Palladium-Catalyzed Carboamination and Carboetherification Reactions for the Synthesis of Heterocycles.

Investigation of the Pd-catalyzed carboamination reaction for the synthesis of substituted piperidines from delta-amino olefins and piperazine heterocycles from amino acid derivatives is described. These reactions are believed to proceed via an unprecedented insertion into a Pd–N bond of the key Pd-amido species. These reactions also proceed with excellent levels of 2,6-diastereocontrol (in many cases, >20:1 dr has been observed). The diastereoselectivity of these reactions is also dependent on the protecting group on the cyclizing nitrogen, where more electron rich aryl protecting groups provide more of the cis-diastereomer, whereas less electron rich protecting groups provide slightly lower diastereoselectivity, still favoring the cis-diastereomer. Our stereochemical model differs from related pyrrolidine cyclizations which also provide the cis-diastereomer. We hypothesized that the nitrogen is pyramidalized in the transition state leading to the piperazine and therefore the alpha-substituent can lie in the pseudoequatorial orientation. In addition to 2,6-disubstituted aryl-protected piperazines coupled with aryl halides, we also extended the methodology to include vinyl-halide coupling partners, Boc-protected piperazines, 2,3-disubstituted piperazines, bicyclic piperazines, and benzopiperazines. The second part of this thesis details intramolecular Pd-catalyzed carboetherification and carboamination reactions for the synthesis of 2-indanyl tetrahydrofurans and 2-indanyl pyrrolidines. These reactions are believed to proceed through an unprecedented macrocyclic insertion into a Pd–O or Pd–N bond to afford products resulting from syn-addition across the olefin. Surprisingly, in the optimization of the carboetherification reactions, we discovered an unprecedented catalyst control on the stereochemical outcome of the reaction. In cases where a monodentate ligand was used in combination with a Pd(0) source, we observed selective formation of the syn-addition diastereomer. When we switched to a catalyst system composed of Pd(0) and a bidentate ligand, we observed formation of the anti-addition diasteromer. We reasoned we were observing a catalyst control of mechanism in the oxypalladation reaction. In the analogous carboamination reactions, we did not observe a complete reversal of diastereoselectivity, but instead erosion of diastereoselectivity. We reasoned this was due to several factors, including the reduced pKa of the aniline versus the alcohol. Further studies to expand the scope of the intramolecular carboetherification and carboamination were also demonstrated.Ph.D.ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/60696/1/jnakhla_1.pd