The Erlenmeyer azlactone reaction

Azlactones (anhydrides of a-acylamino acids) are formed by the condensation of aromatic aldehydes with acyl derivatives of glycine in the presence of acetic anhydride and anhydrous sodium acetate, ua beiizald yde and acetyl- 

The reaction probably proceeds by an initial cyclisation of the acylamlnoacetio acid, followed by a Perkin type of condensation of the aldehyde with the active methylene unit  

Hydrolysis of the azlactone leads to the acylaminocinnamic acid the latter may be be reduced catalytloally (Adams Og catalyst 40 lb. p.s.i.) and thffli hydrolysed by hydrochloric acid to the amino acid. Alternatively, the azlactone (say, of a-benzylaminocinnamic acid) may undergo reduction and cleavage with phosphorus, hydriodic acid and acetic anhydride directly to the a-amino acid (dfp-phenylalanine). 

The azlaotones may be hydrolysed by strong alkali to a-keto acids, for example  

The benzoic acid may be separated by steam distillation or by saturating the aqueous mixture of sodium salts with sulphur dioxide whilst maintaining the temperature below 40° the benzoic acid precipitates and can be separate by filtration or extraction with ether. Acidification of the filtrate with hydrochloric acid liberates the pyruvic acid. The pyruvic acid may be oxidised th hydrogen peroxide to the arylacetic acid, for example  

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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... 

Modification of the Erlenmeyer reaction has been developed using imines of the carbonyl compounds, obtained with aniline," benzylamine or n-butylamine. Ivanova has also shown that an A-methylketimine is an effective reagent in the Erlenmeyer azlactone synthesis. Quantitative yield of 19 is generated by treatment of 3 equivalents of 2-phenyl-5(4ff)-oxazolone (2) (freshly prepared in benzene) with 1 equivalent of iV-methyl-diphenylmethanimine (18) in benzene. Products resulting from aminolysis (20), alkali-catalyzed hydrolysis (21), and alcoholysis (22) were also described. 

Azlactones like 6 are mainly used as intermediates in the synthesis of a-amino acids and a-keto acids. The Erlenmeyer-Pldchl reaction takes place under milder conditions than the Perkin reaction. 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

Bismuth(III) acetate catalyzes the synthesis of azlactones (17) from aromatic aldehydes in moderate to good yields via the Erlenmeyer synthesis. While the standard procedure for azlactone synthesis consists of using a stoichiometric amount of fused anhydrous sodium acetate, 10 mol% of Bi(OAc)3 is sufficient to catalyze the reaction and the crude product is found to be > 98% pure. 

Several improved methods for the preparation of known unsaturated azlactones as well as some interesting new compounds of this type have been reported. Crawford and Little observed that the direct use of 2-phenyl-5-oxazolone (1) in the Erlenmeyer reaction gave much improved yields (35-74%) of unsaturated azlactones with aliphatic aldehydes and with ketones such as acetone and cyclohexanone [Eq, (1)], The usual procedure of mixing a carbonyl compound, hippuric acid, acetic anhydride, and sodium (or lead) acetate affords poor yields in the aliphatic series. 

A variant of the Perkin reaction is the Erlenmeyer-Plochl-azlactone synthesis By condensation of an aromatic aldehyde 1 with an N-acyl glycine 5 in the presence of sodium acetate and acetic anhydride, an azlactone 6 is obtained via the following mechanism ... 

Oxazolones are attacked by a variety of electrophiles at C(4) these reactions, which require the presence of bases, proceed through the enolate anions (197). This type of anion adds to carbonyl compounds, a key step in the Erlenmeyer synthesis of unsaturated azlactones (equation 35) (see Section 4.18.4.3.4). The anions are intermediates in the formation of the amides (198) when oxazolones are treated with enamines (Scheme 15) (71JCS(C)598>. 

Acylaminocarboxylic acids 288 are converted into 5(4//)-oxazolinones 289 by acid anhydrides (Scheme 140). In an extension of this reaction, A-acyl derivatives of glycine 290 react with aldehydes with concomitant cyclization to give azlactones 291 (Scheme 141) this is the basis of the Erlenmeyer synthesis of amino acids. Treatment of amino acid derivatives 292 with PBr3 affords the thiazolidine-2,5-dione 293 (Scheme 142) <1971CB3146>. 

This reaction is related to the Erlenmeyer-Plochl Azlactone Synthesis. 

The starting material for the enantioselective hydrogenation is obtained very elegantly by an Erlenmeyer-Plochl reaction ofvaniUm, N-acetylglycine and acetic anhydride. The azlactone is carefuUy hydrolysed with water and the enamide purified by crystallisation. 

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 ... 

Erlenmeyer reaction The condensation reaction between an aromatic aldehyde and an A-acyl derivative of glycine, in the presence of acetic anhydride and sodium acetate, to give an azlactone. Erythro isomer The stereoisomer of CabxC.lby that is represented by the following diagram using... 

Erlenmeyer-Plochl azlactone and amino acid synthesis. Formation of azlactones by intramolecular condensation of acylglycines in the presence of acetic anhydride. The reaction of azlactones with carbonyl compounds followed by hydrolysis to the unsaturated a-acylamino acid and by reduction yields the amino acid drastic hydrolysis gives the a-oxo acid. 

Plochl, in 1883, prep d the first unsaturated azlactone by the condensation of benzaldehyde with hippuric acid in the presence of acetic anhydride. However, it remained for Erlenmeyer to determine the structure of the product, to extend the reaction to other aldehydes... 

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