Palladium(Ⅱ) Or Copper-Catalyzed 2-(Pyridin-2-yl)Isopropyl Amine-Directed Functionalizations Of C-H Bonds

Transition-metal-catalyzed direct functionalization of C-H bonds has attracted tremendous interest as a valuable tool for the synthesis of natural and unnatural compounds. However, due to the inertness of C-H bonds and the difficulty of achieving high levels of selectivity in distinguishing one bond among the many chemically similar entities in a given molecule, the catalytic functionalization of C-H bonds, especially methylene C(sp3)-H bonds, remains a challenge task. In this dissertation, we developed a new bidentate directing group, 2-(pyridin-2-yl) propan-2-amine (PIP-amine), which was designed according to the gem-dimethyl effect. With the auxiliary of PIP-amine, we then investigated palladium-catalyzed and copper-mediated direct functionalization of C-H bonds, which includes:1. Pd(II)-Catalyzed Alkoxylation of Unactivated C(sp3)-H and C(sp2)-H Bonds Using PIP-amine as Directing GroupWe have developed a palladium-catalyzed methoxylation of unactivated methylene C(sp3)-H bonds and alkoxylation of methyl C(sp3)-H bonds using a new bidentate PIP-amine directing group. The reaction has broad substrate scope and can tolerate a variety of functional groups. Both primary and secondary alcohol could be efficient alkoxyated reagents under mild conditions, providing an efficient protocol for the synthesis of asymmetrical ether. Preliminary DFT calculations reveal that a concerted palladation-deprotonation pathway enabled gem-dimethyl effect is involved.2. Cu(II)-Mediated C-S/N-S Bond Formation via C-H Activation Using PIP-amine as Directing GroupWe have developed a copper-mediated C-S/N-S bond-forming reaction via C-H activation that uses elemental sulfur as the sulfur source using PIP-amine as directing group. The presence of a stoichiometric amount of TBAI is crucial for the success of this transformation. This reaction is scalable and tolerates a wide range of functional groups, providing an efficient means of accessing biologically important benzoisothiazolones. In addition, heterocyclic substrates are compatible with this protocol, which allows synthesis of a variety of unique heteroaryl-fused isothiazolones. The versatility of the benzoisothiazolone moiety renders this protocol highly attractive for both synthetic and medicinal chemistry.3. Copper(I)-Mediated Cross-Dehydrogenative Coupling of Aromatic C(sp2)-H Bonds with TetrahydrofuranWe have developed a copper-mediated cross-dehydrogenative coupling of inert aromatic C(sp2)-H bonds with C(sp3)-H bonds adjacent to oxygen atom with the assistance of PIP-amine directing group. This reaction shows excellent site-selectivity and tolerates a wide range of functional groups, providing a new stratage for direct functionalization of tetrahydrofuran and tetrahydropyran. Preliminary mechanistic studies suggest that this reaction is likely to proceed through an oxonium cation species as the key intermediate.