Resolving Oxygenation Pathways in Manganese-Catalyzed C(sp³)–H Functionalization via Radical and Cationic Intermediates

Abstract

The C(sp 3 )–H bond oxygenation of the cyclopropane-containing mechanistic probes 6- tert -butylspiro[2.5]octane and spiro[2.5]octane with hydrogen peroxide catalyzed by manganese complexes bearing aminopyridine tetradentate ligands has been studied. Mixtures of unrearranged and rearranged oxygenation products (alcohols, ketones, and esters) are obtained, suggesting the involvement of cationic intermediates and the contribution of different pathways following the initial hydrogen atom transfer-based C–H bond cleavage step. Despite such a complex mechanistic scenario, a judicious choice of the catalyst structure and reaction conditions (solvent, temperature, and carboxylic acid) could be employed to resolve these oxygenation pathways, leading, with the former substrate, to conditions where a single unrearranged or rearranged product is obtained in good isolated yield. Taken together, the work demonstrates an unprecedented ability to precisely direct the chemoselectivity of the C–H oxidation reaction, discriminating among multiple pathways. In addition, these results conclusively demonstrate that stereospecific C(sp 3 )–H oxidation can take place via a cationic intermediate and that this path can become exclusive in governing product formation, expanding the available toolbox of aliphatic C–H bond oxygenations. The implications of these findings are discussed in the framework of the development of synthetically useful C–H functionalization procedures and the associated mechanistic features.

Carboxylic Acid Directed γ-Lactonization of Unactivated Primary C–H Bonds Catalyzed by Mn Complexes: Application to Stereoselective Natural Product Diversification

“…Building on the previously proposed mechanism for the intermolecular reactions, a general reaction energy profile for γ-C–H bond lactonization has been computed using 1 as substrate (see SI section 6 for detailed information) and is depicted in Figure , A. , There is ample evidence that the initial Mn II complexes are precatalysts that undergo oxidation to Mn III , which in turn is the catalytically competent species that binds and activates, with the assistance of the metal-bound carboxylic acid, H 2 O 2 to generate the active oxidant . Therefore, a DFT analysis of the catalytic reaction was undertaken starting from Mn III -hydroperoxo ( I q ) formed after H 2 O 2 binding to the Mn III -carboxylato species (Figure , B).…”

Reversible Deactivation of Manganese Catalysts in Alkene Oxidation and H2O2 Disproportionation

“…The synthetic accessibility of the pyridyl amine class of ligands has facilitated variation in the structure of the ligands over the last decade, most notably with the aim to improve enantioselectivity and substrate scope. ,, Electron-donating groups at the para position of the pyridyl moiety generally improve enantioselectivity despite negligible steric influence (Scheme ), , suggesting that they modify the electrophilicity and reactivity of a putative Mn V O species. 18 O-labeling studies, kinetic isotope effects, radical clocks, and Hammett analyses support this assignment. − …”

Transition Metal-Catalyzed Direct Stereoselective Oxygenations of C(sp3)–H Groups

“…In 1979, Groves with co-workers reported the first example of metal-catalyzed C−H hydroxylation, using iron tetraphenylporphyrin complex 1 as a catalyst and iodosylbenzene as a twoelectron oxidant (Figure 1a). 47 This milestone reaction, although formally not exactly matching the category of "catalytic" processes (since the porphyrin performed only 0.5 turnovers, TONs), was inspired by the catalytic cycle of cytochrome P450 40,48 and thus can apparently be regarded as the first intentionally designed biomimetic (catalyst) system. Ten years later, Groves and Viski presented the first transition metal-catalyzed asymmetric version of the benzylic C−H hydroxylation reaction.…”

“…Although the current consensus about the first reaction step is that the latter occurs through hydrogen atom transfer, possible involvement of cationic intermediates was hypothesized on the basis of a significant share of desaturation products formed in the course of hydroxylation of 3,4-dihydroquinolinone derivatives . More recently, the possibility that cationic species could be formed and contribute to the overall reaction outcome in the case of several substrates has been demonstrated experimentally by Costas and Bietti with co-workers . However, given the very limited data on cationic intermediates to date, they are excluded from further discussion herewith.…”

“…The mechanism of C–H oxidation was hypothesized to be similar to the Groves’s oxygen rebound mechanism . It was realized that the asymmetric induction could arise either at the preferential pro - R or pro - S hydrogen abstraction or was determined by the preferential collapse of the C-centered radical at the oxygen rebound step (Scheme ).…”