Oxazolone synthesis

FMF Chen, K Kuroda, NL Benoiton. A simple preparation of 5-oxo-4,5-dihydro-1,3-oxazoles (oxazolones). Synthesis 230, 1979. 

Nearly all of the literature since the 1980s on oxazolone synthesis concerns the 5(4//)-oxazolones. No reports were found on the 2(5)- and 4(5//)-oxazolones. 

The groups of Kirby (302-304) and Battersby (305-307) developed the oxazolone synthesis for preparation of samples of phenylalanine 297 and tyrosine 298 stereospecifically labeled at C-3. The oxazolones 303, of well-... 

Japp also found that benzilic acid gave a tri(d)enyloxazolone product with benzonitrile, and later woik" > demonstrated that this material was (55 Scheme 26). The internal nucleo( e in this case is the caitxmyl oxygen. More recently, extensions of this type of reaction have been iq>plied to the synthesis of steiically hindered pqitidra." A further interesting oxazolone synthesis (56) involves nucleo[riiilic attack by the nitrile on a cyclopropenium intermediate and leading ultimately to formation of the spiro derivative (57 Scheme 27). 

Rao, Y. S., and R. Filler Geometric Isomers of 2-Aryl(aralkyl)-4-arylidene (alkylidene)-5(4H)-oxazolones. Synthesis 1975, 749. 

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... 

Carbamates can be used as protective groups for ammo acids to minimize race-mization in peptide synthesis. Raccmi/ation occurs during the base-catalyzed coupling reaction of an W-protected, catboxyl-uc ivated amino acid, and takes place in the intermediate oxazolone that foro S readily from an N-acyl protected amino... 

The dlenophlle, 3-acetyl-2(3H)-oxazolane, Is an attractive Intermediate for the synthesis of vicinal aminoalcohols with cIs configurations. It reacts with 1,3-dienes, even under quite mild conditions, to form (4+2) cycloadducts. Its high reactivity with deactivated 1,3-dienes Is noteworthy. This property is present also in 2(3H)-oxa201one which can be obtained easily through solvolysis of 3-acetyl-2(3H)-oxa2olone In methanol. 3-Acetyl-2(3H)-oxazolone, on UV irradiation In the presence of a sensitizer, combines easily with olefins to form (2+2) cycloadducts, the hydrolysis of which leads to the class of cis-2-aminocyclobutanols. 

Formation of 5-oxazolones (or azlactones ) (2) by intramolecular condensation of acylglycines (1) in the presence of acetic anhydride is known as the Erlenmeyer-Plochl azlactone synthesis. ... 

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). ... 

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. 

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... 

An interesting new synthesis [Eq. (24)] of the tripeptide dl-phenylalanylphenylalanylglycine (38) from the oxazolone 39 has been reported. ... 

The 4-unsaturated-5-oxazolones provide convenient starting materials for the synthesis of other nitrogen-containing heterocyclic systems. The preparation of tetrazoles and isoquinolines is discussed in Sections II,B, 1 and II,B,2,b. 

Disubstituted 2-oxazolidines as chiral auxiliaries synthesis from 2-oxazolones 97YZ339. 

This procedure offers a reproducible method for the preparation of 2-phenyl-5-oxazolone, which is not commercially available It illustrates that strict attention to detail often smooths out an erratic procedure 2-Phenyl-5-oxazolone is, of course, an important intermediate in the synthesis of a-amino acids and related materials6... 

Compounds of special interest whose preparation is described include 1,2,3-benzothiadiazole 1,1-dioxide (a benzyne precursor under exceptionally mild conditions), bis(l,3-diphenylimida-zolidinylidene-2) (whose chemistry is quite remarkable), 6- di-melhylamino)julvene (a useful intermediate for fused-ring non-benzenoid aromatic compounds), dipkenylcyclopropenone (the synthesis of which is a milestone in theoretical organic chemistry), ketene di(2-melhoxyethyl) acetal (the easiest ketene acetal to prepare), 2-methylcyclopenlane-l,3-dione (a useful intermediate in steroid synthesis), and 2-phenyl-5-oxazolone (an important intermediate in amino acid chemistry). 

Ortho esters, in synthesis of symmetrical trimethine thiazolocyanines, 54 Oxazolone, for neutrocyanines, 27 Oxidation potentials, of dyes, 75 of mesosubstituted dyes, in relation with absorption, 77 of polymethine dyes, 72 Oxidoreduction, relation between sensitizers, and silver halides, 78 4-Oxo-disubstituted 2-aminoselenazoles, table of products, 262 Oxonols, nomenclature of, 26 in synthesis of dimethine neutrocyanines, 62... 

A very attractive and efficient method for the synthesis of L-aminoacids via DKR has been reported by Turner et al. [41a,b]. They employed enzyme-catalyzed ring opening of 5(4H)-oxazolones in combination with a catalytic amount of Et3N. The relatively low pKa of the C-4 proton (8.9) of oxazolones facilitates racemization. Hydrolysis of the ester obtained through DKR, followed by debenzoylation, yields L-aminoacids in excellent enantiomeric excess (99.5%) (Figure 4.16). In their initial studies, they employed Rhizomucor miehei lipase (Lipozyme) as the biocatalyst [41]. More recently, they have obtained excellent results employing CALB [41bj. This method has also been employed by Bevinakatti [41c,d] and Sih [41e,fj. 

The main application of the enzymatic hydrolysis of the amide bond is the en-antioselective synthesis of amino acids [4,97]. Acylases (EC 3.5.1.n) catalyze the hydrolysis of the N-acyl groups of a broad range of amino acid derivatives. They accept several acyl groups (acetyl, chloroacetyl, formyl, and carbamoyl) but they require a free a-carboxyl group. In general, acylases are selective for i-amino acids, but d-selective acylase have been reported. The kinetic resolution of amino acids by acylase-catalyzed hydrolysis is a well-established process [4]. The in situ racemization of the substrate in the presence of a racemase converts the process into a DKR. Alternatively, the remaining enantiomer of the N-acyl amino acid can be isolated and racemized via the formation of an oxazolone, as shown in Figure 6.34. 

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. 

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

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