Preparative Scale Applications of C−H Activation in Medicinal Chemistry

Abstract

C−H activation is an attractive methodology to increase molecular complexity without requiring substrate prefunctionalization. In contrast to well‐established cross‐coupling methods, C−H activation is less explored on large scales and its use in the production of pharmaceuticals faces substantial hurdles. However, the inherent advantages, such as shorter synthetic routes and simpler starting materials, motivate medicinal chemists and process chemists to overcome these challenges, and exploit C−H activation steps for the synthesis of pharmaceutically relevant compounds. In this review, we will cover examples of drugs/drug candidates where C−H activation has been implemented on a preparative synthetic scale (range between 355 mg and 130 kg). The optimization processes will be described, and each example will be examined in terms of its advantages and disadvantages, providing the reader with an in‐depth understanding of the challenges and potential of C−H activation methodologies in the production of pharmaceuticals.

Reduced Graphene Oxide/Few-Layer Phosphorene Binary Heterojunctions as Metal-Free Photocatalysts for the Sustainable Photoredox C–H Arylation of Heteroarenes

“…23,24 Among them, C−H arylation has special importance, especially in synthesizing important organic compounds. 25 C−H arylation is a powerful synthetic tool that can be used in a wide range of applications. It is beneficial for the synthesis of pharmaceuticals and other fine chemicals.…”

“…Cross-coupling reactions are traditionally used for synthesizing these compounds, but they have a major drawback; the necessity of the prefunctionalization of substrates in cross-coupling reactions before the reaction. In this regard, direct C–H bond functionalization has recently attracted the intense attention of researchers since it does not require substrate prefunctionalization. , Among them, C–H arylation has special importance, especially in synthesizing important organic compounds . C–H arylation is a powerful synthetic tool that can be used in a wide range of applications.…”

Cp*Rh(iii)-catalyzed regioselective cyclization of aromatic amides with allenes

“…1 Meanwhile, metal-catalyzed C–H activation reactions have contributed substantially to medicinal chemistry, materials chemistry, and modern organic chemistry. 1,2 In this domain, noble metals such as Pd, Rh, Ir, and Ru, along with cheap metals including Mn, Fe, Co, Ni, and Cu have garnered significant attention over the past decade due to their distinctive catalytic activities. 3 For instance, remarkable achievements have been made by pioneers including Miura, Glorius, Chang, Ellman, Rovis, and Li, as well as by other groups, with respect to Rh( iii )-catalyzed C–H activation reactions.…”

1,2,3-Thiadiazole as a Modifiable and Scalable Directing Group for ortho-C–H Functionalization

“…In the past decades, transition-metal-catalyzed C–H bond functionalization reactions have achieved tremendous advances . They were extensively applied to the rapid assembly of diversified complex molecular structures, particularly in the fields of medicinal chemistry and material science . Numerous directing groups, including heterocycles, bidentate amides, carboxylates, in situ formed imines, etc., have been designed and applied in C–H functionalization to enhance the reactivity and control the site-selectivity .…”