Ketones are found to be catalysts for the decomposition of peroxynitrite. Kinetics, product studies, and B3LYP transition-state calculations together provide consistent evidence for a mechanism involving the formation of dioxirane intermediates.

We found that dioxiranes generated in situ from ketones 1-6 and Oxone underwent intramolecular oxidation of unactivated C-H bonds at delta sites of ketones to yield tetrahydropyrans. From the trans/cis ratio of oxidation products 1a and 2a as well as the retention of the configuration at the delta site of ketone 5, we proposed that the oxidation reaction proceeds through a concerted pathway under a spiro transition state. The intramolecular oxidation of ketone 6 showed the preference for a tertiary delta C-H bond over a secondary one. This intramolecular oxidation method can be extended to the oxidation of the tertiary gamma' C-H bond of ketones 9 and 10. For ketone 11 with two delta C-H bonds and one gamma' C-H bond linked respectively by a sp(3) hydrocarbon tether and a sp(2) ester tether, the oxidation took place exclusively at the delta C-H bonds. Finally, by introducing proper tethers, regioselective hydroxylation of steroid ketones 12-14 have been achieved at the C-17, C-16, C-3, and C-5 positions.

Regioselective oxidation of unactivated C-H bonds has been a challenging problem in organic synthesis. 1,2 Intramolecular oxidation, due to its geometric constraint, has become a very effective approach. In particular, significant progress has been made in remote oxidation of rigid substrates such as steroids. 3,4a,b For flexible substrates, selective oxidation of remote carbons four bonds away from a heteroatom has been successfully achieved by using the radical reactions that undergo intramolecular radical 1,5-hydrogen abstractions (Figure 1). 4 However, for oxidation of more remote C-H bonds in flexible molecules, there is no general method available. 5 Here we report a novel method for selective oxidation of unactivated C-H bonds at the δ site of ketones.Dioxiranes, a new generation of oxidants, have excellent reactivity toward unactivated C-H bonds under mild and neutral conditions. 6 The oxidation reaction is stereospecific and has strong preference for tertiary C-H bonds over secondary ones. 6,7 We previously reported a homogeneous solvent system that allows dioxiranes to be generated in situ from ketones and Oxone at neutral pH. 8 This makes it possible to develop a ketone-catalyzed intramolecular C-H bond oxidation method.We first examined the activities of various ketones in catalyzing oxidation of adamantane under our in situ conditions. As shown in Table 1, 1,1,1-trifluoroacetone and methyl pyruvate were found to exhibit higher activities than fluoroacetone and chloroacetone. These ketone units were then attached to a series of hydrocarbon skeletons and oxidation reactions were carried out at 10 mM concentration (Table 2). Oxidation of linear R-keto esters 1 and 2 was found to give hemiketal 1a (70% yield) and 2a (86% yield), respectively, as the major oxidation products in 24 h (entries 1-2, Table 2). Despite the presence of several other secondary C-H bonds, the δ C-H bonds were selectively oxidized. Methyl 2-oxohexanoate failed to give the desired oxidation product, because its δ C-H bonds are primary and extremely unreactive.In each of the branched substrates 3-8, there is one tertiary C-H bond in addition to several secondary ones, and interestingly, only the δ site was oxidized (entries 3-8, Table 2). Here intermolecular C-H bond oxidation by dioxiranes is unlikely as the reactions of compounds 3-5 proceeded via selective oxidation of secondary C-H bonds despite the presence of tertiary C-H bonds. These results indicate the predominance of stereoelectronic control on the transition state for hydroxylation. Furthermore, the observed regioselectivity (i.e., δ-selectivity) is different from that of a typical intramolecular radical reaction (i.e., γ-selectivity), suggesting the nonradical nature of this oxidation reaction. 9 We propose a concerted C-H bond oxidation mechanism (Figure 2). 6b,7a,c Oxidation of a δ C-H bond generates a δ-hydroxy ketone which cyclizes to give a hemiketal. The hemiketal formation prevents further oxidation at the δ site.For concerted C-H bond oxidation by dioxi...