4-substituted-5 -oxazolones

Ring opening of a 4-(hydroxyalkyl)-substituted oxazolone using dimethylamine gives an amide 245 that can be used as an intermediate in a subsequent intramolecular cyclization to prepare lactones 247 (Scheme 1.19) ... 

Unsaturated 5(4//)-oxazolones have also been used as intermediates to prepare analogues with diverse biological activities. For example, the oxazolone derived from 4-biphenylcarboxaldehyde is a synthetic precursor of the antiinflammatory agent 4-biphenylacetic acid." In addition, 2-substituted oxazolones derived from 2-thioarylbenzaldehydes are starting materials for the preparation of dibenzothie-pine derivatives that are useful to treat schizophrenia." Other oxazolones have been used as intermediates to prepare insecticides and acaricides." ... 

Hydroxy-substituted oxazolones show an additional long-wavelength band in the visible absorption spectra in triethanolamine-acetone mixtures. Prototropic equih-brium constants at different temperatures were determined by detailed studies of this new absorption band. ... 

En route to a total synthesis of an antibacterial natural product indolmycin which contains an amino-substituted oxazolone, a-hydroxy acid 254 was treated with guanidine and KOr-Bu in /-BuOH in the presence of 4 A molecular sieves to produce oxazolone 255 with minimal epimerization of the acidic stereogenic center (Scheme 75) <2001CPB1604>. 

The condensation is also reported to proceed with aromatic Schiff bases, as shown in equation (18). In a more recent publication, the condensation of 2-substituted oxazolones with imines was compared to the corresponding reaction with the parent aldehydes and ketones. When aldehydes are employed in place of imines, better or comparable yields of condensation product (36) are obtained. Two ketones, acetophenone and cyclohexanone, were investigated in this study. In both of these cases, significantly... 

Scheme 3.10 Michael reaction of 4-substituted oxazolones with a,P-unsaturated aldehydes catalyzed by 31c and further transformations carried out on the obtained adducts.

Scheme 4.13 Enantioselective Michael addition of racemic 4-substituted oxazolones to nitroalkenes.

Oxidative dimerization of various 2-benzyloxy-2-thiazoline-5-ones (222) catalyzed by iodine and triethylamine is another example of the nucleophilic reactivity of the C-4 atom (469) (Scheme 112). Treatment of 212 with pyrrolidinocyclohexene yields the amide (223) (Scheme 113). The mechanism given for the formation of 223 is proposed by analogy with the reactivitx of oxazolones with enamines (4701. 4-Substituted 2-phenylthiazol-5(4Hi-ones react with A -morphoiino-l-cyclohexene in a similar manner (562j. Recently. Barret and Walker have studied the Michael addition products... 

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 oxazolones react in the pseudo form with o-phenylenediamine [Eq. (34)] to give substituted quinoxalines (76) in good yield. When R is an isopropyl group, a monoacylated product (77) is also isolated. 

In similar fashion, A-substituted-2(3fT)-oxazolones were prepared directly from the hydroxy-ketone by reaction with urethanes in the presence of pyridine and dimethylformamide or by using isocyanates. 

Oxazolones (azlactones) are a form of activated lactones, so they are included in this section. CAL-B is an effective catalyst for the DKR of various racemic four-substituted-5 (4H)-oxazolones, in the presence of an alcohol, yielding optically active N-benzoyl amino acid esters as illustrated in Figure 6.24 [40]. Enantioselective biotransformations of lactides [72,73] and thiolactones ]74] have also been reported. 

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. 

Table 41 Reaction of (Z)-4-arylmethylene-5(4H)-oxazolones with hydrazides to give substituted 1,2,4-triazole derivatives (Equation 61)...

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

The synthesis of 3-H-oxazol-2-ones was described by Nam et al. [69]. The substituted benzoin 89 was formed from the coupling of 3,4,5-trimethoxy-benzaldehyde 18 with 3-nitro-4-methoxybenzaldehyde, Scheme 22. Reaction with PMB-isocyanate and subsequent cyclization gave the protected oxazolone derivative 90. The PMB group was removed by reflux in TFA and reduction of the nitro-group was performed using Zn to give the combretoxazolone-aniline 91. 

An Indian team carried out the transformation of mercaptotriazole 320 using an oxazolone reagent <2001IJB252> and found that a series of triazolothiazines with the substitution pattern 321 can be obtained in high yields. Treatment of the mercaptotriazole with an unsaturated ketone side chain 322 under basic conditions gave rise to ring closure to 323 <1998JRM2056>. 

Unfortunately, in many cases the reaction is not so straightforward it becomes complicated because of the nature of the activated component. There is another nucleophile in the vicinity that can react with the electrophile namely, the oxygen atom of the carbonyl adjacent to the substituted amino group. This nucleophile competes with the amine nucleophile for the electrophilic center, and when successful, it generates a cyclic compound — the oxazolone. The intermolecular reaction (path A) produces the desired peptide, and the intramolecular reaction (path B) generates the oxazolone. The course of events that follows is dictated by the nature of the atom adjacent to the carbonyl that is implicated in the side reaction. 

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. 

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