Cinnamates, production

Palladium-catalyzed oxidative couplings of aromatic compounds with alkenes in air lead to cinnamate products with TONs attaining 280 (Equations (66) and (67)).67,67a,67b... 

Ruthenium has a rich chemistry of hydroarylation reactions [22], but it has also been used successfully by Milstein and coworkers [23] as a catalyst for oxidative couplings of the Fujiwara-Moritani type (Figure 4.12). Under an atmosphere of carbon monoxide (6 bar), various ruthenium precursors effectively promoted the reaction of acrylates (e.g., 4g) with benzene (2a) to give a 1 1 ratio of the (E)-cinnamate 5i and methyl propionate 12, rather than the expected hydroarylation product methyl 3-phenylpropionate. Added oxygen (2 bar) could partly take over the role of the reoxidant from the alkene, resulting in an increase in the incorporahon of the alkene into the cinnamate product, giving a ratio of up to 3 1 of the arylated to the reduced acrylate. 

Pd on opt-act. polymers (other than poly-amino-acids) hydrogena- tion (—) menthyl-a-pheny 1-cinnamate -> products 56-72 (same obtained with nonopt-act. catalytic polymers) [87]... 

Cinnamic acid is usually prepared by Perkin s reaction, benzaldehyde being heated with sodium acetate in the presence of acetic anhydride. It is probable that the benzaldehyde and the acetic anhydride combine under the catalytic action of the sodium acetate, and the product then readily loses water to give mono-benzylidene acetic anhydride (. ). The latter, when subsequently... 

Cinnamic acid can be readily esterified by the Fischer-Speier method without any risk of the addition of hydrogen chloride at the double bond. Proceed precisely as for the preparation of ethyl benzoate (p. 104), using 20 g. of cinnamic acid and 20 ml. of rectified spirit. When the crude product is poured into water, a sharp separation of the ester is not readily obtained, and hence the addition of about 10 ml. of carbon tetrachloride is particularly desirable. Finally distil off the carbon... 

The cinnamate ester prepared as above (23.2 g. 79 mmol) was added as a solid slowly to refluxing xylene (500 ml) over a period of 3 h at a rate that prevented accumulation of unreacted azidocinnamate in the solution (monitored by gas evolution through a gas bubbler). The solution was refluxed for an additional 2 h after gas evolution ceased. The reaction mixture was cooled and the solvent removed in vacuo. The residue was recrystallized from methanol to give pure product (20.7 g, 99% yield). 

Recall from Section 7 13 that a stereospecific reaction is one in which each stereoiso mer of a particular starting material yields a different stereoisomeric form of the reaction product In the ex amples shown the product from Diels-Alder cycloaddi tion of 1 3 butadiene to as cinnamic acid is a stereo isomer of the product from trans cinnamic acid Each product although chiral is formed as a racemic mixture... 

Other experiments with Gibberellafujikuroi the fungus that produces gibbereUin, indicate that GA production is blocked by BAS 111. Very detailed and carehil experiments conducted with enzymes in ceU-free systems strongly support this mode of action, ie, using /-kaurene oxidase and cinnamate 4-mono-oxygenase isolated from pea apices and soybean suspension cells, and avanone-2-hydtoxylase and dibydroxypterocarpane 6-hydtoxylase from soybean suspension cells (31). 

There are at least two routes currently being used to produce natural benzaldehyde. Principal flavor houses are reported to market a product which is derived from cassia oil. The chief constituent of cassia oil is cinnamic aldehyde which is hydrolyzed into its benzaldehyde and acetaldehyde constituents. This is a fermentative retroaldol reaction. Whether this hydrolysis allows the final benzaldehyde product to be considered natural is of great concern. The FDA has reportedly issued an opinion letter that benzaldehyde produced from cassia oil is not natural (15). 

Benzaldehyde s most important use is in organic synthesis, where it is the raw material for a large number of products. In this regard, a considerable amount of benzaldehyde is utilized to produce various aldehydes, such as cinnamic, methyl cinnamic, amyl cinnamic, and hexyl cinnamic. 

Nearly all uses and appHcations of benzyl chloride are related to reactions of the active haUde substituent. More than two-thirds of benzyl chloride produced is used in the manufacture of benzyl butyl-phthalate, a plasticizer used extensively in vinyl flooring and other flexible poly(vinyl chloride) uses such as food packaging. Other significant uses are the manufacture of benzyl alcohol [100-51-6] and of benzyl chloride-derived quaternary ammonium compounds, each of which consumes more than 10% of the benzyl chloride produced. Smaller volume uses include the manufacture of benzyl cyanide [140-29-4], benzyl esters such as benzyl acetate [140-11-4], butyrate, cinnamate, and saUcylate, benzylamine [100-46-9], and benzyl dimethyl amine [103-83-8], and -benzylphenol [101-53-1]. In the dye industry benzyl chloride is used as an intermediate in the manufacture of triphenylmethane dyes (qv). First generation derivatives of benzyl chloride are processed further to pharmaceutical, perfume, and flavor products. 

The earliest references to cinnamic acid, cinnamaldehyde, and cinnamyl alcohol are associated with thek isolation and identification as odor-producing constituents in a variety of botanical extracts. It is now generally accepted that the aromatic amino acid L-phenylalanine [63-91-2] a primary end product of the Shikimic Acid Pathway, is the precursor for the biosynthesis of these phenylpropanoids in higher plants (1,2). 

Phenyl-2-propenoic acid [621 -82-9] commonly referred to as cinnamic acid, is a white crystalline soHd having a low intensity sweet, honeylike aroma. It has been identified as a principal constituent in the botanical exudates from Styrax IJquidamber orientalis) Benzoin Styrax ben in Pern Balsam [Myroxylon pereirae and Tolu Balsam (]Ayro>ylon balsamum) (4,5). In these, as well as numerous other natural products, it exists both as the free acid and in the form of one or more of its esters, as for example, methyl cinnamate, ben2yl cinnamate [103 1 -3] and cinnamyl cinnamate. 

The chloride is readily available as a by-product of benzyl chloride [100-44-7] production (see Chlorocarbon and chlorohydrocarbons-BENZYL chloride, BENZAL CHLORIDE, AND benzotrichloride). The yield is comparable to the Perkin-based process, but the difficulty associated with removal of trace halogenated impurities makes the resultant cinnamic acid less desirable for many appHcations. 

Economic Aspects. There are no pubhshed production figures for cinnamic acid. Most of the manufactured acid is consumed internally to generate a series of cinnamate esters for flavor and fragrance appHcations. With this in mind, it was possible to estimate a 1990 usage in the range of 175 metric tons. The cinnamic acid that does find its way into the marketplace has been sold for 12—14/kg in dmm quantities. 

Manufacture. A limited, amount of natural cinnamyl alcohol is produced by the alkaline hydrolysis of the cinnamyl cinnamate present in Styrax Oil. Thus treatment of the essential oil with alcohoHc potassium hydroxide Hberates cinnamyl alcohol of reasonable purity which is then subjected to distillation. This product is sometimes preferred in fine fragrance perfumery because it contains trace impurities that have a rounding effect in finished formulations. 

As with poly(vinyl alcohol), poly(vinyl cinnamate) is prepared by chemical modification of another polymer rather than from monomer . One process is to treat poly(vinyl alcohol) with cinnamoyl chloride and pyridine but this is rather slow. Use of the Schotten Baumann reaction will, however, allow esterification to proceed at a reasonable rate. In one example poly(vinyl alcohol) of degree of polymerisation 1400 and degree of saponification of 95% was dissolved in water. To this was added a concentrated potassium hydroxide solution and then cinnamoyl chloride in methyl ethyl ketone. The product was, in effect a vinyl alcohol-vinyl cinnamate copolymer Figure 14.8)... 

The addition of diazomethane to unsaturated esters (1), as ethyl acrylate, methyl crotonate and ethyl cinnamate, was investigated by Auwers who showed that the primary addition product is a A -pyrazoline (2) which rearranges spontaneously to the conjugated A -pyrazoline (3). 

The mi.xtuie of benzaldehyde, sodium acetate, and acetic anhydride is heated to 180 m a sir.all round flask with upright condenser in an oil-bath for about eight houis. The mass is poured out whilst hot into a large round flask (i litre), sodium carbonate added until alkaline, and any unchanged benzaldehyde distilled off with steam. After filtering from undissolved resinous by-products, hydrochloric acid is added, which precipitates the free cinnamic acid in white crystalline flakes. It may be purified by recrystallisation from hot water. Yield, 15—20 grams. 

The synthesis of isoxazolines usually takes the most thermodynamically favorable course to yield solely the more stable isomer. However, cinnamic acids (38) give not only isoxazoline-4-carboxylic acids (39) but also, as a by-product, the less stable isoxazoline-5-carboxylic acids (40)" which on heating undergo retro-addition. ... 

The aldol-like reaction of an aromatic aldehyde 1 with a carboxylic anhydride 2 is referred to as the Perkin reaction. As with the related Knoevenagel reaction, an o ,/3-unsaturated carboxylic acid is obtained as product the /3-aryl derivatives 3 are also known as cinnamic acids. 

Pyrimidinopyrazines related to folic acid have been investigated in some detail for their antimeta-bolic and antineoplastic activities. A related compound, which lacks one nitrogen atom, has been described as an antiproliferative agent, indicating it too has an effect on cell replication. Aldol condensation of the benzaldehyde 99 with ethyl acetoacetate gives the cinnamate 100. This is then reduced catalytically to the acetoacetate 101. Reaction of that keto ester with 2,4,6- triami-nopyrimidine gives the product 102 which is subsequently chlorinated (103) and subjected to hydrogenolysls. There is thus formed piritrexim (104) [17]. 

Cinnamyl Cinnamate.—Tbis ester is known as styracin, and is found in storax and other balsamic products, and possibly also in oil of hyacinths. It has the constitution... 

The column consists of a glass tube of 13-14 mm. internal diameter, 24 cm. long from lower end to the side arm, which has an internal diameter of 7 mm. It is important that these dimensions be observed in order to avoid polymerization of the product. It has been found in checking that better results are obtained by making indentations in the tube at frequent intervals and at different angles these tend to reduce the number of cinnamic acid particles which are carried over with the vapor. A column of the Vigreux type would no doubt also be suitable. 

Reaction 1 is governed by the enzyme phenylalanine ammonia lyase. This enzyme normally conducts the breakdown of L-phenylalanine to from-cinnamic add and ammonia. However, die reaction can be reversed leading to the production of L-phenylalanine from frans-dnnamic add by using excess ammonia. 

As shown in Schemes 10-44 and 10-45, two products may be formed in a Meerwein reaction Scheme 10-44 shows a simple aryl-de-hydrogenation of cinnamic aldehyde, whereas Scheme 10-45 shows an aryl-de-hydrogenation combined with the addition of HC1 to the double bond of the methyl ester of cinnamic acid. No systematic studies have been made as to which of the two products will be formed in a given reaction, what experimental conditions will favor one or the other product, and what substituents or other structural characteristics of the alkene influence the ratio of the two types of product. The addition product can, in most cases, easily be converted... 

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