Azlactones unsaturated

Azlactones, unsaturated aminoacyl-, thermolysis to alkylidenepiper-azinediones, 57, 195... 

Compounds which can formally be considered as anhydro bases can sometimes react with nucleophiles. Thus unsaturated azlactones with Grignard reagents give saturated azlactones (Scheme 50) (65AHC(4)75). 

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... 

Bergmann s synthesis unsaturated azlactones, 6, 226 Berkelheide rearrangement heterophanes, 7, 777 Berninamycin A, 6, 232 Berninamycinic acid appiications, 6, 709 X-ray diffraction, 6, 669 Betahistine as vasodiiator, 2, 5i9 Betaines... 

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). ... 

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 new synthesis of unsaturated azlactones, which is especially useful in cases where the aldehyde is not readily available, has been developed. The reaction involves the nucleophilic displacement of chlorine in 4-chloromethylene-2-phenyl-5(4Z )-oxazolone (6) by a... 

In contrast to the saturated azlactones, the Friedel-Crafts reaction of 2-substituted-4-arylidene-5-oxazolones is quite complex and may follow several different courses, often concurrently, depending on both reaction conditions and structural variations in the arylidene ring. This behavior is readily interpreted in terms of the a,)S-unsaturated carbonyl moiety and the cross-conjugated system containing nitrogen, both of which provide potential reaction sites in addition to the lactone carbonyl group. The reaction has been investigated " ... 

The behavior of unsaturated azlactones with organometallic reagents has been studied in detail. Arylmagnesium halides and phenyllithium attack 4-arylidene-5-oxazolones at the carbonyl carbon to give ring-opened amido tertiary alcohols (26) and oxazolines (27) (by ring closure), usually as mixtures [Eq. (17)]. The nature of the... 

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). ... 

The ring opening reactions of unsaturated azlactones and other lactones - by methanol in the presence of diazomethane are analogous in principle. (The ring closure of pseudouric acid which occurs under the influence of diazomethane can also be understood as an example of base catalysis.)... 

Although imidazolinones are usually resistant to hydrolysis, oxazolinone rings are often easily opened. In acid-catalyzed reactions of this type, water converts azlactones (234) into a-acylamino-a,(3-unsaturated acids (235) (77AHC(2i)l75). 1,3,4-Oxadiazolinones are readily opened by hot water to give hydrazine carboxylic acids which undergo decarboxylation. 

One of the oldest methods for the preparation of DHAs is the ring opening of unsaturated azlactones by attack of a nucleophile on the carbonyl group. Several methods for the synthesis of unsaturated azlactones (Azl) have been developed over the years and the chemistry of these important intermediates has been reviewed/1,2 Following are the methods of their synthesis that have remained in use during the last few decades. 

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 ... 

Thus, the A-chloroacetyl derivatives of Phe 55 and Leu,151 for example, when warmed with acetic anhydride, readily form the requisite unsaturated azlactone by the elimination of one molecule each of water and hydrogen chloride. A series of DHA derivatives of Phe, Tyr, Leu, Nle, Val, and Ala were prepared by this method. However, this method has not been used routinely to prepare DHA derivatives. 

Another method of obtaining unsaturated azlactones is through p-phenylserine [Ser(p-Ph)] derivatives. This method was initially introduced by BergmannJ56 The method involves conversion of (3-phenylserine derivatives 11 into the corresponding APhe azlactones 12 by treatment with an acetic anhydride/sodium acetate solution (Scheme 4). This has remained as one of the most popular methods of synthesis. 

In this case, the amino acid is already oxidized at the (3-position and elimination of the hydroxy group, as the acetate, generates the double bond. Reaction of the unsaturated azlactone and the free base of an amino acid ester produces the dipeptides containing APhe. This approach has been extensively used in the preparation of a series of APhe containing peptides15 63 ... 

Several attempts have been made, especially in recent years, to oxidize saturated to unsaturated azlactones. 64 The oxidation of saturated azlactone 13 with DDQ or o-chloranil in the presence of collidine as a weak base affords the unsaturated azlactone 14 in 40-50% yield (Scheme 5). Breitholle and Stammer 65 reported the preparation of unsaturated azlactone 16 by dehydrobromination of the bromopseudoazlactone 15 (Scheme 5). The pseudoazlactones derived from Ala and Abu tend to dibrominate, but careful reaction conditions allowed their isolation in acceptable yields. 65 This procedure is applicable to the preparation of derivatives of AAla, AAbu, AVal, and ALeu. 66 ... 

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. 

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,... 

The circular dichroism of cis- and trans- 2-oxazolidinones (59 R = H or Me) has been measured (79T2009). Geometrical isomerism round the exocyclic double bond in 4-(aryl-methylene)-5-(4//)-oxazolones (60), the unsaturated azlactones, is a well-studied phenomenon (75S749). It has been shown by X-ray crystallography (74T351) that the stable form of 4-benzylidene-2-phenyl-5(4//)-oxazolone has the (Z) configuration (61). It isomer-izes to the labile (E) form (62) in polyphosphoric acid and the change is reversed in pyridine. 

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>. 

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). 

However, most nucleophiles attack 5-oxazolones at the carbonyl group and the products are derivatives of a-amino acids formed by acyl-oxygen fission. Thus the action of alcohols, thiols, ammonia and amines leads, respectively, to esters, thioesters and amides orthophosphate anion gives acyl phosphates (Scheme 18). The use of a-amino acids in this reaction results in the establishment of a peptide link. Cysteine is acylated at the nitrogen atom in preference to the sulfur atom. Enzymes, e.g. a-chymotrypsin and papain, also readily combine with both saturated and unsaturated azlactones. A useful reagent for the introduction of an a-methylalanine residue is compound (202). Both the trifluoroacetamido and ester groups in the product are hydrolyzed by alkali to give a dipeptide. The alkaline hydrolyzate may be converted into the benzyloxycarbonyl derivative, which forms a new oxazolone on dehydration. Reaction with an ester of an amino acid then yields a protected tripeptide (equation 45). 

Treatment of saturated azlactones with aromatic compounds under Friedel-Crafts conditions gives acylamino ketones in high yield (equation 46). 4-Benzyl-2-methyl-5(4H)-oxazolone undergoes an intramolecular reaction to yield an acetamidoindanone (equation 47). Friedel-Crafts reactions of 4-(arylmethylene)-5(4H)-oxazolones are complicated by the presence of an additional electrophilic centre (cf. 201) and may follow three courses. The unsaturated azlactone (189) adds benzene under the influence of aluminum chloride to form the saturated azlactone (207) in inert solvents (189) undergoes an intramolecular acylation to yield a mixture of the indenone (208) and the isoquinoline (209 Scheme 20). 

Bergmann s synthesis (1926) is still used to prepare unsaturated azlactones containing only alkyl substituents. It consists of the treatment of a-alkyl a- (a-halogenoacyl)amino acids with acetic anhydride and it involves the isomerization of an intermediate 2-methylene-5(2H)-oxazolone. An example is given in equation (153). 

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