Tuning Selectivity in Aliphatic C-H Bond Oxidation of N-Alkylamides and Phthalimides Catalyzed by Manganese Complexes

Site selective C-H oxidation of N-alkylamides and phthalimides with aqueous hydrogen peroxide catalyzed by manganese complexes is described. These catalysts are shown to exhibit substantially improved performance in product yields and substrate scope in comparison with their iron counterparts. The nature of the amide and imide group and of the N-alkyl moiety are shown to be effective tools in order to finely tune site selectivity between proximal (adjacent to the nitrogen) and remote C-H bonds on the basis of steric, electronic, and stereoelectronic effects. Moreover, formation of the alpha-hydroxyalkyl product in good yield and with excellent product chemoselectivity was observed in the reactions of the pivalamide and acetamide derivatives bearing an alpha-CH2 group, pointing again toward an important role played by stereoelectronic effects and supporting the hypothesis that these oxidations proceed via hydrogen atom transfer (HAT) to a high-valent manganese-oxo species. Good product yields and mass balances are obtained in short reaction times and under mild experimental conditions when relatively low loadings of an electron-rich manganese catalyst are used. The potential utility of these reactions for preparative purposes is highlighted in the site-selective oxidation of the pivalamide and phthalimide derivatives of substrates of pharmaceutical interest.