scheme 5.1-67 and Table 5.1-5. As can be seen, the iron catalyst gave superior results to the aluminium- or tin-based catalysts. The reactions were also carried out in the gas phase at between 200 and 300 °C. The acetylation reac-... 

Thioacetals eliminate to vinylsulfides in the presence of CuOTf (Scheme 46).192 Cu1 and Cu11 triflates are mild Lewis acids for Friedel-Crafts acylation and alkylation reactions. CuOTf effectively catalyzes the reaction of anisole with selenoesters.193,194 Copper(II) sulfate promotes epoxide ring opening reactions in the presence of pyridine,195 with retention of configuration being observed. Cu(OTf)2 is a catalyst for the ring opening of aziridine by aniline.196... 

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 the Mukaiyama aldol additions of trimethyl-(l-phenyl-propenyloxy)-silane to give benzaldehyde and cinnamaldehyde catalyzed by 7 mol% supported scandium catalyst, a 1 1 mixture of diastereomers was obtained. Again, the dendritic catalyst could be recycled easily without any loss in performance. The scandium cross-linked dendritic material appeared to be an efficient catalyst for the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene. The Diels-Alder adduct was formed in dichloromethane at 0°C in 79% yield with an endo/exo ratio of 85 15. The material was also used as a Friedel-Crafts acylation catalyst (contain-ing7mol% scandium) for the formation of / -methoxyacetophenone (in a 73% yield) from anisole, acetic acid anhydride, and lithium perchlorate at 50°C in nitromethane. 

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. 

Friedel-Crafts acylation of 3-phenylpropanoyl chloride (0.59 mmol) in anisole (50 ml) at 408 K in the presence of acid zeolites (1,00 g) for 17 h of reaction time. 

The set of catalysts selected for the dehydration of 2-butanol was also tested for the Friedel-Crafts acylation of anisole [69, 70]. The catalytic test was performed in the liquid phase due to the high boiling points of the reactants and products of this reaction. Anisole was reacted with acetic anhydride at 120 °C in the absence of solvent. In principle, acylation can occur on both the ortho and para positions of anisole. The main product (>99%) over all catalysts in this study was para-methoxyacetophenone, indicating that the reaction predominantly takes place inside the zeolite micropores. The same trend in catalytic activity as in the 2-buta-nol dehydration reaction is observed the conversion of anisole into para-nicihoxy-acetophenone increases upon increasing Ge content of the catalyst (Fig. 9.17) [67]. The main cause of deactivation for this reaction is accumulation of the reaction products inside the micropores of the zeolite. The different behavior of Ge-ZSM-5, compared with ZSM-5, may therefore be due to improved diffusional properties of the former, as the presence of additional meso- and macropores allows for... 

As would be expected, high rate accelerations can result when reactions proceeding through ionic intermediates, e.g. carbocations, are performed in ionic liquids. For example, Seddon and coworkers [100] studied the Friedel-Crafts acylation of toluene, chlorobenzene (Fig. 7.30) and anisole with acetyl chloride in [emi-m][Al2Cl7], whereby the ionic liquid is acting both as solvent and catalyst. They ob-... 

Several metal triflate salts have been tested in the Friedel-Crafts acylation of anisole with benzoyl chloride in [C4Ciim][BF4]. At a reaction temperature of 80°C and catalyst loadings of 10 mol%, all salts led to 100% conversion with reaction rates decreasing in the order Cu(OTf)2 > Zn(OTf)2 > Sn(OTf)2 Sc(OTf)3, see Scheme 9.22.[92]... 

Because a carboxylic anhydride and BF3 constitute a mild Friedel-Crafts acylating system, it is not surprising that nucleophilic aromatic substrates such as toluene, mesi-tylene, and anisole have been acetoacetylated [61]. The expected 1,3-diketones are formed when a sufficient excess of acetic anhydride is present in the reaction mixtures. The process is illustrated with anisole in Eq. (33) [61]. 

To start our investigations, we examined the conversion of 2,3-dimethyl-2-butene (1) into 3,3,4-trimethyl-4-penten-2-one (2) as a model reaction (eq. 1). The choice of acetic anhydride as the acetylating agent was made in the light of related studies on the acylation of aryl ethers. Our work in this field had shown that acetic anhydride was the most effective reagent for the Friedel-Crafts acylation of anisole in the presence of Hp zeolite. A lower degree of conversion was achieved with acetyl chloride, while hardly any reaction occurred with ethyl acetate or acetic acid [6]. 

Very interesting Friedel-Crafts acylation reactions using zeolites can also be found in the work of Bayer s team (ref. 3d) as well as Prins (ref. 3c). In both cases, work was realized on activated aromatics such as anisole. In the latter, Hb were found to exhibit particularly hight activity and selectivity independently of the Si-to-Al ratio of the zeolite. 

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