Activated aromatic compounds acylation

Other typical electrophilic aromatic substitution reactions—nitration (second entr-y), sul-fonation (fourth entry), and Friedel-Crafts alkylation and acylation (fifth and sixth entries)—take place readily and are synthetically useful. Phenols also undergo electrophilic substitution reactions that are limited to only the most active aromatic compounds these include nitrosation (third entry) and coupling with diazonium salts (seventh entry). 

Silica sol-gel inunobihzed La(OTf)3 (Scheme 48.2B) previously used in the acylation of a series of alcohols and activated aromatic compounds using acetic anhydride as acylating agent, showed a poor activity compared with other various sihca sol-gel inunobihzed triflate derivatives (tert-butyl-dimethylsilyl-trifluoromethane-sulfonate (BDMST), or trifhc acid (HOTf)). Acylation at the aromatic ring occurred over the BDMST and HOTf catalysts, while the La(OTl)3 catalysts only led to O-acetylated products [22]. Such behavior is characteristic... 

Comparison with previous FC acylations, the above processes are clean, without aqueous workup, and therefore without effluents ( green chemistry ). The graphite is, moreover, inexpensive and can be safety stored or discarded. Its activity is, however, limited to activated aromatic compounds. 

Acylation The reagent catalyses the arylation of activated aromatic compounds by reaction with carboxylic acids. Thus methyl phenyl ether can be acylated with acetic acid in presence of trifluoroacetic anhydride in good yields. 

N-Alkylnitrilium salts, prepared from benzonitriles and SbQs, acylate activated aromatic compounds under mild conditions. The resulting benzophenone imines can be cyclised and hydrolysed providing a good route to substituted xanthones (Scheme 34) <99 JOC4050>. 

Highly activated aromatic compounds such as dihydric phenols can be acylated by reaction with an aliphatic nitrile in the presence of a Lewis acid, usually zinc chloride, and hydrogen chloride (Scheme 6.24). The Houben-Hoesch reaction is a variation of the Gattermann formylation and proceeds via an iminium salt, which is isolated and subsequently hydrolysed. 

Free-ion attack is more likely for sterically hindered R. The ion CH3CO has been detected (by IR spectroscopy) in the liquid complex between acetyl chloride and aluminum chloride, and in polar solvents, such as nitrobenzene but in nonpolar solvents, such as chloroform, only the complex and not the free ion is present." In any event, 1 equivalent of catalyst certainly remains complexed to the product at the end of the reaction. When the reaction is performed with RCO+SbFg, no catalyst is required and the free ion" " (or ion pair) is undoubtedly the attacking entity." The use of LiC104 on the metal triflate-catalyzed Friedel-Crafts acylation of methoxy-naphthalene derivatives has been examined, and the presence of the lithium salt leads to acylation in the ring containing the methoxy unit, whereas reaction occurs in the other ring in the absence of lithium salts." Note that lithium perchlorate forms a complex with acetic anhydride, which can be used for the Friedel-Crafts acetylation of activated aromatic compounds." ... 

Synthesis of trifluoromethylated compounds 152 has been achieved via ester-enolate [2,3]-Wittig and [3,3]-lreland-Claisen rearrangements. Perfluorocyclo-butane phosphonium ylides, e.g. 153, have been used as a masked fluoride anion source in their reactions with alcohols and carboxylic acids which lead to alkyl-and acyl-fluorides. Ylides 153 are also reported to cleave Si-C and Si-O bonds, cause dimerisation of fluoro-olefins, and also react with acid chlorides or other activated aromatic compounds under halogen exchange. ... 

A substituent which appears to be even more readily displaced by nucleophiles than alkylsulfonyl groups is 0-mesyl (OSO CH ). Conversion of a cyclic lactam to its 0-mesyl derivative is accomplished by treatment with methanesulfonyl chloride/Et N in methylene chloride solution displacement takes place readily with dlmethylamine (15 min at 20 in dioxane). This may prove to be a generally useful procedure for replacement of lactam oxygen by other nucleophiles without resorting to intermediate chloro compounds. Note that 2-trlfluoromethanesulfonyloxypyridlne (from 2(lH)-pyridone, NaH, and trifluoromethanesulfonyl chloride) is an effective reagent for cile acylation of activated aromatic compounds with carboxylic acids. 

The antimony pentachloride-benzyltriethyl ammonium chloride complex (SbCls-TEBA, Figure 3.1), shows quite interesting catalytic efficiency in the acylation of activated aromatic compounds (i.e., toluene, xylenes, aryl ethers) with aromatic and chloroacetyl chlorides. Reactions are carried out with SbCls-TEBA (5% mol) in boiling nitromethane, giving ketones in 73%-96% yield. The catalyst has many advantages, such as ready access, minimal toxicity, reusability, insensitivity to atmosphere and moisture. 

Comparable yields are also obtained in the acylation of activated aromatic compounds with carboxylic acids using a substoichiometric amount of bis[(frifluoromefhyl)sulfonyl]amine in [emim][NTf2]. Thus, polyhydroxy-deoxybenzoins 30 can be synfhesized in 55%-74% yield by acylation of polyhydroxylafed aromafic compounds 28 with suitable phenylacetic acids 29 (Scheme 3.6). 

Jang, D. O., Moon, K. S., Cho, D. H., and Kim, J.-G. 2006. Highly selective catalytic Priedel-Crafts acylation and sulfonylation of activated aromatic compounds using indium metal. Tetrahedron Lett. 47 6063-6066. 

Carboxilic acids can react with triflic anhydride and activated aromatic compounds to form the acylated product in a Friedel-Crafts-type acylation reaction (110). This type of Friedel-Crafts acylation can also be apphed to ureas to obtain the corresponding aryl amide. ... 

Friedel-Crafts acylation follows the established activation-orientation rules of electrophilic aromatic substitution. However, the acylation of some highly activated aromatic compounds such as phenols and aromatic amines preferentially occurs at the substituent heteroatom, affording esters or amides instead of the more valuable aromatic ketones. These ort/io-hydroxy- or... 

Graphite can promote the Friedel-Crafts acylation reaction of active aromatic compounds such as anisoles and polymethylbenzenes with acyl halides to afford the corresponding aromatic ketones [101]. In a typical experiment, graphite is added to a mixture of anisole and benzoyl bromide in benzene, and the mixture is heated under reflux for 8h to afford para-methoxybenzophenone in 80% yield. Different acyl halides and several anisoles and polymethylbenzenes are utilized to give the corresponding products in high yields (60-92%). 

Friedel-Crafts acylation usually involves the reaction of an acyl halide, a Lewis acid catalyst, and the aromatic substrate. Several species may function as the active electrophile, depending on the reactivity of the aromatic compound. For activated aromatics, the electrophile can be a discrete positively charged acylium ion or the complex formed... 

Triflates of aluminum, gallium and boron, which are readily available by the reaction of the corresponding chlorides with triflic acid, are effective Fnedel-Crafis catalysis for alkylation and acylation of aromatic compounds [119, 120] Thus alkylation of toluene with various alkyl halides m the presence of these catalysts proceeds rapidly at room temperature 111 methylene chloride or ni-tromethane Favorable properties of the triflates in comparison with the correspond mg fluorides or chlorides are considerably decreased volatility and higher catalytic activity [120]... 

The exact mechanism has still not been completely worked out. Opinions have been expressed that it is completely intermolecular, completely intramolecular, and partially inter- and intramolecular. " One way to decide between inter- and intramolecular processes is to run the reaction of the phenolic ester in the presence of another aromatic compound, say, toluene. If some of the toluene is acylated, the reaction must be, at least in part, interraolecular. If the toluene is not acylated, the presumption is that the reaction is intramolecular, though this is not certain, for it may be that the toluene is not attacked because it is less active than the other. A number of such experiments (called crossover experiments) have been carried out sometimes crossover products have been found and sometimes not. As in 11-14, an initial complex (40) is formed between the substrate and the catalyst, so that a catalyst/substrate molar ratio of at least 1 1 is required. 

Ferrocene behaves in many respects like an aromatic electron-rich organic compound which is activated toward electrophilic reactions.In Friedel-Crafts type acylation of aromatic compounds with acyl halides, ferrocene is lO times more reactive than benzene and gives yields over 80%. However, ferrocene is different from benzene in respect to reactivity and yields in the Friedel-Crafts alkylation with alkyl halides or olefins. The yields of ferrocene alkylation are often very low. and the separations of the polysubstituted byproducts are tedious. 

Carbon monoxide, hydrogen cyanide, and nitriles also react with aromatic compounds in the presence of strong acids or Friedel-Crafts catalysts to introduce formyl or acyl substituents. The active electrophiles are believed to be dications resulting from diprotonation of CO, HCN, or the nitrile.64 The general outlines of the mechanisms of these reactions are given below. 

Catalytic activity of the beta zeolite with enhanced textural properties in the Friedel-Crafts acylation of aromatic compounds... 

Bi salts proved to be as active as RET or other metallic triflates in the FC acylation of aromatic compounds using acyl chlorides or anhydrides [13, 66]. While... 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

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