Manganese Dioxide-Methanesulfonic Acid Promoted Direct Dehydrogenative Alkylation Of Sp~3C-H Bonds Adjacent To A Heteroatom

A manganese dioxide (MnO2)-methanesulfonic acid (CH3SO3H) oxidation system has been developed to efficiently promote direct coupling of benzylic ethers and carbamates with simple ketones via oxidative C-H bond activation. The alkylation proceeds smoothly under air atmosphere to afford the corresponding products in good to excellent yields (53-85%). The employment of the combination of MnO2and CH3SO3H is attractive based on economical and environmental issues. The theme of the article is about the research of the system.At first, We selected the coupling of isochroman and acetophenone as a starting point for our initial studies. And we get the optimized conditions:MnO2(300mol%) and CH3SO3H (0.3mL) in Et2O. With the optimized oxidative cross-coupling conditions in hand, the nucleophilic scope of the transformation was studied. A variety of ketones with electronically varied aromatic and heteroaromatic substituents, as well as propiophenone were accommodated by the reaction conditions. The substituent effect of isochroman on the coupling reaction was subsequently investigated. The success of the MnO2/CH3SO3H system on ether alkylation led us to explore the corresponding nitrogenated substrates because tetrahydroisoquinoline (THIQ) derivatives are common subunits in numerous natural products and pharmaceutically active compounds. Herein, the successful alkylation of N-Cbz THIQs under very mild conditions affords efficient access to structurally diverse THIQs through further functionalization. We have proposed two mechanism for MnO2-mediated oxidative cross-coupling and done some research on them. The first pathway proceeds through an initial benzylic hydrogen atom abstraction to form free radical; The other pathway proceeds through an initial electron transfer from isochroman to form the radical cation. Carbocation can then be accessed through hydrogen atom abstraction or proton abstraction followed by a second electron transfer.