Oxazolone additions

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... 

In contrast to the saturated azlactones, the Friedel-Crafts reaction of 2-substituted-4-arylidene-5-oxazolones is quite complex and may follow several different courses, often concurrently, depending on both reaction conditions and structural variations in the arylidene ring. This behavior is readily interpreted in terms of the a,)S-unsaturated carbonyl moiety and the cross-conjugated system containing nitrogen, both of which provide potential reaction sites in addition to the lactone carbonyl group. The reaction has been investigated " ... 

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)]. 

Difficulties are often encountered in the formation of peptides from a-amino acids which lack an a-hydrogen atom, e.g. a-methylalanine, presumably because of steric hindrance. This problem is obviated by use of the oxazolone 35, an excellent reagent for the addition of a single a-methylalanyl residue to an amine or amino acid [Eq. (22)]... 

The isolation of several pairs of geometric isomers of 4-unsaturated-5-oxazolones has been described. Generally, only one isomer is obtained when an aldehyde reacts with hippuric acid in the presence of acetic anhydride. Occasionally, mixtures have been separated in base-catalyzed reactions. In acetic anhydride-sulfuric acid or in 100% sulfuric acid, a mixture is obtained, and it has been suggested that sulfuric acid inhibits mutarotation of the intermediate addition product 53, which is a mixture of diastereomers (see, e.g., compound... 

Conjugate addition of strong nucleophiles to the >C=N—C=C< moiety, followed by ring opening of the resulting saturated 5 4H)-oxazolone. Thus, 57 reacts with simple or peptidic amino acid esters [Eq. (31)]. Similarly, 62 gives 63 in methanolic 7i-propylamine, and... 

Chlordane interacts with other chemicals to produce additive or more-than-additive toxicity. For example, chlordane increased hepatotoxic effects of carbon tetrachloride in the rat (USEPA 1980 WHO 1984), and in combination with dimethylnitrosamine acts more than additively in producing liver neoplasms in mice (Williams and Numoto 1984). Chlordane in combination with either endrin, methoxychlor, or aldrin is additive or more-than-additive in toxicity to mice (Klaassen et al. 1986). Protein deficiency doubles the acute toxicity of chlordane to rats (WHO 1984). In contrast, chlordane exerts a protective effect against several organophosphorus and carbamate insecticides (WHO 1984), protects mouse embryos against influenza virus infection, and mouse newborns against oxazolone delayed hypersensitivity response (Barnett et al. 1985). More research seems warranted on interactions of chlordane with other agricultural chemicals. 

When Wa = substituted aminoacyl, that is, when Wa-Xaa is a peptide, there is a strong tendency to form an oxazolone. The 2-alkyl-5(4//)-oxazolone that is formed is chirally unstable. Isomerization of the 2-alkyl-5(4//)-oxazolone generates diaste-reomeric products. When Wa = R0C=0, there is a lesser tendency to form an oxazolone. The 2-alkoxy-5(4/7)-oxazolone that is formed is chirally stable. No isomerization occurs under normal operating conditions. Finally, when Wa = R0C=0, an additional productive intermediate, the symmetrical anhydride, can and often does form. 

FIGURE 1.18 2-AI koxy-5(4/7)-oxazol ones as intermediates in reactions of IV-alkoxycarbo-nylamino acids.22 After removal of the symmetrical anhydride from a reaction mixture containing Boc-valine and ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride, the filtrate contained a novel activated form of Boc-valine (20% yield) that was established to be the 2-alkoxy-5(4H)-oxazolone. Slow addition of Boc-valine to ethyl-(3-dimethylamino-propyl)-carbodiimide hydrochloride in dilute solution gave a 55% yield. Petrol = petroleum ether, bp 40-60°. 

The chemistry of the reactions involved in coupling peptides is the same as that for coupling TV-alkoxycarbonylamino acids. However, the oxazolone that is formed by the activated peptide is chirally unstable, it is formed more readily, and there is an added impetus for it to form because the rate of bond formation between segments is lower. In addition, segments usually have to be coupled in polar solvents because they are insoluble in nonpolar solvents, and polar solvents promote the undesirable side reaction. The result is that the number of procedures actually used for coupling peptides is rather small. The methods in question are addressed below. 

DCC or EDC with an additive This is probably the most common method of coupling segments, with HOBt and HOObt competing as the most efficient additives. HOAt may be on par with the other two. The additive is essential to reduce isomerization to acceptable levels (see Sections 2.25 and 2.26). An important variant is supplementation of the reaction mixture with a cupric ion that minimizes or eliminates isomerization by preventing any oxazolone that is formed from enolizing (see Section 7.2). 

The existence of a protonated oxazolone has been demonstrated indirectly by a simple experiment. When p-nitrophenol was added to an excess of 2-alkoxy-5(4//)-oxazolone in dichloromethane, a yellow color appeared. The color persisted until all the p-nitrophenol had been consumed by the oxazolone. The anion of p-nitro-phenol is yellow. The explanation for the color of the mixture is the presence of the p-nitrophenoxide anion that was generated by abstraction of the proton by the oxazolone. In summary, protonation of the O-acylisourea suppresses the side reaction of oxazolone formation as well as the side reaction of A-acylurea formation and accelerates its consumption by enhancing its reactivity and generating an additional good nucleophile that consumes it. Protonation of the oxazolone suppresses epimerization by preventing its enolization and also increases the rate at which it is consumed.4 68 78 79... 

Additives increase efficiency in carbodiimide-mediated reactions by preventing intermediates from undergoing side reactions and by transforming them into activated esters that become the precursors of the peptide products. A-hydroxysuccinimide and 4-hydroxy-3-oxo-3,4-dihydrobenzotriazine are the best nucleophiles or acceptors of activated species. They trap oxazolones before they have time to isomerize. The popularity of HONSu as an additive has diminished considerably during the... 

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