Tertiary alkylamines as effective directing groups for palladium-catalysed C(sp3)-H activation strategies

C-H activation has emerged as a powerful strategy to streamline organic synthesis by exploiting the ubiquitous nature of C-H bonds in any synthetic precursor. Within the last decade, primary and secondary alkylamines have been reported to direct C-H cleavage on a series of palladium-catalysed reactions. The work reported in this dissertation describes the development of a new palladium-catalysed strategy towards the functionalisation of aliphatic tertiary amines. Methyl, methylene, and methine C-H cleavage have been disclosed by exploiting direct coordination of the amine substrate to the palladium metal centre. Subsequent cross-coupling with aryl boron reagents delivered a series of C(sp3)-C(sp2) bond forming transformations. In an attempt to shape a greener, cheaper, and more atom economical reaction, studies towards the replacement of silver additives as terminal oxidants by a combination of oxygen and alkene derivates, and the reduction of palladium catalyst loadings were explored. Pivotal to the success of these discoveries was the use of mono-protected amino acid ligands. Combined experimental and computational analysis revealed that these readily available ligands can prevent amine decomposition by avoiding the geometrical coplanarity needed for β-H elimination processes. The inherent chirality of amino acids enabled the development of asymmetric C-H activation reactions, targeting both methyl and methylene C-H bonds to construct diastereo- and enantioselective aryl-amine motifs.