Azlactones saturated

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). 

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 " ... 

In the presence of freshly sublimed aluminum chloride and under anhydrous conditions, compounds such as 7 react with benzene to form 1,4-addition products, the saturated azlactones 18, in 70-75% yield [Eq. (12)]. If moisture is not excluded, fragmentation of... 

In contrast to these ring-opening reactions, it was observed by Horner and Schwahn that 4-arylidene-(isopropylidene and cyclo-hexylidene)-oxazolones react with alkyl Grignard reagents by conjugate addition to give saturated azlactones 29a as the only products [Eq. (18)]. 

Filler et al. noted that the labile geometric isomer of 7 gives saturated azlactones (18) in 35-40% yields, as well as products of 1,2-addition, when treated with several arylmagnesium bromides. This stereoselectivity appears to be the only reported difference in chemical behavior between isomers of this type. 

Saturated azlactones such as 18 and 29a, whose preparation is discussed in parts 2, b and 3 of this section, are useful intermediates for the synthesis of a variety of j8,j8-disubstituted alanines (32). ... 

The preparation of the less stable isomer (53b) of the oxazolone 53a involves a rather tedious procedure. It has been reported that 53a is rapidly isomerized to 53b in 48% hydrobromic acid saturated with gaseous HBr. In this way four azlactones have been converted into their isomers.It has been established, moreover, that the isomerization is radical-initiated and does not involve a carbonium ion intermediate. The isomerization can be reversed by pyridine. ... 

Saturated 2-vinyl-5(47Z)-oxazolones have been widely used as intermediates for the synthesis of polymeric compounds that will be described in Section 7.3.2.9. Apart from these polymerization reactions, the Diels-Alder reactions of 4-sub-stituted-2-vinyl-5(47/)-oxazolones 134 with cyclopentadiene are reported to give norbomenyl oxazolones 135 that are useful to prepare norbornenyl functionalized resins by azlactone ring-opening addition reactions (Scheme 7.39). 

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 ... 

Of the three aromatic DHAs, APhe, ATyr, and ATrp, APhe is the most frequently used and well studied. The main synthetic strategy used to prepare APhe is through the azlactone method. 1,2 Most of the methods to prepare azlactones of APhe have already been discussed (vide supra). The Z-isomer of APhe is obtained by these methods, whereas the E-isomer is prepared by special methods 134 namely by isomerization of the Z-isomer in saturated HBr, 135-137 by photochemical isomerization/138 or from 2-phenyloxazolinonium perchlorate/139 ... 

Oxazolones (73), the saturated azlactones, have been studied intensively (B-57MI41801, B-57MI41802, 65AHC(4)75,69MI41800,77AHC(21)175). They show carbonyl and C=N absorptions in the 1820 and 1660 cm-1 regions, respectively. Azlactones derived from chiral a-amino acids, e.g. compound (74), can be obtained in optically active forms which racemize easily. The derived salts (75 R2 = H, Me or Ph) likewise exhibit optical activity they show intense carbonyl bands at 1890-1880 and C=N+ absorptions at ca. 1650 cm-. ... 

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). 

The outcome of Grignard reactions on 5(4H)-oxazolones likewise depends on the nature of the substituent at C(4). The saturated azlactone (210) is converted by the action of phenylmagnesium bromide into the tertiary acylamino alcohol shown in equation (48) on the other hand, saturated azlactones are obtained by the action of alkyl Grignard reagents on (arylmethylene)oxazolones (equation 49). This type of oxazolone reacts with arylmag-nesium halides at the carbonyl group in the presence of copper chloride, however, the addition is directed to the methylene carbon atom. 

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... 

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