Oxazolinones

One of the earliest known syntheses of acylenamino acid derivatives (11) consists of the ring opening of 4-alkylidene-(aralkylidene-)-A -oxazolin-5-ones (10) by attack of a nucleophile HY on the carbonyl group. As nucleophiles also readily add to the exocyclic double bond of 

The chemistry of unsaturated oxazolinones has been the subject of several detailed reviews (25, 95, 106, 107, 126, 127, 322, 398) so that attention here will be focussed primarily on those more recent studies not dealt with in the literature cited. Unsaturated oxazolinones for the synthesis of dehydropeptides can be obtained by several different routes  

P) In 1926, Bergmann and Stern described an alternative route to unsaturated oxazolinones (40). Treatment of a-haloacylamino acids with acetic anhydride, usually in the presence of bases such as pyridine or sodium acetate, affords A -or A -oxazolinones (14) and (15), depending on the stabilization of the double bond system by the substituents R [cf. (396, 398). The 2-methyl-4-alkylidene (aralkylidene) oxazolinones obtained by Bergmann et al. (40, 114) and by Greenstein and Price (319) from the chloroacetyl derivatives of Phe, Tyr, Leu, Norleu, Val and Aba, from which the corresponding acetyldehydroamino acids could be obtained by hydrolysis, were most probably A -oxazolinones. In contrast, the product obtained from a-bromopropionyl alanine, which can very readily be cleaved to pyruvic acid, is probably an example of a A -oxazolinone. 

Riordan and Stammer (3S3, 334) chose a,P-dibromoacylamino acids as starting materials in order to favour the A -oxazolinone structure by the additional double bond in the 2-substituent. 

In the reaction of N-chloroacetylphenylserine with acetic anhydride, oxazolinone formation was followed by the elimination, not of HCl, but of H2O, to yield 4-benzylidene-2-chloroacetyl-A -oxazolinone (52). Hydrolysis, followed by treatment with ammonia, afforded the first example (16) of a dehydropeptide in which the dehydroamino acid was not at the N-terminal end. 

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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). 

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

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. ... 

Clarke et al. reported that 2-phenyl-4-[(2-pyridylamino)methylene]-5-oxazolinone 178 (R = R1 = H) isomerized to 3-benzoylamino-4//-pyrido[l, 2-a]pyrimidin-4-one 180 (R = R1 = H) when it stood in ethanolic sodium ethoxide in room temperature (49MI1). Later it was pointed out... 

A wider range of possibilities of preparing cyclic derivatives is offered by the presence of carboxyl and a-amino groups in the molecule. Substituted 5-oxazolinone (Scheme 4.23) is prepared by refluxing with TFA anhydride, and substituted 5-oxazolidinone (Scheme 4.24)by reaction with (halogenated) acetone [117,118]. Thiohydantoins are formed by reaction with isothiocyanate (Scheme 4.25). If R is methyl or phenyl, then the corresponding methyl- or phenylthiohydantoin is produced. Thiohydantoins are usually not volatile enough and for the purposes of GC analyses must be further modified, e.g., by trimethylsilylation [119,120]. 

Dimethylamino-2,2-dimethyl-2//-azirine (27) and 4-isopropyl-2-trifluo-romethyl-5-oxazolinone (28) gave 5-dimethylamino-3-isopropyl-6,6-di-methyl-3,6-dihydro-2(l//)-pyrazinone (29) (MeCN, reflux, N2, 1 h 60% a rational mechanism was suggested) 944 analogues, like 3-allyl-5-dimethy-lamino-6,6-dimethyl-3-phcnyl-3,6-dihydro-2(l//)-pyrazinone (44%),958 were made similarly.944 958... 

A-Aryldithiocarbamic acids enter into Michael-type additions with 4-arylidene-5-oxazolinones... 

In another investigation, 5-acyloxyoxazoles (257) were found to rearrange to 2- and 4-acyl-5-oxazolinones (259 and 260).417 The reaction in the presence of 4-dimethyIaminopyridine proceeds 20,000 times faster... 

In the most commonly detected pathway of racemization azlactones (5(4if)-oxazolones, 5-oxazolinones) are implicated. Proton abstraction from these cyclic intermediates results in a resonance stabilized carbanion... 

Oxazolinones are five-membered azlactones (in some older publications referred to as oxazolones) that can be obtained from a-amino acids, for example, from a-amino isobutyric acid, and carboxylic acids (Scheme 9). 

Scheme 9 Synthesis of 5-oxazolinone starting from a-amino acid and carboxylic acid.

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