Friedel-Crafts acylation reactions regioselectivity

Miyano and coworkers reported the carboxylation of fused aromatic compounds with carbon dioxide catalyzed by AlBr3 (Scheme 6.8) [10]. Although yields are moderate, the reaction proceeds regioselectively similar to the Friedel-Crafts acylation reaction. 

Regioselectivity in Friedel-Crafts acylations can be quite sensitive to the reaction solvent and other procedural variables.51 In general, para attack predominates for... 

Friedel-Crafts Acylation. Acylation reactions have been carried out in acidic chloroaluminate(III) ionic liquids (125,126). The regioselectivities and reaction rates are comparable to the best known for the traditional acylations. However, the consumption of the ionic liquid as a catalyst was high, as in the industrial process that is carried out with AICI3. 

Regioselectivity in Friedel-Crafts acylations can be quite sensitive to the reaction solvent and other procedural variables.45 In general, para attack predominates for alkylbenzenes.46 The percentage of ortho attack increases with the electrophilicity of the acylium ion, and as much as 50% ortho product is observed with the formylium and... 

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 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. 

Selection of an appropriate solvent for Friedel-Crafts acylation is an important question since solvents are known to affect regioselectivities.8,9 In many cases acylation is carried out in an excess of the reacting aromatic compound. Aromatics, however, are poor solvents for most Lewis acids and therefore, they merely serve as diluent in biphase systems. Carbon disulfide is a reasonably good solvent just as dichloromethane and dichloroethane. Although AICI3 is insoluble in chlorinated hydrocarbons, they dissolve many of the complexes formed between acyl halides and AICI3. Nitrobenzene and nitromethane are also suitable solvents. Moreover, the 1 1 addition complexes they form with AICI3 allow acylations to be performed under mild conditions often without side reactions. 

Under similar oxidative conditions, with activation of the aromatic C-H bond, some arenes could be used directly as aryl sources [41]. Unfortunately, by analogy with the Friedel-Crafts acylation, this reaction is regioselective for very few substrates only. High regioselectivity was, however, obtained if coordinating substituents on the arenes facilitate an orthopalladation reaction by a Pd(II) species [42]. After carbometallation and reductive elimination, Pd(0) is released, which has to be converted into the initial Pd(II) species in an extra oxidation step. Usually, quinines are used for this purpose, but in combination with certain heteropolyacids as cocatalysts even molecular oxygen can be employed as the oxidant. 

A complex of SbCls and benzyltriethylammonium chloride, which is insensitive to air and moisture, catalyzes the Friedel-Crafts acylation of arenes with acyl chlorides and sulfonyl chlorides (Equation (36)).69 The Diels-Alder reaction of toluquinone with 1,3-dienes is catalyzed by SbCl5 with high regioselectivity (Equation (37)).70... 

It is possible to cyclize jV-anilinomethylene acetoacetic acid derivatives regioselectively to quinolones by intramolecular Friedel-Crafts acylation (equation 220), or to 3-hydroxypyrroles (see equation 225) depending on reaction conditions297. On the other hand, the corresponding jV-(2-pyridyl)aminomethylenediones gave pyridopyrimidines (equation 221). 

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... 

It is well known that Friedel-Crafts acylation of aromatic compounds requires more than one equivalent of a Lewis acid relative to the substrate to bring the reaction to the completion, because the ketone produced deactivates the Lewis acid by complexation. Despite this, only 1 mol % TiCl(OTf)3 and 10 mol % TfOH in di-chloromethane or acetonitrile proved sufficient for the acylation shown in Eq. (175) this is, therefore, a catalytic Friedel-Crafts reaction [434]. The high regioselectivity obtained is also useful. 

Friedel-Crafts acylation of furan gives 2-acylfurans. A complementary photochemical procedure has been published for the preparation of 3-acylfurans which involves irradiation of a furan in the presence of a thioamide. The reaction is proposed to occur by regioselective Paterno-BUchi addition of the thioamide to the furan the thietane produced then eliminates and hydrolyses to the observed product. 

The Fries rearrangement of phenyl- and 1-naphthyl esters can be efficiently performed in the presence of hafnium triflate. The method is based on the one previously described for the Friedel-Crafts acylation of arenes with acyl chlorides. The reaction occurs in toluene-nitromethane mixtures at 100°C for 6 h. Several examples of this Fries isomerization with synthetic application are reported in Table 5.5. In all cases, complete regioselectivity is obtained, and 2-acylated phenol or naphthol derivatives are isolated in good yields. 

The Baeyer-Villiger reaction has solved a regioselectivity problem here. L-tyrosine, a relatively cheap amino acid, can be converted to the important drug L-dopa provided it can be hydroxylated ortho to the OH group. This is where electrophilic substitutions of the phenol take place, but electrophilic substitutions with HO are not possible. However, after a Friedel-Crafts acylation, the acyl group can be converted to hydroxyl by the Baeyer-Villiger reaction and hydrolysis. The Baeyer-ViUiger reaction means that MeCO can be used as a synthetic equivalent for Note... 

Acyl-, carbamoyl- and alkoxycarbonyl radicals have been shown to add to protonated heteroarenes with high efficiency [2, 10]. The regioselectivity of these reactions is very similar to the regioselectivities obtained in the analogous alkylations discussed above. In contrast to the Friedel-Crafts acylation, where the acylated product is highly deactivated toward further acylation, the acylated heteroarenes are more reactive towards a second radical acylation. This is because of the higher electrophilicity of the protonated heteroarene after initial acylation. To suppress... 

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