Cinnamic acid anhydride synthesis

An acyl transfer agent which can be used for the synthesis of acid anhydrides is obtained from the reaction of an acid chloride with 4-benzylpyridine (equation 24). In this way benzoic acid anhydride and cinnamic acid anhydride were obtained in 72% and 57% yields, respectively. As the intermediate, 1-acyl-4-benzylidene-l,4-dihydropyridines, can be isolated, Ais procedure should be well suited for the preparation of mixed anhydrides. Mixed aromatic and aliphatic anhydrides can be prepared with 2-ben-zoylthio-l-methylpyridinium chloride and salts of carboxylic acids. These reactions are carried out in aqueous solution. Iliey make use of the high reactivity of esters of thiocarboxylic esters towards nucleophiles. The mixed anhydrides of benzoic acid with 3-phenylpropanoic acid, phenoxyacetic acid, isobu-tyric acid, p-toluic acid and cinnamic acid were formed in 82, 79,61,91 and 66% yields, respectively. 

Coumarin is usually prepared by heating salicylaldehyde with acetic anhydride and sodium acetate (i.e., the Perkin cinnamic acid synthesis, p. 23 6), whereby the 0" hydroxy-cinnamic acid (I) undergoes cyclisation to coumarin. Coumarins having substituents in the benzene ring can often be similarly prepared. 

Manufacture. The most widely employed method for the commercial synthesis of (H)-cinnamic acid uti1i2es ben2aldehyde, acetic anhydride, and anhydrous sodium or potassium acetate in a condensation reaction commonly referred to as the Perkin reaction (11). 

Cinnamic acid synthesis from aryl aldehyde and acetic anhydride. 

The Perkin synthesis of cinnamic acids is considered to involve reaction of the enolate anion derived from the acid anhydride with the aldehyde, giving rise to the alkoxide (391). Intramolecular acylation follows and the resulting /3-acyloxy derivative undergoes elimination to the unsaturated acid (Scheme 125). 

Examples of the use of these methods are given in Expts 5.148 and 5.149. The use of an acyl chloride or acid anhydride is the method of choice for the synthesis of phenyl esters (e.g. phenyl cinnamate see also Section 9.6.6), which cannot be prepared by the direct esterification methods described above. 

A modified Perkin procedure is illustrated in the synthesis of a-phenyl-cinnamic acid in which benzaldehyde is condensed with phenylacetic acid in the presence of acetic anhydride and triethylamine. Presumably equilibria are set up which result in the formation of either a mixed anhydride, phenylacetic acetic anhydride or the symmetrical phenylacetic anhydride. 

Malonic acid itself can react with aldehydes in the presence of piperidine by way of a Knoevenagel condensation. A decarboxylation occurs after the condensation, and this decarboxylation cannot be avoided. Figure 13.55 shows how the overall reaction can be employed for the synthesis of cinnamic or sorbic acid. This reaction sequence occurs under much milder conditions than the Perkin synthesis of cinnamic acids. (The Perkin synthesis consists of the condensation of aromatic aldehydes with acetic acid anhydride in the presence of sodium acetate.)... 

Cinnamic Acid by Perkin s Reaction.—Cinnamic acid has the constitution assigned to it above as is proven by the following synthesis from benzaldehyde by condensation with sodium acetate in the presence of acetic anhydride. 

The Perkin reaction involves the condensation of a carboxylic acid anhydride and an aldehyde in the presence of a weak base, often the sodium or potassium salt of the acid or triethylamine, to give unsaturated carboxylic acids (equation 1). The first example of this reaction was described by Perkin in 1868 and involves a synthesis of coumarin by heating the sodium salt of salicylaldehyde with acetic anhydride (equation 2). The reaction is generally applicable only to aromatic aldehydes and is particularly useful for the preparation of substituted cinnamic acids, as illustrated by equation (3). ... 

As exemplified by equation (2), the Perkin condensation of o-hydroxybenzaldehydes is an important method for the synthesis of substituted coumarins. An interesting variation on this procedure has been reported recently. Heating a mixture of o-fluorobenzaldehyde, 2-thiopheneacetic acid, acetic anhydride and triethylamine affords directly the coumarin (20 equation 13) instead of the expected cinnamic acid (21). The reaction proceeds similarly with several arylacetic acids. The reaction presumably proceeds through the cinnamic acids (21). The observed product can conceivably arise by direct nucleophilic displacement involving the carboxylate or by an elimination/addition (benzyne) mechanism. The authors note that when 2-fluorobenzaldehyde is replaced by its 2-bromo analog in this reaction, the substituted cinnamic acid (22) is the major product and the corresponding coumarin (20) is obtained only in low yield. It is suggested that since it is known that fluoride is displaced more rapidly in nucleophilic aromatic substitution reactions, while bromo aromatic compounds form benzynes more rapidly, this result is consistent with a nucleophilic displacement mechanism. 

C1SH 2 mol wt 228.29. C 94.70%, H 5.30%. Synthesis by a Pschorr reaction from diazotized -(2-naphthyl)-2-amino-cinnamic acid Cook, J. Chem. Soc. 193t, 2524. From di-phenylmethylsoccinic anhydride Heweit, J. Chem. Soe. 

Cinnamic acid is manufactured by the so-called Perkin synthesis, which has been applied to the preparation of a large number of unsaturated acids. When benzoic aldehyde is heated with anhydrous sodium acetate in the presence of acetic anhydride, condensation takes place as the result of the loss of water CeHs.CHO + CHg.COONa = CeHB.CHrCH.COONa + H2O A similar condensation takes place between benzoic aldehyde and homologues of acetic acid. The hydrogen atoms which are eliminated from the salt of the fatty acid are those in the a-posi-tion —... 

The simplest synthesis of coumarins is a special case of the Perkin condensation i.e. the condensation of an aromatic aldehyde with an anhydride. ortho-Hydroxy-trans-cinnamic acids cannot be intermediates since they do not isomerise under the conditions of the reaction nor can O-acetylsalicylaldehyde be the immediate precursor of the coumarin, since it is not cyclised by sodium acetate on its own. ... 

A convenient synthesis of anhydrides has been described by the reaction of potassium or sodium salts of carboxylic acids with activating halides (ethyl chloroformate, cyanuric chloride and benzyl chloroformate) in acetonitrile in the presence of 18-crown-6. Using this procedure, cinnamic acid, p-nitrobenzoic acid, benzoic acid, acetic acid and propionic acid are also converted into their anhydrides (Scheme 30). 

Synthesis. DL-iyrosine is synthesized in 46% over-all irield by the method of Lamb and Robson (491). 4-(p-Metboxybenzylidene)-2-phenyl-5-oxasolone (A) is prepared in 62% yield from anisaldehyde, acetic anhydride, hippuric acid and sodium acetate. The crude product ni recrystallized from bmizene. o-Benzoylamino-p-metiMn cinnamic acid... 

Perkin Synthesis. This synthesis is a well-known organic reaction yielding cinnamic acid from an aromatic aldehyde and an anhydride. Commonly, sodium acetate has been used in the reaction as a base catalyst. However, significant increase in yield was found when cesium acetate was used instead of sodium acetate (eq 6). In fact, yields were shown to increase up to 10 times with certain aryl substrates when cesium acetate was substituted for sodium acetate. ... 

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