4- -oxazolones alkylation

There are no reports that alkylation of a 2,4-oxazolidinedione generates a 2-alkoxy-4(5f/)-oxazolone. Alkylation of the sodium or potassium salt of a... 

Ammomethylene)-5(4/i/)-oxazolones 412 have also been used as starting materials to prepare unsaturated oxazolones. Alkylation of the exocyclic nitrogen gives 4-(A,A-disubstituted-l-aminoalkylidene)-5(4/f)-oxazolones 413 that are intermediates for peptides, pharmaceuticals and pesticides (Scheme 7.133). Heterocyclic rings such benzimidazole or benzotriazole have been prepared as well (Scheme 7.134). ... 

To minimize racemization, the use of nonpolar solvents, a minimum of base, low reaction temperatures, and carbamate protective groups (R = O-alkyl or O-aryl) is effective. (A carbamate, R = O-r-Bu, has been reported to form an oxazolone that appears not to racemize during base-catalyzed coupling.) ... 

Carbamates can be used as protective groups for amino acids to minimize racem-ization in peptide synthesis. Racemization occurs during the base-catalyzed coupling reaction of an A-protected, carboxyl-activated amino acid and takes place in the intermediate oxazolone that forms readily from an A-acyl-protected amino acid (R = alkyl, aryl) ... 

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)]. 

The hetero ring in 4-(l -hydroxyalkylidene)-5-oxazolones is cleaved by alcoholic HCl to form alkyl a-acylaminoacylacetates, which cyclize to oxazole-4-carboxylates [Eq. (25)]. This rearrangement occurs directly in alkali, and a carbon-14 tracer study has substantiated a mechanism involving ring opening followed by the alternative ring closure. ... 

When an a-amino acid is treated with an anhydride in the presence of pyridine, the carboxyl group is replaced by an acyl group and the NH2 becomes acylated. This is called the Dakin-West reaction The mechanism involves formation of an oxazolone. The reaction sometimes takes place on carboxylic acids even when an amino group is not present. A number of N-substituted amino acids, RCH-(NHR )COOH, give the corresponding N-alkylated products. 

FMF Chen, NL Benoiton. 4-Alkyl-5(2//)-oxazolones from IV-formylamino acids. Int J Pept Prot Res 38, 285, 1991. 

COUPLING, 2-ALKYL-5(4H)-OXAZOLONE FORMATION AND GENERATION OF DIASTEREOISOMERS FROM ACTIVATED PEPTIDES... 

FIGURE 1.9 Coupling, 2-alkyl-5(4//)-oxazolone formation and generation of diastereoiso-mers from activated peptides. 

When Wa = substituted aminoacyl, that is, when Wa-Xaa is a peptide, there is a strong tendency to form an oxazolone. The 2-alkyl-5(4//)-oxazolone that is formed is chirally unstable. Isomerization of the 2-alkyl-5(4//)-oxazolone generates diaste-reomeric products. When Wa = R0C=0, there is a lesser tendency to form an oxazolone. The 2-alkoxy-5(4/7)-oxazolone that is formed is chirally stable. No isomerization occurs under normal operating conditions. Finally, when Wa = R0C=0, an additional productive intermediate, the symmetrical anhydride, can and often does form. 

PURIFIED 2-ALKYL-5(4H)-OXAZOLONES FROM N-ACYLAMINO AND N-PROTECTED GLYCYLAMINO ACIDS... 

IZ Siemion, K Nowak. New method of synthesis of 2-phenyl-4-alkyl-oxazolones-5. Rocz Chem 43, 1479, 1960. 

V-alkoxycarbonylamino add (Figure 1.10, path B) did not occur without immediate expulsion of the alkyl group, giving the amino-acid Af-carboxyanhydride (see Section 7.13). 2-Alkoxy-5(47/)-oxazolones are now recognized as intermediates in coupling reactions and are products that are generated by the action of tertiary amines on activated A-alkoxy carbonyl amino adds (see Section 4.16).20 22... 

FIGURE 7.6 Decomposition of a mixed anhydride (A) to the 2-alkoxy-5(4//)-oxazolone and the alkyl carbonate.9 The latter is in equilibrium with the anion whose reaction (B) with a second molecule of anhydride produces pyrocarbonate and the acid anion whose reaction (C) with a third molecule produces the symmetrical anhydride. The oxazolone eventually reacts with the alcohol to give the ester. (D) Acyloxonium ions formed by reaction of the anhydride with dimethylformamide and tetrahydrofuran. 

TABLE 5.5. SYNTHESIS OE 5-ALKYL-3-ARYL-4-HALO-2(3H)-OXAZOLONES FROM iV-ARYL-iV-(HYDROXY)-a-HALO ACYLACETAMIDES... 

The reaction of aliphatic and aromatic ketone oximes 97 with a dialkyl carbonate 98 in the presence of K2CO3 at 180-190 °C yields 3-alkyl-4,5-disubstituted-2(3//)-oxazolones 104 in 22-48% yields. Mechanistically, it is proposed that N-alkylation of the initially formed oxime O-carbonate 99 yields 100, which affords the enamine 101 in the presence of base. A [3,3] sigmatropic rearrangement ensues to produce 102, which then cyclizes to 104. In cases where 97 contains two methylene groups in proximity to the C=N bond, one of which is benzylic, the above reaction sequence is regioselective for the benzylic methylene group (Fig. 5.25 Table 5.6, Fig. 5.26). ... 

TABLE 5.6. 3-ALKYL-4,5-DISUBSTITUTED-2(3H)-OXAZOLONES EROM OXIMES AND DIAEKYECARBONATES"... 

Acetyl-2(3//)-oxazolone 84 serves as a good 1,3-dipolarophile in the [3+2] cycloaddition to A-alkyl-a-phenylnitrones 239, giving a mixture of the four possible isomers 240-243, but with the predominant formation of the exo-syn adduct 240 (Fig. 5.59). Diastereoselective cycloadditions proceed when mixtures of optically active 3-(2-exo-alkoxy-l-apocamphanecarbonyl)-2(3/7)-oxazolones and A-benzyl- and A-ferf-butyl-a-phenylnitrones are heated at 110 °C ... 

The alkylation of the 2(3/f)-oxazolones 289 with Meerwein s salt (Et30 BF4 ) occurs readily and in excellent yield, thus providing an efficient route to the 2-ethoxyoxazoles 290. Although the yield of 290 (R = Me) is low, the process can be carried out on large scale starting from commercially inexpensive acetoin (Fig. 5.69). ... 

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