Dissertation Defense: Ting-An Chen
Candidate: Ting-An Chen
Major: Chemistry
Advisor: Timothy H. Warren, Ph.D.
Copper Catalyzed sp3 C-H Functionalization
Creating C-C bonds is crucial in organic synthesis, drawing significant research attention for efficient C-C coupling protocols. While late transition metals have been effective in transforming sp2 C-H bonds into various functional groups like alkyl, alkenyl, aryl, and alkynyl groups, sp3 C-H functionalization is still developing. Our goal is to provide new approaches to sp3 C-H functionalization using environmentally friendly earth-abundant metals.
The Warren group has utilized β-diketiminate copper(I) catalyst with di-tert-butyl peroxide as oxidant to achieve sp3 C-H functionalization. Using acetophenone as the reactant, we unveiled a novel pathway for direct sp3 C-H acetylation. The critical intermediate, a copper(II) enolate, can either undergo self-dimerization or engage in C-C cross-coupling with an alkyl radical.
In the past, sp3 C-H alkenylation had inherent challenges, either with substrates featuring highly acidic C-H bonds for alkenylation or being restricted to styrenylation. We have developed a catalytic sp3 C-H alkenylation method using alkenylboronic esters via the radical relay mechanism. Additionally, we observed the key reaction intermediate [CuII]-CH=CMe2 exhibits a strong radical character at the sp2 α-carbon. This radical nature makes it prone to dimerization, radical capture, and hydrogen atom transfer (HAT), as characterized through both computational and experimental studies. Particularly noteworthy is the potential of the [CuII]-alkenyl intermediate for HAT, which can serve as a novel reagent for generating radicals in other types of radical coupling reactions.
Furthermore, we discovered a system of capable of performing sp3 C-H borylation using diboron species ((RO)2B-B(OR)2) on cyclohexane without the need for a metal catalyst. We also conducted an in-depth investigation into the mechanism of metal-free C-H borylation. However, this metal-free borylation method is only effective with cyclohexane substrate. To broaden the substrate scope, we employed the radical relay method and utilized a copper(I) β-diketiminate catalyst for benzylic C-H borylation. Additionally, we observed that the transmetalation rate for forming copper(II) boryl intermediates is influenced by the steric hindrance of the diboron species.