Palladium-Catalyzed Cyclopropanation Reactions and Site Selectivity in Palladium-Catalyzed Oxidative Cross-Coupling Reactions.

This thesis describes our efforts at the discovery, optimization, and mechanistic study of two new and fundamentally different Pd–mediated reactions for the construction of bicyclic cyclopropanes as well as biaryl products. Palladium–catalyzed intramolecular carbocyclizations of alkenes and alkynes allow the assembly of complex carbo- and heterocycles from readily available starting materials. We have demonstrated the development of a tandem Pd-catalyzed bis-cyclization/oxidative cleavage sequence with enyne substrates resulting in the formation of cyclopropyl-containing fused heterocycles. Using a PdII catalyst such as Pd(OAc)2, a stoichiometric oxidant such as iodobenzene diacetate, as well as a bidentate ligand such as bipyridine, the assembly of complex bicycles can be achieved with inversion of the starting alkene geometry. Stereochemical and electronic studies indicate the reaction proceeds via a PdII/IV catalytic cycle and has important implications for PdIV reductive elimination processes. This reaction has shown to be tolerant of substituted aryl groups, esters, and tosyl protected amines. Both the synthetic scope and recent mechanistic investigations of this reaction will be discussed in detail. The second major topic discussed in this thesis is a detailed investigation of the factors controlling site selectivity in the Pd-mediated oxidative coupling of 1,3-disubstituted and 1,2,3-trisubstituted arenes (Aryl–H) with cyclometalating substrates (L~C–H). The influence of both the concentration and the steric/electronic properties of the quinone promoter are studied in detail. In addition, the effect of steric/electronic modulation of the carboxylate ligand is discussed. Finally, we demonstrate that substitution of the carboxylate for a carbonate X-type ligand leads to a complete reversal in site selectivity for many arene substrates. The origins of these trends in site selectivity are discussed in the context of the mechanism of Pd-catalyzed oxidative cross-coupling. The final topic of this thesis addresses our efforts at developing a catalytic system for oxidative cross-coupling with new control of site selectivity. A variety of oxidation protocols are described which thus far have failed to produce catalytic turnover.