Acylation reactions carboxylic acids

The reaction of lithio derivatives with appropriate electrophiles has been utilized in the preparation of alkyl, aryl, acyl and carboxylic acid derivatives. Representative examples of these conversions are given in Scheme 79. Noteworthy is the two-step method of alkylation involving reaction with trialkylborane followed by treatment with iodine (78JOC4684). 

Diaryl sulfones can be formed by treatment of aromatic compounds with aryl sulfonyl chlorides and a Friedel-Crafts catalyst. This reaction is analogous to Friedel-Crafts acylation with carboxylic acid halides (11-14). In a better procedure, the aromatic compound is treated with an aryl sulfonic acid and P2O5 in polypho-sphoric acid. Still another method uses an arylsulfonic trifluoromethanesulfonic anhydride (ArS020S02CF3) (generated in situ from ArS02Br and CF3S03Ag) without a catalyst. ... 

These reactions were demonstrated with pure enzymes or various biological media such as human peripheral blood mononuclear cells uninfected or infected with HIV. In the latter case, highly promising antiviral results were obtained. Furthermore, a variety of amino acyl residues, carboxylic acid ester moieties, and aryl substituents X have been reported. 

Acy 1-4-amino-1,5-dihydro-2-pyrrolones (6) (type Z in Scheme 1) possess the features of cyclic enaminediones. The push-pull-7r system decreases the nucleophilicity of the amino group. Therefore N-acylation with carboxylic acid chlorides requires relatively drastic conditions (dioxane, 100°C, K2C03). In particular, the reaction of the highly reactive DMF-acetal 8 to formamidine 9 succeeds only while refluxing in benzene (87TH1). (See Fig. 3.)... 

Because they are readily available from a number of synthetic reactions, carboxylic acids are the most common starting materials for the preparation of the other members of this family. Conversion of a carboxylic acid to an acyl chloride provides access to any of the other derivatives because the acyl chloride is at the top of the reactivity scale. Bui how can the acyl chloride be prepared from the acid when the acid is lower on the reactivity scale This can be accomplished by using an even more reactive compound to drive the equilibrium in the desired direction. The reagent that is employed in the vast majority of cases is thionyl chloride, SOCl2. Phosphorus trichloride, PC13, and phosphorus pentachloride, PC15, are also used occasionally. Examples are provided in the following equations ... 

The acylation of carboxylic acids with 2,4,6-trichlorobenzoyl chloride gives mixed anhydrides A (Figure 6.14). Triethylamine must be present in this reaction to scavenge the released HC1. Anhydrides A contain two different acyl groups. In principle, both of them could be attacked by a nucleophile. However, one observes the chemoselec-tive attack on the acyl group that originates from the acid used. This is because the... 

This reaction involves an acylating reagent (acyl halides, carboxylic acids or anhydrides) in the presence of an activator, usually a Lewis acid. However, as a result of the complexation of this Lewis acid with the formed ketone, more than one mole of catalyst is required per mole of reagent. It cannot be reused because the ketone is isolated after hydrolysis of the complex. Such is the dilemma of Friedel-Crafts acylation (refs. 4-6) in the presence of the traditional catalyst, aluminum chloride (eqn. 2). 

Acylations with carboxylic acids and anhydrides have been carried out with sulfuric acid as both solvent and catalyst, the reactive acylating agents from acyl halides probably being haloacyloxonium ions. Trifluoroacetic anhydride offers a rather milder reagent for reactions of carboxylic acids, with mixed anhydrides being likely intermediates. However, polyphosphoric acid remains the most widely used dehydrating agent for acylations by carboxylic acids. 

Anisole can be acylated with carboxylic acids over ZSM-5 catalyst. The reaction is carried out in a batch reactor under reflux for 2 d. Table 4.12 shows fhe resulfs obfained utilizing carboxylic acids with different chain length. Prom propanoic acid to stearic acid, the conversion decreases from 92% to 1%, showing a trend opposite to that observed with REY zeolites. This behavior can be ascribed to the small micropore size of ZSM-5, in which the formation of large molecules is difficulf (for penfanoic to octanoic acid) or impossible (for longer-chain carboxylic acids). The poor conversion of AAC can be affribufable to the low reflux temperature. 

Chiral 2-thiazolidinethiones, e.g., 40, prepared from cysteine esters by the reaction with carbon disulfide23, are used for the enantiotopic differentiation of methylene groups (Section C.). Similarly, carbon disulfide reacts with amino alcohols such as (5)-2-amino-J-butanol or (S)-2-amino-3-methyl-1-butanol (valinol) to give the 2-thiazolidinethiones (S)-ETT 42 and (S)-IPTT 4124 which have been used as auxiliaries (after Y-acylation with carboxylic acids and dicyclo-hexylcarbodiimide) in acylimonium ion cyclizations (Section D.I.4.5.). 

The aromatic acylation with carboxylic acids (Eq. 3) instead of acid anhydrides and acyl chlorides has attracted interest, because it is an environmentally benign reaction, resulting in the formation of water as the only by-product. It has been attempted with zeolites and clays as catalysts. Heteropoly acids have proved to be more active catalysts for this... 

We have now investigated further the importance of the modification of the zeolite on its activity in catalysing the acylation reaction. Of particular interest was the application of the rare-earth (RE) exchanged zeolites to acylation reactions using acid chlorides. Previous studies had either tested the RE modified zeolite systems with the carboxylic acid [3,4] or applied only the H-form of the zeolite to the acid chloride system [5-7]. We were interested in the role of the rare-earth cation in enhancing the activity of the catalyst with the acid chloride. 

The safe and stable diazomethane substitutes arylsulphonyldiazomethane and trimethylsilyldiazomethane have both been shown to be acylated by carboxylic acid chlorides. Subsequent Wolff rearrangement then provides new and safe alternatives for the Arndt-Eistert reaction (Scheme 59). 

Kedrowski and Dougherty developed a one-pot, four-step room temperature protocol for the synthesis of allylphosphonates (6) from acyl chlorides/carboxylic acids (5) via a Wolff-Kishner-type reductive deoxygenation (Scheme 3). This method offers a low-temperature alternative to the Arbuzov reaction that works well for a variety of aliphatic acids and shows a functional group tolerance similar to that of other hydrazone-forming reactions. The investigators also proposed a mechanism for this transformation (Scheme 4). 

Heteropoly acid, aluminum dodecatungstophosphate AIPW12O40, was found to be an effective catalyst for the Friedel-Crafts acylations using carboxylic acid, acetic anhydride, and benzoyl chloride (Scheme 6.9) [11]. Nonhydroscopic nature and relatively high catalytic activity of this heteropoly acid, for example, as compared with Sc(OTf)3 or In(OTf)3, should be noted. Reactions were conducted under solvent-free conditions. 

The conversion of an aliphatic carboxylic acid into the a-bromo- (or a-chloro ) acid by treatment with bromine (or chlorine) in the presence of a catal3rtic amount of phosphorus tribromide (or trichloride) or of red phosphorus is known as the Hell-Volhard-Zelinsky reaction. The procedure probably involves the intermediate formation of the acyl halide, since it is known that halogens react more rapidly with acyl haUdes than with the acids themselves ... 

The reaction of trivalent carbocations with carbon monoxide giving acyl cations is the key step in the well-known and industrially used Koch-Haaf reaction of preparing branched carboxylic acids from al-kenes or alcohols. For example, in this way, isobutylene or tert-hutyi alcohol is converted into pivalic acid. In contrast, based on the superacidic activation of electrophiles leading the superelectrophiles (see Chapter 12), we found it possible to formylate isoalkanes to aldehydes, which subsequently rearrange to their corresponding branched ketones. 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

Acyl chlorides are readily available They are prepared from carboxylic acids by reaction with thionyl chloride... 

Friedel-Crafts acylation of aromatic compounds (Section 12 7) Acyl chlorides and carboxylic acid anhydrides acylate aromatic rings in the presence of alumi num chloride The reaction is electrophil ic aromatic substitution in which acylium ions are generated and attack the ring... 

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