Development of intermolecular C-H functionalization methods for acceptor-acceptor diazo compounds

Abstract

Given the recent progress made with donor-acceptor (D-A) carbene C-H functionalization, as well as the functional diversity of acceptor-acceptor (A-A) carbenes, surprisingly little investigation has been conducted by the chemical community toward uncovering the latent potential of these species to functionalize C-H bonds under intermolecular manifolds. This thesis showcases the development of a catalytic intermolecular C(sp2)-H functionalization through the pursuit of beta,gamma-unsaturated-gamma-heteroatom carbonyl frameworks. Density functional theory (DFT) calculations provide insight that expands the scope of this method and enables the tuning of selectivity. DFT plays a more prominent role in a second project where it is used to build a chemical space map describing how the intermolecular C(sp3)-H insertion reactivity of A-A carbenes varies with the steric and electronic nature of the acceptor groups. This insight is then leveraged to discover a new synthetically useful class of A-A carbenes that utilizes intramolecular H-bonding to stabilize the intermolecular C-H insertion transition state. In a third pursuit, a dual C-H functionalization protocol is developed to access highly substituted indole building blocks from alpha-diazo-beta-keto nitrile and enol ether starting materials. Together, the advancements in this thesis provide the seed and structure for further growth in this promising field.