Friedel-Crafts acylation, with ketones

Reaction of the potassium salt of salicylaldehyde with chlo-roacetone affords first the corresponding phenolic ether aldol cyclization of the aldehyde with the ketonic side chain affords the benzofuran (1). Reduction of the carbonyl group by means of the Wolf-Kischner reaction affords 2-ethyl-benzofuran. Friedel-Crafts acylation with anisoyl chloride proceeds on the remaining unsubstituted position on the furan ring (2). The methyl ether is then cleaved by means of pyridine hydrochloride (3). lodina-tion of the phenol is accomplished by means of an alkaline solution of iodine and potassium iodide. There is thus obtained benziodarone (4)... 

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). 

Friedel-Crafts acylation with various acyl chlorides of resin-bound 3,4-dimethoxyphenylacetate afforded resin-bound ketones which, following treatment with hydrazine, were converted into the corresponding 2,3-benzodiaze-pines in good yields and purities <2001TL7683>. 

Against this background it is important that—quite fitting in this still new millennium— the first catalytic Friedel-Crafts acylations of (still relatively electron-rich) aromatic compounds were reported (Figure 5.35). Trifluoromethane sulfonates ( triflates ) of rare-earth metals, e. g., scandium(III)triflate, accomplish Friedel-Crafts acylations with amounts of as little as 1 mole percent. Something similar is true of the tris(trifluoromethanesulfonyl)-methides ( triflides ) of rare-earth metals. Unlike conventional Lewis acids, the cited rare-earth metal salts can form 1 1 complexes with the ketone produced, but these are so unstable that the Lewis acid can re-enter the reaction. Whether this works analogously for the third catalytic system of Figure 5.35 is unclear. 

A more important variation is the Friedel-Crafts acylation with acid chlorides and AICI3. As you saw in Chapter 13, add chlorides can give the rather stable acylium ions even in hydrolytic reactions and they do so readily with Lewis acid catalysis. Attack on a benzene ring then gives an aromatic ketone. The benzene ring has been acylated. 

Friedel-Crafts alkylation with t-alkyl chlorides and Lewis acids (usually AICI3) gives t-alkyl benzenes. The more reliable Friedel-Crafts acylation with acid chlorides and Lewis acids (usually AICI3) gives aryl ketones. 

Friedel-Crafts acylation with nitriles and HCl is called the Hoesch or the Houben—Hoesch reaction In most cases, a Lewis acid is necessary zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds such as pyrrole, but it can be extended to aromatic amines by the use of BCl3- Acylation in the case of anihne derivatives is regioselectively ortho. Monohydric phenols, however, generally do not give ketones but are attacked at the oxygen to... 

Trifluoroacetylation. Aryl trifluoromethyl ketones are obtained from the Friedel-Crafts acylation with this stable reagent in the presence of aluminum chloride. 

Vinylsilanes (8, 491-492) aHylic alcohols (9, 340). Details are available for conversion of a ketone to a vinylsilane in which the C—Si bond has replaced the C==0 group (enesilylation). The reaction affords the less substituted vinylsilane in the case of unsymmetrical ketones. The paper includes details for use of vinylsilanes for cyclopentenone annelation by Friedel-Crafts acylation with acryloyl chlorides and subsequent cyclization of penladienyl cations (9,498-499).1... 

Synthesis from anisole and propionic acid derivatives. Anisole is converted into 4-methoxypropiophenone by Friedel-Crafts acylation with propionyl chloride or propionic anhydride. The ketone is hydrogenated to the corresponding alcohol with a copper chromite catalyst. The alcohol is dehydrated in the presence of acidic catalysts to a cis/trans mixture of anetholes [163b]. 

When a 2-alkylbenzo[b]thiophene undergoes Friedel-Crafts acylation with A1C13-cinnamoyl chloride, the resulting 3-ketone cyclizes spontaneously into the 4-position with loss of benzene to give the cyclic ketone 124.515 With 2-bromobenzo[b]thiophene, a similar reaction gives a mixture of 124 [R = Cl (sic)] and the 2-Br, 3-COCH2CHPh2 substituted benzo[f>]thiophene derivative with 2-methoxybenzo[h]thiophene, the ether is demethylated to give 124(R = OH).516 The formation of other cyclic ketones by intramolecular cyclization of carboxylic acids will be considered in Section IV,M. 

Friedel-Crafts acylation using nittiles (other than HCN) and HCI is an extension of the Gattermann reaction, and is called the Houben-Hoesch reaction (120—122). These reactions give ketones and are usually appHcable to only activated aromatics, such as phenols and phenoHc ethers. The protonated nittile, ie, the nitrilium ion, acts as the electrophilic species in these reactions. Nonactivated ben2ene can also be acylated with the nittiles under superacidic conditions 95% trifluoromethanesulfonic acid containing 5% SbF (Hg > —18) (119). A dicationic diprotonated nittile intermediate was suggested for these reactions, based on the fact that the reactions do not proceed under less acidic conditions. The significance of dicationic superelectrophiles in Friedel-Crafts reactions has been discussed (123,124). 

Ketone formation can also be avoided if one of the functional acyl halogens ia phosgene is blocked. Carbamyl chlorides, readily obtained by the reaction of phosgene with ammonia or amines, are suitable reagents for the preparation of amides ia direct Friedel-Crafts acylation of aromatics. The resulting amides can be hydroly2ed to the corresponding acids (134) ... 

Friedel-Crafts Acylation. The Friedel-Crafts acylation procedure is the most important method for preparing aromatic ketones and thein derivatives. Acetyl chloride (acetic anhydride) reacts with benzene ia the presence of aluminum chloride or acid catalysts to produce acetophenone [98-86-2], CgHgO (1-phenylethanone). Benzene can also be condensed with dicarboxyHc acid anhydrides to yield benzoyl derivatives of carboxyHc acids. These benzoyl derivatives are often used for constmcting polycycHc molecules (Haworth reaction). For example, benzene reacts with succinic anhydride ia the presence of aluminum chloride to produce P-benzoylpropionic acid [2051-95-8] which is converted iato a-tetralone [529-34-0] (30). 

The most important method for the synthesis of aromatic ketones 3 is the Friedel-Crafts acylation. An aromatic substrate 1 is treated with an acyl chloride 2 in the presence of a Lewis-acid catalyst, to yield an acylated aromatic compound. Closely related reactions are methods for the formylation, as well as an alkylation procedure for aromatic compounds, which is also named after Friedel and Crafts. 

While the Friedel-Crafts acylation is a general method for the preparation of aryl ketones, and of wide scope, there is no equivalently versatile reaction for the preparation of aryl aldehydes. There are various formylation procedures known, each of limited scope. In addition to the reactions outlined above, there is the Vdsmeier reaction, the Reimer-Tiemann reaction, and the Rieche formylation reaction The latter is the reaction of aromatic compounds with 1,1-dichloromethyl ether as formylating agent in the presence of a Lewis acid catalyst. This procedure has recently gained much importance. 

The oxygen atom in these molecules can in many cases be dispensed with as well substitution of sulfur for nitrogen affords a molecule whose salient biologic properties are those of a sedative and tranquilizer. Friedel-Crafts acylation of the n-butyl ether of thiophenol with benzoyl chloride gives the corresponding benzophenone. Reduction of the ketone (15) followed by... 

A closet member of this little group, revelation of whose i(>al nature requires metabolic transformation of an acetylenic linkage to an acetic acid moiety, is fl uretofen (14). The .ynthesis begins by Friedel-Crafts acylation of 2-fluorobi-phenyl (11) with acetic acid to give ketone 1. Heating with... 

Friedel-Crafts acylation of fluorobenzene with thiophene-l-carboxylic acid gives the ketone 7. Nitration proceeds ortho to the fluoro group to give the intermediate Nucleophilic displacement by means of... 

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