First-Row (3d) Metal Catalysis in Aromatic Systems: Toward Late-Stage C-H Functionalization of Complex Molecules

Abstract

Late-stage functionalization (LSF) has emerged as a powerful strategy for the direct modification of structurally complex molecules, enabling rapid access to valuable analogues and offering a stepand resource-economical platform for molecular diversification. Transition-metal catalysis has played a central role in advancing these transformations. However, to date, late-stage metal-catalyzed C-H functionalization has relied predominantly on noble transition metals. First-row (3d) transition metals are more abundant, less expensive, and generally less toxic, making them attractive alternative for sustainable LSF applications. In addition, they offer complementary reactivity to their noble metal congeners. This review focuses in the intersection of 3d-metal catalysis, C-H activation, and late-stage functionalization, with particular emphasis on the modifications of aromatic systems in complex molecules. A critical analysis of the key challenges associated with the use of 3d metals in these transformations, including issues related to catalyst reactivity and stability, as well as the chemoand regio-selectivity is provided. By examining the advancements and limitations over the past decade, this review aims to offer insights into emerging strategies to overcome these challenges and to guide the development of more efficient and sustainable methodologies in transition-metal catalyzed C-H functionalization.

Keywords:
3d metals; C-H activation; late-stage functionalization; sustainable chemistry; transition metals