Azlactones ring opening

Saturated 2-vinyl-5(47Z)-oxazolones have been widely used as intermediates for the synthesis of polymeric compounds that will be described in Section 7.3.2.9. Apart from these polymerization reactions, the Diels-Alder reactions of 4-sub-stituted-2-vinyl-5(47/)-oxazolones 134 with cyclopentadiene are reported to give norbomenyl oxazolones 135 that are useful to prepare norbornenyl functionalized resins by azlactone ring-opening addition reactions (Scheme 7.39). 

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... 

In contrast to these ring-opening reactions, it was observed by Horner and Schwahn that 4-arylidene-(isopropylidene and cyclo-hexylidene)-oxazolones react with alkyl Grignard reagents by conjugate addition to give saturated azlactones 29a as the only products [Eq. (18)]. 

The ring opening reactions of unsaturated azlactones and other lactones - by methanol in the presence of diazomethane are analogous in principle. (The ring closure of pseudouric acid which occurs under the influence of diazomethane can also be understood as an example of base catalysis.)... 

The method described above may be used for the preparation of a wide variety of butenolides substituted in the arylidene ring with either electron-withdrawing or electron-releasing substituents. y-Lactones such as a-benzylidene-7-phenyl-A 1 -bu-tenolide are isoelectronic with azlactones, but have received much less attention. Like the azlactone ring, the butenolide ring may be opened readily by water, alcohols, or amines to form keto acids, keto esters, or keto amides.7 a,-Benzylidene-7-phenyl-A3,1 -butenolide is smoothly isomerized by aluminum chloride to 4-phenyl-2-naphthoic acid in 65-75% yield via intramolecular alkylation. 

Figure 3.9 An azlactone reacts with amine groups through a ring-opening process, creating amide bond linkages with the attacking nucleophile.

The Calculated Reaction Path of the Alcoholytic Ring Opening of Azlactones... 

Scheme 4 Model system for the DFT-calculations of the alcoholytic ring opening of azlactones...

Fig. 1 The reaction path of the alcoholytic ring opening of azlactones geometries and relative electronic energies (kJ mol" ) of the stationary points (B3LYP/6-311++G(d,p)// B3LYP/6-31++G(d,p), gas phase)...

Clearly, upon using the enantiomeric catalyst [(S,S) instead of (R,R)] the opposite enantioselectivity of the overall process results. However, this effect is also seen with catalysts that are of analogous configuration, but not derived from trans-1,2-diaminocyclohexane (DACH). For example, the pseudo-ephedrine derived catalyst shown in Scheme 5, having (5)-configuration at the centers of chirality, shows some preference for the (5)-azlactone kinetically favors the (5)-azlactone in alcoholytic ring opening [37]. 

Scheme 5 Pseudo-ephedrine derived catalyst which favors the ring opening of ( S)-azlactones...

Scheme 7.20 Ring opening of azlactone with immobilized lipase Cal b to the (S)-y-fluoroleucine ethyl ester.

One of the oldest methods for the preparation of DHAs is the ring opening of unsaturated azlactones by attack of a nucleophile on the carbonyl group. Several methods for the synthesis of unsaturated azlactones (Azl) have been developed over the years and the chemistry of these important intermediates has been reviewed/1,2 Following are the methods of their synthesis that have remained in use during the last few decades. 

The planar chiral DMAP derivative 79a proved successful also in the dynamic kinetic resolution of racemic azlactones by ring-opening with alcohols (Scheme... 

This process relies on rapid base-induced racemization of the azlactone and rate-limiting ring opening by the alcohol nucleophile. In this process the DMAP derivative 79a acts as both Bronsted-basic and as nucleophilic catalyst. With 2-propanol as reagent enantiomeric excesses up to 78% were achieved for the product amino acid esters [87]. 

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). 

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