Include 2 -oxazolones

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-... 

Compounds of special interest whose preparation is described include 1,2,3-benzothiadiazole 1,1-dioxide (a benzyne precursor under exceptionally mild conditions), bis(l,3-diphenylimida-zolidinylidene-2) (whose chemistry is quite remarkable), 6- di-melhylamino)julvene (a useful intermediate for fused-ring non-benzenoid aromatic compounds), dipkenylcyclopropenone (the synthesis of which is a milestone in theoretical organic chemistry), ketene di(2-melhoxyethyl) acetal (the easiest ketene acetal to prepare), 2-methylcyclopenlane-l,3-dione (a useful intermediate in steroid synthesis), and 2-phenyl-5-oxazolone (an important intermediate in amino acid chemistry). 

Oxazolones (azlactones) are a form of activated lactones, so they are included in this section. CAL-B is an effective catalyst for the DKR of various racemic four-substituted-5 (4H)-oxazolones, in the presence of an alcohol, yielding optically active N-benzoyl amino acid esters as illustrated in Figure 6.24 [40]. Enantioselective biotransformations of lactides [72,73] and thiolactones ]74] have also been reported. 

The anions of CDs may also function as simple basic catalysts towards acidic substrates included in their cavities. Such was observed by Daffe and Fastrez (1983) who studied the deprotonation and hydrolysis of oxazolones in basic media containing CDs. Also, in a paper dealing mainly with catalysis by amylose, it was noted that CDs catalyse the deprotonation of long chain /3-keto esters in basic aqueous DMSO (Cheng et al., 1985) no saturation kinetics were found for CDs, indicating weak substrate binding under the conditions used. 

Other examples include the intramolecular radical cyclization of 3-bromoaIkyl-2(3fl)-oxazolones 192 and 196 with tributyltin hydride/azobisisobutyronitrile to give the pyrrolooxazolidinones 194,198, and 199. The 2,5-disubstituted pyrrolidine derivatives 195 are produced enantioselectively (Fig. 5.49). 

The activated phosphorus reagents 269 and 270 are conventionally prepared by the reaction of 2(3//)-oxazolone with the corresponding phosphorus chlorides in the presence of triethylamine. The phosphorus chlorides employed include phosphoryl chloride, thiophosphoryl chloride, mono- and dichlorophosphates, and phosphinic chloride (Fig. 5.66). 

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... 

The 4(5//)-oxazolone ring system has been and continues to be a rich source of interesting chemistry that has produced a number of useful compounds including trimethadione, dimethadione, famoxadone, chlozolinate, and vinchlozolin. In addition, such diverse areas of research as nonlinear optical materials, photographic and luminescence dyes, antidiabetic, antiulcer, antibacterial, and antitumor agents continues to provide a strong stimulus for further developments in this area. 

This procedure is an excellent method to prepare 1,4-dicarbonyl compounds 163 (Scheme 7.48) and, using triethylamine, has been extended to include other activated double bonds.Thus, the starting a-amino acids can be considered as nucleophilic acyl equivalents. Representative examples of 5(47/)-oxazolones prepared via Michael additions are shown in Table 7.18 (Fig. 7.20). 

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. 

Other compounds smdied as chiral catalysts include a- and p-cyclodextrins that were used in the hydrolysis of oxazolones although the enantioselectivity in the ring-opening reaction was rather low. When a phenyl group is present at C-2 in these systems the enantioselectivity of the reaction is somewhat higher. 

Wittig olefination of 5(4//)-oxazolones with triphenylphosphonium methylides affords product mixmres that depend on the ylide and the starting oxazolone. ° The product mixtures can include, apart from the expected 5(4//)-oxazolylideneace-tates, 5-oxazoleacetates, and other byproducts. Nevertheless, Wittig reaction of ethyl (triphenylphosphoranylidene)acetate with a 4,4-disubstituted-5(4//)-oxazo-lone 285 affords the corresponding ethyl 5(4//)-oxazolylideneacetates 286 in satisfactory yields (Scheme 7.93 Table 7.24, Fig. 7.26). 

Finally, reaction of 2,4-diphenyl-5(4//)-oxazolone 322 with 4-phenyl-A -tosyl-1-azabuta-1,3-diene was found to be highly dependent on the experimental conditions. At room temperature the sole product was 323 that arises from alkylation of 322 by addition at the imine carbon. However, heating 322 and 4-phenyl-A-tosyl-1-azabuta-1,3-diene gave rise to several products including a 2-pyridone 324, 2,3,6-triphenylpyridine 325, and the pentasubstituted pyrroles 326 and 327. The authors postulated two different reaction mechanisms. Here, both a 1,3-dipolar cycloaddition of the oxazolone and a nucleophilic addition of the oxazolone are possible and that may account for the formation of 324—327. The marked differences in reactivity of 4-phenyl-A-tosyl-l-azabuta-l,3-diene relative to A-alkyl- or A-aryl-1-aza-1,3-dienes was attributed to the powerful electron-withdrawing nature of the tosyl group (Scheme 7.107). ... 

If the anion of 2-(2 -hydroxyphenyl)-5(4/l/)-oxazolone 336 is used as a ligand, bis-chelate complexes 337 of copper(II), nickel(II), and zinc(II) have been prepared from the corresponding metal acetates. Alternatively, 336 and 2-(2 -aminophenyl)-5(4//)-oxazolone 340 can act as ligands with metals including palladium(II), platinum(II), ruthenium(II), nickel(II), and copper(II) to produce a variety of structurally diverse complexes 338, 339, and 341 as shown in Schemes 7.109 and 7.110. ° ... 

Other amino acid precursors have been used as starting materials in the Erlenmeyer reaction. A classical reaction of oxazolones is ring opening to give dehydroamino acid derivatives but there are a number of examples when the reverse reaction has been exploited including cyclizations of A-benzoyl-a,p-dehydrophen-ylalanine," a-(acetylamino)cinnamic esters," and 2-(acylamino)-2-alkenamides (Scheme 7.118)." ... 

Other alcohols ring-open unsaturated oxazolones including glycerol that was used to prepare monoglycerides of acylamino acids.In addition, alcoholysis with 3,4,4-trifluorobut-3-enol leads to amino acid fluorobutenyl esters that are used as pesticides.Finally, (dimethylamino)ethanol and other amino alcohols have also been used to obtain the corresponding aminoalkyl esters. 

Diamines have also been used to ring-open unsaturated 5(477)-oxazolones. Here, one amino group reacts with the oxazolone while the other amino group is used to incorporate other substituents. Examples include aliphatic diamines,o-phenylenediamines, ° ° and p-phenylenediamines. ° ° ... 

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. 

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. 

These include the four possible diastereomeric spirocyclopropane derivatives 633, 685, 634, and 686 resulting from methylene insertion into the double bond and a spirocyclopropane 687 derived from methylene insertion into the double bond of a homologated 5(4f/)-oxazolone. The amount of 687, the cis/trans selectivity and both the cis and trans diastereoselectivities depend on the reaction conditions. Use of nonpolar solvents avoids formation of 687. In addition, the cis/trans selectivity and both cis and trans diastereoselectivities are very high such that the major compound 633 can be isolated in 75% yield (Scheme 7.216). ... 

Other structural features of unsaturated-5(4//)-oxazolones can be deduced from crystallographic data including the effect on planarity of substituents on the exocyclic double bond. For example, 4-benzylidene-5(4//)-oxazolones show a completely planar conformation that favors strong electronic conjugation in both (2)990 isomers. The same effect has been reported for other 4-arylidene-... 

Many aspects of the chemistry of the oxazolones have been considered in this chapter including the extensive use of these compounds as key intermediates for the synthesis of interesting and valuable products. 

It would require a Herculean effort to prepare a complete discussion and review of every report related to the synthesis, reaction, or application of an oxazole while tabulating every oxazole, oxazolone, oxazoline, and chiral bis(oxazoline) prepared and evaluated during the period of 1983-2001. Such an undertaking is beyond the scope of this review. Furthermore, the ease with which electronic databases, including the patent literature, can be searched, the data retrieved, and the information tabulated would render such a project somewhat redundant. 

Rather, the intent of the current project is to provide the reader with a discussion and leading examples of significant advances made in the synthesis, reactions, and applications of mononuclear oxazoles, oxazolones, oxazolines, and chiral bis(oxazolines) during this time frame. The material focuses on the more recent literature, although an update of the older synthetic literature is included wherever possible. In an effort to be selective, references to relevant reviews of material, not discussed in a chapter, are provided. Completely reduced oxazoles, that is, oxazolidines as well as benzo-fused derivatives, are outside the scope of this review. 

Tables are included in every chapter. Wherever possible, these contain a variety of selected examples to provide the reader with the scope and hmitations of synthetic methods and reactions. However, in some cases a table will contain only the examples reported. No attempt has been made to provide an exhaustive compilation of every oxazole, oxazolone, or oxazoline prepared since 1983.

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