Oxazolones Erlenmeyer

Formation of 5-oxazolones (or azlactones ) (2) by intramolecular condensation of acylglycines (1) in the presence of acetic anhydride is known as the Erlenmeyer-Plochl azlactone synthesis. ... 

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. 

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. 

There are four possible classes of bis-5(4H)-oxazolones (cf. 8-11). Compounds of type 8 may be prepared by the Erlenmeyer reaction on dialdehydes. The compound in which R is derived from the 4,4 -dialdehyde of diphenyl ether (R = CgHs) is a recent example. ... 

When 4-benzyhdene-2-methyl-5-oxazolone (45) is prepared by the Erlenmeyer procedure, a light yellow product is generally isolated. Rufenacht showed that pure 45 is white and that the colored... 

The first procedure to prepare unsaturated 5(4//)-oxazolones was the Erlenmeyer synthesis" " that was described more than one hundred years ago and is still used extensively with some variations in the experimental conditions. In general, the reaction employs an acylamino acid, for example, A-acetyl- or A-benzoylglycine are the most common, and a carbonyl compound, usually an aldehyde, in the presence of a cyclodehydrating agent such as acetic anhydride (Scheme 7.114). Hundreds of unsaturated oxazolones 363 have been obtained via this procedure and these compounds are valuable intermediates for the synthesis of many interesting organic compounds. 

The Erlenmeyer synthesis usually proceeds with a very high degree of stereoselectivity to favor the thermodynamically more stable (Z) isomer that is easily isolated by recrystallization. In some cases, the (Z) isomer is the only product obtained. This general methodology has been used extensively to prepare of a wide variety of unsamrated oxazolones. 

A limited number of references have appeared that use ketones as the carbonyl component. The first example reported that acetophenones condense with N-benzoylglycine under Erlenmeyer conditions to afford a mixture of (Z)- and ( )-unsaturated-5(4//)-oxazolones 364 and 365 in which the (Z)-isomer 364 is the major compound, obtained in moderate to good stereoselectivity (Scheme 7.115). The pure (Z) isomer was obtained by recrystallization of the mixture. 

Mechanistic studies of the Erlenmeyer reaction suggest that the reaction proceeds through initial rapid and reversible formation of the saturated oxazolone followed by an aldol condensation of the latter with the carbonyl compound and subsequent dehydration. ... 

Other amino acid precursors have been used as starting materials in the Erlenmeyer reaction. A classical reaction of oxazolones is ring opening to give dehydroamino acid derivatives but there are a number of examples when the reverse reaction has been exploited including cyclizations of A-benzoyl-a,p-dehydrophen-ylalanine," a-(acetylamino)cinnamic esters," and 2-(acylamino)-2-alkenamides (Scheme 7.118)." ... 

Bis-4-arylidene-5(4//)-oxazolones are easily obtained from aromatic dialdehydes by the Erlenmeyer synthesis. Such bis(oxazolones) react with a,co-diamines to provide a convenient approach to macrolactams.Tandem Erlenmeyer condensation-macrolactamization (TECM) has been used to prepare analogues of naturally occurring, biologically active cyclic peptides such as bastadin-5. 

Condensation of A -acylglycines with carbonyl compounds, the Erlenmeyer synthesis, continues to be exploited to prepare of a wide variety of unsaturated-5(47/)-oxazolones. The reaction is performed in the presence of a cyclodehydrating agent and recently bismuth(lll) acetate has been evaluated in this capacity. Alternatively, unsaturated 5(47/)-oxazolones can be obtained from hippuric acid and a carbonyl compound or from the appropriate dehydroamino acid derivative using 3-(aIkoxycarbonyl)benzotriazole-l-oxides as the cyclodehydrating agent. 

The Erlenmeyer reaction has also been used to prepare new 4-arylmethylene-2-[3-chlorobenzo[Z ]thien-2-yl]-5(4//)-oxazolones 800 from the appropriate A-acylgly-cine 799 and several aldehydes (Scheme 7.244). °° The pharmacological activity of these compounds as antibacterial and antiinflamatory agents has been studied. 

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>. 

Ivanova, G. A modification of the Ploechl-Erlenmeyer reaction. I. Synthesis of 2-phenyl-4-diphenylmethylene-5(4H)-oxazolone. Tetrahedron 1992,48, 177-186. 

Diaz, J. L., Villacampa, B., Lopez-Calahorra, F., Velasco, D. Synthesis of polyconjugated carbazolyl-oxazolones by a tandem hydrozirconation-Erlenmeyer reaction. Study of their hyperpolarizability values. Tetrahedron Lett. 2002, 43, 4333-4337. 

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-... 

Arylidene-2-phenyl-5(47/)-oxazolones (azlactones) 121 were prepared via Erlenmeyer synthesis from aromatic aldehydes 119 and hippuric acid 120 employing calcium acetate under solvent-free conditions with microwaves irradiation <04TL425>. 

With the same kind of molecule and the same method of synthesis, 4-arylidene-2-phenyl-5(41-f)-oxazolones were synthesized by the Erlenmeyer reaction from aromatic aldehydes and hippuric acid using calcium acetate under solvent-free conditions (Eq. 27) [113] ... 

The reduction of a-benzoylaminoacrylic acids with an equivalent amount of 3% sodium amalgam as originally described by Erlenmeyer has been improved in several ways. - In a modification of the pro-cedure, a-benzoylaminopropionic acids are obtained in 62-80% yields by treating aqueous solutions of the sodium salts of a-benzoylaminoacrylic acids with a large excess of sodium amalgam. This method is not always satisfactory 2-phenyl-4-(3, 4, 5 -trimethoxybenzal)-5-oxazolone is not reduced, 1 and a-benzoylamino-d-(4-methoxy-l-naphthyl)-... 

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