Studies on the Development of Palladium-Catalyzed Alkene Difunctionalization Reactions for the Synthesis of Nitrogen-Containing Heterocycles

Abstract

Alkene difunctionalization reactions have proved chemists with a valuable and versatile tool to efficiently increase the molecular complexity of carbocycles and heterocycles in a single synthetic step. This dissertation focuses on the study and development of Pd–catalyzed alkene diamination of N-heterocycles with an emphasis on alkene diamination to generate 1,2-diamines, ligand considerations for alkene diamination, and methods to generate polycyclic N-heterocycles. These reactions efficiently form 2 new bonds (C–N/C–N and C–N/C–C) and 1 – 2 new rings in a single step, up to 2 new stereoisomeric sites from simple starting materials and provides new and important methodology for the synthesis of functionalized heterocycles. My work has involved the development of Pd–catalyzed alkene diamination reactions; the progress of this field by other labs is described in Chapter 1 and divided by the choice of the transition-metal catalyst. Typically, this chemical reactivity has shown to have some significant limitations such as stoichiometric transition metal sources, needed for added oxidants, limited nucleophile and electrophile scope, or lack of stereospecificity. My studies on alkene diamination (described in Chapter 2) have involved the coupling of aminobenzoate electrophiles with urea and guanidine nucleophiles that contain an unactivated alkene. These reactions produce cyclic ureas and guanidine heterocycles bearing a pendant (di)alkylamino group. During this study, through NMR studies and side product isolation, it was observed that 1,3-dicarbonyl ligands (β-diketones) were the active ligands in this transformation and the mechanistic data is most consistent with a Pd(II)/(IV) catalytic sequence. Using acac derived ligands, we were able to expand the previously limited electrophile scope of the transformation and more efficiently promote the formation of cyclic ureas, guanidines, and lactams. Structural and electronic considerations of 1,3–dicarbonyl derivatives were also investigated (described in Chapter 3). From these studies, it was found that keeping the alkyl backbone of acac-like derivatives unsubstituted was critical for a competent catalyst system. Additionally, o–hydroxyacetophenone (and their imine) derivatives mimicked the reactivity of acac-like derivatives. There was a general trend that increasing electron-donating capabilities of the ligand led to more competent reactivity. Exploring the reactivity of this ligand class, including our most optimized ligand, for the formation of other heterocyclic products did not lead to any competent reactivity. The progress of transition-metal catalyzed C–N bond forming reactions, including early work in the Wolfe lab is described in Chapter 4. This work has shown that the synthesis of heterocycles can be accomplished through Pd–catalyzed N–arylation of primary amines as well as alkene carboamination reactions where a nucleophile with a tethered alkene is coupled with an exogenous electrophile. Later work has shown that the same reactivity is possible where the nucleophile, alkene, and electrophile is tethered into one substrate. My work in this field is described in Chapter 5 in which a sequential N–arylation/alkene carboamination strategy is described to generate polycyclic N–heterocycles commonly observed in therapeutic, natural product, and materials compounds. These reactions allow for the efficient synthesis of 6/6 and 5/6 polycyclic heterocycles from simple starting materials. Stereochemical explanation for the 6/6 and 5/6 ring systems is also described.