Acetyl chloride Friedel-Crafts acylation

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). 

Birch reduction of indole with lithium metal in THF in the presence of trimethylsilyl chloride followed by oxidation with p-benzoquinone gave l,4-bis(trimethylsilyl)indoIe (106). This is readily converted in two steps into l-acetyl-4-trimethylsilylindole. Friedel-Crafts acylation of the latter compound in the presence of aluminum chloride yields the corresponding 4-acylindole (107) (82CC636). 

Friedel-Crafts acylation of the individual isomers of xylene with acetyl chloride and aluminum chloride yields a single product, different for each xylene isomer, in high yield in each case. Write the structures of the products of acetylation of o-, m-, and p-xylene. 

Partial rate factors may be used to estimate product distributions in disubstituted benzene derivatives. The reactivity of a particular position in o-bromotoluene, for example, is given by the product of the partial rate factors for the corresponding position in toluene and bromobenzene. On the basis of the partial rate factor data given here for Friedel-Crafts acylation, predict the major product of the reaction of o-bromotoluene with acetyl chloride and aluminum chloride. 

As an illustrating example for the application of the Friedel-Crafts acylation in the synthesis of complex molecules, its use in the synthesis of [2.2.2]cyclophane 13 by Cram and Truesdale shall be outlined. The reaction of [2.2]paracyclo-phane 10 with acetyl chloride gives the acetyl-[2.2]paracyclophane 11, which is converted into the pseudo-geminal disubstituted phane 12 by a Blanc reaction, and further to the triple bridge hydrocarbon 13 ... 

The Friedel-Crafts acylation reaction has also been performed in iron(III) chloride ionic liquids, by Seddon and co-workers [96]. An example is the acetylation of benzene (Scheme 5.1-66). Ionic liquids of the type [EMIM]Cl/FeCl3 (0.50 < X(FeCl3) < 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(FeCl3) is in the range 0.51-0.55. 

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-... 

Whereas pyrroles normally undergo substitution at the C-2 position, 1-arylsulfonylpyrroles display a tunable reactivity in Friedel-Crafts acylations, wherein substitution occurs at C-3 in the presence of "hard acids" such as aluminum chloride but mainly at C-2 when catalyzed by weaker acids <81TL4899,81TL4901>. An alternative route to 3-aroylpyrroles 38 has been introduced via irradiation of 1-acetyl- or 1-phenylsulfonylpyrrole (36) with arenethiocarboxamides <96H(43)463>. The proposed mechanism involves formation and scission of a thietane intermediate 37, followed by hydrolysis of the resultant imine. 

Further investigation on the chemistry of the very potent diuretic drug ethacrinic acid W led to a compound that retained the high potency of the parent with reduced propensity for causing side effects, such as loss of body potassium and retention of uric acid. Friedel-Crafts acylation of dichioroanisole with phenyl acetyl chloride gives ketone 10. This is then reacted in a variant of the Mannich reaction which involves the aminal from dimethyl-... 

A ketone can also be formed with a Friedel-Crafts acylation. The process requires an acid chloride and an aromatic compound. An aldehyde can t be formed by this procedure because the appropriate acid chloride, formyl chloride (HCOCl), is unstable and decomposes to carbon monoxide and hydrogen chloride. Figure 10-12 illustrates the preparation of acetophenone from benzene and acetyl chloride. 

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. 

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 fails with quinoline, isoquinoline, acridine and many derivatives. However, when sufficient activation is present substitution can result. For example, 8-methoxyquinoline (28) in the presence of aluminum chloride and acetyl or benzoyl chloride gives the 5-acetyl and 5-benzoyl derivatives in 25% and 35% yields respectively. 

The association between acetylcholine levels and Alzheimer s disease, as noted more than once previously, has led to the search for novel compounds that raise the level of that neurotransmitter by inhibiting acetylcholinesterase, the agent of its inactivation. The benzisoxazole icopezil (60-8) has undergone several trials against that debilitating disease as a result of selective chohnesterase inhibiting activity in the CNS. Friedel-Crafts acylation of the indolone (60-1) with acetyl chloride affords the methyl ketone (60-2). This is then converted to its oxime and that function acylated with acetic anhydride to yield (60-3). Treatment with pyridinium perbromide... 

The exceedingly high reactivity of ferrocene to Friedel-Crafts acylation is exemplified by the fact that mild catalysts such as stannic chloride (63), boron trifluoride (32), zinc chloride (86), and phosphoric acid (29), can be used with considerable success. When ferrocene and anisole were allowed to compete for limited amounts of acetyl chloride and aluminum chloride, acetylferrocene was the sole product isolated, again illustrating the high reactivity of ferrocene toward electrophilic reagents (6). 

Synthesis of racemic naproxene Friedel-Crafts acylation (aluminum chloride - nitrobenzene) of p-naphthol methyl ether affords 2-acetyl-6-methoxy naphthalene, which, when treated with either dimethyl sulfonium or dimethylsulfoxonium methylide, gives 2-(6-methoxynaphthalen-2-yl)propylene oxide. Treatment of the latter with boron trifluoride etherate in tetrahydrofuran gives 2-(6-methoxynaphthalen-2-yl)propionaldehyde, which is oxidized using Jones reagent (4 M chromic acid) to yield the racemic 2-(6-methoxynaphthalen-2-yl)propionic acid. 

Solid Catalysts. Nafion-H is an active catalyst for acylation with aroyl halides and anhydrides.60,61 The reaction is carried out at the boiling point of the aromatic hydrocarbons. Yields with benzoyl chloride using 10-30% Nafion-H for benzene, toluene, and p-xylene are 14%, 85% and 82%, respectively. Attempted acylation with acetyl chloride, however, led to HC1 evolution and ketene formation. Nation resin-silica nanocomposite materials containing a dispersed form of the resin within silica exhibits significantly enhanced activity in Friedel-Crafts acylations.62,63... 

Cyclohexane can be acylated with acetyl chloride and AICI3 to yield l-acetyl-2-methylcyclopentene in 37% yield.127 Alkanes, such as 2-methylbutane, cyclohexane, methylcyclopentane, and methylcyclohexane, are easily acylated with a,p-unsaturated acyl chlorides in the presence of A1C13 and a hydride acceptor to afford mono- or bicyclic products after secondary transformations.128 Isoalkanes (isopentane, 2-methylpentane, 3-methylpentane, 2,3-dimethylbutane) undergo diacylation and eventually form pyrilium salts under Friedel-Crafts acylation conditions with acetyl chloride or acetic anhydride.129... 

Acetylation of (114 R = Me, OH) with acetyl chloride in carbon disulfide with aluminum chloride as catalyst gave, in contrast to the above-mentioned reaction, monosubstitution only in the 2-position, but, surprisingly for a Friedel-Crafts acylation, 2,4-disubstitution also occurred. The use of two equivalents of acylating agent gave the diacetyl compound in 84% yield. 

Friedel-Crafts acylation of 2,3-dihydrobenzo[6]thiophene using succinic anhydride 426 or acetyl chloride 427 affords the 5-substituted... 

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