From Reactivity and Regioselectivity to Stereoselectivity: An Odyssey of Designing PIP Amine and Related Directing Groups for C-H Activation

Improving the reactivity and selectivity is a long pursuing goal in C-H functionalization reactions. In line with this goal, a well-designed bidentate 2-(pyridine-yl)isopropyl amine (PIP amine) directing group was developed by our group to achieve the activation of unbiased methylene C(sp(3))-H activation, which also found its broad applications in C-H activation reactions catalyzed by base metals, such as Cu, Ni, Co and Fe, to form various C-C and C-X bonds. Moreover, PIP amine has also been applied in the strategic step toward the total synthesis of aeruginosin marine natural products. Its highly tunable structure has triggered the design of a series of chiral auxiliaries for diastereoselective C-H activation. More recently, Pd(II)-catalyzed enantioselective functionalization of unbiased methylene C(sp(3))-H bonds enabled by the cooperative effects between PIP amine and chiral ligands with axially chiral binaphthyl scaffold has also been realized. In this account, we briefly summaries the journey of developing PIP amine for C-H activation, from controlling the reactivity and regioselectivity to stereoselectivity.