Palladium-Catalyzed Methylene C(sp~3)-H Functionalizations Directed By The Newly Developed Bidentate Pip Amide Auxiliary

Direct C-H bond functionalizations provide straightforward and atom economic alternatives for preparing a wide variety of synthetically useful structural motifs in organic chemistry. However, compared to the extensively studied C(sp2)-H bond activations, achieving C(sp3)-H bond activations remain challenging, not to mention the more sterically hindered methylene C(sp3)-H bonds. The powerful directing strategy lent us light to work on this problem by designing a new bidentate directing group. In this dissertation, we describe systematic research on the development and reactivity of PIP amide in aspects of palladium(II)-catalyzed methylene C(sp3)-H functionalizations, including the following contents:1. Stereoselective Synthesis of Chiral a-Amino-β-Lactams through Palladium(II)-Catalyzed Sequential Monoarylation/Amidation of C(sp3)-H BondsThe first stereoselective synthesis of a-amino-β-lactams using C(sp3)-H activation method was developed using a newly developed bidentate PIP amide auxiliary. These synthetically and medicinally important products were obtained via palladium(II)-catalyzed sequential C(sp3)-H monoarylation/amidation of an easily accessable alanine derivative. Remarkable functional group tolerance, controlled mono-selectivity in the arylation step, together with excellent chemo- and diastereoselectivity in the amidation step were achieved with this method.2. Pd(Ⅱ)-Catalyzed C(sp3)-H Arylation Toward Synthesis of Unnatural Amino AcidsThe stereoselective synthesis of unnatural β-aryl-α-amino acids was achieved via palladium(Ⅱ)-catalyzed monoarylation of methyl, methylene, and benzylic C(sp3)-H bonds using PIP amide directing group. Monoarylations of the β-methyl C(sp3)-H bonds in alanine derivative provides efficient synthetic access to a variety of phenylalanine derivatives, whereas the subsequent arylations at the newly formed benzylic positions make for β,β-diaryl-a-amino acids diastereoselectively in a programmed manner. Mechanistic experiments suggest that DMPU facilitates methyl C(sp3)-H activation, while CuF2 enhances monoselectivity. Several palladium(II) intermediates have been isolated and characterized. Studies on their reactivity proved that they might be possible reactive intermediates on the catalytic cycle, in both primary and secondary C(sp3)-H arylations.3. Pd(Ⅱ)-Catalyzed Arylation of Unactivated Methylene C(sp3)-H Bonds with Aryl Halides Using a Removable AuxiliaryMethylene C(sp3)-H arylation of aliphatic amides catalyzed by palladium(II) was achieved via two complementary methods, in which aryl bromides and aryl iodides were involved respectively. The protocol possesses good efficiency and excellent functional group tolerance in both aryl halides and aliphatic amides, making it a valuable alternative towards the preparation of β-arylated carboxylic acid derivatives.4. Stereoselective Synthesis of Chiral β-Fluoro α-Amino Acids via Pd(Ⅱ)-Catalyzed Fluorination of Unactivated Methylene C(sp3)-H Bonds:Scope and Mechanistic StudiesFor the first time, a Pd(II)-catalyzed direct β-methylene C(sp3)-H fluorination by an inner-sphere mechanism was demonstrated. This protocol provided an easy, site-and diastereoselective access to an array of β-fluorinated α-amino acids from commercially available a-amino acids. The isolated palladacycle proceeded stoichiometric fluorination at room temperature within 5-10 min, displaying the potential for the synthesis of valuable 18F-lableled amino acids in radiochemistry. Mechanism involving direct C-F reductive elimination from a high-valent palladium intermediate proved to be reasonable according to preliminary mechanistic studies. Further applications in medicine and biology could be anticipated since the research may enable the synthesis of novel peptide-based drugs and probes.