Of an aldehyde with hippuric acid

The Erlenmeyer amino acid synthesis962 depends on condensation of an aldehyde with hippuric acid this gives an alkylidene azlactone, which is an intermediate in the synthesis, being converted into an <%-amino acid by reduction and hydrolysis. 

The last of the nonessential amino acids to be considered here is tyrosine (Tyr, Y). Although a number of different methods have been used in the synthesis of this amino acid, the one shown here, which presumably requires the intermediacy of an azlactone, has a generality (viz., the condensation of an aldehyde with hippuric acid) that allows similar syntheses of other amino acids too. 

In 1959, Crawford and Little reported superior yields of 3 in reactions of aromatic aldehydes by using isolated, crystalline 2-phenyloxazol-5-one (2, Ri = Ph) compared to direct reaction with hippuric acid (1, Ri = Ph). An early report by Boekelheide and Schramm on the use of ketones in the Erlenmeyer azlactone synthesis includes treatment... 

The isolation of several pairs of geometric isomers of 4-unsaturated-5-oxazolones has been described. Generally, only one isomer is obtained when an aldehyde reacts with hippuric acid in the presence of acetic anhydride. Occasionally, mixtures have been separated in base-catalyzed reactions. In acetic anhydride-sulfuric acid or in 100% sulfuric acid, a mixture is obtained, and it has been suggested that sulfuric acid inhibits mutarotation of the intermediate addition product 53, which is a mixture of diastereomers (see, e.g., compound... 

The preparation of the first unsaturated azlactone was reported in 1883 by Plochl/40 who condensed benzaldehyde with hippuric acid in presence of acetic anhydride. This approach was later used by Erlenmeyer/41 who extended the procedure to include other aldehydes and also established the usefulness of azlactones as intermediates in the synthesis of DHAs. The method involves the condensation of an A-acylglydne 4 with aldehydes and ketones in the presence of acetic anhydride and anhydrous sodium acetate (Scheme 2)J41 t5l Other catalysts such as copper(II) acetate/46 lead acetate/47,48 potassium carbonate/49 or potassium hydrogen carbonate 50 have also been used. The reaction proceeds via formation of an azlactone 5, which then condenses with the appropriate aldehyde or ketone to give unsaturated azlactone 6. Reaction of 6 with a nucleophile such as OH, OR, or NHR leads to the corresponding A-acyl-DHA derivatives 7. Reaction with the sodium salt of an amino acid gives a DHA containing dipeptide acid. 51 ... 

An important variation of the Perkin reaction is the Erlenmeyer azalactone synthesis exemplified by equation (4), involving condensation of an aldehyde and an N-acylglycine derivative in the presence of acetic anhydride and sodium acetate. Although this reaction, analogous to the classical Perkin condensation, was initially limited to the use of aromatic aldehydes, Baltazzi and Robinson reported that the use of lead acetate and THF allowed the preparation of several azalactones derived from aliphatic aldehydes (equation 15). The results for the condensation of several aldehydes and ketones with hippuric acid (28) under these conditions are shown in Table 2. The reaction proceeds through the intermediate (26) (intramolecular condensation of 25), which reacts with the aldehyde in Perkin fashion to provide the so-called azalactone product (Scheme 8). It is the formation of such oxazolones from acylamino acids which is be-... 

The methylene groups of hippuric acid and malonic acid are much more reactive than that of acetic acid. They may be caused, therefore, to condense with aldehydes under much milder conditions, e.g. by the action of pyridine. The use of malonic acid forms an extension of Perkin s reaction to the aliphatic series (Doebner), e.g. 

Another amino acid synthesis is called the azlactone synthesis. Remember from before that an azlactone is an oxazolone (see 95). When glycine (52) is converted to its AT-benzoyl derivative (112 known as hippuric acid) by reaction with benzoyl chloride, treatment with acetic anhydride (AC2O) gives the azlactone 113. This is the reaction presented in the preceding section (see compormd 95). Compound 110 has the common name of hippuric acid azlactone. As with the thiohydantoin, the -CH2- unit in 113 is susceptible to an enolate anion condensation reaction with aldehydes (Chapter 22, Section 22.7.2), and reaction with 2-methylpropanal in the presence of pyridine gives azlactone 114. Catalytic hydrogenation of the alkene unit (Chapter 19, Section 19.3.2) and acid hydrolysis lead to the amino acid leucine (55). 

For instance, N-benzoyl glycine (26, hippuric acid) can be transformed to a 4-alkylidene azlactone (27) by treatment of 26 and an aldehyde (a) with Ac20/Na0Ac via intermediate formation of the azlactone 25 and (b) with polyp hosphoric acid via intermediate formation of alkylidene hippuric acid (28). Under the conditions of (b), ketones can be used in the Erlenmeyer synthesis. 

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