Silver‐Free C−H Activation: Strategic Approaches towards Realizing the Full Potential of C−H Activation in Sustainable Organic Synthesis

Abstract

The activation of carbon−hydrogen bonds is considered as one of the most attractive techniques in synthetic organic chemistry because it bears the potential to shorten synthetic routes as well as to produce complementary product scopes compared to traditional synthetic strategies. However, many current methods employ silver salts as additives, leading to stoichiometric metal waste and thereby preventing the full potential of C−H activation to be exploited. Therefore, the development of silver‐free protocols has recently received increasing attention. Mechanistically, silver can serve various roles in C−H activation and thus, avoiding the use of silver requires different approaches based on the role it serves in a given process. In this Review, we present the comparison of silver‐based and silver‐free methods. Focusing on the strategic approaches to develop silver‐free C−H activation, we provide the reader with the means to develop sustainable methods for C−H activation.

Controlling Reactivity and Selectivity in the Nondirected C–H Activation of Arenes with Palladium

“…Further key challenges concern the scalability of these processes from economic and ecological points of view. While some related protocols have been rendered silver-free, ,,, the use of silver as either terminal oxidant, halide scavenger, or Lewis acid or a combination thereof is still the standard case. The prohibitive nature of such additives on large scales immediately implies the need for further research toward general solutions to render these protocols silver-free.…”

“…Interestingly, Ritter et al were able to use Cu(II) salts as oxidants, resulting in a silver-free protocol. 35 Another common functional group in bioactive molecules, synthetic intermediates, or functional molecules is the alkyne motif. Gratifyingly we were able to apply our catalyst design to enable an arene-limited nondirected C−H alkynylation of arenes (Scheme 5).…”

“…Notably, the selectivity in the dual-ligand enabled systems is again more strongly influenced by steric effects than the pyridone-based system. Interestingly, Ritter et al were able to use Cu­(II) salts as oxidants, resulting in a silver-free protocol …”

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

“…Because of the exceptional features of fluorinated derivatives, tremendous developments and discoveries have been made in this blossoming research area, with a high interest for fundamental research as well as the industry [ 6 – 11 ]. Among them [ 2 , 5 , 12 – 18 ], the direct functionalization of a simple C–H bond by transition-metal catalysis [ 19 – 43 ] became an important tool offering new retrosynthetic disconnections. In this context, a strong interest from the scientific community was shown towards the challenging synthesis of fluorinated molecules by transition-metal-catalyzed C–H bond activation [ 44 – 50 ], allowing the functionalization of complex molecules and even for late-stage functionalization strategy [ 51 – 53 ] for the synthesis of natural products [ 42 , 54 – 59 ].…”

A Cheap and Efficient Oxidant (n-Bu)4NNO3-Enabled C(sp2)– and C(sp3)–H Olefination at Room Temperature

“…Moreover, a vast majority of olefination reactions require environmentally unfriendly and expensive metal salt oxidants such as Ag salts and Cu salts to ensure the efficient catalytic cycle, which results in the limitation of their broad application. While many scientists have attempted to replace traditional oxidants with electrochemistry and made great progress in recent years, the cost and service life of an electrode and the electric energy consumption are still big problems that cannot be ignored. Hence, developing a universal mild condition with a cheap and efficient oxidant to facilitate C–H olefination is highly desirable .…”