Copper-Catalyzed Regioselective Intramolecular Oxidative α-Functionalization of Tertiary Amines: An Efficient Synthesis of Dihydro-1,3-Oxazines

摘要

Oxidative coupling reactions, especially through cross-dehy-drogenative coupling (CDC) of C—H bonds, which avoids the prefunctionalization of substrates, have recently been in focus for being more atom economical, directive, and environmentally benign than other cross-coupling reactions. Among the CDC reactions, the functionalization of sp~3 C—H bonds adjacent to a nitrogen atom has generally been achieved utilizing transition metal catalysts with co-oxidants, such as tert-butylhydroperoxide (TBHP), H2O2, molecular oxygen, and others, to generate iminium ion species, which in turn react with various nucleophiles. For this purpose, metals such as Ru, Fe, Rh, V, and others are often used. However, copper salts retain many advantages, such as ready availability, low cost, high efficiency and low toxicity, and have turned out to be the most efficient catalysts for the α-functionalization of tertiary amines. More recently, homogeneous copper catalysis have also been used to achieve the selective aerobic oxidative functionalization of C-H bonds. However, such copper-catalyzed functionalization, whether under aerobic or anaerobic conditions, is mainly confined to the benzylic position of N-phenyltetrahydroiso- quinoline. Examples relating to the activation of non-benzylic methyl/methylene C—H, are scarce. Hence, despite significant development in recent years, still more research in this area is required to enhance the selectivity and substrate scope. Looking for synthetic advances in regiocontrolled C—H functionalization, we became interested in the design of a synthetic strategy for a copper-catalyzed aerobic oxidative/ dehydrogenative a-functionalization of tertiary amines with subsequent intramolecular sp3 C-O bond formation.