Ligand Directed Pd-Catalyzed C-H Activation: Mechanistic Insights and Synthetic Applications.

Carbon–hydrogen functionalization provides an attractive strategy for late-stage derivatization of complex molecules. In particular ligand-directed C–H activation allows for the selective functionalization of the C–H bond proximal to the ligand. However, complex mixtures of products could potentially result from multiple C–H transformations especially in pharmaceutically relevant molecules containing multiple ligands. In order to address this challenge, and allow for predictable selectivities, a systematic investigation of the factors that determine the relative directing group abilities in Pd-catalyzed C–H bond acetoxylations of 2-benzylpyridine derivatives was undertaken. Analysis of the data indicated a direct and quantitative correlation between the basicity of a ligand and its relative reactivity. Furthermore, understanding the mechanism of these transformations is necessary for optimization and development of novel reactions. In this regard, a detailed investigation of the mechanism of the Pd-catalyzed C–H acetoxylation and chlorination of 2-ortho-tolylpyridine derivatives was conducted. C–H activation was found to be rate-determining for both transformations; however, the electronic requirements for C–H activation in PdCl2-catalyzed chlorination differ significantly from those for Pd(OAc)2-catalyzed acetoxylation. A comparison of the implicated transition states is used to rationalize how the difference in ligand environment affects the electronic requirements of the rate-determining step. In addition to mechanism, a new Pd/polyoxometalate-catalyzed method for coupling of alkanes and alkenes was developed. Interception of the palladacycle formed upon C–H activation of 2-alkylpyridine derivatives with electron deficient olefins provides a new synthetic tool for quickly installing functionality and building new motifs from two less readily available starting materials. This approach provides access to bicyclic structures that are found in biologically relevant molecules. The alkene can also be revealed to render it available for subsequent transformations. Most current methods for C–H acetoxylation are limited to oxidants that are expensive and generate toxic waste. This work also describes the development of a new Pd-catalyzed reaction for directed C–H acetoxylation that uses nitrate as a redox co-catalyst in conjunction with O2 as the terminal oxidant and acetic acid as the acetate source. This provides an extremely inexpensive and non-waste-generative alternative to commonly used oxidants.Ph.D.ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91600/1/kstowers_1.pd