Investigation of Strain-Activated Trapping Reactions of 1,2-Cyclohexadiene: Intramolecular Capture by Pendent Furans and Styrenes

Abstract

1,2-Cyclohexadiene is a small carbocyclic allene that as a reactive intermediate can be utilized in a variety of reaction pathways. The chemical literature around this species is largely limited to various methods of generation and simple trapping reactions. Little research exists on methods to control these intermediates and enable their more prominent use in synthesis. One popular method to control a reaction is to move from an intermolecular to intramolecular framework, where more of the factors affecting a reaction can be controlled. In this thesis the development of new intramolecular trapping reactions of 1,2-cyclohexadiene will be discussed with a focus on [4+2] and [2+2] modes of cycloaddition with furans and styrenes respectively.Chapter 1 will provide a detailed overview of the origins of 1,2-cyclohexadiene including its synthesis, structural investigations, trapping reactions and mechanistic studies; modern synthetic efforts with the intermediate and similar compounds will also be described. This review of the relevant literature will serve as a primer to discuss the new results described in this thesis.Chapter 2 shows the development of a state-of-the-art intramolecular trapping reaction of 1,2-cyclohexadiene using pendent substituted furans. This [4+2]-cycloaddition reaction was enabled via a modular synthetic sequence that allowed the production of a variety of starting materials and allowed the initial scope of this new methodology to be explored. This mild cycloaddition proceeded in high regio- and diastereoselectivity and allowed access to versatile hetero-tetracycles. Efforts to manipulate these complex hetero-carbocycles were examined and a surprising retro [4+2]-cycloaddition was discovered.Chapter 3 continues the development of intramolecular trapping reactions of 1,2-cyclohexadiene with new substrates that contain a styrene moiety and undergo [2+2]-cycloaddition. The chemical nature of the double bond on the styrene was shown to be vital to reaction efficacy and interesting trends were demonstrated through carefully selected substrates. Efforts to synthesize an intermediate in the total synthesis of isocomene are also described.Chapter 4 will tie the [4+2] and [2+2]-cycloaddition reactions together and discuss exciting future directions for this chemistry. The chemical utility of 1,2-cyclohexadiene, as reported in this thesis, will be discussed and a broad overview of what the future may hold for this reactive intermediate will be evaluated.