Michael reaction oxazolones

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... 

TABLE 7.18. SYNTHESIS OF SATURATED 2,4,4-TRISUBSTITUTED 5(4il)-OXAZOLONES BY REACTION OF SATURATED 5(4//)-OXAZOLONES WITH MICHAEL ACCEPTORS... 

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. 

Azoles or azines with an amino group at C-2 have also been used as bis(nucleophiles) to prepare a variety of fused heterocychc systems. In these cases, the geometry of the bis(nucleophile) permits reaction with both electrophilic centers of the oxazolone. Thus, initial Michael reaction and subsequent ring... 

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). 

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. 

Although it is well known that sulfur nucleophiles are excellent candidates for Michael reactions, they have scarcely been examined with unsaturated oxazolones. Nevertheless, 4-methyltoluene-a-thiol reacts with 4-benzylidene-2-methyl-5 (4//)-oxazolone 614 to give 615 as a mixture of erythro and threo isomers (Scheme 7.197). ° ... 

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). ° ... 

For carbon nucleophiles sequential addition of 2-potassio-2-nitropropane and oxygen to 4-arylidene-2-phenyl-5(47/)-oxazolones 623 has been reported (Scheme 7.200). The process involves a Michael reaction of the 2-nitropropane anion followed by reaction with molecular oxygen and elimination of nitrous acid to yield 2-aryl butenoic acid imides 626. 

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). ... 

Like most other aspects of the luzopeptin effort, deblocking of hard-won dipeptides 106 and 107 turned out to be a delicate proposition. In derivatives of proline and pipecolinic acid, the serine segment had been extricated from its protective webbing by A-deacetylation with pyrrolidine in aeetonitrile and Kunieda cleavage of the oxazolone. However, reaction of 106 with pyrrolidine furnished 109 (30%) as the sole identifiable compound. Evidently, pyrrolidine was basic enough to promote p-elimination of acetate and subsequent Michael-type addition to intermediate 108, a significant fraction of which may have been lost to polymerization. Other amines, such as ethylamine, diethylamine. 

Scheme 3.10 Michael reaction of 4-substituted oxazolones with a,P-unsaturated aldehydes catalyzed by 31c and further transformations carried out on the obtained adducts.

Reaction of the mesoionic oxazolone 620 with acetylenedicarboxylic ester 621 gave the cycloadduct 622 in aprotic solvents and the Michael adducts... 

The availability of a general procedure to prepare 4-alkyl-2-(trifluoromethyl)-5(2F0-oxazolones 12 from a-amino acids and TFAA, and taking into account the tautomerization process, has led to many efforts to direct the alkylation reaction toward C-2 or C-4. For example, in the presence of triethylamine, Michael addition of 12 occurs at C-2 when tert-butylacrylate is used as electrophile. The resulting... 

The vinyl substituent at C-2 can also act as a Michael acceptor and reaction with certain nucleophiles gives rise to 1,4-addition compounds. For example, p-toluene-sulfonic acid catalyzed addition of thiols to 2-vinyl- or 2-isopropenyl-5(47/)-oxazolones 136 gave, almost exclusively, the Michael adducts 137 that were used... 

The behavior of 2-substituted- or 2-unsubstituted-5(4//)-oxazolones is completely different. Reaction of electrophiles with 2-substimted-5(47/)-oxazolones usually occurs at C-4, whereas reaction of electrophiles with 2-unsubstituted-5(47/)-oxazolones affords the corresponding 5(2//)-oxazolones. The best example of the behavior of 2-unsubstituted-5(47/)-oxazolones involves 4-isopropyl-5(47/)-oxazolone 143, the anion of which can be considered as a formyl anion equiva-lent. ° ° Thus, reaction of 143 with a catalytic amount of triethylamine gives 144 that reacts with a,p-unsaturated carbonyl compounds to afford Michael adducts or with aldehydes to produce the corresponding aldol adducts. Mild acid hydrolysis of 145 yields the corresponding aldehydes (Scheme 7.42). 

Bis(trifluoromethyl)-5(2//)-oxazolone undergoes decarboxylation on treatment with trimethyl phosphite. The resulting 1,3-dipole may be trapped by methyl propio-late [171]. The initial P-C bond formation is favored because the alternative mode of reaction would form a weak P-N bond. This counter-Michael addition also generates an a-d-ard system which becomes fragmentable. 

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>. 

In 2008, jOTgensen and coworkers developed an extremely powerful methodology for the synthesis of ot,a-disubstituted amino acids via a Michael addition of oxazolones to enals [28]. The reaction was catalyzed by catalyst 28 and renders the final amino acid precursors in good yields and excellent diastereo- and enantioselectivities when a bulky benzhydryl substituent was present at C2 of the oxazolone (Scheme 33.8). 

---