Palladium-Catalyzed Alkene Difunctionalization Reactions: Synthesis of Functionalized Carbocycles and Mechanistic Investigations

Abstract

Metal-catalyzed alkene difunctionalization reactions have given chemists powerful tools to quickly increase the chemical complexity of molecules in a single step. This dissertation focuses on the development of new Pd-catalyzed alkene difunctionalization reactions for the construction of functionalized carbocycles. Specifically, treatment of 2-allylphenyl triflate, or related acyclic 1,5-dienyl triflates, with enolate nucleophiles in the presence of a palladium catalyst and a base generates either four- or five-membered carbocyclic products. These reactions form two new bonds and a ring in a single transformation, with generally high levels of diastereoselectivity. The reactions described in this dissertation provide new and important methodology for the synthesis of functionalized carbocycles. Previous work in the Wolfe lab, as described in Chapter 1, laid the foundation for coupling reactions between exogenous nucleophiles and aryl or alkenyl bearing tethered alkenes. These studies focused on the use of nitrogen, oxygen, and indole nucleophiles, which were incorporated into the carbocyclic products. In Chapter 2, my work details a significant expansion of nucleophile scope by incorporating stabilized carbanions, including malonates, esters, and ketone enolates, as exogenous nucleophiles in our Pd-catalyzed alkene difunctionalization reactions. The products of these reactions are formed in good yields and good diastereoselectivity, >20:1 relative to the bridging carbon when utilizing alkenyl triflates as the coupling partner. The mechanism of reaction is proposed to go through a Pd(0)/Pd(II) cycle that involves oxidative addition of the aryl/alkenyl triflate to Pd(0), followed by anti-carbopalladation and subsequent reductive elimination. My work has also included development of a regiodivergent variant of our Pd-catalyzed alkene difunctionalization reactions, as described in Chapter 3. Alkenyl triflates, with geminal “R” groups relative to the vinyl triflate, bearing tethered alkenes were coupled with malonate nucleophiles for the formation of either methylene cyclobutanes or methylene cyclopentanes. Two unique catalyst systems were employed to select for the desired regioselectivity. The mechanism governing the formation of the cyclopentane product appears to be analogous to our previous reported Pd(0)/Pd(II) cycle and described above. Preliminary mechanistic studies involving the synthesis of a deuterated alkene starting material and its stereoselective reaction with diethyl malonate suggest the four-membered ring products are formed by oxidative addition followed by a syn-migratory insertion and subsequent stereo-retaining, reductive elimination from the metal center. To the best of our knowledge, this is the first example of an sp3-sp3 C-C bond forming reductive elimination from Pd(II) with a malonate nucleophile. Additional scope and studies of Pd-catalyzed alkene difunctionalizations are described in Chapter 4. Preliminary results incorporating exogenous nitrile nucleophiles as coupling partners are described. Preliminary results utilizing nitrogen nucleophiles in the regiodivergent Pd-catalyzed cyclization are described. Lastly, preliminary efforts to construct heterocycles with exogenous nucleophiles as coupling partners are described.