5-Oxazolone ring

The last comprehensive review of the chemistry of oxazolones covered the literature through 1954. Most of the studies up to that time stemmed from either interest in the role of azlactones as precursors of a-amino acids and peptides or the monumental studies on penicillin, which, for a time, was thought to possess an oxazolone ring, rather than the correct jS-lactam moiety. 

The first derivatives of the 4(5/f)-oxazolone ring system 1 were prepared almost 90 years ago when Traube and Ascher described the synthesis of 2-amino-4(5H)-oxazolones (pseudohydantoins) 2 via condensation of guanidine with a-hydroxy esters (Scheme 6.1). This is quite remarkable in that it was 36 years later before Sheehan and Izzo prepared the hrst example of a simple 2-aryl analogue via... 

The naturally occurring 4(5//)-oxazolone antibiotic indolmycin 69 (Fig. 6.13) has been a focus of several synthetic programs since the structure was first elucidated by Schach von Wittenau and Els nearly 40 years ago. ° These syntheses can be broadly classified as either involving classical cyclization to construct the 4(5/7)-oxazolone ring or as elaboration of an existing 4(5//)-oxazolone. The classical cyclization routes will be discussed at this time, whereas routes involving elaboration of an existing 4(57/)-oxazolone will be described in Section 6.3.3. 

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. 

In a similar way, propargyl esters of A -benzoyl-a-amino acids have been converted into a-allenyl-a-amino acid esters 113 by cyclization to oxazoles 111 followed by Claisen rearrangement to the 4-allenyl-2-phenyl-5(4//)-oxazolones 112. Oxazolone ring opening with methanol then afforded 113 (Scheme 7.32). ... 

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. 

X-ray analysis of the saturated 5(4f/)-oxazolone from A-benzyloxycarbonyl-(Aib)40H 798 (Fig. 7.67) has been determined. The oxazolone ring is nearly planar. The conformation of the amino acid residue preceding the residue of the ring system is semiextended although the Aibj and Aib2 residues are folded. 

The sequence with oxazole 73 also proves to be applicable to systems in which the double bond of the allylic alcohol fragment is incorporated into a heteroaromatic ring, such as in furfuryl alcohol (77a) and thiophene-2-methanol (77b).28 After hydrolysis of the oxazolone ring with water, V-benzoyl-3,3,3-trifluoro-2-(2-methyl-3-furyl)alanine (79a) and /V-benzoyl-3,3,3-trifluoro-2-(2-melhyl-3-thienyl)alanine (79b) are obtained. The 2-methylene helerocyclcs 78 originally formed in the Claisen rearrangement undergo rearomatizalion under the reaction conditions. 

When the 2-(5-oxo-2-oxazolin-4-yl)thiazolidine-4-carboxylate (311) is heated in benzene, the penicillic acid derivative (312) is formed. This is a result of attack of the thiazolidine nitrogen at the imino-ether rather than at the carbonyl group of the oxazolone ring to form the five-membered ring in preference to a four-membered ring (74JHC823). 

Rhodanines have been obtained from 3-formyI-lO-methylpheno-thiazine and its 5,5-dioxide. From these two aldehydes and also from 2-formyl- and 2-formyl-lO-methylphenothiazine, azlactones have been prepared, and their physical properties and oxazolone ring-opening reactions have been investigated. ° ... 

Alkylidene- and 4-arylidene-5(4/0-oxazolones, which are versatile intermediates for the synthesis of didehydroamino acids, offer another site, Ca, for reaction. The propensity for nucleophiles to attack at this position has been exploited in the synthesis of other heterocycles. A -Acyldithio-carbamic acids add in Michael fashion, and the intermediates undergo cyclization with concomitant oxazolone ring opening to furnish 2-thioxo-l,3-thiazin-4-ones (87) (Scheme 27) <92S919>. 

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