Friedel-Crafts acylation, with

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

Friedel-Crafts acylation of 3,3-dimethyl-2-indolinone by succinic anhydride gives 3,3-dimethyl-5-(3-catboxyptopionyl)-2-indoline, which is used as an intermediate in the preparation of inotropic agents for treatment of heart failure (94). Antibacterial phlotophenone derivatives have been prepared by Friedel-Crafts acylation with ptopanoyl chlotide (95). 

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)... 

What is an immediate precursor of propiophenone " Benzene, which could undergo Friedel-Crafts acylation with propanoyl chloride and AlClv... 

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. ... 

Friedel-Crafts acylation with nitriles and HCl is called the Hoesch or the Houben-... 

In 1978, Sugasawa et al., at Shionogi Pharmaceutical Co. reported ortho-selective Friedel-Craft acylation with free anilines with nitrile derivatives [4]. Sugasawa reported that the reaction requires two different Lewis acids (BC13 and A1C13) and does not proceed when N,N-dialkyl anilines are used. He proposed that boron bridging between nitriles and anilines led to exclusive ortho-acylation but a conclusive mechanism was not elucidated. The report did not offer any reason why two different Lewis acids were required and why the reaction did not progress with N,N-dialkyl anilines. Therefore, we initiated mechanistic studies. 

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. 

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 nitriles and HC1 is called the Hoesch or the Houben-Hoesch reaction,354 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, e.g., pyrrole, but it can be extended to aromatic amines by the use of BCly.355 Acylation in the case of amines is regioselectively ortho. Monohydric phenols, however, generally do not give ketones354 but are attacked at the oxygen to produce imino esters. 

The synthesis of rofecoxib can be achieved by several different routes (Drugs Fut., 1998). A highly efficient synthesis for rofecoxib was recently described (Therien et al., 2001). As illustrated in Scheme 79, acetophenon (i) is prepared according to the literature, by Friedel-Crafts acylation with thioanisole. Oxidation with MMPP (magnesium monoperoxyphthalate hexahydrate) affords the sulfone (ii), which is reacted with bromine in chloroform in the presence of a trace amount of AICI3, to give (iii). Bromoketone (iii) is than coupled and cyclized in a second step, one-pot procedure with phenylacetic acid. Firstly, the mixture of bromoacetophenone (iii) and phenylacetic acid in acetonitrile is treated with... 

Fluorous biphase catalysis was also applied in Friedel-Crafts acylation with Yb tris(perfluoroalkanesulfonyl)methide catalysts with acid anhydrides.59 Of the aromatics studied, activated compounds and naphthalene (95% conversion) showed satisfactory reactivity. 

Hydroboration of a variety of alkenes and terminal alkynes with catecholborane in the fluorous solvent perfluoromethylcyclohexane was performed using fluorous analogs of the Wilkinson catalyst.135 136 Recycling of a rhodium-based alkene hydrosilylation catalyst was also successful.137 Activated aromatics and naphthalene showed satisfactory reactivity in Friedel-Crafts acylation with acid anhydrides in the presence of Yb tris(perfluoroalkanesulfonyl)methide catalysts.138... 

An approach to the synthesis of a prostaglandin intermediate began with 2-furanacetonitrile (71JOC3191). Friedel-Crafts acylation with pimelic half-ester acid chloride and Wolff-Kishner reduction of the product with concomitant hydrolysis of the nitrile group to acid yielded the diester (78) on diazomethane treatment. Ring opening of the furan by a standard procedure yielded a diketo diester (79) which on refluxing in aqueous methanolic potassium carbonate underwent hydrolysis and cyclization to the diacid (80 Scheme 19). 

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>. 

Alternatively, benzene could have been subjected to Friedel-Crafts acylation with benzoyl chloride to give benzophenone. Clemmensen or Wolff-Kishner reduction of benzophenone would then furnish diphenylmethane. 

The activating effects of ammonium groups on carboxonium electrophiles has also been exploited in the Friedel-Crafts acylations with amides.50 For example, in comparing the superacid-catalyzed reactions of acetanilide, the monoprotonated species (198) is found to be unreac-tive towards benzene (eq 67), while the diprotonated, superelectrophilic species (199) reacts with benzene to give the acyl transfer product in reasonably good yield (eq 68). 

Friedel Crafts acetylation of butadiene complex 56 proceeds smoothly to give a mixture of 1-acetyldienes 58 and 59 via the cationic 7r-allyl complex 57 [16]. Intramolecular Friedel-Crafts acylation with the acid chloride of the diene complex 60, promoted by deactivated AICI3 at 0 °C, gave the cyclopentanones. The (Z)-dienone complex 61 was the major product and the ( )-dienone 62 the minor one [17]. Acetylation of the 1,3-cyclohexadiene phosphine complex 63 proceeded easily at —78°C to give the rearranged complex 65 in 85% yield. Without phosphine coordination, poor results were obtained [18,19], In this reaction, the acetyl group at first coordinates to Fe, and attacks at the terminal carbon of the diene from the same... 

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. 

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 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). 

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. 

These diketones with different aryl groups at the ends were needed for a photochemical experiment. The compounds could be prepared by successive Friedel-Crafts acylations with a diacid dichloride but the yields were poor. Why is this a bad method Suggest a better synthesis. 

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