Novel benzyne insertion reactions & medium-ring synthesis by oxidative C-H coupling
Pintori, Didier Gil
This thesis is divided into two main chapters, which are focused on two separated and uncorrelated research areas. The first part of this thesis is dedicated to the research I carried out in benzyne chemistry and the second part is focused on catalytic C-H bond activation. In the first place, a novel insertion reaction of arynes into the nitrogen-carbonyl σ-bond of amides has been investigated as a rapid and powerful approach for the preparation of valuable ortho-disubstituted arenes. Readily available aromatic amides undergo smooth insertion when treated with O-triflatophenyl silane aryne precursors, producing versatile anthranilic derivatives in good to excellent yields. The process is entirely metal-free and has been expanded to the synthesis of biologically active heterocycles such as acridones and acridines. Secondly, the synthesis of medium-sized ring systems by intramolecular oxidative CH bond coupling has been explored. Despite the abundance of biologically active natural products featuring mediumsized rings, the synthesis of such ring systems using classical synthetic routes faces many challenges and has led to a dearth of medium ring compounds in medicinal chemistry. In contrast to the more facile 5-membered ring synthesis by oxidative C-H coupling, medium ring synthesis has not been previously reported using this approach. The chemistry, which requires zero pre-functionalisation of the substrates, is catalysed by palladium and has been exemplified using heteroaromatic substrates at the core of numerous biologically active molecules. The mechanism of the reaction has also been studied and a catalytic cycle has been proposed.