Perkin reaction cinnamic acid synthesis

Enol phosphate synthesis from a-halocarbonyls and trialkylphosphites. General scheme  

X = Cl, Br, I, secondary or tertiary halides are required to prevent the Michaelis-Arbuzov reaction. 

Cinnamic acid synthesis from aryl aldehyde and acetic anhydride. 

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Perkin Reaction (Perkin cinnamic acid synthesis) The Reaction ... 

Application of the Perkin cinnamic acid synthesis to salicylaldehydes provides a coumarin synthesis of some renown. The reaction itself has been reviewed <42OR(l)2l0) and some discussion of its value in coumarin synthesis is contained in other reviews (37CB(A)83, 45CRV(36)l). 

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. 

Chapter IV. a-Chloromethylnaphthalene (IV,23) benzylamine (Gabriel synthesis) (IV,39) i r.N -dialkylanilines (from amines and trialkyl orthophosphates) (IV,42) a-naphthaldehyde (Sommelet reaction) (IV,120) a-phenyl-cinnamic acid (Perkin reaction using triethylamine) (IV,124) p-nitrostyrene (IV,129) p-bromonaphthalene and p naphthoic acid (from 2 naphthylamine-1 -sulphonic acid) (IV,62 and IV,164) diphenic acid (from phenanthrene) (IV,165). 

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). 

Use of the Knoevenagel reaction (67OR(l5)204), in which a benzaldehyde reacts with an activated methylene compound in the presence of an amine, goes some way to overcoming the inherent difficulties of the Perkin synthesis of coumarins (see later). In order to obtain the coumarin rather than the usual cinnamic acid, a 2-hydroxy substituent must be present... 

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). 

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.)... 

This is the simplest case of the reaction but it has been mostly used in the synthesis of higher members of the unsaturated acid series, e.g., the nine carbon acid, nonylenic acid, which is prepared from the seven carbon aldehyde known as oenanthylic aldehyde, or oenanthol, obtained from castor oil. Even more important than its application in the synthesis of higher acids of the ethylene series is the use of the reaction in the synthesis of aromatic unsaturated cLcids derived from benzene and containing an unsaturated side chain (see cinnamic acid. Part II). The reaction is known as the Perkin Synthesis or as the Perkin-Fittig Synthesis from the men who suggested and explained it. 

In the laboratory of D. Ma, the asymmetric synthesis of several metabotropic glutamate receptor antagonists derived from a-alkylated phenylglycines was undertaken. The preparation of (S)-1-aminoindan-1,5-dicarboxylic acid (AIDA) started with the Perkin reaction of 3-bromobenzaldehyde and malonic acid. The resulting ( )-cinnamic acid derivative was hydrogenated and the following intramolecular Friedel-Crafts acylation afforded the corresponding indanone, which was then converted to (S)-AIDA. 

Further steps in the synthesis of coumarin via the ortho-hydroxy benzaldehydes involve a Perkin reaction. Here, in the first instance, a cinnamic acid is obtained. The cinnamic acids are obtained more conveniently by the Wittig reaction of the aldehydes with the stable phosphoranes, Ph3P=C—COOEt. Indeed lithiation... 

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. 

Recently, it has been reported that significantly higher yields are obtained and shorter reaction times required in the Perkin synthesis of cinnamic acids when sodium acetate is replaced by cesium acetate. ... 

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