Oxidative Difunctionalizations of Alkenes

Thesis (Ph.D.)--University of Washington, 2012A plethora of natural products and valuable pharmaceuticals contain nitrogen heterocycles. Many of those scaffolds can be achieved by difunctionalizations of tethered aminoalkenes. The main focus of this dissertation is the development of more efficient methods of alkene difunctionalizations that lead to substituted piperidines and pyrrolidines. Palladium-catalyzed method featured incorporation of alcohols to yield exo-cyclized products. Diamination and aminofluorination methods were developed under metal-free conditions with hypervalent iodine as oxidant and showed high preference for endo cyclization. A scope of carbamate-protected aminoalkenes were cyclized in presence of palladium catalyst and alcohol solvents acted as external nucleophiles. Primary and secondary alcohols and acetic acid were suitable nucleophiles and afforded cyclic aminoethers and aminoesters in good yields. This method was highly regioselective for formation of 5-exo products. Interestingly, use of a palladium catalyst with halide ligands in polar solvents favored endo cyclization. Oxidative difunctionalizations under metal-free conditions were also developed. Hypervalent iodine reagents served as oxidants and were activated by strong Bronsted acids. Diamination products were achieved by employing various sulfonimides as external sources of nitrogen while tetrafluoroboric acid effectively gave aminofluorination products. The counterions of these Bronsted acids were incorporated into the product to yield substituted amino- and fluoropiperidines with high preference for endo cyclization. We sought to develop an enantioselective version of aminofluorination method by employing chiral iodine reagents. In order to make the use of chiral reagents practical conditions with catalytic amount of iodine were developed. Alternative oxidants such as xenon difluoride and meta-chloroperoxybenzoic acid were used to reoxidize the aryl iodide and products were afforded in yields comparable with conditions employing stoichiometric amounts of hypervalent iodine. Chiral iodine reagents were also tested in catalytic amounts and afforded products in very good yields but did not induce enantioselectivity