5-Oxazolones ketones

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. 

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. 

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>. 

TABLE 5.1. SYNTHESIS OF 3-ARYL-5-tert-BUTYL-2(3H)-OXAZOLONES FROM ETHYL A-ARYLCARBAMATES AND a-BROMO KETONES"... 

TABLE 5.3. CYCLIZATION OF a-IMINO KETONES TO 4,5-DIPHENYL-2(3il)-OXAZOLONES AND 2-THIONES ... 

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). ... 

The 2(3//)-oxazolones may be synthesized by the direct condensation of three components. Thus, a mixmre of a-halo ketones 123, carbon dioxide, and primary amines can be heated at 80-100 °C under gas pressure of 50 kg/cm to result in the direct formation of 3-substituted 2-oxazolones 124 in 4-25% yield (Fig. 5.30). " ... 

The 1,3-dipolar cycloaddition of a-keto carbenoids to the polar double bond of heterocumulenes provides a direct access to five-membered heterocycles. The reaction of a-diazo ketones 132 with phenyl isocyanate in the presence of a Rh2(OAc)4 catalyst affords the 1,3-cycloadduct, 3-phenyl-2(3//)-oxazolones 133 (Fig. 5.32). ... 

The condensation of a 2-aminobenzoxazole 141 with a-bromo ketones 142 gives 2(3/f)-oxazolones 148 on heating in ethanol. Isotope labeling studies with have shown that the additional oxygen that is incorporated into the ring is derived from the solvent, ethanol (Fig. 5.36). ... 

The nature of the arylthio substituent at C-4 of a 5(277)-oxazolone dictates which of two different synthetic strategies can be used. The first involves the use of sodium cyanodithioformate and the corresponding ketone as starting materials. The reaction occurs through a thiazolone 45 that must be alkylated on the sulfur atom followed by treatment with Hg(OAc)2 to afford the corresponding 4-(alkylthio)-5(2//)-oxazolone 47. The second strategy involves the addition of thiophenol to... 

Two different methods have also been described for the synthesis of 4-alkoxy-5(2//)-oxazolones 50. In the first case, 4-(phenylthio)-5(277)-oxazolones 48 are oxidized to the 4-phenylsulfinyl derivatives that react with the alcohol present in the reaction medium to afford the corresponding 4-alkoxy derivatives. Alternatively, 4-alkoxy-5(2//)-oxazolones 50 have been obtained by condensation of iminooxalates and ketones in acidic medium. (Scheme 7.12 Table 7.7, Fig. 7.8 Table 7.8, Fig. 7.9). 

TABLE 7.5. SYNTHESIS OF 4-(ALKYLTHIO)-5(2H)-OXAZOLONES FROM SODIUM CYANODITHIOFORMATE, KETONES AND ALKYLATING AGENTS-... 

TABLE 7.8. SYNTHESIS OE 4-ALKOXY-5(2H)-OXAZOLONES FROM IMINOOXALATES AND KETONES OR ALDEHYDES ... 

Oxazolone At-oxides 91 have been obtained by heating a solution of 5-isonitroso-2,2-dimethyl-l,3-dioxane-4,6-dione 90 with the corresponding ketone in toluene. It has been postulated that the reaction occurs through an intermediate nitrosoketene that is generated from 90 via loss of CO2 and acetone, respectively. 

Alkylation of oxazolones with a-halo ketones under phase-transfer catalysis generated an enolate 155 from initial alkylation at C-4 that immediately translac-tonized to produce an enol lactone 156 (Scheme 7.46)." Selected examples of 5(47/)-oxazolones prepared via alkylation are shown in Table 7.17 (Fig. 7.19). 

In some cases, the product depends on the nature of the acylating agent. Acylation of 182 with 2,2-difluoro-4-pentenoic acid anhydride leads to acylation at C, whereas acylation with 2,2-difluoro-4-pentenoic acid choride yields the 5-acyloxyoxazole 185 as the major compound. The 5-acyloxyoxazole can be rearranged to the 5(47/)-oxazolone 183 upon treatment with 4-(dimethylamino)pyridme. Treatement of 183 with anhydrous oxalic acid promotes decarbonylation to give fluorinated a-amino ketones 184 (Scheme 7.55). Selected examples of 4-acyl-5(4//)-oxazolones are shown in Table 7.20 (Fig. 7.22). 

Imines and Carbonyl Compounds. Simple 2-alkyl(aryl)-5-(4//)-oxazolones like 191 can react with aldehydes, ketones, imines, and oximes to afford the corresponding unsaturated analogues 192 (Scheme 7.58). In some cases, this procedure is especially advantageous over the classical one-pot synthesis.The chemistry of unsaturated 5(4//)-oxazolones like 192 will be discussed in detail in Section 7.4. 

Halogenation Reactions. Chlorination of 4-acyl-2-phenyl-5(4f/)-oxazolones 213 with sulfuryl chloride leads to the corresponding 4-chloro derivatives 214 (Scheme 7.66). These compounds are useful intermediates in organic synthesis. In particular, hydrolytic cleavage of 214 affords a-chloro-a-acylamino ketones... 

Saturated oxazolones undergo an acylaminoacylation reaction with aromatic compounds in the presence of Lewis acids to give amino ketones. Subsequent cyclodehydration of these amino ketones then affords 2,5-diaryloxazoles. Some examples of 2,5-diaryloxazoles prepared in this manner are shown in Table 7.23 (Fig. 7.25). 

The same reaction applied to 2-styryl-5(4/l/)-oxazolone 282 gives simultaneous acylation and alkylation of the arene to produce the corresponding a-acylamino ketones 283. ° Cyclodehydration of 283 then readily affords a 2,5-disubstimted oxazole (e.g. 284 as shown in Scheme 7.92). 

A limited number of references have appeared that use ketones as the carbonyl component. The first example reported that acetophenones condense with N-benzoylglycine under Erlenmeyer conditions to afford a mixture of (Z)- and ( )-unsaturated-5(4//)-oxazolones 364 and 365 in which the (Z)-isomer 364 is the major compound, obtained in moderate to good stereoselectivity (Scheme 7.115). The pure (Z) isomer was obtained by recrystallization of the mixture. 

Hydrogenation of the double bond in dehydroamino acids prepared from unsaturated 5(4H)-oxazolones derived from unsymmetrical ketones gives rise to two stereogenic centers. As a consequence, four stereoisomers are possible. If the hydrogenation of each geometric isomer is performed separately, then the erythro and threo pair of enantiomers can be obtained independently. In this respect, the unsaturated oxazolones from 2-butanone have been prepared as a Z/E) mixture. The mixture was separated and each stereoisomer was independently converted to the erythro and threo pairs of enantiomers. ... 

The mechanism of the aminolysis and the electronic effects of substituents at C-2 or C-4 on the kinetics of amide bond formation have been studied. In some cases, ring opening with amines occurs with partial isomerization of the exocyclic double bond. However, with more hindered compounds, such as unsaturated oxazolones derived from ketones, ring opening is stereospecific.Ring opening using diamines has also been described. Selected examples of dehydroamino acid amides prepared by aminolysis of unsaturated 5(4//)-oxazolones are shown in Table 7.40 (Fig. 7.51). 

A number of recent papers have appeared in the literature related to the synthesis of saturated 5(477)-oxazolones that were not yet covered in our contribution. 4-Acyl-2,4-dialkyl-5(477)-oxazolones 776 have been obtained from A-acylglycines. Thus, cyclization of an A-acylglycine in the presence of thionyl chloride affords a monosubstituted 5(477)-oxazolone 775. Acylation of 775 with an aroyl chloride in the presence of magnesium chloride occurred at C-4 to produce 776. Hydrolysis and decarboxylation of 776 gave the A-acylamino ketones 777 that are valuable intermediates to prepare oxazoles 778 (Scheme 7.236). 

A -Acylamino aromatic ketones 790 can be prepared by arylation of saturated oxazolones in the presence of Lewis acids. Cyclodehydration of 790 leads to 2,5-diaryloxazoles 791. For example, saturated 5(4//)-oxazolones 789 from 7/-benzoyl-alanine or A-benzoylvaline undergo Friedel-Crafts arylation to afford substituted A-benzoylphenacylamines 790. In the presence of POCI3, 790 cyclizes to produce 5-aryl-2-phenyloxazoles 791 (Scheme 7.241). ... 

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