Friedel-Crafts acylation reaction using carboxylic acids as acylating agents

Dehydrative Friedel-Crafts acylation reaction of aromatic compounds with carboxylic acids as acylating agents was investigated in the presence of Lewis acid- or Brønsted acid-catalyst. Various metal triflates and bis(trifluoromethanesulfonyl)amides showed catalytic activity at high temperature, among which Eu(NTf₂)₃ proved to be the most effective and efficiently catalyzed the acylation reaction of alkyl- and alkoxybenzenes with aliphatic and aromatic carboxylic acids at 250 °C. Bi(NTf₂)₃ was more effective than Eu(NTf₂)₃ at lower temperature, but proved to be hydrolyzed in the presence of a small amount of water to give HNTf₂ and [Bi₆O₄(OH)₄(H₂O)₆](NTf₂)₆. The structure of the latter compound was confirmed by a single crystal X-ray analysis. Among five Brønsted acids, HOTf, HNTf₂, HCTf₃, TsOH, and Nafion^® SAC-13, HNTf₂ has proved to be the most efficient catalyst and more effective than Eu(NTf₂)₃ for the acylation of p-xylene with heptanoic acid at 220 °C or lower temperature. HNTf₂ catalyzed the acylation of anisole with carboxylic acids in high yields in refluxing toluene with azeotropic removal of water.     

Lewis acid-catalyzed Friedel-Crafts acylation reaction using carboxylic acids as acylating agents

Rare-earth metal Lewis acids, in particular Eu(NTf₂)₃, were found to be efficient catalysts for Friedel-Crafts acylation reaction using aliphatic as well as aromatic carboxylic acids as acylating agents at high temperature.     

Scandium triflate-catalyzed intramolecular Friedel-Crafts acylation with Meldrum's acids: insight into the mechanism

The intramolecular Friedel-Crafts acylation of arenes with Meldrum's acid derivatives catalyzed by Sc(OTf)₃ was reported as a mild and general entry into functionalized 1-indanones. Mechanistic investigations were undertaken to determine the rate-determining step in the acylation sequence using Meldrum's acid, as well as to examine the role of the Lewis acid catalyst. Enolizable Meldrum's acid derivatives react via an acyl ketene intermediate under thermal conditions, while quaternized Meldrum's acid derivatives are thermally stable and only act as effective Friedel-Crafts acylating agents in the presence of a Lewis acid catalyst. The acylation was postulated to proceed through direct acylation of a Lewis acid-activated carbonyl. In the catalytic Friedel-Crafts acylation of Meldrum's acids, triflic acid appeared to be the active catalytic species, with Sc(OTf)₃ serving as a very mild and convenient reagent for its delivery.     

Amino acids as selective sulfonamide acylating agents

Acylation of antimalarial and bacteriostatic sulfonamides with N-protected amino acids and peptides was carried out using standard peptide coupling methods. These acylation reactions are regioselective for the N⁴ nitrogen atom of diazine-containing sulfonamides. In contrast, only N¹ coupling was found for sulfisoxazole, an isoxazole-based sulfonamide. Computational studies suggest that a combination of geometrical, thermodynamic and electronic factors are responsible for the different reactivities reported.     

Conversion of 2-alkylcinnamaldehydes to 2-alkylindanones via a catalytic intramolecular Friedel-Crafts reaction

The preparation of indanones by the intramolecular acylation of 3-arylpropanoic acids or halides requires the use of noncatalytic acid promoters. In the presence of 5-10 mol % FeCl(3), in situ generated dimethyl acetals of (E)-2-alkylcinnamaldehydes cyclize to 1-methoxy-2-alkyl-1H-indenes in good-to-high yields. The 1-methoxyindenes were converted in high yield into 2-alkylindanones by treatment with triethylamine, to effect isomerization to the isomeric enol ethers, followed by acid-catalyzed hydrolysis. Thus, a catalytic, intramolecular Friedel-Crafts reaction leading to 2-alkylindanones from 2-alkylcinnamaldehydes was developed.     

N-methoxy-n-methylamides as effective acylating agents

Readily preparable N-methoxy-N-methylamides couple in good yields with Grignard and organolithium reagents to produce ketones, and are reduced with hydrides to afford aldehydes.     

Active esters as acylating reagents in the Friedel-Crafts reaction: trifluoromethanesulfonic acid catalyzed acylation of ferrocene and pyrene

The Friedel-Crafts acylation of electron-rich arenes (ferrocene and pyrene) with N-hydroxysuccinimidyl, 2,3,5,6-tetrafluorophenyl and phenyl esters of benzoic and p-methoxybenzoic acid, activated by superacidic trifluoromethanesulfonic acid is reported. The reactive acylating intermediate in this system is presumably an acyl triflate or its protonated form.     

New catalytic approaches in the stereoselective Friedel-Crafts alkylation reaction

After more than 125 years, the Friedel–Crafts alkylation is still one of the most studied and most utilized reactions in organic synthesis. What is the secret of this astonishing success? Perhaps the great versatility in scope and applicability continues to justify its crucial role in the synthesis of more and more complex molecules. However, it has taken more than a century for asymmetric catalytic versions of this reaction to be developed and subsequently extended to a range of aromatic compounds and alkylating agents. Herein we review recent developments in the design and use of catalytic and stereoselective strategies for the alkylation of aromatic systems and synthesis of a wide range of polyfunctionalized enantiomerically enriched compounds.     

Synthesis of various acylating agents directly from carboxylic acids

Abstract

A straightforward synthesis of acylating reagents such as Weinreb and MAP amides from aromatic, aliphatic carboxylic acids, and amino acids using PPh₃/NBS combination is described. A chemo-selective modification of the carboxylic acid group into Weinreb amide in the presence of more reactive aldehydes and ketones is presented. All reactions were performed at ambient temperature under air using undried commercial grade solvent. Furthermore, the present methodology could be performed at a gram scale under inert-free reaction conditions. In addition, 7-azaindoline amide auxiliary (used for catalytic asymmetric aldol- and Mannich-type reactions), which behaves like Weinreb amide is also synthesized under similar reaction conditions.     

Synthesis of 1-tetralones by intramolecular Friedel-Crafts reaction of 4-arylbutyric acids using Lewis acid catalysts

Intramolecular Friedel-Crafts reaction of 4-arylbutyric acids efficiently proceeded in the presence of catalytic amounts of Lewis acids such as Bi(NTf₂)₃ and M(OTf)₃ (M=Bi, Ga, In and rare-earth metals) to form 1-tetralones. Chroman-4-one and thiochroman-4-one were also obtained in good yields from 3-phenoxypropionic acid and 3-phenylthiopropionic acid, respectively.     

Benzothiazines in synthesis. Eight-membered ring formation in an intramolecular Friedel-Crafts reaction

Treatment of certain benzothiazines bearing allylic bromides side chains with indium tribromide resulted in the formation of eight-membered rings in addition to the expected six-membered rings.     

Acylmethanesulfonamides as new acylating agents for primary amines

A new, simple and efficient procedure for the preparation of secondary amides through internal condensation of acylmethanesulfonamides ammonium salts is described. The selective acylation of mixed primary-secondary amines could be an attractive application of the new method.     

Reducing agents as components in catalytic systems of the Heck reaction

Using of reducing agents for arylation of alkenes has been found to increase the activity of the catalytic system and allow to avoid the use of traditional tertiary amines as bases in the Heck reaction.     

A highly enantioselective catalytic intramolecular Stetter reaction

A family of chiral triazolium salts has been developed for inducing the asymmetric intramolecular Stetter reaction. The use of an aminoindanol-derived catalyst affords optimal results, with the product keto esters formed in 82-97% ee and very good chemical yield. Aromatic and aliphatic aldehydes are equally competent substrates for this reaction. The reaction conditions are reasonably mild and allow the isolation of the newly formed stereocenter without epimerization, although the presumed carbenic intermediates are strong bases.     

Preparation of six isomeric bis-acylporphyrins with chromophores reaching the near-infrared via intramolecular Friedel-Crafts reaction

We describe the preparation of six diketones based on the frameworks of five bis-naphthoporphyrins and one perinaphthoporphyrin. All diketones derive from meso-tetraarylporphyrins having incorporated two carbonyl groups, each one connected to one beta-pyrrole carbon and one ortho carbon atom from a meso-aryl group. These compounds were all produced in good yield by intramolecular Friedel-Crafts acylation, either from porphyrins meso-substituted by o-carboxyphenyl or o,o'-dicarboxyphenyl substituents or from porphyrins bearing carboxy groups attached to the pyrrolic beta-positions. Although the former reaction does not show significant regioselectivity when run on nickel complexes, the opposite is true for the corresponding free bases. All diketones show a spectacular bathochromic shift of the UV-vis absorption, the longest wavelength bands absorbing in the 700-825 nm range. Two compounds were structurally characterized by X-ray diffraction. In the case of the diketone, whose carbonyl groups are attached to vicinal pyrrolic beta-positions, a significant intermolecular interaction between the two carbonyl groups and an aromatic hydrogen atom was detected.     

Convenient access to polysubstituted 1-indanones by Sc(OTf)3-catalyzed intramolecular Friedel-Crafts acylation of benzyl Meldrum's acid derivatives

[reaction: see text] The intramolecular Friedel-Crafts acylation of benzyl Meldrum's acids is catalyzed by Sc(OTf)(3) under mild reaction conditions. Several polysubstituted 1-indanones have been prepared.     

Amino acids as selective acylating agents: regioselective N-acylation of imidazolidin-4-one derivatives of the antimalarial drug primaquine

The acylation of bioactive primaquine-based imidazolidin-4-ones was studied using N^α-Boc-protected glycine as acylating agent. Two synthesis routes, eight different coupling methods and seven distinct solvents were compared. Mild carbodiimide-based couplings on high dielectric constant solvents such as DMF or MeCN increased acylation yields, whereas alcohols inhibited carbodiimide-mediated acylations to take place. Achievement of the synthetic goals was limited by the size of the imidazolidin-4-one ring substituents R¹, R² and R³, but resort to MW-assisted synthesis allowed overcoming such obstacle, though with very modest reaction yields. All reactions involving a Boc-protected amino acid were regioselective, independent of reaction conditions employed. In contrast, regioselective acetylation of the imidazolidin-4-ones could only be achieved by resort to very mild coupling procedures.     

Heteroacyl azides as acylating agents for aromatic or heteroaromatic amines

The possibility of formation of substituted heterocyclic amides from heteroacyl azides and aromatic or heteroaromatic amines was investigated. Although acylation proceeded in some cases under mild reaction conditions, formation of N,N′-disubstituted ureas was the main process at elevated temperatures.     

Research in the field of heterocyclic chemistry. XL. Organic acids as intramolecular condensing agents for arylamide hydroxy acids

It is shown that the basic properties of arylamides of diarylglycolic acids are determined not only by the nature of the aryl radicals of the acid part of the molecule, but also by the extent to which hydrogen atoms of the amino groups are substituted. Formation of carbonium salts of arylamides is considerably influenced by the nature of the solvent. Intramolecular condensation of tertiary arylamides of 4, 4-dimethoxy- and 4, 4-dimethylbenzylic acids gives a number of new 1-alkyl (aryl)-3, 3-diaryloxindoles. Ethyl N-n-propyl- and N-isobutyloxanilate and N,N-diethylamide-4, 4-dimethoxybenzylate are described for the first time.For part XXXIX see [1].