Abstract

The development of new chemical transformations based on catalytic functionalization of unactivated C–H bonds have the potential to simplify the synthesis of complex molecules dramatically. Transition metal catalysis has emerged as a powerful tool with which to convert these unreactive bonds into carbon–carbon and carbon–heteroatom bonds, but the selective transformation of aliphatic C–H bonds is still a challenge. The most successful approaches involve a ‘directing group’, which positions the metal catalyst near a particular C–H bond, so that the C–H functionalization step occurs via cyclometallation. Most directed aliphatic C–H activation processes proceed through a five-membered-ring cyclometallated intermediate. Considering the number of new reactions that have arisen from such intermediates, it seems likely that identification of distinct cyclometallation pathways would lead to the development of other useful chemical transformations. This lecture describes our work towards the discovery and development of palladium-catalysed C–H bond activation mode that proceeds through a four-membered ring cyclopalladation pathway. The chemistry described here leads to the selective transformation of a methyl group that is adjacent to an unprotected secondary amine into synthetically versatile nitrogen heterocycles. Also described is the evolution of this strategy into a general C–H functionalization platform that could simplify the synthesis of aliphatic primary and secondary amines, a class of small molecules that are particularly important features of many important molecules of function.