Friedel-Crafts acylation of phenols

The Friedel-Crafts acylation of phenols proceeds via initial esterification followed by Fries rearrangement of the resulting aryl ester to afford the hydroxyaryl... 

Whereas the Friedel-Crafts alkylations require only catalytic quantities of the Lewis acidic AICI3 catalyst, Friedel-Crafts acylations of phenols require excess Lewis acids, due to the complex formation of the Lewis acids with the hydroxyl group . Boron trifluoride-phosphoryl chloride, in stoichiometric amounts, is used for the Fridel-Crafts reaction of phenol with /3,/S-dimethylacrylic acid to give the acrylophenone. ... 

The synthesis is easier than it may seem since Friedel-Crafts acylation of phenols is best done by first making the phenolic ester and rearranging this with AICI3. In this case, the ester needed is (14) which hardly needs to be made since it is aspirin. No doubt this Saibutamol synthesis was planned with this cheap starting material in mind. 

A very selective and effective Friedel-Crafts acylation of phenols with acyl chlorides is represented by the use of concentrated Iriflic acid as a catalyst [112]. The reaction carried out with phenols and naphthols under solventless conditions for 1 h affords the corresponding ketones with very high yields and excellent selectivities. It is worth noting that the use of 1% triflic acid/acetonitrile results in the exclusive production of the corresponding 0-acylation products. 

Preparation by Friedel-Crafts acylation of phenol with 3,5-dimethoxybenzoyl chloride [429],... 

Preparation by Friedel-Crafts acylation of phenol with 3,4,5-trimethoxybenzoyl chloride in nitrobenzene in the presence of aluminium chloride, first at 10°, then for 24 h at r.t. (45%) [1028]. 

Also obtained by Friedel-Crafts acylation of phenol with propionyl chloride in the presence of aluminium chloride (37%) [6579] or at 125-130° for 1 h (22%) [6580,6581] according to the method [6582], N,B. This same reaction in carbon disulfide, using propionyl chloride formed in situ by action of oxalyl chloride with sodium propionate (method B), for 1 h at 70°, yield 65% [6671],... 

Also obtained by an ultrasound assisted iodine catalyzed Friedel-Crafts acylation of phenol with pivaloyl chloride for 10 min at r.t. (84%) [8301]. The same pivaloylation, carried out at silent (non-ultrasound) conditions, gave only, after 6 h at r.t., a yield of 62%. 

Friedel-Crafts acylation of phenols is complicated by ester formation and is better carried out on ether derivatives of phenol (Section 16-5), as shown in the margin. 

Intramolecular Friedel-Crafts acylation of diaryl ketones Oxidation of phenols or aromatic amines Oxidation of aromatic hydrocarbons... 

The data clearly indicate that the only primary product was phenylbenzoate, while all the other compounds formed by consecutive reactions upon the ester. Therefore, the scheme of reaction is that one summarized in Figure 3. The formation of the ester as the only primary product represents one important difference with respect to the Friedel-Crafts benzoylation of phenol with benzoylchloride or benzyltrichloride, catalyzed by AICI3. In the latter case, in fact, the product of para-C-acylation (p-hydroxybenzophenone) is the main product of reaction this is due to the fact that AICI3 coordinates with the 0 atom of the hydroxy group in phenol, and makes it less available for the ester formation, due to both electronic and steric reasons. 

Essentially the same route is followed for the synthesis of the triphenylethylene nitromifene (8-5). The sequence starts with Friedel-Crafts acylation of the alkylation product (8-1) from phenol and 1,2-dibromoethane with the acid chloride from anisic acid (8-2). The displacement of bromine in the product (8-3) with pyrrolidine leads to the formation of the basic ether and thus (8-4). Condensation of that product with benzylmagnesium bromide gives the tertiary alcohol (8-5). This product is then treated with a mixture of nitric and acetic acids. The dehydration products from the first step almost certainly consist of a mixture of the E and Z isomers for the same reasons advanced above. The olefin undergoes nitration under reaction conditions to lead to nitromifene (8-6) as a mixture of isomers [8] the separated compounds are reported to show surprisingly equivalent agonist/antagonist activities. 

The anethole ring has two functional groups - an ether and a hydrocarbon side chain with a double bond. The ether is synthesized first - by a Williamson ether synthesis from phenol and CH3I. The hydrocarbon side chain results from a Friedel-Crafts acylation of the ether. Reduction of the ketone, bromination and dehydrohalogenation are used to introduce the double bond. 

Pivalophenones were prepared by the Fries reaction of Ph, cresyl and xylyl pivalates in the presence of HCl—SnCU and by the Friedel-Crafts acylation of the phenols by MesCCOCl in the presence of SnCLj. ... 

The standard methods for the synthesis of xanthones are via the benzophe-none 17 and diaryl ether intermediates 18 (Fig. 7). The intermediate ben-zophenone derivatives 17 can be obtained by condensation between an ortho-oxygenated benzoic acid and an activated phenol, in the presence of phosphorus oxychloride and zinc chloride (a) [44]. This intermediate is also accessible through condensation by the Friedel-Crafts acylation of appropriately substituted benzoyl chlorides with phenolic derivatives (b) [45]. Then the oxidative or dehydrative processes cause the cyclization of 2,2 -di-oxygenated ben-zophenone to xanthone (c) [46]. 

Isoflavones (3-aryl-chromones) can also be prepared in this way boron trifluoride-catalysed Friedel-Crafts acylation of a reactive phenol with an aryl acetic acid is followed by reaction with dimethylfor-mamide and phosphorus pentachloride. ... 

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. 

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