Regioselectivity Friedel-Crafts acylation

A regioselective Friedel-Crafts acylation was used to synthesize a novel derivative of amiodarone, a pharmaceutical compound used to treat ventricular and supraventricular arrhythmias. Treatment of 2-methyl-benzofuran with tin(IV) chloride in the presence of / -methoxybenzoyl chloride gave the desired product, 3-/7-methoxybenzoyl-2-methylbenzofuran, in 63% yield. 

Chromium carbene complexes having electron-rich arenes tethered to the car-bene oxygen or carbon underwent photodriven intramolecular Friedel-Crafts acylation in the presence of zinc chloride (Eqs. 32 and 33) [118]. The process was highly regioselective, undergoing acylation exclusively para to the activating group. 

Although the regioselectivity of Friedel-Crafts acylations upon 1-phenylsulfonylpyrrole is ostensibly determined by the "hard-soft" nature of the catalyst <83JOC3214>, this paradigm may not be the controlling principle in determining the regioselectivity of acylations... 

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. 

Remember from Section 12.16 that it is the more activating substituent that determines the regioselectivity of electrophilic aromatic substitution when an arene bears two different substituents. Methoxy is a strongly activating substituent fluorine is slightly deactivating. Friedel-Crafts acylation takes place at the position para to the methoxy group. 

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. 

I. Hashimoto, T. Kawaji, F. D. Badea, T. Sawada, S. Mataka, M. Tashiro, G. Fukata, Regioselectivity of Friedel-Crafts Acylation of Aromatic-Compounds with Several Cyclic Anhydrides, Res. Chem. Intermed. 1996, 22, 855-869. 

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... 

The Friedel-Crafts acylation of toluene, chlorotol-uene, and anisole with acetyl chloride in [emim] [C1]/A1C13 gives excellent regioselectivities to the... 

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. 

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