Carboxylic acids, as acylating agents

Applying 3 mol of the Lewis acid, the carboxylic acid itself can also serve as the acylating agent. In fact, this observation led to the successful application of carboxylic acids as acylating agents. 

Kawamura, M., Cuiy, D. M., and Shimada, S. 2006. Friedel-Crafts acylation reaction using carboxylic acids as acylating agents. Tetrahedron 62 9201-9209. 

The mesoporous aluminosilicate AlMCM-41-type material, prepared from BEA zeolite seeds, can be utilized as catalyst in the acylation of anisole with acyl chloride with the aim of improving the transport of the reactants, especially for the relatively hindered molecules such as octanoyl chloride. The catalyst shows good activity, being para-octanoyl anisole obtained in 90% yield after 1 h. As commonly observed, the use of carboxylic acid as acylating agent results in a slower process (-20% yield after 26 h) due to its lower electrophilicity and the production of water that inhibits the active sites of the zeolite, as previously observed by Beers et al. ... 

Carboxylic anhydrides are more powerful than the free acids as acylating agents and convert ammonia and primary and secondary amines into amides, generally smoothly and in very good yield. The equation... 

By virtue of their fused /3-lactam-thiazolidine ring structure, the penicillins behave as acylating agents of a reactivity comparable to carboxylic acid anhydrides (see Section 5.11.2.1). This reactivity is responsible for many of the properties of the penicillins, e.g. difficult isolation due to hydrolytic instability (B-49MI51102), antibacterial activity due to irreversible transpeptidase inhibition (Section 5.11.5.1), and antigen formation via reaction with protein molecules. 

As acylating agent, a carboxylic anhydride may be used instead of the acyl halide. The reaction then yields the arylketone together with a carboxylic acid, each of which forms a complex with the Lewis acid used. The catalyst therefore has to be employed in at least twofold excess ... 

A carboxylic acid may also be employed directly as acylating agent, without being first converted into an acyl halide in that case a protic acid is used as catalyst. 

A-(tert-Butoxycarbonyl)azetidine-2-carboxylic acid is obtained by reaction of azetidine-2-carboxylic acid with Boc-N3, m 112 Boc20, 113-"4 or 2-(fert-butoxycarbonyloxyimino)-2-phe-nylacetonitrile. 115 In a similar manner, the Fmoc derivative is prepared by the standard procedure using Fmoc-OSu as acylating agent.1"6 For derivatives of azetidine-2-carboxylic acid, see Table 4. 

As reported in the literature, the acylation of aromatic hydrocarbons can be carried out by using zeolites as catalysts and carboxylic acids or acyl chlorides as acylating agents. Thus toluene can be acylated by carboxylic acids in the liquid phase in the presence of cation exchanged Y-zeolites (ref. 1). The acylation of phenol or phenol derivatives is also reported. The acylation of anisole by carboxylic acids and acyl chlorides was obtained in the presence of various zeolites in the liquid phase (ref. 2). The acylation of phenol by acetic acid was also carried out with silicalite (ref. 3) or HZSM5 (ref. 4). The para isomer has been generally favoured except in the latter case in which ortho-hydroxyacetophenone was obtained preferentially. One possible explanation for the high ortho-selectivity in the case of the acylation of phenol by acetic acid is that phenylacetate could be an intermediate from which ortho-hydroxyacetophenone would be formed intramolecularly. 

Cs2.5 for the acylation. Anisole and /j-xylene are acylated with benzoic anhydride and acetic anhydride in the presence of Cs2.5 without the dissolution of this catalyst. Carboxylic acids are much less reactive as acylating agents than the corresponding anhydrides because of the liberation of water. But when the water is removed, the acylation proceeds smoothly 214). Although the reaction of benzene with acetic acid is attractive in prospect, there is no report of heteropoly compounds as catalysts for this reaction. 

Carboxylic acids and acid anhydrides also serve as acylating agents in Friedel-Crafts reactions. We consider these acylating agents in Chapters 20 and 21 when we study the reactions of carboxylic acids and their derivatives. 

Whereas acyl chlorides and carboxylic acid anhydrides can be reduced to aldehydes using Na2[Fe(CO>4] e.g. Scheme 10) most esters cannot, because of their low reactivity as acylating agents. However, Na2[Fe(CO)4] does give low yields of aldehydes (<40%) with esters of aromatic alcohols. ... 

Acylthio-3-nitropyridines, prepared from the corresponding carboxylic acids, have been used as acylating agents when the corresponding acid chlorides are unstable [426]. 

A-Acylation is one of the most important synthetic methods in the chemistry of A -aminoazoles, and is widely used in various heterocyclizations as well to protect the amino group. There are numerous papers devoted to acylation of practically all types of N-aminoazoles, with the exception of A-aminopyrazole. As acylating agents, carboxylic acids... 

In this chapter, only special examples of stoichiometric acylation will be commented. For example, reactions showing extraordinary level of regiose-lectivity promoted by proximity or metal template effects are described. Moreover, examples of efficient use of carboxylic acids and esters as acylating agents under soft experimental conditions in combination with ecocompatible solvents are stressed as new and practicable synthetic methods. Studies on the highly efficient multistep s)mthesis of polyfunctional compounds via bis-acylation and alkylation-acylation processes are commented upon, and some mechanistic details are also shown. 

The dealuminated Y(30) zeolite efficiently promotes the benzoyla-tion of 2-butylbenzofuran with para-anisoyl chloride or para-anisic acid the reaction is performed at 180°C in 1,2-dichlorobenzene (Table 4.6), and leads to the three acylated isomers 15,16, and 17 with a good initial selectivity in the 3-acylated derivative 15. The selectivity decreases with time due to the consecutive deacylation of this compound, followed by a reacylation that favors the formation of the other two isomers (mainly, the 6-acylated one). As expected, lower activity is observed when the carboxylic acid is utilized as acylating agent. 

The rate of reaction of carboxylic esters with amines can often be increased by using as acylating agents esters that exchange their alcohol residues with particular ease. With this in mind Schwyzer781 recommends the use of cyano-methyl esters, RCOOCH2CN. The cyanomethyl esters of N-protected amino acids react readily even at room temperature with amino esters and are thus particularly suitable for peptide synthesis. Also, phenyl trifluoroacetate has been recommended for trifluoroacetylation of amino acids and peptides.782 The possibilities offered by such activated esters for peptide synthesis are reviewed in the monograph by Schroder and Liibke.783... 

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