5-Oxazolones heterocyclics

Synthetic versatility of 2-oxazolone heterocycle for stereocontrolled construction of 2-amino alcohols 97YGK1018. 

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. 

Avenoza A., Busto J. H., Cativiela C., Peregrina G. M. and Zurbano M. M. The use of 4-Hetaryliden- and 4-Aryliden-5(4H)-Oxazolones as Dienophiles in the Diels-Alder Reactions in Targets in Heterocyclic Systems-Chemistry and Properties vol 3. 1999, Eds. Attanasi O. A. and Spinelli D., Pb. Soc. Chim. Ital. Keywords hetero-Diels-Alder reactions... 

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 parent 2(3/i/)-oxazolone moiety functions as a bifunctional leaving group when carboxyl groups are activated for acylations and condensations, similar to other five- and six-membered heterocycles such as imidazole, triazole, and 2-pyridinethiol. The excellent leaving ability of a 2(3//)-oxazolone moiety has led to the development of versatile reagents. Thus, 3-acyl- and 3-alkoxycarbonyl-2(3//)-oxazolones serve as ready-to-use -type agents for the regioselective and chemoselective N-protection of amino alcohols, amino phenols and polyamines. 

Additional examples of the utility of ring cleavage and recyclization of 4(5Ff)-oxazolones to prepare interesting heterocycles have been described (Scheme 6.16). Ttreatment of 4-aminothymol 53 with 54 in refluxing pyridine yields the 4-imidazolidinones 55 evaluated as antimicrobial and antimbercular agents. The authors listed an extensive series of analogues (25 compounds) but reported a yield for only one example, 55 (63% for Ri = Ph, R2 = 4-MeO—CeKt). Condensation of 2-phenyl-4(5F/)-oxazolone 56 with substituted hydrazines affords excellent yields of the 1,2,4-triazoles 57, important precursors to the previously unknown l(r/)-l,2,4-triazole-5-carboxaldehydes 58. Representative examples are shown in Table 6.3 (Fig. 6.8). 

The classical cyclization routes to pemoline 68 and similar 2-amino-4(5/7)-oxazolone analogues continue to be refined and improved. For example, Japanese workers have prepared an extensive series of heterocyclic analogues, 100, via several classical routes including cyclization of ot-hydroxy esters or activated acids... 

Weiss and co-workersprepared a series of oxazohnylidene steroids 343 as luminescence dyes for application as potential intracellular diagnostic agents (Scheme 6.72). The key intermediate 2-aryl-5,5-dimethyl-4(57/)-thiooxazolones 341 were readily available from the corresponding 4(57/)-oxazolones 339. Reaction of 341 with 342, generated in situ from the hydrazone 340, gave 343 as expected. It was not possible to prepare 343 from 3-thio-androsta-l,4-dien-17-one since the requisite corresponding heterocyclic diazo compounds could not be prepared. 

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... 

Cyclizations with perfluoroacylating agents seem to be quite general for the synthesis of 5(2i7)-oxazolones with aromatic substituents directly bonded to the heterocyclic ring. For example, perfluoroacylation of a solution of an arylgly-cine containing a phosphorus trihalide affords 4-aryl-2-(perfluoroalkyl)-5(2//)-oxazolones (Table 7.1, Fig. 12) Similar results were obtained when amino nitriles were used as starting materials. ... 

Phosphites and 2,2-bis(trifluoromethyl)-5(2//)-oxazolone 71 react with elimination of carbon dioxide to give 2-aza-4-phospha-l,l-bis(trifluoromethyl)-l,3-butadiene 72 that can be used as a synthon for the previously unknown hydrogen-substituted nitrile ylide 72a in [3 + 2]-cycloaddition reactions. Examples of cycloadditions of 72a with dipolarophiles to give heterocyclic compounds 12t-ll are shown in Scheme 7.18. 

Alkylation. Saturated 5(47/)-oxazolones are readily available compounds that can be easily obtained from a wide variety of natural amino acid derivatives. These heterocyclic compounds can be considered as nucleophilic synthons of a-amino acids and their most exploited reactivity, apart from oxazolone ring opening, is the reaction at C-4 with a variety of electrophiles. 

In some cases, ring opening of oxazolones and subsequent cyclization of the intermediate leads to new heterocyclic systems. For example, reaction of saturated 5(47/)-oxazolones with hydrazonoyl halides under phase-transfer conditions yields the 5-pyrazolones 249. Ring opening of 248 with 2-aminothiophenol generates benzothiazoles 250 (Scheme 7.80). ... 

Mesoionic oxazolones (munchnones) 297 can be generated by cyclodehydration of N-substituted a-amino acids 295 or by alkylation of oxazolones 296 (Scheme 7.98). These compounds are reactive and versatile 1,3-dipoles that undergo cycloaddition reactions with dipolarophiles to generate a variety of heterocyclic systems. In particular, this is an extremely versatile methodology to prepare pyrroles that result from elimination of carbon dioxide from the initial cycloadduct. Numerous examples have appeared in the literature in recent years and several have been selected for discussion. The reader should consult Part A, Chapter 4 for an extensive discussion and additional examples. 

Alternatively, a spacer can be inserted between the heterocyclic rings to further modify the properties of the polymer. Although various spacers have been used, aromatic rings are probably the most frequently employed. In this case, 2,2 -(p-phenylene)bis[4,4 -dimethyl-5(4//)-oxazolone] 330 is the most common monomer (Fig. 7.34). Again, representative examples are described in selected references... 

Heterocyclic aldehydes have been used as the carbonyl component and yield the corresponding 4-(heteroarylmethylene)-2-substimted-5(4//)-oxazolones that are also valuable synthetic intermediates. Examples of (heteroarylmethylene)-5(4//)-oxazolones of particular interest that have been synthesized include oxazolones derived from furfural," pyrazolecarboxaldehyde," and chromonecarboxalde-... 

Iminophosphoranes derived from readily available ot-azidocinnamates react with aroyl chlorides to give the corresponding 2-aryl-4-arylidene-5(4//)-oxazolones 37 2 500,501 AjteiTjatively, these iminophosphoranes are converted to the corresponding 2-arylamino-4-arylidene-5(4//)-oxazolones 373 via heterocyclization of an intermediate carbodiimide as shown in Scheme 7.119 (Table 7.32, Fig. 7.43). ° ... 

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. ... 

Ammomethylene)-5(4/i/)-oxazolones 412 have also been used as starting materials to prepare unsaturated oxazolones. Alkylation of the exocyclic nitrogen gives 4-(A,A-disubstituted-l-aminoalkylidene)-5(4/f)-oxazolones 413 that are intermediates for peptides, pharmaceuticals and pesticides (Scheme 7.133). Heterocyclic rings such benzimidazole or benzotriazole have been prepared as well (Scheme 7.134). ... 

Bromo-1 -(dimethylaminoethylidene)] -2-phenyl-5(47/)-oxazolone 426, obtained by bromination of 424, reacts with A, Al-dimethyl-Al -heteroarylformamidines to afford the interesting heterocyclic unsaturated oxazolones 428 (Scheme 7.140). ... 

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. ... 

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. 

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. 

Hydrazinolysis products obtained from oxazolones 528 are versatile synthetic intermediates and can be further elaborated to a variety of different heterocycles depending on the substituents and on the experimental conditions. For example, N-aminoimidazolones 529, isolated from reaction of 528 and hydrazine, have been acylated ° or condensed with carbonyl compounds to produce 530 and 531, respectively. On the other hand, ring-opening 528 with hydrazine affords a dehydroamino acid hydrazide 532. Condensation of 532 with aldehydes yields a hydrazone 533 that can be cyclized to an A -iminoimidazolone 534 (Scheme 7.168). ... 

Reaction of unsaturated 5(4//)-oxazolones with bis(nucleophiles) opens the way for the preparation of diverse heterocyclic compounds depending on the nucleophilic atoms of the reagent. First, if we consider nitrogen-containing bis(nucleo-philes), the reaction of anthranilic acid with unsaturated oxazolones 550 gives rise to substituted 3,l-benzoxazin-4-ones 551 (Scheme 7.174). " °... 

Both reactions have been utilized to prepare heterocyclic compounds such as pyrazoles 681 (X = A -Ph) and isoxazoles 681 (X = O) as shown in Scheme 7.214. " Starting from an unsaturated 5(4//)-oxazolone 677, either a cycloaddition-ring-opening reaction sequence (677 678 680) or a ringopening-cycloaddition reaction sequence (677 679 680) affords the same product. 

The synthesis of new heterocyclic structures with interesting pharmacological properties will be the objective of numerous research groups during the coming years. Oxazolones will be critical intermediates to prepare new specifically substituted heterocycles as chemists design molecules for improved pharmacological properties. For material scientists, polymerization reactions of oxazolones will be an important tool to prepare polymers with specific physical and chemical characteristics. 

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