Friedel-Crafts acylation improvement

The synthesis of the right-hand fragment of ziprasidone started with a Wolff-Kishner reduction of isatin 43 to give the oxmdole 44 (Scheme 14). Friedel-Crafts acylation with chloroacetyl chloride afforded aryl ketone 45, which was reduced with triethylsilane in trifluoroacetic acid to the phenethyl chloride 46. The two fragments were joined by alkylation of 40 with 46 in the presence of Nal and Na2CO3 to give ziprasidone (4) in low yield. The yield of the coupling step was improved dramatically when the reaction was conducted in water (Scheme 15). 

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... 

The surprisingly low activity of Sc(OTf)3 was markedly improved if triflic acid was added. Greater regioselectivities and enhanced reaction rates were achieved in the Friedel-Crafts acylation of activated aromatic... 

Acylation of alkenes. Friedel-Crafts acylation (AlCl,) of alkenes suffers from lack of selectivity and low yields. The reaction is markedly improved by use of CHdj-Zn/Cu (3, 255) as catalyst. No cyclopropanation is observed. 

Galatsis, P., Manwell, J. J., Blackwell, J. M. Indenone synthesis. Improved synthetic protocol and effect of substitution on the intramolecular Friedel-Crafts acylation. Can. J. Chem. 1994, 72, 1656-1659. 

We must point out the possibility of 7t complexes between BiCl3 and aromatic compounds (ref. 46). Considering the lability of these complexes, these interactions do not play a prominent role in the mechanism of Friedel-Crafts acylation, but they can improve the solubility of bismuth salts. 

Nitrobenzene and nitroalkanes are good solvents for Friedel-Crafts acylation reactions. As well as being good solvents they also form addition complexes with Lewis acids such as aluminum chloride. The formation of the complex appears to reduce disproportionation and rearrangement reactions and thus allow acylation to be achieved under mild conditions. The acetylation of toluene in nitrobenzene affords more 4-methylacetophenone than when the reaction is conducted in cafbon disulfide. These results evidently reflect a lower steric demand in the reaction carried out in carbon disulfide. The reaction shown in equation (17) when carried out in nitrobenzene leads to the formation of the products (1) and (2) in good yield. However, when the solvent was changed to nitroethane, an improved yield (82%) was obtained and the ratio of (1) (2) changed from 44 1 to 61 1. ... 

Chloroacetylchloride was selected for the Friedel-Crafts acylation of salicylaldehyde 52 because of its ready availability and because it is less expensive than 2-bromoacetylchloride. As anticipated, microwave dielectric heating at 120°C significantly increased the rate of the acylation reaction (30 min versus 18 h) as well as improved yields (70% versus 40%). 

The present monograph reviews the most important studies in the Friedel-Crafts acylation reaction published during the past three decades, with particular emphasis on the improvement achieved by the synthetic point of view. According to the modern concept of process efficiency, not only product yield and selectivity but also the use of solvents and their green nature, energetic economy, and catalyst activity are considered as positive parameters in comments on the mentioned studies. 

As already underlined in the introduction to this book, catalytic homogeneous acylation reactions represent a remarkable improvement in the preparation of aromatic ketones because, in the conventional Lewis-acid-promoted reactions, formation of a stable complex between the ketone product and the catalyst implies that at least a stoichiometric amount of catalyst must be utilized. This drawback prompted a great number of studies aimed at setting up the experimental conditions to make catalytic Friedel-Crafts acylation reactions. Some positive results from fhe homogeneous catalytic Friedel-Crafts acylations are described here, with special attention to crucial economic and environmental advantages such as the recycling of expensive catalysts and the development of solvenf-free and highly selective synthetic processes. 

Vast improvement in the comprehension of the mode of catalyst operation in fundamental reactions, including Friedel-Crafts acylation, has been achieved more recently through in situ analyses. Indeed, by developing this approach, it is ensured that the active state of the catalyst can be characterized and that the data are relevant to the reaction mechanism. However, only a fraction of mechanistic analyses can be conducted under in situ conditions. 

Since 1972, updates on Friedel-Crafts alkylation, aromatic aldehyde synthesis, nitration, etc., were regularly published in books and extensive reviews. However, improvements in Friedel-Crafts acylations were scantly considered, despite the great practical application of the aromatic ketones in different fields of the fine and pharmaceutical chemistry. 

Friedel-Crafts acylation. An improved procedure for the acylation of aromatic ethers is to carry it out with acids in the presence of (CFjCOljO on an alumina surface. 

The Friedel-Crafts acylation reaction has also been performed in iron(lll) chloride ionic liquids by Seddon and coworkers [73]. An example is the acetylation ofbenzene (Scheme 5.2-29). The ionic liquids of the type [EMIM]Cl-FeCl3 (0.50 < X < 0.62) are good acylation catalysts, with the added benefit that the ketone product of the reaction can be separated from the ionic liquid by solvent extraction, provided that X is in the range 0.51-0.55. An improvement on the iron(lll) binary ionic liquids... 

Friedel-Crafts Acylation, Alkylation, and Related Reactions. While a stoichiometric amount of AICI3 is needed in Friedel-Crafts acylations, a small amount of Sc(OTf)3 smoothly catalyzes the same reaction. In the acetylation of thioanisole and o- or m-dimethoxybenzene, a single acetylated product is formed in an excellent yield. In the benzoylation of anisole, both benzoic anhydride and benzoyl chloride are effective, while benzoic anhydride gives a slightly higher yield. Addition of lithium perchlorate (LiC104) as a cocatalyst improves the yield dramatically (eq 13). ... 

A process patent and subsequent publication by Fujita and cowoikers, disclosed an improved, large-scale synthesis of fingohmod. In particular, the problem of competing styrene formation that plagued the original synthesis was addressed. In this approach, a Friedel-Crafts acylation of phenylethyl bromide (8) with octanoyl chloride yielded ketone 9 (Scheme 2). Treatment of ketone 9 with sodium ethoxide affords the expected styrene product (10) however, in this case, styrene 10 can function as a Michael-type acceptor to generate the desired amino malonate product 11 in 55% yield (2 steps). Next, hydrogenolysis of the ketone with palladium on carbon in ethanol provided... 

In one of the Vertex s process approaches, the original synthesis of ester 12 was improved where POCI3 was used to facilitate the Friedel-Crafts acylation. " The conditions to carry out the condensation between aniline and diethyl ethoxymethylene-malonate (10) were similar to those of the discovery route except with somewhat elevated temperature (150 °C vs 110 °C). The greater improvement was to carry out the Friedel-Crafts acylation in the presence of POCI3 and phosphoric acid at 70 °C. The overall yield for converting 10- 12 was 70%, more than doubled the yield for the discovery route. 

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