2-(Pyridin-2-yl)isopropyl (PIP) Amine: An Enabling Directing Group for Divergent and Asymmetric Functionalization of Unactivated Methylene C(sp3)-H Bonds.

Directing group (DG) assistance provides a good solution to the problems of reactivity and selectivity, two of the fundamental challenges in C(sp3)-H activation. However, the activation of unbiased methylene C(sp3)-H bonds remains challenging due to the high heterolytic bond dissociation energy and substantial steric hindrance. Two main strategies have been developed thus far, that is, use of a strongly coordinating bidentate DG pioneered by Daugulis and use of a weakly coordinating monodentate DG accelerated by pyridine-type ligands, as disclosed by Yu. The seminal work by Daugulis sparked significant interest in the application of the monoanionic bidentate auxiliary in aliphatic C-H activation reactions. Our research has focused on enabling the divergent functionalization and enantiotopic differentiation of unactivated methylene C-H bonds. Inspired by the structure of bidentate 8-aminoquinoline and the accelerating effect of the gem-dimethyl moiety in cyclometalations, we developed a strongly coordinating bidentate 2-(pyridine-yl)isopropyl (PIP) amine DG consisting of a pyridyl group, a gem-dimethyl moiety, and an amino group, which enabled the divergent functionalization of unactivated β-methylene C(sp3)-H bonds to forge C-O, C-N, C-C, and C-F bonds with palladium catalysts. The exclusive β-selectivity was ascribed to the preferential formation of kinetically favored [5,5]-bicyclic palladacycle intermediates. DFT calculations revealed that the well-designed gem-dimethyl group was responsible for the lowered energy and compressed bite angle of the key transition state related to C-H cleavage.More recently, the combination of PIP amine with axially chiral ligands was found to promote asymmetric functionalization of unbiased methylene C(sp3)-H bonds, a challenging research topic in the area of C-H activation that remains to be addressed. Two different types of axially chiral ligands, namely, non-C2-symmetric chiral phosphoric acids (CPAs) and 3,3'-disubstituted BINOLs, have been developed. The former enabled Pd(II)-catalyzed inter- and intramolecular arylation of unbiased methylene C(sp3)-H bonds with high enantioselectivity, whereas the latter promoted a series of asymmetric functionalization reactions, such as alkynylation, arylation, alkenylation/aza-Wacker cyclization, and intramolecular amidation. The unexpectedly high stereocontrol compared with other bidentate DGs might be attributable to steric communication between the ligand and gem-dimethyl moiety of PIP amine. Thus far, the combination of PIP amine DG with 3,3'-disubstituted BINOL ligands is arguably the most general strategy for asymmetric functionalization of unbiased methylene C(sp3)-H bonds. Finally, the ease of installation and removal of PIP under mild conditions and synthetic applications are described.