5 -Oxazolones exocyclic double bond

One strategy to prepare saturated 5(4//)-oxazolones from unsaturated oxazo-lones takes advantage of the reactivity of the exocyclic double bond. In this context, numerous reactions have been explored including reductions, Michael reactions, cycloaddition reactions, and many others. These reactions will be discussed in the context of the reactivity of the exocyclic double bond of the unsaturated oxazolones and will be described in Section 7.4.3. 

Much effort has been invested to use oxazolones as intermediates for the synthesis of polymers. Probably the most important group of oxazolones used for this purpose is the 2-alkenyl-4,4-disubstituted-5(4//)-oxazolones. The reactivity of the exocyclic double bond at C-2 can be exploited to prepare new functionalized oxazolones as well as for copolymerization with other monomers. This possibility, together with the facile ring opening with nucleophiles, has opened very interesting routes to new polymers of industrial interest. 

There are cases in which appropriate modification of one unsaturated oxazolone yields a new unsaturated oxazolone analogue. Most of the examples described in the literature involve modification of the substituent on the exocyclic double bond. For example, a series of 4-[2-hydroxy-3-(aminomethyl)benzylidene]-5(4//)-oxazo-lones 382 that were evaluated for bactericidal and fungicidal activities were obtained from Mannich reaction of 4-(2-hydroxybenzylidene)-5(4//)-oxazolones 381 (Scheme 7.123). ... 

The exocyclic double bond of 4-arylidene-5(47/)oxazolones 383 reacts with diazomethane in a 1,3-dipolar cycloaddition reaction to give the corresponding... 

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). 

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. 

Some examples of the Michael reaction on the exocyclic double bond of an unsaturated oxazolone have been discussed in previous sections. The synthesis of unsaturated 5(4//)-oxazolones from unsaturated 5(4/l/)-oxazolones via an addition-elimination sequence and the sequential reaction of unsaturated 5(4/i/)-oxazolones with a l,3-bis(nucleophile) have already been considered. This section will review Michael additions exclusively and, in this respect, a wide array of nucleophiles has been studied. 

Other structural features of unsaturated-5(4//)-oxazolones can be deduced from crystallographic data including the effect on planarity of substituents on the exocyclic double bond. For example, 4-benzylidene-5(4//)-oxazolones show a completely planar conformation that favors strong electronic conjugation in both (2)990 isomers. The same effect has been reported for other 4-arylidene-... 

On the other hand, as synthetic equivalents of amino acids, unsaturated oxazolones are and will continue to be very important intermediates for the synthesis of new non-proteinogenic a-amino acids, particularly for the asymmetric synthesis of these compounds using diastereo- or enantioselective methodologies. In addition, the exocyclic double bond will continue as an important focus to build new constrained amino acids for the design of peptides with improved properties. 

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. 

The use of 4-heteroarylmethylene- and 4-aryhnethylene-5(47/)-oxazolones as dienophiles in the Diels-Alder reaction has been recently reviewed. More recently the reactivity of the exocyclic double bond of 4-(alkoxymethylene)-5(4//)-oxazolones with several dienes has been assessed. Reaction of 4-(methoxymethyl-ene)-2-phenyl-5(477)-oxazolone and 1,3-butadiene requires the presence of Et2AlCl as a catalyst and even then the Diels-Alder cycloadduct is obtained in low yield. 

The circular dichroism of cis- and trans- 2-oxazolidinones (59 R = H or Me) has been measured (79T2009). Geometrical isomerism round the exocyclic double bond in 4-(aryl-methylene)-5-(4//)-oxazolones (60), the unsaturated azlactones, is a well-studied phenomenon (75S749). It has been shown by X-ray crystallography (74T351) that the stable form of 4-benzylidene-2-phenyl-5(4//)-oxazolone has the (Z) configuration (61). It isomer-izes to the labile (E) form (62) in polyphosphoric acid and the change is reversed in pyridine. 

H)-OxazoIones (78) are unstable with respect to the 4//-isomers (79) however, the 2-trifluoromethyl derivatives are unique in that the 2//-forms (78 R1 = CF3) are favoured (62LA(658)128). This was evident from the NMR spectra of numerous derivatives containing phenyl or alkyl groups at C(4) (64CB2023). While 2,2-disubstituted 5(2//)-oxazolones (80) have a fixed structure, the 2-methylene derivatives, such as 2-benzylidene-4-methyl-5(2H)-oxazolone (81), are in potential tautomeric equilibrium with 5(4//)-oxazolones, e.g. (82). However, compound (81) exists entirely in this form, no doubt because it is stabilized by conjugation of the phenyl group with the exocyclic double bond. 

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... 

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