Unsaturated 5 -oxazolones, synthesis

The first procedure to prepare unsaturated 5(4//)-oxazolones was the Erlenmeyer synthesis" " that was described more than one hundred years ago and is still used extensively with some variations in the experimental conditions. In general, the reaction employs an acylamino acid, for example, A-acetyl- or A-benzoylglycine are the most common, and a carbonyl compound, usually an aldehyde, in the presence of a cyclodehydrating agent such as acetic anhydride (Scheme 7.114). Hundreds of unsaturated oxazolones 363 have been obtained via this procedure and these compounds are valuable intermediates for the synthesis of many interesting organic compounds. 

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. ... 

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. ... 

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. 

Sulfur ylides are among the most interesting carbon nucleophiles and their synthetic importance has been recently reviewed.One especially interesting use of these ylides is their application to the synthesis of cyclopropane derivatives using unsaturated oxazolones. For example, stabilized sulfur yhdes react with unsaturated oxazolones 629 via a Michael reaction to give oxazolone spirocyclopropanes 630 as shown in Scheme 7.202 and Table 7.46 (Fig. 7.57), whereas the less stabilized sulfur ylides give ring-opened products 631 as the major compounds (Scheme 7.202). ... 

On the other hand, as synthetic equivalents of amino acids, unsaturated oxazolones are and will continue to be very important intermediates for the synthesis of new non-proteinogenic a-amino acids, particularly for the asymmetric synthesis of these compounds using diastereo- or enantioselective methodologies. In addition, the exocyclic double bond will continue as an important focus to build new constrained amino acids for the design of peptides with improved properties. 

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,... 

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). ... 

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... 

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. 

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... 

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. 

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). ... 

TABLE 7.30. SYNTHESIS OE UNSATURATED 5(4i7)-OXAZOLONES EROM iV-ACYLGLYCINES AND CARBONYL COMPOUNDS... 

TABLE 7.32. SYNTHESIS OF UNSATURATED 5(4/T)-OXAZOLONES VIA CYCLIZATION OF a,P-DIDEHYDROAMINO ACIDS OR a,P-UNSATURATED CARBODIIMIDES... 

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... 

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). ... 

In general, the reaction of unsaturated 5(4//)-oxazolones 497 with nitrogen nucleophiles effects ring opening to give the corresponding unsaturated acylamino amides 498 (Scheme 7.158). Depending on the nucleophile, for example, amines, hydrazines, oximes, and so on, the products obtained can be cyclized and this process allows the synthesis of a wide variety of new heterocyclic compounds. 

Amino acids " " and aminobenzoic acids " " react as nitrogen nucleophiles to effect ring opening of unsaturated 5(4//)-oxazolones. Cyclization of the intermediate acylamino amide has opened the way for the synthesis of new series of imidazolones that now incorporate a carboxylic acid moiety into the N-1 substituent. These compounds are readily further elaborated into derivatives with diverse biological activity. 

In contrast, ethyl 3-oxo-4-(triphenylphosphoranylidene)butyrate behaves as a C,0-bis(nucleophile) when reacted with unsaturated 5(4//)-oxazolones 584 with a leaving group at the exocyclic p-carbon. In this case, initial Michael reaction generates 585 that eliminates HX to produce a resonance stabihzed ylide 586. Cyclization of 586 with ring opening leads to the interesting ylide intermediate 587 used for the synthesis of 2//-pyran-2-ones (Scheme 7.185). 

During the last two decades, the importance of the dipolarophilic nature of unsaturated 5(4/l/)-oxazolones has been widely recognized and studied with a variety of 1,3-dipoles. Among the systems studied, diazoalkanes, particularly diazomethane, are the most frequently used and have opened the way for the synthesis of aminocyclopropanecarboxyhc acid derivatives. 

Condensation of A -acylglycines with carbonyl compounds, the Erlenmeyer synthesis, continues to be exploited to prepare of a wide variety of unsaturated-5(47/)-oxazolones. The reaction is performed in the presence of a cyclodehydrating agent and recently bismuth(lll) acetate has been evaluated in this capacity. Alternatively, unsaturated 5(47/)-oxazolones can be obtained from hippuric acid and a carbonyl compound or from the appropriate dehydroamino acid derivative using 3-(aIkoxycarbonyl)benzotriazole-l-oxides as the cyclodehydrating agent. 

TABLE 7.30 SYNTHESIS OF UNSATURATED 5(4//)-OXAZOLONES FROM N-ACYLGLYCINES AND CARBONYL COMPOUNDS, 212... 

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