2-methyl-5 -oxazolones

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... 

Heterogeneous catalysts modified by the addition of chiral substances have been used to hydrogenate olefins asymmetrically, but only a few effective chiral heterogeneous catalyst systems have been found. Palladium deposited on silk fibroin was used to hydrogenate 4-benzylidene-2-methyl-5-oxazolone asymmetrically to give, after hydrolysis, optically active phenylalanine (Fig. lc). The optical purity1 of the product was found to be dependent on the origin of the fibroin and its chemical pretreatment (4-6). 

Hippuric acid has often been replaced in these reactions by A-acetylglycine Herbst and Shemin,964 for example, used it with benzaldehyde when preparing 4-benzylidene-2-methyl-5-oxazolone in 75% yield. 

On the other hand, addition of diazomethane to the ester 18 [from (Z)-4-benzylidene-2-methyl-oxazolone and ( —)-iV-methylephedrine] and photolysis of the resultant 4,5-dihydro-3/f-pyr-azole gave a 57% yield of a mixture of diastereomers (66 34). Separation of the major dia-stereomer 19 by column chromatography and hydrolysis gave (— )-l-amino-2-phenylcycloprop-ane-1-carboxylic acid (-)-(17). ... 

Diazoalkanes add to the carbon-carbon double bonds of 2,3-diphenylthiirene 1-oxide and 1,1-dioxide. The adducts lose SO or SO2 to give pyrazoles and related compounds (Scheme 103) (80CB1632). Mesoionic oxazolones (75CLH53), 4-methyl-5-phenyl-l,2-dithiolene-3-thione (80JOU395) and pyrylium betaines (72JOC3838) react similarly via intermediate adducts (Scheme 104). Enamines (Scheme 96) and ynamines add to the double bond of 2,3-diarylthiirene 1,1-dioxides to give acyclic and cyclic sulfones by a thermal. 

Oxazol-5(2H)-one, 2-benzylidene-4-methyl-tautomerism, 6, 186 Oxazol-5(2ff)-one, 2-methylene-isomerization, 6, 226 Oxazol-5(2H)-one, 2-trifluoromethyl-acylation, 6, 201 Oxazol-5(4ff)-one, 4-allyl-thermal rearrangements, 6, 199 Oxazol-5(4H)-one, 4(arylmethylene)-Friedel-Crafts reactions, 6, 205 geometrical isomerism, 6, 185 Oxazol-5(4ff)-one, 4-benzylidene-2-phenyl-configuration, 6, 185 photorearrangement, 6, 201 Oxazol-5(4ff)-one, 4-benzyl-2-methyl-Friedel-Crafts reactions, 6, 205 Oxazol-5(4ff)-one, 4-methylene-in amino acid synthesis, 6, 203 Oxazol-5(4ff) -one. 2-trifluoromethyl-hydrolysis, 6, 206 Oxazolones... 

The 2,2-bis(tnfluoromethyl)-4-methyl-2f/-5-oxazolone, readily available from 2,2-bis(trifluoromethyl)-l,3-oxazolidin-5-one, is a synthetic equivalent of activated pyruvate [90] (equation 16). 

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. 

Methyl-2-phenyl-5-oxazolone (22) reacts with excess phenyl-magnesiuin bromide to give 2-benzainido-1,1-diphenyl-1-propanoP (23). With excess ethylmagnesium bromide, 22 forms a dimer, N,N -... 

The member of this class which has been studied most thoroughly is 2-benzylidene-4-methyl-5(2 )-oxazolone (57). This compound may be prepared by ring closure of either 3-bromo-2-phenylacetamido-propionic acid or A-(a-halophenylacetyl)alanine (56) [Eq. (30)]. These reactions presumably proceed via unstable halogeno-5(4IT)-oxazolones, which rapidly lose hydrogen halide. 

A reversal of the 5 4H) 5 2H) equilibrium was established by demonstrating the presence of 4-isopropyl-2-trifluoromethyl-5(2fl )-oxazolone as an intermediate in the reaction of A-TFA-l-valine with the methyl ester of L-valine [Eq. (35)] using gas chromatography. The resulting product is a mixture of 74% l,l- and 26% d,l-A-TFA dipeptide methyl ester (see Section II, B, 4). 

Catalytic asymmetric hydrogenation is a relatively developed process compared to other asymmetric processes practised today. Efforts in this direction have already been made. The first report in this respect is the use of Pd on natural silk for hydrogenating oximes and oxazolones with optical yields of about 36%. Izumi and Sachtler have shown that a Ni catalyst modified with (i ,.R)-tartaric acid can be used for the hydrogenation of methylacetoacetate to methyl-3-hydroxybutyrate. The group of Orito in Japan (1979) and Blaser and co-workers at Ciba-Geigy (1988) have reported the use of a cinchona alkaloid modified Pt/AlaO.i catalyst for the enantioselective hydrogenation of a-keto-esters such as methylpyruvate and ethylpyruvate to optically active (/f)-methylacetate and (7 )-ethylacetate. 

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 reaction of 5(4H)-oxazolones (32) and miinchnones with triphenylvinylphos-phonium bromide (33) provides a mild synthesis of substituted pyrroles (34) (Scheme 11). The cycloaddition-elimination reactions of 5-imino-l,2,4-thiadiazolidin-3-ones with enamines and ester enolates produce 2-iminothiazolidines. " Chiral isomtinchnone dipoles show jr-facial diastereoselectivity with IV-phenyl- or A -methyl-maleimide in refluxing benzene. ... 

Three synthetic approaches for benzopyrones have been developed that use Gly as starting material. Hippuric acid was transformed with acetic anhydride into 2-phenyl-5(4//)oxazolone or further into its 4-ethoxy-methylene derivative, then reacted with cyclic 1,3-dicarbonyI compounds (such as like dimedone) to form 100 [90LA501 92H(33)843]. On the other hand, when hippuric acid was transformed into methyl 2-benzoyl-amino-3-dimethylaminopropenoate, it reacted with resorcinol to give a 7-hydroxybenzopyrone derivative (89JHC1273). 

The reaction of ethyl A-arylcarbamates 3 with l-bromo-3,3-dimethyl-2-buta-none or l-bromo-3-ethyl-3-methyl-2-pentanone 4 in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) results in the one-step synthesis of 3-aryl-5-ferf-butyl-2(3/T)-oxazolones 7 in fair to good yields (Fig. 5.2 Table 5.1, Fig. 5.3). This method is efficient for the preparation of bulky 5-substimted-2(37f)-oxazo-lones. 

Certain erythro-2-wamo alcohols such as ( )-ephedrine 150, ( )-A -methyl-ephedrine 151 and ( )-conhydrine 153 are synthesized with complete stereochemical control by the catalytic hydrogenation of the corresponding 4,5-disubstituted 2(3/i)-oxazolone derivatives 22 and 27, followed by ring opening (Fig. 5.37). ... 

The Friedel-Crafts type acylation of 4-methyl-2(3/7)-oxazolone 256 with acyl chlorides in the presence of AICI3 proceeds smoothly to give the 5-acyl -methyl-2(3F/)-oxazolones 257 (Fig. 5.62). ... 

The 5-methyl-2(37f)-oxazolone sulfonamide derivatives 265 are obtained from the sulfonamides 263 via bromination and subsequent Stille coupling reaction with tetramethyltin in the presence of palladium catalyst (Fig. 5.64). °... 

Condensation of 3-nosyloxy-2-keto esters 305 with methyl carbamate in refluxing toluene in the presence of p-toluenesulfonic acid provides 2(3/7)-oxazolone -carboxylates 306 in good yields (41-80%). Alternatively, condensation of 3-bromo-2-keto esters 307, derived from the bromination of a-keto esters with CuBr2, with methyl carbamate in the presence of AgOTf and p-toluenesulfonic acid under similar conditions provides the 2(3//)-oxazolone-4-carboxylates 306 in comparable yields (30-79%) (Fig. 5.78 Table 5.15, Fig. 5.79). ... 

Treatment of the A -mesyloxyamide 310 with sodium hydride yields 5-ethoxy-3-methyl-2(37/)-oxazolone 311. This intramolecular cyclization is considerably enhanced under sonication (Fig. 5.81). ... 

Benkovic and co-workers also isolated spirocyclic 2-amino-4(5/7)-oxazolones during their studies on pterin-dependent amino acid hydroxylases (Scheme 6.24). Reaction of 91 with 0-methyl hydroxylamine or semicarbazide at pH 4.8 yielded 92a and 92b, respectively. The authors showed that 92 does not simply result from reaction of the corresponding oxazolidinedione with either reagent. Further, by using H2 0 as the solvent they demonstrated that there was no incorporation into the product. Two different but precedented mechanisms were proposed to account for this rearrangement. The stereochemistry of 92b was confirmed by single-crystal X-ray. 

In fact, the first saturated pseudoxazolone reported, 4-methyl-2-(trifluoro-methyl)-5(2//)-oxazolone, was incorrectly assigned as the tautomeric 5(4//)-oxazolone and only later did nuclear magnetic resonance (NMR) smdies establish the correct structure. This compound was synthesized from alanine and trifluoro-acetic anhydride (TFFA). This methodology constitutes, under standard conditions, the most general procedure for the synthesis of 5(2//)-oxazolones. 

Difluoroacetic anhydride reacts similarly with alanine and this process affords 2-(difluoromethyl)-4-methyl-5(277)-oxazolone 7. Treatment of 7 with hydrogen bromide in acetic acid in the presence of ethanethiol yields 8 that was converted to 3,3-difluoroalanine 11 in several steps as shown in Scheme 7.3. ° This reaction opened the way to prepare p,(3-difluoro amino acids. 

The use of mixed anhydrides derived from Al-acyl-a-amino acids has become an interesting strategy for synthesis of saturated 5(4//)-oxazolones 101 (Scheme 7.26). For example, reaction of Al-acyl-a-amino acids with methyl chloroformate in the presence of Al-methylmorpholine affords racemic 5(47/)-oxazolones. 

In the cases where optically active substrates were used as starting materials, chiral, saturated 5(47/)-oxazolones were obtained with good enantiomeric excesses (ee). Oxazolones derived from Al-formyl-a-amino acids are better prepared using isopropenyl chloroformate, rather than methyl chloroformate, in the presence of N-methylmorphohne. ... 

Alkylation of 2,4-disubstituted-5(477)-oxazolones can be conveniently performed via phase-transfer catalysis. For example, the substrate and an alkyl halide are dissolved in an organic solvent and stirred with an aqueous sodium carbonate solution containing tetrabutylammonium bromide as a phase-transfer catalyst. 4,4-(Diarylmethyl)-2-phenyl-5(4/f)-oxazolones can be prepared in one-step by dialkylation of 146 using magnesium methyl carbonate and the corresponding... 

Michael Reaction. 5(47/)-Oxazolones undergo base-catalyzed conjugate addition to activated unsaturated compounds to afford the corresponding C-4 Michael adducts. For example, base-catalyzed addition of a 4-monosubstituted-5(4//)-oxazolone 157 to methyl propiolate yields a mixture of diastereomeric methyl 3-(5-oxo-2-phenyl-2-oxazolin-4-yl)acrylates 158. Hydrolytic ring opening of 158 and subsequent oxidation with lead tetraacetate affords 3-acylacrylates 160... 

When carbonyl compounds are used as electrophiles reaction with 4-monosub-stituted-5(4//)-oxazolones affords substituted serines after subsequent hydrolytic ring opening of the initial aldol product. As an example, 4-methyl-2-phenyl-5(4//)-oxazolone 193, prepared from alanine, reacts with benzaldehyde in a base-catalyzed addition to give, after hydrolysis, a 3 1 mixture of threo- and... 

Monosubstituted-5(4//)-oxazolones behave differently upon reaction with imines. Here, 4-methyl-2-phenyl-5(4/7)-oxazolone 196 (Ri = Ph, R2 = Me) reacts with imines derived from 2-furancarboxaldehyde or 2-thiophenecarboxaldehyde to give 3-amino-p-lactams 197. On the other hand, 196 reacts with chlorosul-fonyl isocyanate in a [2 + 2] cycloaddition to give dioxazabicycloheptanones 198 as shown in Scheme 7.60. ... 

Reaction of carbon disulfide with 2-phenyl-5(4//)-oxazolone 146 followed by S-alkylation with a methyl hahde gives 4-[bis(methylthio)methylene]-2-phenyl-5(4//)-oxazolone. The solvolysis and aminolysis of this compound have also been studied. ... 

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