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

Abstract

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.