Acylamino acids, azlactonization

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. Thus beiizaldehyde and acetyl-... 

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). ... 

In the third transition state (TS3), the neutral catalyst is recovered by transferring the proton back from the catalyst to the substrate. In other words, the (former) azlactone ether oxygen atom deprotonates the tertiary ammonium ion. For proton transfer, again an LBHB is formed (N-0 distance 2.479 A, <(0,H,N)=166.2°). In the product complex, the catayst is neutral and the A-acylamino acid ester is bound in its iminol form to the catalyst (Product(iininol)). Finally, an additional 66.6 kJ moF are gained by the subsequent iminol-amide tautomerization (Product(ainide)) (Fig. 1). 

The standard procedure for the preparation of 5(4/J)-oxazolones is dehydration of a-acylamino acids with acetic anhydride (equation 150). Saturated azlactones lacking a substituent at C(4) are rather sensitive and difficult to isolate and in such cases it is... 

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. 

Dehydration of (V-acylamino-acids generates azlactones these are in equilibrium with mesoionic species, which can be trapped by reaction with alkynes, final loss of carbon dioxide giving the aromatic pyrrole. 

For organic syntheses, oxazol-5(4//) Ones 17 are of importance [79]. They are known by the trivial name of azlactones and are obtained by cyclodehydration of 77-acylamino acids 16 with acetic anhydride ... 

The preparation of unsaturated azlactones is effected smoothly and quantitatively by heating the acylamino acid with an excess of acetic anhydride on a steam bath for five to fifteen minutes. > > > The... 

The action of acetic anhydride on an a-acylamino acid in aqueous solution yields an azlactone, provided that a basic catalyst, such as sodium acetate, is present. Unsaturated azlactones are prepared readily by this method. Saturated azlactones are obtained in poor yields since they undergo hydrolysis rapidly in aqueous solution. Optically active a-acylamino acids are racemized under these conditions as a result of the temporary formation of the azlactone. ... 

Saturated a-acylamino acids are prepared by acylation of o-amino acids or, less frequently, by reduction of the corresponding unsaturated compounds. It sometimes is possible to effect both the preparation of the o cylamino acid and the formation of the azlactone by heating the amino add with a large excess of acetic anhydride. Leucine and phenylalanine give excellent yields of azlactones under these conditions. However, this method is not satisfactory with alanine, diiodotyrosine, isovaline," or a-amiiioisobutyric acid," which yield products of high molecular weight. 

Unsaturated a-acylamino acids usually are obtained from the corresponding azlactones. Reconversion of the unsaturated acid to the azlactone is not, therefore, a reaction of any great preparative importance. A few o-acylaminoacrylic acids have been prepared by the reac- tion of an o-keto add with an amide ... 

But the formation of azlactones as intermediates cannot explain all the observations made in this field. Thus it has been mentioned already that ketene racemizes AT-methyltryptophan. Carter and Stevens (1940) state that certain acyl derivatives of ir-proline and W-methyl-n-phenyl-alanine are rapidly racemized by the action of acetic anhydride in glacial acetic acid. In the same paper it is also reported that the addition of various azlactones to a solution of benzoyl-p-methoxyphenylalanine in acetic acid produces fairly rapid racemization of the acyl derivative. An azlactone can obviously not be formed from a compound such as proline, and there is no evidence that structures such as XLIII exist and even if they exist, there is no apparent reason why they should be so easily racemized. There is a possibility of the transient formation of a dipolar structure such as XLV, which is analogous to the formula proposed for sydnones (Baker and Ollis, 1946). But a more likely explanation is that both ketene and acetic anhydride can form mixed anhydrides with acylamino acids, which can then rearrange to form azlactones and acetic acid. Reference has already been made to the action of ketene on carboxylic acids to produce mixed anhydrides and similar reactions have been observed with acetic anhydride. The marked racemization of such structures is partly explained by the strongly electronegative character of the anhydride group. Such an explanation is supported by the findings... 

Tajima obtained a-acylamino-a-alkoxy esters from a-acylamino acid esters reacting with DCCD/ROH (476). The intermediate azlactones underwent autoxidation which was followed by DCCD-supported hydroxy-alkoxy-exchange. An electrochemical synthesis of N-acyl-2-alkoxyproline derivatives was reported by Horikawa et al. (477). 

Synthesis of Unsaturated Azlactones from N-Acylamino Acids. J. Org. Chem. 

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. 

Shaw and McDowellhave prepared imidazolone derivatives by cyclization of a-acylamino amides. In a variation of this reaction the azlactone (30) was gradually converted to the hydroxamic acid (31) by methanolic hydroxylamine. Sodium methoxide and hydroxylamine readily gave the acyclic hydroxamic acid (32) which could be cyclized to 31 by dilute acid. Benzyloxyurea has been used in the sjrnthesis of pyrimidine hydroxamic acids (33) by reaction with /S-diketones followed by catalytic hydrogenation of the benzyl group. Protection... 

An alternative to the azlactone procedure for the preparation of short-chain dehydropeptides 19 is offered by the direct condensation of an a-oxo acid 17 on heating with one equivalent of a carboxylic acid amide or by the treatment of an a-oxo acid 17 with a nitrile in the presence of dry HC1 gas (Scheme 6). If the former reaction proceeds with the condensation of two molecules of amide per molecule of a-oxo acid, then the corresponding a,a-bis(acylamino) aliphatic acid 18 is formed, which on warming with acetic acid results in partial deamidation with formation of the corresponding dehydropeptide 19. 

Cyclization of a-(acylamino)acrylohydrazides (684) with sodium hydroxide or acetic acid/acetic anhydride is the most commonly used method for preparing l,2,4-triazin-6-ones (685) <78HC(33)189, p.258). But since the acrylohydrazides (684) are usually made by hydrazinolysis of azlactones (c/. also 586 -> 588, Section 2.19.4.1.4), this method can also be treated as a [4+2] atom fragment method. 

A solution of sodium hydroxide in aqueous methanol is an effective reagent for hydrolyzing azlactones. It converts an azlactone into the a-acylamino ester, which is saponified. The reaction proceeds rapidly and under less drastic conditions than those required when aqueous alkali is used. In this connection it should be noted that prolonged action of alkali may hydrolyze the o-acylaminoacrylic acid to the of-keto acid. 

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