Unsaturated 5 -oxazolones, ring opening

The behavior of unsaturated azlactones with organometallic reagents has been studied in detail. Arylmagnesium halides and phenyllithium attack 4-arylidene-5-oxazolones at the carbonyl carbon to give ring-opened amido tertiary alcohols (26) and oxazolines (27) (by ring closure), usually as mixtures [Eq. (17)]. The nature of the... 

Michael Reaction. 5(47/)-Oxazolones undergo base-catalyzed conjugate addition to activated unsaturated compounds to afford the corresponding C-4 Michael adducts. For example, base-catalyzed addition of a 4-monosubstituted-5(4//)-oxazolone 157 to methyl propiolate yields a mixture of diastereomeric methyl 3-(5-oxo-2-phenyl-2-oxazolin-4-yl)acrylates 158. Hydrolytic ring opening of 158 and subsequent oxidation with lead tetraacetate affords 3-acylacrylates 160... 

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. 

In general, the reaction of unsaturated 5(4//)-oxazolones 497 with nitrogen nucleophiles effects ring opening to give the corresponding unsaturated acylamino amides 498 (Scheme 7.158). Depending on the nucleophile, for example, amines, hydrazines, oximes, and so on, the products obtained can be cyclized and this process allows the synthesis of a wide variety of new heterocyclic compounds. 

The mechanism of the aminolysis and the electronic effects of substituents at C-2 or C-4 on the kinetics of amide bond formation have been studied. In some cases, ring opening with amines occurs with partial isomerization of the exocyclic double bond. However, with more hindered compounds, such as unsaturated oxazolones derived from ketones, ring opening is stereospecific.Ring opening using diamines has also been described. Selected examples of dehydroamino acid amides prepared by aminolysis of unsaturated 5(4//)-oxazolones are shown in Table 7.40 (Fig. 7.51). 

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. ° ° ... 

Amino acids " " and aminobenzoic acids " " react as nitrogen nucleophiles to effect ring opening of unsaturated 5(4//)-oxazolones. Cyclization of the intermediate acylamino amide has opened the way for the synthesis of new series of imidazolones that now incorporate a carboxylic acid moiety into the N-1 substituent. These compounds are readily further elaborated into derivatives with diverse biological activity. 

Therefore, suitable unsaturated oxazolones can be used as intermediates to prepare dehydropeptides wherein the synthetic strategy used will depend on the position of the double bond in the final compound. If the double bond is located in the N-terminal amino acid, ring opening of the oxazolone 516 with the appropriate amino acid or peptide generates the desired dehydropeptide 517 directly. 

A variety of N,S-bis(nucleophiles) react with unsaturated 5(47/)-oxazolones to produce triazolo-l,3-thiazin -ones 570 and 1,3-thiazin-4-ones 572. Mechanistically, Michael addition of the bis(nucleophile) to 569 and 571 followed by ring opening with concomitant cyclization leads to the observed products. 

In contrast, ethyl 3-oxo-4-(triphenylphosphoranylidene)butyrate behaves as a C,0-bis(nucleophile) when reacted with unsaturated 5(4//)-oxazolones 584 with a leaving group at the exocyclic p-carbon. In this case, initial Michael reaction generates 585 that eliminates HX to produce a resonance stabihzed ylide 586. Cyclization of 586 with ring opening leads to the interesting ylide intermediate 587 used for the synthesis of 2//-pyran-2-ones (Scheme 7.185). 

Unsaturated 5(4H)-oxazolones undergo a Friedel-Crafts reaction with aromatic hydrocarbons in the presence of a Lewis acid. In particular, a 2-aryl-4-benzylidene-5(4H)-oxazolone 598 reacts with o- or p-xylene in the presence of aluminum chloride via ring opening and subsequent dearylation to yield 599 as indicated in Scheme 7.191. ... 

Finally, the intramolecular ring opening of unsaturated 5(4//)-oxazolones derived from 2-hydroxybenzaldehyde is noteworthy. Here, the condensation of hippuric acid and 2-hydroxybenzaldehyde under classical conditions gives a 3-(acylamino)coumarin 602 directly without isolation of an intermediate oxazo-... 

Classical ring-opening reactions of unsaturated oxazolones are the most well studied reactions and generate a wide variety of interesting products. However, reactions of the exocyclic double bond have also been investigated and open the way to a tremendous variety of new possibilities. 

It is well known that hydrogenation of dehydroamino acid derivatives derived from ring opening of unsaturated 5(4H)-oxazolones affords new racemic amino acids and, in some cases, enantiomerically pure compounds. On the other hand, a number of attempts have been made to hydrogenate the double bond of the unsaturated oxazolone itself. For example, 4-benzyl-2-methyl-5(4//)-oxazolone was prepared from 4-benzylidene-2-methyl-5(4H)-oxazolone using Raney Ni as a catalyst. This process is reported to be a general procedure to prepare saturated oxazolones directly (Scheme 7.194). 

Organophosphorous compounds have also been used as nucleophiles with unsaturated oxazolones. Initially, Michael reaction of a trialkyl- or dialkylphosphite gives 617 or 619 that undergo subsequent ring opening to yield a 2-acylamino-3-phosphonyl-618 or 2-acylammo-3-phosphinyl-620 derivative of the corresponding carboxylic acid, respectively (Scheme 7.198). ° ... 

Previously, Friedel-Crafts alkylation of unsaturated oxazolones with xylenes leading to the ring-opened products was described in Section 7.4.2.7. In contrast,... 

Sulfur ylides are among the most interesting carbon nucleophiles and their synthetic importance has been recently reviewed.One especially interesting use of these ylides is their application to the synthesis of cyclopropane derivatives using unsaturated oxazolones. For example, stabilized sulfur yhdes react with unsaturated oxazolones 629 via a Michael reaction to give oxazolone spirocyclopropanes 630 as shown in Scheme 7.202 and Table 7.46 (Fig. 7.57), whereas the less stabilized sulfur ylides give ring-opened products 631 as the major compounds (Scheme 7.202). ... 

Both reactions have been utilized to prepare heterocyclic compounds such as pyrazoles 681 (X = A -Ph) and isoxazoles 681 (X = O) as shown in Scheme 7.214. " Starting from an unsaturated 5(4//)-oxazolone 677, either a cycloaddition-ring-opening reaction sequence (677 678 680) or a ringopening-cycloaddition reaction sequence (677 679 680) affords the same product. 

Acylation of A- vinyl phosphazenes 805 derwed from dehydroaspartic acid esters gwes A-acylated dehydroaspartic acid esters 806 as well as the corresponding unsaturated-5(477)-oxazolones 807. Subsequent nucleophilic ring opening of 807 affords A-acylated dehydroaspartic acid derivatives 808 (Scheme 7.247). ° ... 

The reactivity of unsaturated 5(477)-oxazolones can be divided in two main categories according to the reaction site, ring-opening reactions, and reactions of the exocyclic double bond. 

H)-Oxazolones react readily with nucleophiles, C(5) and C(2) be ing possible sites for attack, and, in the case of unsaturated azlactones, C(a) as well (see 199-201). It has been proved by using water labelled with lsO that the acid-catalyzed hydrolysis of unsaturated azlactones proceeds by alkyl-oxygen fission (equation 42). The formation, hydrolysis and reduction of 4-methylene-5(4H)-oxazolones is a well-established method for the synthesis of a-amino acids, e.g. phenylalanine (equation 43). The addition of hydrazoic acid to 5(4H)-oxazolones without methylene groups at C(4) likewise occurs exclusively at C(2) to yield tetrazoles by ring-opening and recyclization (equation 44). 

The difference is interestingly exemplified in the differing modes of reaction of hydrazoic acid with some alkylidene (and arylidene) oxazolone derivativesThe alkylidene compound 174 behaves as an a, -unsaturated carbonyl compound with the hydrazoic acid adding to the exocyclic double bond. A subsequent ring opening with further addition leads to the formation of the diazide 175 (equation 75). In contrast the exocyclic double bond of the arylidene compound 176 is unreactive, and nucleophilic attack occurs at the... 

Unsaturated azlactones ordinarily do not react readily with hot alcohols. However, if either an acid > or a base is added to the ethanol, the oxazolone ring is opened rapidly with the formation of an a-acyl-aminoacrylic ester. With sodium hydroxide or alkoxide the reaction is complete in three to five minutes at room temperature. > With sodium carbonate as catalyst a short period of refluxing is required. Azlactones also react rajadly with higher alcohols in the presence of the sodium alkoxide. ... 

---