Reaction 4- oxazolones

M Goodman, CB Glaser. Mechanistic aspects of oxazolone reactions with a-nucleo-philes. J Org Chem 35, 1954, 1970. 

Urea, thiourea, and 5-alkylisothiouronium halides have also been used as bis(nucleophiles) in reactions with unsaturated oxazolones. Reaction with urea and thiourea leads to the corresponding imidazolones. The use of... 

The pyrazolone-3-carboxyhc acid (71) has been isolated by reaction of oxazolone (70) with hydrazonyl chloride (eq. 18) (46). 

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... 

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.) ... 

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). ... 

Comforth has reviewed literature reports and independently studied the special cases of reaction of 1 with salicylaldehyde and with 2-acetoxybenzaldehyde. Coumarins (10) are afforded in the condensation of 1 with salicylaldehyde or its imine, whereas when 2-acetoxybenzaldehyde is used, acetoxy oxazolone 12 is the major product. The initial aldol condensation product between the oxazolone and 2-acetoxybenzaldehyde is the 4-(a-hydroxybenzyl)oxazolone 11, in which base-catalyzed intramolecular transacetylation is envisioned. The product 9 (R = Ac) can either be acetylated on the phenolic hydroxy group, before or after loss of acetic acid, to yield the oxazolone 12, or it can rearrange, by a second intramolecular process catalyzed by base and acid, to the hydrocoumarin, which loses acetic acid to yield 10. When salicylaldehyde is the starting material, aldol intermediate 9 (R = H) can rearrange directly to a hydrocoumarin. Comforth also accessed pure 4-(2 -hydroxyphenylmethylene)-2-phenyloxazol-5(4//)-one (13) through hydrolysis of 12 with 88% sulfuric acid. 

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. 

Several improved methods for the preparation of known unsaturated azlactones as well as some interesting new compounds of this type have been reported. Crawford and Little observed that the direct use of 2-phenyl-5-oxazolone (1) in the Erlenmeyer reaction gave much improved yields (35-74%) of unsaturated azlactones with aliphatic aldehydes and with ketones such as acetone and cyclohexanone [Eq, (1)], The usual procedure of mixing a carbonyl compound, hippuric acid, acetic anhydride, and sodium (or lead) acetate affords poor yields in the aliphatic series. 

The reaction of hippuric acid with a three-fold excess of trifluoro-acetic anhydride gives a 90% yield of 2-phenyl-4-(2, 2, 2 -trifluoro-l -hydroxyethylidene)-5-oxazolone (2). This compound is also obtained... 

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... 

There are four possible classes of bis-5(4H)-oxazolones (cf. 8-11). Compounds of type 8 may be prepared by the Erlenmeyer reaction on dialdehydes. The compound in which R is derived from the 4,4 -dialdehyde of diphenyl ether (R = CgHs) is a recent example. ... 

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 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)]. 

Saturated 2,2 -bis-5-oxazolones (10) react with diamines under mild conditions to form polyamides (34) of high molecular weight in quantitative yield [Eq. (21)]. These polymers are composed of dicarboxylic acid, a-amino acid, and diamine units in a regular arrangement of both head-to-tail and tail-to-tail amide groups. They represent a cross between conventional polyamides and a-amino acid homopolymers. A feature of this polymerization is that no small molecules such as H2O, NHg, or CO2 are lost during reaction. 

The conversion of a 4-arylazo-5-oxazolone into a 1,2,4-triazole by reaction with a Grignard reagent is mentioned in Section II, B, 3. In HiTnilar fashion, the rearrangement of compound 30 to derivatives of 3-carboxy-l,5-diphenyl-lfl -l,2,4-triazoles (40) proceeds readily in the presence of strong nucleophiles [Eq. (26)]. This transformation undoubtedly occurs by ring opening and dehydrative cychzation, and, indeed, the acyclic amide and hydrazide 41 have been isolated. ... 

The oxazolone 43, prepared by reaction of 0-methylcaprolactim (42) with compound 1, undergoes a ring-opening reaction with methanolic HCl and cyclizes in alkaline medium to 1,5-pentamethyl-ene-2-phenylimidazole-4-carboxylic acid (44), which can be decar-boxylated easily. 

Arylidene-5-oxazolones undergo a ring-opening reaction with aromatic thiols and a second mole of thiol is then incorporated to give products such as 48. ... 

The isolation of several pairs of geometric isomers of 4-unsaturated-5-oxazolones has been described. Generally, only one isomer is obtained when an aldehyde reacts with hippuric acid in the presence of acetic anhydride. Occasionally, mixtures have been separated in base-catalyzed reactions. In acetic anhydride-sulfuric acid or in 100% sulfuric acid, a mixture is obtained, and it has been suggested that sulfuric acid inhibits mutarotation of the intermediate addition product 53, which is a mixture of diastereomers (see, e.g., compound... 

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). 

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. 

The isolation in poor yield of 2,5,5-triphenyl-4(5f )-oxazolone (82) by reaction of benzilic acid with benzonitrile in concentrated sulfuric acid was claimed by Japp and Findlay. Cornforth, however, suggested that the reactions of this product, m.p. 136°, could be accounted for more satisfactorily by the isomeric 5(4i ) structure 83. 

Enantioselective free-radical reactions of oxazolon-2-ones 99ACR163. 

Diethylamino-4-(4-methoxyphenyl)-isothiazole 5,5-dioxide 6 is (95T(51)2455) a highly reactive partner in 1,3-dipolar cycloadditions with several dipoles. Azomethine yhdes, such as oxazolones 7 and miinchnones 8, afforded with 6 bicychc pyrrolo[3,4-d]isothiazole 5,5-dioxides 9, 10, 11 in satisfactory yield. The regioselectivity of the reaction was excellent. The thermal behavior of these new bicychc systems was investigated. When heated at their melting point or shghtly above, triarylpyrroles 12, 13 were obtained through SOj and AtiV-diethylcyanamide ehmination. 

Reaction of the mesoionic oxazolone 620 with acetylenedicarboxylic ester 621 gave the cycloadduct 622 in aprotic solvents and the Michael adducts... 

Acetic anhydride, condensation with and acetylation of glycine, 46, 1 in cyclization of c-formylphenoxy-acetic acid to coumarone, 46, 28 in cyclization of hippuric acid to 2-phenyl-5-oxazolone, 47, 101 reaction with N-nitroso-N-phenyl-glycine to yield 3-phenylsydnone, 46,96... 

Hippuric acid, cyclization to 2 phenyl-5 oxazolone with acetic anhydride, 47,101 Holarrhimine, 46, 61 Hydrazine, reaction with cinnamalde-hyde, 47, 99... 

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