pecially, interest in the synthesis and pharmacological evaluation of numerous pyrazolidine-3,5-diones as AT1 angiotensin II receptor antagonists and study of the inhibition of the enzyme activity for prostaglandin H synthase has increased [140,141]. In order to synthesize functionalized pyrazolidine-3,5-dione derivatives with potent biological activities, the pyrazolidine-3,5-diones were selected as the second choice of heterocyclic diamides in the manganese(III)-catalyzed aerobic oxidation. Therefore, the reactions were investigated with particular attention being paid to the use of a combination of a catalytic amount of manganese(III) acetate and air. In this case, the oxidation also led to free double hydroperoxides in excellent yields, instead of cyclic peroxides as in the reaction of the barbituric acids (Scheme 24) [142, 143].

The structural assignment of the bis(hydroperoxyethyl)pyrazolidine-3,5-diones was based on their 1H NMR, 13C NMR, and IR spectra, as well as their elemental analyses. The exact structure of one of these was also confirmed by X-ray crystallography. The most characteristic feature of the bis(hydroperoxyethyl)pyrazolidine-3,5-diones was that two hydroperoxy groups are individually hydrogen-bonded to the two amide carbonyl oxygens since the interatomic distance between the carbonyl oxygen and the peroxy oxygen was found to be 2.688 A [143]. The hydrogen bonding is stronger in the solid state than that in solution. A similar stabilization of the hydroperoxy group was also observed in 5,5-bis(hydroperoxy-2,2-diphenylethyl)barbituric acid in which the corresponding interatomic distances were 2.73 A and 2.81 A, respectively [137]. The hydroperoxy O - O bond length (1.465 A) in the bis(hydroperoxyethyl)pyrazolidine-3,5-dione was analogous to those of the bis(hydroperoxyethyl)barbituric acid (1.450 A and 1.464 A). In addition, unlike many alkylhydroperoxides, the bis(hydroperoxyethyl)pyrazolidine-3,5-diones as well as the bis(hydroperoxyethyl)barbituric acids were found to be thermally stable at ambient temperature [144] and to prolonged ex-

Scheme 24 Manganese(III)-catalyzed double 2-hydroperoxyalkylations of 1,2-disubstitu-ted pyrazolidine-3,5-diones posure to sunlight or visible light [145], which could also be attributed to stabilization by strong hydrogen bonding.

Reaction Using 4-Hydroxy-1H-quinoMn-2-ones

A variety of quinoline alkaloids exists in plants, and it is known that the quinoline alkaloids exhibit a wide range of biological activities [146]. Naturally occurring quinine and artificial chloroquine are the most well-known antimalarial agents using the quinoline skeleton (Fig. 1) [147-149]. Since the development of the reaction scheme of the quinoline-fused cyclic peroxides might also be significant in order to find a new class of artificial antimalarial reagents, the 4-hydroxy-1ff-quinolin-2-ones were selected as the third choice of heterocyclic 1,3-dicarbonyl compounds in the manganese(III)-catalyzed aerobic oxidation.

Use of a 0.1 equivalent of manganese(III) acetate toward the substrate 4-hydroxy- 1ff-quinolin-2-one did not afford the expected cyclic peroxide, but the bis(hydroperoxide) analogous to the manganese(III)-catalyzed autoxidation of the barbituric acids and pyrazolidine-3,5-diones. Prolongation of the reaction period and the use of 0.5 equivalents of the catalyst resulted in increased yields (Scheme 25) [150].

X-ray crystallography indicated that the two hydroperoxy groups seemed to be stabilized by intramolecular hydrogen bonding with the quinoline-dione carbonyls since the interatomic distance between the carbonyl oxygen and peroxy oxygen was 2.712 A and 2.756 A, respectively. A similar stabilization of the hydroperoxy group was observed in the 5,5-bis(2-hydroperoxyethyl)barbituric acid (2.73 A and 2.81 A) and 4,4-bis(2-hydro-peroxyethyl)pyrazolidine-3,5-dione systems (2.688 A) [137,142,143].

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