Azlactone hydrolysis

Azides, see Acyl azides Azines, ring dehydrogenation, 680 Azlactones, hydrolysis to a-keto acids, 344... 

Hydrolysis of the azlactone leads to the acylaminooinnamic acid the latter may be be reduced catal3rtlcally (Adams PtOj catalyst 40 lb. p.s.i.) and then 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 (d/ p phenylalanine). 

Although imidazolinones are usually resistant to hydrolysis, oxazolinone rings are often easily opened. In acid-catalyzed reactions of this type, water converts azlactones (181) into a-acylamino-a,/3-uhsaturated acids (182) (77AHC(21)175). 1,3,4-Oxadiazolinones are readily opened by hot water to give hydrazine carboxylic acids which undergo decarboxylation. 

Ring fission occurs readily in many of these compounds. For example, azlactones, i.e. 4JT-oxazolin-5-ones containing an exocyclic C=C bond at the 4-position (508), are hydrolyzed to a-benzamido-a,/3-unsaturated acids (509), further hydrolysis of which gives a-keto acids (510). Reduction and subsequent hydrolysis in situ of azlactones is used in the synthesis of a-amino acids e.g. 508 -> 507). 

Azlactones — see also l,3-Oxazolin-5-ones Erlenmeyer synthesis, 6, 202 hydrolysis, S, 64, 101 tautomerism, 6, 186 unsaturated... 

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). ... 

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. 

A number of new j8-substituted alanines have been prepared from unsaturated azlactones by the usual reduction-hydrolysis procedures. An interesting example is the synthesis of DL-jS-ferrocenylalanine (33). ... 

Ethyl o-nitrophenylpyruvate and o-nitrophenylpyruvic acid 14-21 have been prepared by condensation of o-nitrotoluene with diethyl oxalate in the presence of potassium ethoxide,4 14 sodium ethoxide,16-20 or sodium methoxide.21 Sodium ethoxide is less reactive, however, and cannot be substituted successfully for potassium ethoxide in the present procedure, as it gives a very poor yield and poor quality of precipitated sodium salt. With sodium ethoxide the reaction does not appear to go to completion even under the conditions of refluxing ethanol usually employed,16-21 which are considerably more severe than the room temperature conditions employed with potassium ethoxide in the present procedure. o-Nitrophenylpyruvic add has also been prepared by hydrochloric acid hydrolysis of o-nitro-a-acetamino-dnnamic azlactone.4... 

Hydroxyphenylpyruvic acid has been prepared by alkaline hydrolysis of the azlactone of a-benzoylamino- -acetoxycin-namic acid 7 and by a two-step hydrolysis of the azlactone of a-acetamino- -acetoxycinnamic acid.8 p-Hydroxyphenylpyruvic acid has also been prepared by alkaline hydrolysis of 5-( -hy-droxybenzal)-3-phenylhydantoin.9 The procedure described here is adapted from published directions for the preparation of -hydroxyphenylpyruvic-3-C14 acid.5 5-( -Hydroxybenzal)hy-dantoin is prepared according to the method of Boyd and Robson.10... 

Hydroxyphenylpyruvic acid plays an important role in the biogenesis of compounds with a phenylpropane skeleton, and it has been used as substrate in several enzyme studies. Published procedures for its preparation are unsatisfactory in many ways. The alkaline hydrolysis of the azlactone of a-bcnzoylamino- -acetoxycinnamic acid 7 makes necessary a tedious separation of the resulting benzoic acid, and the yield is only 34% based on -hydroxybenzaldehyde. The hydrolysis of 5- ( -hydroxybenzal)-3-phenylhydantoin 9 requires a separation of phenylurea. Finally, the two-step cleavage of the azlactone of a-acetamino- -acetoxycinnamic acid 8 does not proceed easily, and impure products are obtained. In applying this procedure to the synthesis of a carboxyl-labeled -hydroxyphenylpyruvic acid, the overall yield was only 9%.u It must be kept in mind that any prolonged isolation procedure will cause some decomposition of this sensitive compound. 

BERGMANN AZLACTONE PEPTIDE SYNTHESIS. Conversion of an aoetylated amino add and an aldehyde into an azlactone with an alkylcnc side chain reaction with a second amino add with a second amino acid with mig opening and formation of an acylated unsaturated dipeptide, followed by catalytic hydrogenation and hydrolysis to the dipeptide. 

The azlactone formed from benzo[6]thiophene-2-carboxaldehyde and hippuric acid reacts with hydriodic acid and red phosphorus to give a-amino-/9-(2-benzo[6]tbienyl)propionic acid, and with sodium hydroxide to give a-benzamido-j8-(2-benzo[6]thienyl)acrylic acid.477 A series of a-amino-j8-(5-substituted-3-benzo[6]thienyl)propionic acids (312 R = H) has been prepared by hydrolysis of the product of... 

A general route to aryl-substituted pyruvic acids (e.g. phenylpyruvic acid, Expt 5.175) is the acid hydrolysis of 2-acetamido-3-arylacrylic acids (19), which are themselves formed by hydrolysis of the corresponding azlactones (18) (cf. Expt 8.21) with water. 

This method is mainly restricted to the synthesis of amino acids with aromatic side-chains since the required unsaturated azlactones [e.g. (30)] are most readily prepared using aromatic aldehydes. Typically, benzaldehyde condenses under the influence of base with the reactive methylene group in the azlactone (29) which is formed by the dehydration of benzoylglycine (28) when the latter is heated with acetic anhydride in the presence of sodium acetate (cf. Expt 8.21). The azlactone ring is readily cleaved hydrolytically and compounds of the type (30) yield substituted acylaminoacrylic acids [e.g. (31)] on boiling with water. Reduction and further hydrolysis yields the amino acid [e.g. phenylalanine,... 

H)-Oxazolones react readily with nucleophiles, C(5) and C(2) be ing possible sites for attack, and, in the case of unsaturated azlactones, C(a) as well (see 199-201). It has been proved by using water labelled with lsO that the acid-catalyzed hydrolysis of unsaturated azlactones proceeds by alkyl-oxygen fission (equation 42). The formation, hydrolysis and reduction of 4-methylene-5(4H)-oxazolones is a well-established method for the synthesis of a-amino acids, e.g. phenylalanine (equation 43). The addition of hydrazoic acid to 5(4H)-oxazolones without methylene groups at C(4) likewise occurs exclusively at C(2) to yield tetrazoles by ring-opening and recyclization (equation 44). 

It was mentioned in the beginning that azlactones and oxazinones are activated amino acid derivatives. In the KR discussed here, the remaining oxazinone enantiomer can be reacted further, in the crude reaction mixture, with nucleophiles. For example, treatment with resin-bound and N-terminally nonprotected peptides results in coupling with a P-amino acid. Heating of the homogeneous crude reaction mixture (typically toluene as solvent) with dilute aqueous hydrochloric acid results in hydrolysis of the unreacted oxazinone enantiomer and precipitation of the corresponding N-acyl P-amino acid. The latter can be isolated in excellent enantiomeric purity by simple filtration. The filtrate contains the P-amino acid ester of opposite configuration (Berkessel et al. 2005). 

Hydrolysis of certain unsaturated azlactones with aqueous sodium hydroxide followed by treatment with dilute hydrochloric acid yields... 

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. 

Acetic anhydride reacts with an a-amino acid in the expected way, under mild conditions, to give the N-acetyl derivative, but also to set up an equilibrium with the carboxy group to form a mixed anhydride. More vigorous conditions promote the cyclisation of the mixed anhydride to the oxazol-5(4H)-one (the azlactone in Figure 4.1), which undergoes racemisation via the oxazole tautomer under the reaction conditions. Hydrolysis at the end of the process gives the racemised amino acid, so the net result is useful in the conversion of a natural L-amino acid into its D-enantiomer through racemisation, followed by resolution of the racemate (Chapter 6). 

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