Transition-Metal-Catalyzed C(sp3)–H Bond Activation through Coordination-Assisted and Radical Mechanisms: Recent Advances and Mechanistic Insight

The direct functionalization of unactivated C(sp³)–H bonds is crucial for the synthesis of organic compounds, enabling the efficient generation of C(sp³)–X bonds (X = carbon, heteroatom) in natural products and pharmaceuticals. Despite the natural inertness of these bonds and the challenges associated with regioselectivity in alkanes, various approaches, primarily coordination-assisted and radical methods, have been developed to address these issues and enable effective catalytic activation. This review provides a comprehensive overview of transition-metal-catalyzed direct functionalization of nonactivated C(sp³)–H bonds. It analyzes the literature published since 2021 to showcase the most advanced methods available today and their respective limitations. This review reveals that, during this time, most efforts have concentrated on coordination-assisted methods, whereas fewer radical mechanisms have been investigated for C(sp³)–H bond activation. However, radical mechanisms are important because they often occur under milder conditions and typically use simpler starting materials, which are crucial for our needs. In this review, we divide reactions according to the type of metal employed (Pd, Co, Ni, Fe, Ru, Rh, Ir, or Cu) and then further on the basis of their mechanisms: coordination-assisted transition-metal mechanisms and radical mechanisms. Additionally, we occasionally categorize the reactions of metals on the basis of different directing groups: (i) native directing groups, (ii) exo directing groups, and (iii) traceless directing groups. This review underscores that effectively addressing the challenges associated with C(sp³)–H bond activation, including regioselectivity and the activation of flexible and stable C(sp³)–H bonds, relies on the employment of appropriate ligands in the reactions. The use of these ligands is examined in detail throughout the review.

Graphical Abstract

The direct functionalization of unactivated C(sp³)−H bonds is crucial for chemical synthesis, enabling the efficient creation of C(sp³)–X bonds (X = carbon, hetroatom) in natural products and pharmaceuticals. However, the inherent inertness of these bonds and regioselectivity issues in alkanes pose significant challenges for effective catalytic systems. In this review, we organize reactions according to the type of metal employed (Pd, Co, Ni, Fe, Ru, Rh, Ir, or Cu) and then further on the basis of their mechanisms: radical mechanisms and coordination-assisted transition-metal mechanisms.