Catalytic methods for constructing C-F and C-N bonds via manganese-catalyzed C-H activation

P450 enzymes can catalyze highly selective oxidations of unactivated C(sp3)-H bonds. The mechanism of this reaction comprises an initial hydrogen abstraction from the substrate by an oxoiron(IV) porphyrin cation radical species (compound I), and a subsequent OH recombination of the substrate radical to a hydroxoiron(IV) intermediate (compound II). We recently discovered that, in a manganese-based P450 model system, the common oxygen rebound scenario of substrate radicals could be diverted to the formation of C-X bonds in the presence of certain anionic axial ligands X. In light of this finding, a variety of novel C-H transformations have been developed in the present thesis. In chapter 2, I have synthesized and characterized two trans-difluoromanganese(IV) complexes, MnIV(L)F2 (L = porphyrin or salen) and demonstrated their fluorine transfer reactivity to alkyl radicals to afford fluorination products. This result constituted the mechanistic foundation for the later discoveries of series of radical fluorination reactions in our laboratory. The third chapter concentrates on adapting the Mn-catalyzed fluorination reactions developed in our laboratory for 18F radiolabeling. We have successfully developed the first direct 18F labeling method of aliphatic C-H bonds. The method enabled a fast 18F labeling of targeted molecules, and ten bioactive molecules were 18F-labeled in a single step without the need of synthesizing activated labeling precursors. The fluorine transfer reactivity of fluoromanganese(IV) species makes it possible to convert other radical reactions into fluorinations. Following this strategy, in chapter 4, I've developed the first decarboxylative fluorination reaction based on nucleophilic fluoride reagent. This reaction represents a targeted fluorination methodology, which complemented our C-H fluorination reactions. An 18F version of this decarboxylative reaction was also established. In the final chapter, I've extended the heteroatom rebound catalysis to include C-H azidation. With this method, a variety of bioactive molecules including antimalarial artemisinin were readily azidated. The reaction could also be performed enantioselectively with chiral manganese salen catalysts. Our success in Mn-catalyzed fluorinations and azidation has demonstrated the heteroatom rebound catalysis as a general strategy to develop novel C-H transformations.