Oxazolinone

The cyclic carbonate of benzoin (4,5-diphenyl-l,3-dioxol-2-one, prepared from benzoin and phosgene) blocks both hydrogen atoms of primary amines after dehydration acid stable, easily crystallizable Sheehan oxazolinones are formed, which are also called Ox derivatives. The amine is quantitatively deblocked by catalytic hydrogenation in the presence of 1 equiv. of aqueous acid (J.C Sheehan, 1972, 1973 M.J. Miller, 1983). An intelligent application to syntheses of acid labile -lactams is given in the previous section (p. 161). 

Aldehydes and ketones react with azolinones. The reaction between aldehydes and 2-phenyl-5-oxazolinone (131 Y = H), formed in situ from PhC0NHCH2C02H and AC2O, gives azlactones (131 Y = RCH). Similar reactions are given by 4-thiazolidinones, e.g. (132) gives (133) (79AHC(25)83), and 4-imidazolinones. In pyrazolin-5-ones the 4-position is sufficiently activated for condensation to occur with ketones in acidic media (Scheme 8) (66AH06)347). 

Although imidazolinones are usually resistant to hydrolysis, oxazolinone rings are often easily opened. In acid-catalyzed reactions of this type, water converts azlactones (181) into a-acylamino-a,/3-uhsaturated acids (182) (77AHC(21)175). 1,3,4-Oxadiazolinones are readily opened by hot water to give hydrazine carboxylic acids which undergo decarboxylation. 

Methyl-2-phenyl-5-oxazolinone (196) with phenylmagnesium bromide gives (197) (65AHC(4)75). 

Compounds of types (286) and (287) are in tautomeric equilibria with 4- or 5-hydroxyazoles. However, the non-aromatic form is sometimes by far the most stable. Thus oxazolinone derivatives of type (287) have been obtained as optically active forms they undergo racemization at measurable rates with nucleophiles (77AHC(21)175). Reactions of these derivatives are considered under the aromatic tautomer. 

Only one procedure in this category emerged from the present survey. Thus treatment of 1,2-benzenediamine (372) with 3,3-bis(trifluoromethyl)-5-oxazolinone (373, R = H) in ethyl acetate containing a trace of acetic acid at room temperature for a short time afforded 2(l//)-quinoxalinone (374, R = H) in 92% yield 3-methyl- (374, R = Me), 3-isopropyl- (374, R = Pr"), 3-phenyl- (374, R = Ph), and 3-benzyl-2(l//)-quinoxalinone (374, R = CH2Ph) were made similarly in 60-80% yield. ... 

Oxazolium oxides can also be made by (V-alkylation of oxazolinones.145... 

Hydroxymethylation (formaldehyde) of nitro-imidazole 76 affords 77, which is oxidized to aldehyde 78. To prepare the other fragment for this convergent synthesis, reaction of epichlorohydrin with morpholine leads to the aminoepoxide 79, which is reacted with hydrazine to afford 80. Reaction of this substituted hydrazine with dimethyl carbonate affords oxazolinone 81 by sequential ester interchange reactions. Condensation of 81 with aldehyde 78 affords the antitricho-... 

Although oximes are ambident nucleophiles, a neat regioselectivity allows the formation of oxazolinones. The alpha effect, which is especially relevant for the substimtion of R2C=NO anions at a carbonyl carbon, may offer a good explanation for the Bac2/Bai2 sequence ((9-methoxycarbonylation and A-methylation... 

Scheme 4.15 Proposed mechanism for the synthesis of iV-methyl oxazolinones from oximes.

OzTaetoprim, 302 Oxawniquine, 372 Oxantel, 303 Oxaprozin, 263 Oxazepam, 402 Oxazole synthesis, 263 Oxazolinone synthesis,... 

The oxazolinone substituents R then direct the approach of the aldehyde. Because of the differing steric encumbrance provided by 1 and 3, the products have the opposite configuration at the new stereogenic sites. The acyl oxazolidinones are easily solvolyzed... 

The syntheses in Schemes 13.36 and 13.37 illustrate the use of chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.36 establishes the configuration at the carbon which becomes C-4 in the product. This is an enolate alkylation in which the steric effect of the oxazolinone substituents directs the approach of the alkylating group. Step C also uses the oxazolidinone structure. In this case, the enolborinate is formed and condensed with the aldehyde intermediate. This stereoselective aldol condensation establishes the configuration at C-2 and C-3. The configuration at the final stereocenter is established by the hydroboration in step D. The selectivity for the desired stereoisomer is 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methyl-alkenes in which the remainder of the alkene constitutes a relatively bulky 135... 

It is evident from the structure of the oxazol-5(4//)-one, also sometimes called an azlactone or oxazolinone, why it is so susceptible to epimerization. Removal of the a-proton generates a five-membered ring with six n-electrons, an aromatic system according to the Hiickel 4n + 2 rule (Scheme 5). 

B. E. Maryanoff, Oxazoles and Oxazolines in Organic Synthesis, Oxazolinones, in J. Turchi, The Chemistry of Heterocyclic Compounds, 45, 963 (1986). 

Racemic 6-benzoyloxycyclocitral (246) has been converted to (S)-6-hydroxycyclo-citral (248) via the oxazolinone (247). (248) was obtained in 63% enantiomeric excess247). 

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