The development of catalytic methods to chemoselectively oxidize C–H bonds in the presence of amines and azoles is a major research interest in the Center for Site-Selective C–H Functionalization (CCHF). Motivation for these studies stems from the ubiquity of N-functional groups and heterocycles in active pharmaceutical ingredients (APIs) and natural products. A recent collaborative effort between the Du Bois and Sigman laboratories has led to the development of a new catalytic protocol for sp3 C–H hydroxylation. Reactions are performed in aqueous acid using cis-[Ru(dtbpy)2Cl2] (dtbpy=4,4’-di-tert-butyl(2,2’-bipyridine)) as a catalyst to enable oxidation of substrates possessing basic amine functional groups. Tertiary and benzylic C–H hydroxylation is strongly favored over N- oxidation for numerous amines and heterocycles. With terpene-derived substrates, similar trends in reactivity towards tertiary and benzylic C–H bonds are observed. Hydroxylation of chiral tertiary centers is enantiospecific in spite of the ionizing strength of the reaction medium. Preliminary kinetics experiments show a marked difference in reactivity between isomeric cis- and trans-Ru precatalysts suggesting that the catalyst is configurationally stable under the reaction conditions and supporting a high-valent cis-Ru(oxo) species as the active oxidant. Current studies are aimed at delineating active oxidizing catalyst states and mechanisms of catalyst degradation (using techniques such as pressurized sample infusion high-resolution mass spectrometry (PSI-HRMS), 19F NMR, and electrochemistry) in order to facilitate the engineering of a second- generation catalyst. By developing a catalyst with improved turnover number (TON), we anticipate an extension of the current substrate scope to more complex amine that are not effectively oxidized using the optimized first- generation protocol.

Ruthenium-catalyzed C–H hydroxylation of amines: Reaction development and mechanistic considerations

255th National Meeting (2018)

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