Palladium-Catalyzed Alkene Difunctionalization Reactions: Synthesis of Functionalized Heterocycles and Mechanistic Investigation

Alkene difunctionalization reactions have allowed chemists to rapidly increase the complexity of molecules in a single transformation. This dissertation focuses on the development of Pd-catalyzed alkene difunctionalization for the synthesis of carbocycles, cyclic ureas and guanidines, and lactams. These reactions form two new bonds and a ring in a single step, providing new and important methodology for the synthesis of functionalized heterocycles. Early work in the Wolfe lab, described in Chapter 1 of this dissertation, laid the groundwork for the synthesis of heterocycles via Pd-catalyzed alkene difunctionalization reactions where a nucleophile with a tethered alkene is coupled with an exogenous electrophile. In later work, this three-component reaction was altered to instead have the nucleophile be the external piece. In Chapter 2, my work in this field is described, in which indole and pyrrole derivatives are coupled with aryl or alkenyl triflates bearing tethered alkenes to afford 3-cyclopentylindole derivatives. The products of this reaction are formed in moderate to good yields with excellent >20:1 diastereoselectivity when employing alkenyl triflates as the coupling partner. The mechanism of this transformation is proposed to proceed via a Pd(0)/Pd(II) catalytic cycle. My work has also involved the development of Pd-catalyzed alkene diamination reactions; the progress by others in this field is described in Chapter 3. My studies on alkene diamination involved the coupling of O-acylated hydroxylamine derivatives with guanidines or ureas bearing pendant alkenes. These reactions produced cyclic guanidine and urea products bearing attached dialkylaminomethyl groups. The initial work on this transformation is detailed in Chapter 4. The products were formed in good to excellent yields with three different amine electrophiles. Additionally, we found the reaction proceeded with up to 7:1 dr favoring anti-addition to the double bond. The imperfect stereocontrol results from competing syn-aminopalladation vs anti-aminopalladation. Further studies on the scope and mechanism of these new Pd-catalyzed alkene diamination reactions are described in Chapter 5. Through NMR studies and isolation and characterization of side products, we discovered that our initially proposed Pd(0)/Pd(II) catalytic cycle is not operating. We have evidence to suggest the diamination reaction is proceeding through a Pd(II)/Pd(IV) catalytic cycle. Additionally, control experiments revealed that acac, not the phosphine ligand JackiePhos, is the critical ligand for Pd in this transformation. From these discoveries, we have been able to utilize acac-derived ligands to promote previously difficult or unsuccessful reactions for the formation of cyclic ureas, guanidines, and lactams. In addition, unexpected reactions, as well as efforts to develop an in situ preparation of the electrophiles, are also described.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/162839/1/jakirsch_1.pd