4,4-disubstituted-5 -oxazolones

Disubstituted 2-oxazolidines as chiral auxiliaries synthesis from 2-oxazolones 97YZ339. 

Ortho esters, in synthesis of symmetrical trimethine thiazolocyanines, 54 Oxazolone, for neutrocyanines, 27 Oxidation potentials, of dyes, 75 of mesosubstituted dyes, in relation with absorption, 77 of polymethine dyes, 72 Oxidoreduction, relation between sensitizers, and silver halides, 78 4-Oxo-disubstituted 2-aminoselenazoles, table of products, 262 Oxonols, nomenclature of, 26 in synthesis of dimethine neutrocyanines, 62... 

P Wipf, H Heimgartner. 2. Synthesis of peptides containing a,a-disubstituted a-amino acids by the azirine/oxazolone method. Helv Chim Acta 73, 13, 1990. 

FIGURE 7.34 Decomposition of the symmetrical anhydride of A-methoxycarbonyl-valine (R1 = CH3) in basic media.2 (A) The anhydride is in equilibrium with the acid anion and the 2-alkoxy-5(4//)-oxazolone. (B) The anhydride undergoes intramolecular acyl transfer to the urethane nitrogen, producing thelV.AT-fcwmethoxycarbonyldipeptide. (A) and (B) are initiated by proton abstraction. Double insertion of glycine can be explained by aminolysis of the AA -diprotected peptide that is activated by conversion to anhydride Moc-Gly-(Moc)Gly-0-Gly-Moc by reaction with the oxazolone. (C) The A,A -diacylated peptide eventually cyclizes to the IV.AT-disubstituted hydantoin as it ejects methoxy anion or (D) releases methoxycarbonyl from the peptide bond leading to formation of the -substituted dipeptide ester. 

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). ... 

TABLE 5.6. 3-ALKYL-4,5-DISUBSTITUTED-2(3H)-OXAZOLONES EROM OXIMES AND DIAEKYECARBONATES"... 

Certain erythro-2-wamo alcohols such as ( )-ephedrine 150, ( )-A -methyl-ephedrine 151 and ( )-conhydrine 153 are synthesized with complete stereochemical control by the catalytic hydrogenation of the corresponding 4,5-disubstituted 2(3/i)-oxazolone derivatives 22 and 27, followed by ring opening (Fig. 5.37). ... 

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). 

Treatment of the alkenyl bromides 210 with tributyltin hydride in the presence of AIBN involves an intramolecular radical addition to the 2(3/f)-oxazolone moiety, resulting in the diastereoselective formation of the oxazolidinopiperidines 211. These are readily converted to the protected 2,6-disubstituted 3-hydroxypiperidine derivatives 212 (Fig. 5.51). ... 

Smith and co-workers adapted Sheehan and Izzo s original synthesis of 2-aryl-4(57/)-oxazolones and developed a general synthesis of 2-aIkylA(57/)-oxazo-lones. Teatment of an acid halide with AgNCO followed by diazomethane produced 344 that were immediately converted to the 2-alkylA-oxazole triflates 345. The authors noted that ethanol-free diazomethane was required to prepare 344. The oxazole triflates 345 were, in turn, key intermediates leading to a variety of 2,4-disubstituted oxazoles required for natural products (Scheme 6.73). 

The procedure is also useful for the synthesis of 4,4-disubstituted 5(477)-oxazolones. For example, cyclization of a 2-aryl(hetaryl)carbonylamino-2-arylpro-pionic acid afforded the corresponding oxazolones 99 (R3 = Me) that were evaluated as selective herbicides. ... 

Alkylation of saturated 5(4//)-oxazolones at C-4 is a well-known reaction that can be achieved under a wide variety of conditions. Numerous articles have described this reaction as a means to prepare 4,4-dialkyl-5(477)-oxazolones 147 that are valuable intermediates to prepare ot,ot-disubstituted a-amino acids. For instance,2-phenyl-5(4//)-oxazolone 146 readily obtained from hippuric acid and A,A -dicyclohexylcarbodiimide (DCC), is alkylated at C-4 with allyl, benzyl, or phenacyl halides if the reaction is conducted in dipolar aprotic solvents in the presence of weak bases. Hydrolysis of the resulting 5(477)-oxazolones leads to a,a-dialkylglycines 148 (Scheme 7.43). 

Alkylation of 2,4-disubstituted-5(477)-oxazolones can be conveniently performed via phase-transfer catalysis. For example, the substrate and an alkyl halide are dissolved in an organic solvent and stirred with an aqueous sodium carbonate solution containing tetrabutylammonium bromide as a phase-transfer catalyst. 4,4-(Diarylmethyl)-2-phenyl-5(4/f)-oxazolones can be prepared in one-step by dialkylation of 146 using magnesium methyl carbonate and the corresponding... 

It has also been reported that some 4-substimted-5(47/)-oxazolones 166 undergo Michael addition to triphenylvinylphosphonium bromide to give the corresponding 4,4-disubstituted-5(47/)-oxazolones 167 from which ring opening... 

TABLE 7.20. SYNTHESIS OF SATURATED 4-ACYL-2,4-DISUBSTITUTED 5(4H)-OXAZOLONES VIA ACYLATION OF 2,4-DISUBSTITUTED 5(4H)-OXAZOLONES AT C-4... 

It was also reported " that the reaction of 4,4-disubstituted-2-(trifluoromethyl)-5(4f/)-oxazolones 251 with 2,2-dimethyl-3-(dimethylamino)-2//-azirine afforded 5-(dimethylamino)-3,6-dihydropyrazin-2(l//)-ones 252 (Scheme 7.81). In this case, the reaction only occurs when electron-withdrawing substituents are present at C-2 of the oxazolone. 

Racemization is not encountered when 4-unsubstituted-5(477)-oxazolones or 4,4-disubstituted-5(477)-oxazolones are used as reagents. Indeed, 4-unsubstituted-5(47/)-oxazolones function as glycine synthons in the synthesis of A-acylglycyl-a-amino acids. For example, aminolysis of 2-(trifluoromethyl)-5(47/)-oxazolone with a-methylphenylalanine affords A-(trifluoroacetyl)glycyl-a-methylphenylalanine. 4,4-Disubstituted-5(4//)-oxazolones, readily available by alkylation of the monosubstituted derivatives, are very useful intermediates in the synthesis of peptides that incorporate ot,ot-disubstituted amino acids. As an example, 4-(aryl-methyl)-2-phenyl-4-(trifluoromethyl)-5(4//)-oxazolones 260 are key intermediates... 

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). 

Cycloaddition reactions of A -(phenylmethylene)benzenesulfonamide with meso-ionic oxazolones 311 produces 2,5-disubstituted imidazoles 313 in a highly regio-selective process via cycloreversion of cycloadduct 312 and subsequent loss of benzenesulhnic acid. 

Much effort has been invested to use oxazolones as intermediates for the synthesis of polymers. Probably the most important group of oxazolones used for this purpose is the 2-alkenyl-4,4-disubstituted-5(4//)-oxazolones. The reactivity of the exocyclic double bond at C-2 can be exploited to prepare new functionalized oxazolones as well as for copolymerization with other monomers. This possibility, together with the facile ring opening with nucleophiles, has opened very interesting routes to new polymers of industrial interest. 

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). ... 

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). ... 

Examples of homooligomer series of new model peptides that incorporate the a,a-disubstituted amino acid 2, l l,2 l",2" 3,4-dibenzocyclohepta-l,3-diene-6-amino-6-carboxylic acid (Bip) have been obtained using 5(47/)-oxazolones 787 as key intermediates (Scheme 7.240). °° ... 

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