Michael addition oxazolones

Oxidative dimerization of various 2-benzyloxy-2-thiazoline-5-ones (222) catalyzed by iodine and triethylamine is another example of the nucleophilic reactivity of the C-4 atom (469) (Scheme 112). Treatment of 212 with pyrrolidinocyclohexene yields the amide (223) (Scheme 113). The mechanism given for the formation of 223 is proposed by analogy with the reactivitx of oxazolones with enamines (4701. 4-Substituted 2-phenylthiazol-5(4Hi-ones react with A -morphoiino-l-cyclohexene in a similar manner (562j. Recently. Barret and Walker have studied the Michael addition products... 

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... 

This procedure is an excellent method to prepare 1,4-dicarbonyl compounds 163 (Scheme 7.48) and, using triethylamine, has been extended to include other activated double bonds.Thus, the starting a-amino acids can be considered as nucleophilic acyl equivalents. Representative examples of 5(47/)-oxazolones prepared via Michael additions are shown in Table 7.18 (Fig. 7.20). 

It has also been reported that some 4-substimted-5(47/)-oxazolones 166 undergo Michael addition to triphenylvinylphosphonium bromide to give the corresponding 4,4-disubstituted-5(47/)-oxazolones 167 from which ring opening... 

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. 

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. 

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. 

Scheme 4.13 Enantioselective Michael addition of racemic 4-substituted oxazolones to nitroalkenes.

SCHEME 5.47. Michael addition of oxazolones to various electrophiles. 

Scheme 1.12 Silylated biarylprolinol-catalysed Michael additions of oxazolones to a,P-unsaturated aldehydes.

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). 

For the competition between C4 and C2 in the organocatalytic Michael additions of oxazolones, see (a) Balaguer, A.-N., Companyo, X., Calvet, T., Font-Bardia,... 

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... 

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... 

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. 

OxazoIones are alkylated at position 4 by alkyl halides, allyl halides and electrophilic alkynes, such as methyl propiolate (equation 36). In contrast, 2-phenyloxazolones react with methyl vinyl ketone at both C(4) and C(2) to yield a mixture of Michael adducts (equation 37). If the phenyl substituent is replaced by the bulky 2,4,6-trimethylphenyl group the addition is directed exclusively to C(4) (81CB2580). Alkylation of 5(4//)-oxazolones is a key step in the synthesis of ketones from a-amino acids (Scheme 16). The outcome of this sequence is the union of the electrophilic fragment R3 with the group R2CO the amino acid thus functions as the equivalent of an acyl anion (78AG(E)450). 

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. 

---