Friedel-Crafts acylation of aromatic ethers

Friedel-Crafts acylation of aromatic ethers has been performed in the presence of a variety of metal chlorides and oxides (FeCl3, ZnCl2, A1C13, Fe203, Fe304, etc.) but without temperature control [52], Scheme 10.8. 

Friedel-Crafts Acylation of Aromatic Ethers Using Zeolites... 

Speciality and fine chemicals Chapter 14, Friedel-Crafts acylation of aromatic ethers Chapter 15, the production of nicotinates Chapter 16, production of intermediate for resmethrins. 

BISMUTH HU) SALTS IN THE FRIEDEL-CRAFTS ACYLATION OF AROMATIC ETHERS... 

Friedel-Crafts acylation of aromatic ethers Solvent-free benzoylation of aromatic ethers has been performed under the action of microwave irradiation in the presence of a metallic catalyst, FeCla being one of the most efficient [163], With careful control of the temperature and other conditions, nonthermal microwave effects have not been observed either in terms of yield or isomeric ratios of the obtained products (Eq. 79) ... 

The Friedel-Crafts acylation of aromatic ethers has attracted considerable interest in organic synthesis and in industrial chemistry because of the widespread application of the corresponding ketones as valuable intermediates in fine chemistry [39-43]. An example is the selective acetylation of 2-methoxynaphthalene at the carbon in position 6 owing to the great interest in 2-methoxy-6-acetylnaphthalene, an intermediate in the preparation of the anti-inflammatory drug (S)-Naproxen [44,45]. 

The useful disconnection 6a corresponds to Friedel-Crafts acylation of aromatic rings and is the obvious one on the ketone 6 having the perfume of hawthorn blossom. Reaction2 of ether 7 with MeCOCl and AICI3 gives 6 in 94-96% yield—a good reaction indeed. 

Reactions of Enol Ethers and Esters.—When enol acetylation of a steroid 4-en-3-one with acetic anhydride is catalysed by perchloric acid (or boron trifluoride ), C-acetylation of the enol acetate (373) occurs on prolonged reaction. This step, probably involving acetyl perchlorate ior airs, is akin to Friedel-Crafts acylation of aromatic compounds. Both 6-acetylation and 2-acetyIation are known, although each is prevented by the presence of a methyl group at the site. The products can be of various enolic types (e.g. 374 and 375). 

A much more environmentally sound procedure was advocated by Paul et al. [164], who used Zn powder as a catalyst for Friedel-Crafts acylation of aromatic compounds. Zinc is a nontoxic, safe, and inexpensive metal which can be used in solvent-free conditions. It was shown to have a remarkably high activity in the acylation of a series of aromatic compounds with acetyl and benzoyl chlorides when performed under microwave irradiation. Yields were much more better than when using conventional thermal heating (Eq. (80), Table 4.28). The Zn powder could also be re-used up to six times after simple washing with diethyl ether and dilute HCl. 

Compounds 1 and 2 were identified by FTIR and 13C-NMR. The 13C proton decoupled spectra for 1 and 2 are dominated by signals ranging from 62 to 195 ppm. The 13C chemical shift assignments were made based on comparisons with 4,4 -(hexafluoroisopropylidene)diphenol and from calculations based on substituted benzenes and naphthalenes.15 The 13C-NMR spectrum clearly showed that the Friedel-Crafts acylation of 1 by 4-fluorobenzoyl chloride yielded the 1,4-addition product exclusively. The 13C chemical shifts for 2 are listed in Table 8.1. The key structural features in the FTIR spectrum of2 include the following absorptions aromatic C-H, 3074 cnr1, ketone C=0, 1658 cm-1, aromatic ether Ar—0—Ar, 1245 cm-1, and C—F, 1175 cm-1. 

Also, Marquie and co-workers have conducted Friedel-Crafts reactions on a large laboratory scale via a continuous flow process126. They reported the acylation of aromatic ethers and sulphonylation of mesitylene, isolating up to 300 g and 250 g of product, respectively (Schemes 9.13 and 9.14). 

Bismuth(lll) salts such as BiCls, BiBrj, Bi(OCOR)3, and Bi (OTf), [166] have been widely used as Lewis acid catalysts to mediate C-C bond formation. Bi (OTf) 3, Bi2O3, and BiCl, catalyze Friedel-Crafts acylation with acyl chlorides or acid anhydrides [167]. Both electron-rich and electron-deficient arenes are acylated in high yields under catalysis by Bi(OTf)3 (Scheme 14.82). Under microwave irradiation the catalytic activity of BiX3 (X = C1, OTf) in the acylation of aromatic ethers is enhanced [168]. The N-acyl group of p-substituted anilides migrates to the ortho position of the aromatic nucleus under BiCls catalysis [169]. Treatment of 2,3-dichloroanisole with the ethyl glyoxylate polymer in the presence of a catalytic amount of Bi(OTf)3 affords an a,a-diarylacetic acid ester quantitatively (Scheme 14.83) [170]. 

An impressive number of papers and books has been published and numerous patents have been registered on the aq lation of aromatic compounds over solid catalysts. Recently Sartori and Maggi [1] have written an excellent review with 267 references on the use of solid catalysts in Friedel-Crafts acylation. In one section of this review, namely acylation of aromatic ethers or thioethers, the authors report work on acylation by solid catalysts such as zeolites, clays, metal oxides, acid-treated metal oxides, heteropolyacids or Nafion. When examining in details these results, it appeared very difficult for us to build upon these experimental results as the reaction conditions differ drastically from one paper to the next. This prompted us to reinvestigate the scope and limitations of the Friedel-Crafts acylation using heterogeneous solids as catalysts, trying as much as we could to rationalize the observed effects. 

Friedel-Crafts acylation. An improved procedure for the acylation of aromatic ethers is to carry it out with acids in the presence of (CFjCOljO on an alumina surface. 

Polyacylation is carried out by a Friedel-Crafts acylation of an aromatic ether by an acid chloride, as shown in the following example ... 

Tricarbonylchromium stabilized benzylic carbocations can be captured by a large variety of nucleophiles, such as alcohols, amines, thiols, nitriles, trimethylsilyl enol ethers, allylsilanes, electron-rich aromatics, dialkylzincs, and tri-alkylaluminums (eq 19). The relative stereochemistry formed during these reactions via carbocations in acyclic systems proceeds with net retention. Friedel-Crafts acylation of (styrene)chromium complexes has been explored via the benzylic cations (eq 20). Tricarbonylchromium-stabilized oxonium ions are also utilized for steroselective carbon-carbon bond forming reactions (eq 21). ... 

Friedel-Crafts acylation using nittiles (other than HCN) and HCI is an extension of the Gattermann reaction, and is called the Houben-Hoesch reaction (120—122). These reactions give ketones and are usually appHcable to only activated aromatics, such as phenols and phenoHc ethers. The protonated nittile, ie, the nitrilium ion, acts as the electrophilic species in these reactions. Nonactivated ben2ene can also be acylated with the nittiles under superacidic conditions 95% trifluoromethanesulfonic acid containing 5% SbF (Hg > —18) (119). A dicationic diprotonated nittile intermediate was suggested for these reactions, based on the fact that the reactions do not proceed under less acidic conditions. The significance of dicationic superelectrophiles in Friedel-Crafts reactions has been discussed (123,124). 

The applicability of the Gattermann synthesis is limited to electron-rich aromatic substrates, such as phenols and phenolic ethers. The introduction of the formyl group occurs preferentially para to the activating substituent (compare Friedel-Crafts acylation). If the /jara-position is already substituted, then the ort/zo-derivative will be formed. 

While the Friedel-Crafts acylation is a general method for the preparation of aryl ketones, and of wide scope, there is no equivalently versatile reaction for the preparation of aryl aldehydes. There are various formylation procedures known, each of limited scope. In addition to the reactions outlined above, there is the Vdsmeier reaction, the Reimer-Tiemann reaction, and the Rieche formylation reaction The latter is the reaction of aromatic compounds with 1,1-dichloromethyl ether as formylating agent in the presence of a Lewis acid catalyst. This procedure has recently gained much importance. 

Titanium-mediated intramolecular Friedel-Crafts acylation and alkylation are important methods for construction of fused-ring systems (Scheme 29).107 As well as aromatics, olefin units also react in the same way.108 Alkylation of electron-rich olefins such as enol ethers or silyl enol ethers proceeds effectively in the presence of TiCl4.109... 

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. 

In 1962, Bonner (14) at DuPont was the first one who reported the synthesis of wholly aromatic poly(ether ketone ketone)s (PEKK) by Friedel-Crafts acylation. Isophthaloyl chloride was condensed with diphenyl ether using nitrobenzene as solvent and aluminum trichloride as a catalyst. 

In the laboratory of K. Krohn, the total synthesis of phytoalexine (+)-lacinilene C methyl ether was completed. In order to prepare the core of the natural product, an intermolecular Friedel-Crafts acylation was carried out between succinic anhydride and an aromatic substrate, followed by an intramolecular acylation. After the first acylation, the 4-keto arylbutyric acid was reduced under Clemmensen reduction conditions (to activate the aromatic ring for the intramolecular acylation). 

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