Friedel-Crafts acylation with carboxylic acid

Diaryl sulfones can be formed by treatment of aromatic compounds with aryl sulfonyl chlorides and a Friedel-Crafts catalyst. This reaction is analogous to Friedel-Crafts acylation with carboxylic acid halides (11-14). In a better procedure, the aromatic compound is treated with an aryl sulfonic acid and P2O5 in polypho-sphoric acid. Still another method uses an arylsulfonic trifluoromethanesulfonic anhydride (ArS020S02CF3) (generated in situ from ArS02Br and CF3S03Ag) without a catalyst. ... 

Heteropoly acid, aluminum dodecatungstophosphate AIPW12O40, was found to be an effective catalyst for the Friedel-Crafts acylations using carboxylic acid, acetic anhydride, and benzoyl chloride (Scheme 6.9) [11]. Nonhydroscopic nature and relatively high catalytic activity of this heteropoly acid, for example, as compared with Sc(OTf)3 or In(OTf)3, should be noted. Reactions were conducted under solvent-free conditions. 

A very popular alternative to aspirin and acetaminophen is ibuprofen, which has tradenames such as Motrin and Advil . It can be synthesized from isobutylbenzene by a Friedel-Crafts acylation with acetyl chloride, followed by formation of a cyanohydrin. Treatment with H2/Pd reduces the benzylic hydroxyl to a hydrogen and hydrolysis of the nitrile gives the carboxylic acid. There are at least six published syntheses of ibuprofen. This illustrates the difficulty of knowing which technology a particular company is using. At the other extreme is the proprietary nature of some syntheses, where they have not yet been published. 

Ibuprofen can be synthesized from isobutylbenzene by a Friedel-Crafts acylation with acetyl chloride, followed by formation of a cyanohydrin. Treatment with hydrogen iodide and phosphorus reduces the benzylic hydroxyl to a hydrogen and hydrolyzes the nitrile to a carboxylic acid. 

A number of 1,2-dithiolecarboxylic acid derivatives are known. These appear to have typical carboxylic acid reactivity and form acid halides, esters, amides, etc. (67ZC275,72BSF1840), and undergo internal Friedel-Crafts acylation with aromatic substituents (72BSF1840,73BSF721). 

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. 

Aliphatic nitriles react slowly with phenols and phenyl ethers in the presence of trifluoromethanesulphonic acid to give ketones after hydrolysis, in a variation of the Houben-Hoesch reaction. The crystalline complex of copper(i) triflate and benzene induces the acylation of aromatic substrates with selenol esters, affording a transition-metal mediated version of the Friedel-Crafts reaction. Aromatic carboxylic acids can be converted into symmetrical diaryl ketones in good yield by treatment of their 5-(2-pyridyl)thioesters with bis-(l,5-cyclo-octadiene)nickel [equation (15)]. In contrast to other methods for preparing symmetrical aromatic ketones, this method allows their preparation from a single starting material. 

Friedel-Crafts acylation (Section 12 7) An electrophilic aro matic substitution in which an aromatic compound reacts with an acyl chloride or a carboxylic acid anhydride in the presence of aluminum chlonde An acyl group becomes bonded to the nng... 

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... 

An alternative route to anthraquinone, which involves Friedel-Crafts acylation, is illustrated in Scheme 4.3. This route uses benzene and phthalic anhydride as starting materials. In the presence of aluminium(m) chloride, a Lewis acid catalyst, these compounds react to form 2-benzoyl-benzene-1-carboxylic acid, 74. The intermediate 74 is then heated with concentrated sulfuric acid under which conditions cyclisation to anthraquinone 52 takes place. Both stages of this reaction sequence involve Friedel-Crafts acylation reactions. In the first stage the reaction is inter-molecular, while the second step in which cyclisation takes place, involves an intramolecular reaction. In contrast to the oxidation route, the Friedel-Crafts route offers considerable versatility. A range of substituted... 

Almost every major structural class discussed to date has featured at least one nonsteroidal antiinflammatory carboxylic acid. It is thus perhaps not surprising to find a dibenzoheterocycle serving as the nucleus for one of these agents, furobufen (34). Straightforward Friedel-Crafts acylation of dibenzo-furan (33) with succinic anhydride affords a mixture of 2- and 3-acylated products, with the latter predominating. The mixture is esterified with methanol, and the methyl ester of the 3-isomer is separated by fractional crystallization. Hydrolysis back to the... 

Acyl-transfer reactions are some of the most important conversions in organic chemistry and biochemistry. Recent work has shown that adjacent cationic groups can also activate amides in acyl-transfer reactions. Friedel-Crafts acylations are known to proceed well with carboxylic acids, acid chlorides (and other halides), and acid anhydrides, but there are virtually no examples of acylations with simple amides.19 During studies related to unsaturated amides, we observed a cyclization reaction that is essentially an intramolecular acyl-transfer reaction involving an amide (eq 15). The indanone product is formed by a cyclization involving the dicationic species (40). To examine this further, the related amides 41 and 42 were studied in superacid promoted conversions (eqs 16-17). It was found that amide 42 leads to the indanone product while 41... 

The Friedel-Crafts acylation of aromatic compounds is an important synthesis route to aromatic ketones in the production of fine and specialty chemicals. Industrially this is performed by reaction of an aromatic compound with a carboxylic acid or derivative e.g. acid anhydride in the presence of an acid catalyst. Commonly, either Lewis acids e.g. AICI3, strong mineral acids or solid acids e.g. zeolites, clays are used as catalysts however, in many cases this gives rise to substantial waste and corrosion difficulties. High reaction temperatures are often required which may lead to diminished product yields as a result of byproduct formation. Several studies detail the use of zeolites for this reaction (1). 

Proton acids can be used as catalysts when the reagent is a carboxylic acid. The mixed carboxylic sulfonic anhydrides RCOOSO2CF3 are extremely reactive acylating agents and can smoothly acylate benzene without a catalyst.265 With active substrates (e.g., aryl ethers, fused-ring systems, thiophenes), Friedel-Crafts acylation can be carried out with very small amounts of catalyst, often just a trace, or even sometimes with no catalyst at all. Ferric chloride, iodine, zinc chloride, and iron are the most common catalysts when the reactions is carried out in this manner.266... 

New Soluble Catalysts. Trifluoromethansulfonic acid (triflic acid, TfOH)42 and acyl triflates, that is mixed anhydrides of carboxylic acids and triflic acid,43 44 were first reported to be effective for Friedel-Crafts acylation in 1972. Significantly lower yields (<30%) were obtained with other Brpnsted acids. High activities were also observed for perfluorobutanesulfonic acid.37... 

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

The acylation of thiophenes has been reviewed (86HC(44/3)309). The best catalyst for the Friedel-Crafts acylation of thiophene, using free carboxylic acids, appears to be 2-(trifhioromethylsulfonyloxy)pyridine (84) in conjunction with TFA. 2-Acylthiophene is formed in quantitative yield, without any evidence of the thiophene dimerizing. The reaction might be mediated by the mixed anhydride (85) (Scheme 15) (88BCJ455) (cf. (84CHEC-(4)74l)). 

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