From unsaturated 5 -oxazolones

One strategy to prepare saturated 5(4//)-oxazolones from unsaturated oxazo-lones takes advantage of the reactivity of the exocyclic double bond. In this context, numerous reactions have been explored including reductions, Michael reactions, cycloaddition reactions, and many others. These reactions will be discussed in the context of the reactivity of the exocyclic double bond of the unsaturated oxazolones and will be described in Section 7.4.3. 

There are cases in which appropriate modification of one unsaturated oxazolone yields a new unsaturated oxazolone analogue. Most of the examples described in the literature involve modification of the substituent on the exocyclic double bond. For example, a series of 4-[2-hydroxy-3-(aminomethyl)benzylidene]-5(4//)-oxazo-lones 382 that were evaluated for bactericidal and fungicidal activities were obtained from Mannich reaction of 4-(2-hydroxybenzylidene)-5(4//)-oxazolones 381 (Scheme 7.123). ... 

Ethoxymethylene)-2-phenyl-5(47/)-oxazolone 404, readily available from hippuric acid and triethyl orthoformate, has also been used as a starting material for other unsaturated oxazolones via addition-elimination reactions. Nitrogen nucleophiles are most commonly used and amines give rise to 4-(aminomethyl-ene)-2-phenyl-5(4//)-oxazolones 405 (Scheme 7.130 Table 7.37, Fig. 7.48) which, in many cases have been evaluated as antihypertensives. 

Heterocyclic amines also react as nucleophiles and, in this context, indole reacts with 404 to yield the unsaturated oxazolone 406, an intermediate in the synthesis of tryptophan (Scheme 7.13It is noteworthy that 406 is the product of carbon-carbon bond formation. Imidazole also reacts with 404 but in this case the product is 396, identical with that obtained from the 4-(chloromethylene) derivative 395. ... 

One of the fundamental cleavage reactions of the heterocyclic ring in unsaturated oxazolones is the conversion to acids or esters. This process leads to dehydroamino acid derivatives from which a wide variety of amino acids are prepared by hydrogenation. The side chain of the final amino acid is determined by the aldehyde used to prepare the unsaturated oxazolone. For example, benzalde-hyde and an A -acylglycine afford 2-acylaminocinnamic acids 434 after hydrolysis of the oxazolone 433. In turn, 434 are excellent precursors to phenylalanine. 

The hydrolysis and alcoholysis reactions have been extended to the heterocyclic series. A systematic study has been published of the hydrolysis of unsaturated oxazolones derived from a selection of heterocyclic aldehydes. A detailed study of the synthesis and stereospecific hydrolysis and methanolysis of the (Z) and ( ) isomers of 2-methyl (or phenyl)-4-(thienylmethylene)-5(4F/)-oxazo-lones 435 and 437 has also been described (Scheme 7.144). The synthesis of 2-acylamino-3-(indol-3-yl or carbazol-3-yl)acryhc acid derivatives as potential antifertility agents via oxazolone hydrolysis has also been published. ... 

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. ... 

Synthesis oe Heterocyclic Compounds. In some cases, dehydroamino acids obtained from unsaturated 5(477)-oxazolones have been used as intermediates to prepare other heterocyclic compounds. For example, reaction of 2-benzoylamino-3-substituted-2-alkenoic acids 485 with alkyl or arylisothiocyanates affords 4-aryl-methylene-l,2-disubstituted-5-oxo-4,5-dihydroimidazoles 486 (Scheme 7.155). ... 

Depending on the reaction conditions used for hydrolysis, either 3-benzoyl-amino-5-methylpyran-2-one 489 or 3-methylpyrrole 492 have been obtained from the 3-ethoxy-2-methylpropanal derived unsaturated oxazolone 487 (Scheme 7.156). ... 

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). 

It is well known that hydrogenation of dehydroamino acid derivatives derived from ring opening of unsaturated 5(4H)-oxazolones affords new racemic amino acids and, in some cases, enantiomerically pure compounds. On the other hand, a number of attempts have been made to hydrogenate the double bond of the unsaturated oxazolone itself. For example, 4-benzyl-2-methyl-5(4//)-oxazolone was prepared from 4-benzylidene-2-methyl-5(4H)-oxazolone using Raney Ni as a catalyst. This process is reported to be a general procedure to prepare saturated oxazolones directly (Scheme 7.194). 

Catalytic hydrogenation of the exocychc double bond of several oxazolones 611, in the presence of acetic acid, gives a-acylamino alcohols 613 via the saturated derivatives 612 (Scheme 7.196). Selected examples of amino acid derivatives and amino alcohols available from reduction of unsaturated oxazolones are shown in Table 7.45 (Fig. 7.56). 

Some examples of the Michael reaction on the exocyclic double bond of an unsaturated oxazolone have been discussed in previous sections. The synthesis of unsaturated 5(4//)-oxazolones from unsaturated 5(4/l/)-oxazolones via an addition-elimination sequence and the sequential reaction of unsaturated 5(4/i/)-oxazolones with a l,3-bis(nucleophile) have already been considered. This section will review Michael additions exclusively and, in this respect, a wide array of nucleophiles has been studied. 

Since (Z)- and ( )-stereoisomers of unsaturated oxazolones can be obtained using appropriate isomerization procedures, cis and trans isomers of cyclopropane derivatives can be obtained in a stereoselective manner, although special care must be taken with experimental conditions to obtain the best stereoselectivity. Both racemic cis- and fraui-l-amino-2-phenylcyclopropanecarboxylic acid 641 and 644 have been obtained from the corresponding (Z)- or ( )-4-benzylidene-2-phenyl-5(4//)-oxazolone 621 and 642 using diazomethane. Care was taken to affect the... 

The chiral adduct 753, obtained from the unsaturated oxazolone 632 derived from (R)-glyceraldehyde and Danishefsky s diene, has been conveniently elaborated to the valuable azabicyclic intermediate 844 used for the synthesis of... 

Bunuel, E. Gil, A. M. Diaz-de-Villegas, M. D. Cativiela, C. Synthesis of constrained prolines by Diels—Alder reaction using a chiral unsaturated oxazolone derived from (R)-glyceralde-hyde as starting material. Tetrahedron 2001,... 

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 5-oxazolones or oxazolin-5-ones are very interesting heterocyclic compounds that have been used as intermediates in the synthesis of a variety of organic molecules. Two structural classes are possible, the 5(27T)-oxazolones (or 3-oxazo-lin-5-ones) and 5(47T)-oxazolones (or 2-oxazolin-5-ones). These structures differ only in the position of the double bond. Apart from the presence of the heteroatoms (N and O), the carbonyl group and the double bond, the 2- or 4-position, respectively, can be saturated or unsaturated. The isomeric 5-oxazolones are... 

TABLE 7.10. 2-(TRIFLUOROMETHYL)PYRROLES FROM REACTION OF 5(2/7)-OXAZOLONES WITH ELECTRON-DEFICIENT UNSATURATED COMPOUNDS... 

Enamines and Formamidines. Enamines, prepared from methylpyridines, methyl-pyridazines, methylpyrimidines or methyltriazine, and A, A -dimethylformamide dimethylacetal or ferf-butoxybis(dimethylamino)methane, react with 2-phenyl-5(4//)-oxazolone 146 to afford the unsaturated 5(477)-oxazolones 199 and 201 that are intermediates in the synthesis of fused pyridones 200 and pyridotriazi-nones 202, respectively (Scheme 7.61). ... 

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." ... 

Isocyanides have also been used to prepare unsaturated 5(4//)-oxazolones and they are particularly useful for the synthesis of 4-(aminomethylene)-5(4//)-oxazo-lones 374. For instance, cyclization of an unsaturated isocyanide obtained from condensation of alkyl isocyanoacetates and lactam acetals has been reported (Scheme 7.120). ° ... 

TABLE 7.34. SYNTHESIS OF UNSATURATED 5(4/f)-OXAZOLONES FROM A-ACYLAMINO ACID DERIVATIVES AND VILSMEIER-HAACK REAGENT... 

Reaction of unsaturated 5(4//)-oxazolones with appropriate nucleophiles affords new unsaturated 5(4//)-oxazolone analogues used as intermediates to prepare a variety of interesting compounds. 4-(Chloromethylene)-5(4/i/)-oxazolones react with a variety of nucleophiles. For example, 4-(chloromethylene)-2-phenyl-5(4F/)-oxazolone 395 reacts with imidazole to afford 4-[(imidazol-l-yl)methyl-ene]-2-phenyl-5(4F/)-oxazolone 396. The authors found no evidence for the product derived from carbon-carbon bond formation, that is, 4-[(imidazol-4-yl)methylene]-2-phenyl-5(4//)-oxazolone (Scheme 7.126). 

TABLE 7.39. A-ACYL DEHYDROAMINO ACIDS AND ESTERS FROM HYDROLYSIS AND ALCOHOLYSIS OF UNSATURATED 5(4H)-OXAZOLONES... 

Unsaturated 5(4//)-oxazolones derived from aromatic and heterocyclic aldehydes including phthalic anhydride/ antipyrine/ " chromone/ indoles/ pyridines/" ° quinolines/" diazines/" benzoxazoles/" and benzimidazoles " " have been prepared. Reaction with nitrogen nucleophiles and subsequent cycliza-tion leads to the expected 5(477)-imidazolones. 

TABLE 7.41. iV-ACYLAMINO ACID AMIDES FROM REDUCTIVE AMINOLYSIS OF UNSATURATED 5(4i7)-OXAZOLONES... 

Alternatively, if the dehydroamino acid is C-terminal or is central in the peptide chain, then the oxazolone precursor to the dehydropeptide must be in position two in order to apply this methodology (Scheme 7.165). The requisite unsaturated 5(4//)-oxazolone intermediate 518 is obtained from the appropriate precursors following standard cyclization procedures and avoiding experimental conditions that would epimerize the chiral center. This methodology has been applied to access analogues of important peptides including dehydroaspartame, somatostatin, and dermorphin. In these cases, a dehydroamino acid was incorporated into the peptide backbone to study the relationship between conformational restriction and biological properties of the modified peptide. 

TABLE 7.43. 2-STYRYL-l-SUBSTITUTED IMIDAZOLONES FROM REACTION OF UNSATURATED 5(4ff)-OXAZOLONES WITH SCHIFF BASES... 

Finally, the intramolecular ring opening of unsaturated 5(4//)-oxazolones derived from 2-hydroxybenzaldehyde is noteworthy. Here, the condensation of hippuric acid and 2-hydroxybenzaldehyde under classical conditions gives a 3-(acylamino)coumarin 602 directly without isolation of an intermediate oxazo-... 

TABLE 7.45. AMINO ACID, AMINO ESTER AND AMINO ALCOHOL DERIVATIVES FROM HYDROGENATION OF UNSATURATED 5(4//)-OXAZOLONES... 

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