Coumarins Perkin reaction

Basic catalysts other than alkali acetates have been employed in the Perkin reaction thus salicylaldehyde condenses with acetic anhydride in the presence of triethylamine to yield coumarin (tlie lactone of the cis form of o-hydroxy-cinnamio acid) together with some of the acetyl derivative of the trans form (o-acetoxycoumaric acid) ... 

Perkin Reaction. A product of significant commercial importance, coumarin [91-64-5] is made by the reaction of sahcylaldehyde with acetic anhydride and sodium acetate, a Perkin reaction (61). 

The Perkin reaction is of importance for the iadustrial production of coumarin and a number of modifications have been studied to improve it, such as addition of a trace of iodine (46) addition of oxides or salts of metals such as iron, nickel, manganese, or cobalt (47) addition of catalytic amounts of pyridine (48) or piperidine (49) replacement of sodium acetate by potassium carbonate (50,51) or by cesium acetate (52) and use of alkaU metal biacetate... 

As the chemical industry expanded, Perkin continued his own scientific research in the peace of his private laboratory. He had not lost his touch. Among the synthetic methods he discovered is one now called the Perkin reaction. He used it to make a synthetic substitute for a vegetable substance called coumarin, which has a pleasant, vanillalike odor. Coumarin spawned the synthetic perfume business and made luxurious scents available to all. Once again, a Perkin chemical started a new industry, albeit a modest one in comparison with dyes and pharmaceuticals. Despite the worldwide impact of Perkins discoveries, he was not knighted by the British monarchy until 1906, the fiftieth anniversary of his discovery of mauve. The world chemistry community feted him lavishly that year, and he traveled to the United States collecting further honors. A year later, at the age of 69, he died peacefully, at home. 

Until the late 1890s, coumarin was obtained commercially only from natural sources by extraction from tonka beans. Synthetic methods of preparation and industrial manufacturing processes were developed starting principally from ortho-creso (Raschig process), phenol (Pechmann reaction) and salicylaldehyde (Perkin reaction). Various methods can be used to obtain coumarin from each of these starting materials. In order to be suitable for perfumery uses, synthetic coumarin must be highly pure (Bauer et al., 1988 Boisde Meuly, 1993). 

Two failures of the Perkin reaction should be reported 5-nitro-coumarin gives a 3,4-dibromide, but alkaline treatment does not lead to 5-nitrocoumarilic acid,812 further, 2//-naphtho[l, 2-6]pyran-2-one (366) is brominated not on the heterocycle, but in position 6.813... 

Perkin Synthesis of Coumarin.—Coumaric acid and coumarin may be synthesized by the Perkin reaction for synthesizing unsaturated aromatic acids (p. 698). These syntheses are of historical interest as the two compounds obtained were the first onesprepared by this reaction. Instead of taking a simple aromatic aldehyde it is only necessary to take a phenol aldehyde viz., salicylic aldehyde,... 

India does not produce any quantity of synthetic coumarin. Some quantities of coumarin are produced from natural resources. Atul produces both o-cresol (at Ankleshwar) and phosgene (at Atul). Unfortunately, they have not considered this product seriously, apparently because, they just do not have the right technology. Some companies are, however, working on the synthesis of the product from o-cresol, phenol, and also salicylaldehyde (Perkin reaction) [30]. 

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). ... 

In 1874 Perkin retired from manufacturing and returned to chemical research. He discovered a reaction (the Perkin reaction) for producing unsaturated carboxylic acids. He also synthesized coumarin, an accomplishment that laid the foundation for the synthetic perfume industry. Perkin died on July 14, 1907, at the age of sixty-nine, see also Dyes. 

In the course of this reaction, derivatives of coumarin-3-carboxylic acid are produced. This synthesis proceeds under much milder conditions than the condensation based on the Perkin reaction which involves condensation of salicylaldehydes with acetic anhydride/acetate. 

Coumarin, mp 68°C, is a colourless crystalline compound it is the aromatic principle in woodruff and also occurs in other plants, e.g. lavender and melilot. Coumarin is prepared from salicylaldehyde by a Perkin reaction with acetic anhydride or by cyclocondensation with 1,1-dimorpholinoethene [27] ... 

The reaction of phenol with chloroform and alkali (dichlorocarbene) at 65 to 70 °C gives salicylaldehyde (Reimer-Tiemann synthesis), from which coumarin is produced by reaction with acetic anhydride and sodium acetate at 135 to 155 °C (Perkin reaction). Coumarin is used as a perfume and fragrance. 

Retrosynthetic analysis of the target coumarin skeleton provides two major synthetic routes (Figure 10.1). Route A requires an aromatic o-hydroxy carbonyl compound and a two-carbon fragment observed in Knoevenagel and Perkin reactions reflecting the [4h-2] approach for the construction of six-membered heterocycles. Route B represents the reaction between phenols and three carbon fragments associated with the Pechmann cyclization. In recent years, newer synthetic methodologies have also been applied to the synthesis of a variety of coumarins that have avoided the use of concentrated sulfuric acid. The present chapter reviews various... 

Perkin s later years were as productive as his earlier ventures. He developed methods for the preparation of aminoacetic add. He established the stmctural relationships between tartaric, fumaric, and maleic adds, and synthesized dn-namic acid. This last endeavor led to the development of what is now known as the Perkin reaction.The reaction is widely used to prepare unsaturated adds from aromatic aldehydes. These studies led to his synthesis of coumarin (actually it was the first condensation product he obtained with the dassic reaction see also www)-t> Experiment [3Aadv])- Other areas investigated by Perkin dealt with the relationship of physical properties and chemical structure. 

Coumarin is prepared from sahcylaldehyde by a Perkin reaction with acetic anhydride or by cyclocondensation with 1,1-dimorphohnoethene [41] ... 

Aliphatic aldehydes give low or no yields of acid. Coumarin can be prepared by a Perkin reaction of salicylaldehyde and acetic anhydride in the presence of triethylamine (eq 33). 

Production. Coumarin is currently produced by Perkin synthesis from salicyl-aldehyde. In the presence of sodium acetate, salicylaldehyde reacts with acetic anhydride to produce coumarin and acetic acid. The reaction is carried out in the liquid phase at elevated temperature. 

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... 

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). 

The vigorous conditions which are necessary serve to detract from the value of the Perkin synthesis, leading to the production of tarry material which adversely affects the yield of coumarin. Difficulties encountered in the synthesis of substituted o-hydroxybenzaldehydes also limit the application of this route. The obvious advantages of the method are that there are no doubts about the orientation of the product and that, unlike the Pechmann reaction, formation of the isomeric chromones is not possible. 

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