Bidentate Directing Group-Assisted Regioselective Functionalization Of C-H Bond

Over the last two decades, the use of metal-mediated direct C-H functionalization has grown rapidly as it enables the conversion of ubiquitous C-H bonds of organic molecules into diverse functional groups in a single synthetic operation. Transition-metal catalyzed ligand-directed C-H functionalization reactions have received significant attentions, especially the strong coordination bidentate directing groups because they facilitate catalytic functionalization of inert sp3 C-H bonds, and also reflect unique reactivity in some non-noble metals catalyzed direct functionalization of C-H Bonds.This dissertation mainly focused on the studies of bidentate directing group-assisted transition-metal-catalyzed C-H transformations, which include:1. Efficient Synthesis of Chiral a-Hydroxy Acids via Palladium-Catalyzed C(sp3)-H Alkylation of Lactic Acidα-hydroxy acids (AHAs) containing alkyl groups at β-position are prevalent in numerous pharmaceuticaHly important compounds. Lactic acid, the simplest chiral AHA, is a versatile building block in medicinal and synthetic organic chemistry. We herein report the study of Pd-catalyzed alkylation of lactic acid in the assistance of 8-aminoquinoline auxiliary. A wide range of alkyl iodides with various synthetically useful functional groups are compatible with the reaction conditions, providing a practical and straightforward alternative to access chiral a-hydroxy acids. The new reactions have been applied to the synthesis of isotope-labeled molecules and more complex products with sugar groups.2. A Palladium-Catalyzed C(sp3)-H Arylation of Lactic Acid for the Practical Synthesis of Chiral β-Aryl-a-Hydroxy Acidsα-hydroxy acids (AHAs), especially the AHAs containing aryl groups at β-position, are found to be significant structural motifs in numerous bioactive natural products and pharmaceutical molecules. Herein, we introduce a systematic study of Pd-catalyzed arylation of lactic acid employing 8-aminoquinoline auxiliary as our directing group. The protocol is found to be compatible with a broad range of synthetically useful functional groups, thus providing a practical route to chiral β-aryl-a-hydroxy acids. Further, the new reaction has also been applied to the synthesis of pharmaceutically important a-hydroxy acids, such as LY519818 and Tesaglitazar.3. Copper-Mediated Hydroxylation of Arenes and Heteroarenes Directed by a Removable Bidentate AuxiliaryFunctionalized phenols are an important structural motif in nature and have extensive application in pharmaceuticals, agrochemicals, and material science. Therefore, the direct hydroxylation of arenes to phenols has been the topic of extensive research interests, and tremendous progress has been made on the direct C-H hydroxylation reactions catalyzed by the expensive, second-row transition metals, such as palladium and ruthenium. we have developed an effective less expensive copper-mediated hydroxylation of arenes and heteroarenes directed by a removable bidentate auxiliary. This procedure is scalable and compatible with a wide range of functional groups.