Fe(II)-Induced Decomposition of 1,2,4-Trioxolanes
J. Am. Chem. Soc., Vol. 121, No. 28, 1999 6557
Scheme 1. Metal-Induced Reduction of Endoperoxides,
Inner-Sphere Electron Transfer Mechanism
together with ketones 4-6 (entry 1 in Table 1). Interestingly,
the reduction of the unsymmetrical ozonides 1b (R1 ) Ph, R2
) mesityl) and 1c (R1 ) H, R2 ) Ph) resulted in the selective
formation of one of the two possible carboxylic acids (entries
2 and 3). Namely, 3b (R2 ) mesityl) from 1b and 3a from 1c
were obtained in high yields, respectively. In the case of the
reaction of the ozonide 1b, the ketones 4-6 were also formed
in similar yields observed for the reduction of 1a (compare
entries 1 and 2). For the ozonide 1c, although 1-butanal was
detected by 1H NMR (270 MHz) of the crude reaction mixture,
only benzoic acid 3a could be isolated.
To verify the mechanism for the production of 3-6, isotope
labeling studies were performed in the reduction of the ozonide
1a. First of all, the 18O-tracer experiments were examined by
using the 18O-labeled ozonide 18O-1a (18O, 77%),12 in which
the ethereal oxygen was labeled by 18O atom (eq 2). The labeled
ozonide 18O-1a was prepared by an electron transfer photooxy-
genation13 of the 18O-labeled epoxide 18O-7 (18O-77%), which
was prepared by the epoxidation of 1,2-diphenylcyclopentene
by using 18O-labeled m-CPBA as depicted in eq 2 (see
were examined in the presence of stoichiometric amounts of
Fe(II)SO4 in THF/H2O (1/1) under an argon atmosphere for
typically 16 h (eq 1). The reactions proceeded cleanly, giving
the decomposition products 3-6 in high yields (eq 1 and Table
1).
From the reaction of the symmetrical ozonide 1a (R1 ) R2
) Ph), benzoic acid 3a (R2 ) Ph) was obtained quantitatively
(5) Fe(II)-induced decomposition of endoperoxides: (a) Turner, J. A.;
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Experimental Section). The 18O content (%) of the epoxide 18O-7
was calculated from the relative mass peak intensities of 236
(M+) and 238 (M + 2+), comparing with those of the unlabeled
epoxide 7 (see Table 3). The 18O contents (%) reported below
were determined by a similar method.
By the careful mass spectroscopic analyses of the products
3-6 formed in the reduction of the ozonide 18O-1a (18O, 77%),
interestingly, only benzoic acid 3a was found to contain almost
the same amount of 18O-atom (18O, 76%; entry 4). Other
products 4-6 did not contain 18O atom derived from the ethereal
oxygen of the ozonide 18O-1a. Next, the Fe(II)-induced decom-
position of the ozonide 1a was performed in the presence of
18O-labeled H2O (18O, 10%; entry 5). As expected, the 18O
content of benzoic acid 3a did not exceed the natural amount
of 18O-atom (ca. 0.2%). However, products 4-6 did contain
18O-atom from H218O: 4 (18O, 9.3%); 5 (18O, 7.7%); 6 (18O,
6.0%) (entry 5). In the keto-alcohol 6, only the carbonyl oxygen
contained external 18O atom (18O, 6.0%), proved by the
following mass spectroscopic evidence: (1) no (M + 4) peak
in the mass spectra was observed; (2) the fragment peak (C6H5-
CO+, 105) did contain the similar amounts of 18O atom (18O-
4.9%). These results clearly suggest that the carbonyl oxygens
(7) For Pd-, Sn-, or Rh-induced decomposition of endoperoxides, see:
(a) Suzuki, M.; Noyori, R.; Hmanaka, M. J. Am. Chem. Soc. 1981, 103,
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(9) Antimalarial activity of ozonides: (a) Barbosa, L.-C.; Cutler, D.;
Mann, J.; Kirby, G. C.; Warhurst, D. C. J. Chem. Soc., Perkin Trans. 1
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(10) For the definition for inner- and outer-sphere electron transfer, see;
Eberson, L. In Electron Transfer Reactions in Organic Chemistry; Springer-
Verlag: Berlin, 1987.
(11) For steric effects as quantitative probes for inner- and outer-sphere
electron transfer mechanism, see: Fukuzumi, S.; Wong, C. L.; Kochi, J.
K. J. Am. Chem. Soc. 1980, 102, 2928.
(12) The 18O contents (%) was determined on the basis of those of the
epoxide 18O-7 (18O, 77%).
(13) Schaap, A. P.; Siddiqui, S.; Balakrishman, P.; Lopez, L.; Gagnon,
S. D. Isr. J. Chem. 1983, 23, 415.