The synthesis of amides remains one of the most important transformations and it is one of the more frequently performed reactions. In the pharmaceutical industry, the formation of the amide group is ...pivotal and among the more important transformations in the design of the synthetic plan. This review presents an overview of only very recent contributions, published in the last three years, to highlight the latest progress in this “dateless” reaction, with a special focus on metal‐free methodologies. New, more efficient and/or greener stoichiometric methods, as well as catalytic strategies, have been discussed, either for the “classic” coupling approach between an amine and a carboxylic acid (or its activated equivalent) or for more innovative approaches, mainly involving oxidation procedures to generate amides starting from amines.
The amide function is unarguably of primary importance, being the constituent of natural and synthetic polymers and found in a wide variety of bioactive molecules. This review will discuss specifically the very recent advances in the area of amide synthesis, specially focusing on metal‐free strategies, based either on stoichiometric or on catalytic methods that were published in the last three years.
Acid additive effects in the Ir-catalyzed C–H amidation of arylphosphoryl compounds were examined. Structure of catalytically active metal species was elucidated: mono-cationic iridium catalyst ...Cp∗Ir(III)(OAc)(NTf2) being mainly responsible for the C–H bond activation. Mechanistic studies revealed a dual role of carboxylic acid additive operating both in the generation of an iridacyclic intermediate and in the protodemetalation process to release amidated products. The fact that asymmetric C–H amidation was achieved albeit in moderate enantioselectivity by using chiral carboxylic acid supports our proposal especially with regard to the role of acid additive.
Display omitted
During the past decade, visible light photocatalysis has become a powerful synthetic platform for promoting challenging bond constructions under mild reaction conditions. These photocatalytic systems ...rely on harnessing visible light energy for synthetic purposes through the generation of reactive but controllable free radical species. Recent progress in the area of visible light photocatalysis has established it as an enabling catalytic strategy for the mild and selective generation of nitrogen-centered radicals. The application of visible light for photocatalytic activation of amides, hydrazones, and imides represents a valuable approach for facilitating the formation of nitrogen-centered radicals. Within the span of only a couple of years, significant progress has been made for expediting the generation of amidyl, hydrazonyl, and imidyl radicals from a variety of precursors. This Perspective highlights the recent advances in visible light-mediated generation of these radicals. A particular emphasis is placed on the unique ability of visible light photocatalysis in accessing elusive reaction manifolds for the construction of diversely functionalized nitrogen-containing motifs and as a platform for nontraditional bond disconnections in contemporary synthetic chemistry.
Herein, multiple types of chiral Os(II) complexes have been designed to address the appealing yet challenging asymmetric C(sp3)−H functionalization, among which the Os(II)/Salox species is found to ...be the most efficient for precise stereocontrol in realizing the asymmetric C(sp3)−H amidation. As exemplified by the enantioenriched pyrrolidinone synthesis, such tailored Os(II)/Salox catalyst efficiently enables an intramolecular site‐/enantioselective C(sp3)−H amidation in the γ‐position of dioxazolone substrates, in which benzyl, propargyl and allyl groups bearing various substituted forms are well compatible, affording the corresponding chiral γ‐lactam products with good er values (up to 99 : 1) and diverse functionality (>35 examples). The unique performance advantage of the developed chiral Os(II)/Salox system in terms of the catalytic energy profile and the chiral induction has been further clarified by integrated experimental and computational studies.
Based on a computer‐aided ligand design, the first chiral Os(II)/Salox catalytic system is realized to address the appealing yet challenging asymmetric γ‐C(sp3)−H amidation of dioxazolones with precise site‐/enantioselectivity control and diverse functionality. The catalytic energy profile and the chiral induction mode of the developed chiral Os(II)/Salox system are also further clarified by integrated experimental and computational studies.
β-Lactams are important scaffolds in drug design and frequently used as reactive intermediates in organic synthesis. Catalytic reactions featuring intramolecular C–H amidation of alkyl carboxamide ...substrates could provide a straightforward disconnection strategy for β-lactam synthesis. Herein, we report a streamlined method for asymmetric synthesis of β-aryl β-lactams from propanoic acid and aryl iodides via Pd-catalyzed sequential C(sp3)–H functionalization. The lactam-forming reaction provides an example of PdII-catalyzed enantioselective intramolecular C(sp3)–H amidation reaction and proceeds up to 94% ee. The use of a 2-methoxy-5-chlorophenyl iodide oxidant is critical to control the competing reductive elimination pathways of the PdIV intermediate to achieve the desired chemoselectivity. Mechanistic studies suggest that both steric and electronic effects of the unconventional aryl iodide oxidant are responsible for controlling the competing C–N versus C–C reductive elimination pathways of the PdIV intermediate.
C−N bond formation reactions have garnered a lot of interest in recent years due to the predominance of nitrogen‐containing compounds in most pharmacological medications. Since traditional approaches ...have several limitations, the transition metal‐catalyzed C−H amidation/amination process has arisen as a more atom‐friendly option. Because there are so many distinct kinds of C−H bonds in organic molecules, selective amidation of C−H bonds has always been a challenge. In this scenario, the directing‐group‐assisted C−H amidation has received considerable attention, especially with inexpensive metal cobalt, due to its unique properties and efficiency. We summarize recent developments in cobalt‐catalyzed directing‐group‐aided C−H bond amidation reactions in this review. We briefly discuss the evolution of directing group preferences and their function in the site selection.
A procedure for the Cp*CoIII‐catalyzed direct CH amidation of arenes with dioxazolone has been developed. This reaction proceeds under straightforward and mild conditions with a broad range of ...substrates, including anilides. A comparative study on the catalytic activity of Group 9 {Cp*MCl2}2 complexes revealed the unique efficiency of the cobalt catalyst.
Pick of the bunch: A variety of arenes, including anilides, underwent direct CH amidation with dioxazolones in the presence of a cobalt catalyst with a Cp* ligand under mild and straightforward reaction conditions (see scheme; Piv=pivaloyl). A comparative study of Group 9 Cp*MIII complexes revealed the unique ability of the cobalt catalyst to promote this transformation efficiently.
Ir‐catalyzed sp2 C−H amidation of aldehydes with various anilines as stoichiometric or catalytic directing groups was accomplished. A wide range of substrates were selectively amidated in good to ...excellent yields with broad functional group tolerance. The iridacycle complexes were isolated, characterized, and proved as key intermediates. Kinetic studies and Hammett plots provided detailed understandings of this amidation. According to the mechanism, the electron‐rich ArSO2N3 was proved effective for intermolecular sp3 C−H amidation.
Cat power: Ir‐catalyzed C−H amidation of aldehydes with various anilines as stoichiometric or catalytic directing groups was accomplished (see scheme). A wide range of substrates were selectively amidated in good to excellent yields with broad functional group tolerance. The iridacycle complexes were isolated, characterized, and proved as key intermediates. Kinetic studies and Hammett plots provided detailed understandings of this amidation.
Direct Amidation of Esters by Ball Milling Nicholson, William I.; Barreteau, Fabien; Leitch, Jamie A. ...
Angewandte Chemie International Edition,
September 27, 2021, Letnik:
60, Številka:
40
Journal Article
Recenzirano
The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a ...large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs) and agrochemicals as well as the gram‐scale synthesis of an active pharmaceutical, all in the absence of a reaction solvent.
Mechanochemical ball‐milling enabled the direct amidation of esters through simple coupling under basic conditions (see scheme). A wide range of esters underwent amidation by this method with an array of primary and secondary amides without the need for a bulk solvent, catalysts, or additives.
PDF
