Challenging Isomerization Reactions Enabled by Excited-State Redox Events

Abstract

This dissertation describes applications of excited-state electron transfer in realizing a series of challenging isomerization reactions. In chapter one, the development of modular ring expansion of cyclic aliphatic alcohols harnessing excited-state proton-coupled electron transfer (PCET)-based methods is discussed. In these reactions, the activation of the strong O−H bond in an alkenol substrate, which is concurrently catalyzed by an excited-state oxidant and a weak Brønsted base, forms a key alkoxy radical intermediate. This alkoxy radical intermediate then mediates a C−C bond cleavage event to furnish an enone and a tethered alkyl radical. Recombination of this alkyl radical with the revealed olefin acceptor produces a ring-expanded ketone product. The regioselectivity of this C–C bond-forming event can be reliably controlled via substituents on the olefin substrate, providing a means to convert a simple N-membered ring substrate to either n+1 or n+2 ring adducts in a selective fashion. In the chapter two, I will describe the development of a series of skeletal isomerization reactions of alkenols enabled by PCET, including 1,3-alkyl transposition of acyclic allylic alcohols that forms β-functionalized ketones, n−2 and n−1 aliphatic ring contraction of alkenols bearing endocyclic olefins, and ring isomerization of methylidenecycloalkanols via intramolecular 1,3-alkyl transposition. These reactions were developed on the basis of findings described in the chapter one. In addition, the mechanism of 1,3-alkyl transposition of acyclic allylic alcohols was revealed. Insights from mechanistic studies led to a modified reaction protocol that improves reaction performance for challenging substrates. The chapter three of this dissertation describes a method utilizing excited-state redox events and chromium catalysis to positionally isomerize olefin against a thermochemical bias, providing a non-Boltzmann distribution of olefin regioisomers - a reaction outcome that is not possible to obtain through conventional ground state methods. These reactions leveraged the large differences in oxidation potentials between positional olefin isomers. The higher oxidation potential of the less substituted olefin isomer renders it inert to further oxidation by the excited-state oxidant, enabling it to accumulate in solution over the course of the reaction. A broad range of isopropylidene substrates are accommodated, including enol ethers, enamides, styrenes, 1,3-dienes, and tetrasubstituted olefins.