Structural Characterization of N‐Alkylated Twisted Amides: Consequences for Amide Bond Resonance and N−C Cleavage

Herein, we describe the first structural characterization of N‐alkylated twisted amides prepared directly by N‐alkylation of the corresponding non‐planar lactams. This study provides the first experimental evidence that N‐alkylation results in a dramatic increase of non‐planarity around the amide N?C(O) bond. Moreover, we report a rare example of a molecular wire supported by the same amide C=O‐Ag bonds. Reactivity studies demonstrate rapid nucleophilic addition to the N?C(O) moiety of N‐alkylated amides, indicating the lack of n_N to π^*_C=O conjugation. Most crucially, we demonstrate that N‐alkylation activates the otherwise unreactive amide bond towards σ N?C cleavage by switchable coordination.     

Transition‐Metal‐Free Activation of Amides by N−C Bond Cleavage

The amide bond N?C activation represents a powerful strategy in organic synthesis to functionalize the historically inert amide linkage. This personal account highlights recent remarkable advances in transition‐metal‐free activation of amides by N?C bond cleavage, focusing on both (1) mechanistic aspects of ground‐state‐destabilization of the amide bond enabling formation of tetrahedral intermediates directly from amides with unprecedented selectivity, and (2) synthetic utility of the developed transformations. Direct nucleophilic addition to amides enables a myriad of powerful methods for the formation of C?C, C?N, C?O and C?S bonds, providing a straightforward and more synthetically useful alternative to acyl‐metals.     

Copper‐Catalyzed Direct Sulfoximination of Heteroaromatic N‐Oxides by Dual C−H/N−H Dehydrogenative Cross‐Coupling

A dual C?H/N?H dehydrogenative coupling of quinoline‐type N‐oxides with sulfoximines that leads to N‐(hetero)arylsulfoximines in high yields has been realized by using a catalytic amount of CuBr in air. The method does not require any additional ligand, base, reactivity modifier or oxidant and provides a practical route towards a series of sulfoximidoyl‐functionalized quinolines and derivatives.     

Nitroxyl‐Radical‐Catalyzed Oxidative Coupling of Amides with Silylated Nucleophiles through N‐Halogenation

A nitroxyl‐radical‐catalyzed oxidative coupling reaction between amines with an N‐protecting electron‐withdrawing group (EWG) and silylated nucleophiles was developed to furnish coupling products in high yields, thus opening up new frontiers in organocatalyzed reactions. This reaction proceeded through the activation of N‐halogenated amides by a nitroxyl‐radical catalyst, followed by carbon–carbon coupling with silylated nucleophiles. Studies of the reaction mechanism indicated that the nitroxyl radical activates N‐halogenated amides, which are generated from N‐EWG‐protected amides and a halogenation reagent, to give the corresponding imines.     

Recent Advances in the Metal‐Catalyzed Activation of Amide Bonds

The amide functional group is commonly found in peptides, proteins, pharmaceutical compounds, natural products, and polymers. The synthesis of amides is typically performed by using classical approaches that involve the reaction between a carboxylic acid and an amine in the presence of an activator. Amides are thought to be an inert functional group, because they are unsusceptible to nucleophile attack, owing to their low electrophilicity. The reason for this resistance is clear: the resonance stability of the amide bond. However, transition metal catalysis can circumvent this stability by selectively rupturing the N?C bond of the amide, thereby facilitating further cross‐coupling or other reactions. In this Focus Review, we discuss the recent advances in this area and present a summary of methods that have been developed for activating the amide N?C bond by using precious and non‐precious metals.     

Single and Twofold Metal‐ and Reagent‐Free Anodic C−C Cross‐Coupling of Phenols with Thiophenes

The first electrochemical dehydrogenative C−C cross‐coupling of thiophenes with phenols has been realized. This sustainable and very simple to perform anodic coupling reaction enables access to two classes of compounds of significant interest. The scope for electrochemical C−H‐activating cross‐coupling reactions was expanded to sulfur heterocycles. Previously, only various benzoid aromatic systems could be converted, while the application of heterocycles was not successful in the electrochemical C−H‐activating cross‐coupling reaction. Here, reagent‐ and metal‐free reaction conditions offer a sustainable electrochemical pathway that provides an attractive synthetic method to a broad variety of bi‐ and terarylic products based on thiophenes and phenols. This method is easy to conduct in an undivided cell, is scalable, and is inherently safe. The resulting products offer applications in electronic materials or as [OSO]²⁻ pincer‐type ligands.     

Efficient Synthesis of Diaryl Ketones by Nickel‐Catalyzed Negishi Cross‐Coupling of Amides by Carbon–Nitrogen Bond Cleavage at Room Temperature Accelerated by a Solvent Effect

The first Negishi cross‐coupling of amides for the synthesis of versatile diaryl ketones by selective C?N bond activation under exceedingly mild conditions is reported. The cross‐coupling was accomplished with bench‐stable, inexpensive precatalyst [Ni(PPh₃)₂Cl₂] that shows high functional‐group tolerance and enables the synthesis of highly functionalized diaryl ketone motifs. The coupling occurred with excellent chemoselectivity favoring the ketone (cf. biaryl) products. Notably, this process represents the mildest conditions for amide N?C bond activation accomplished to date (room temperature, <10 min). Considering the versatile role of polyfunctional biaryl ketone linchpins in modern organic synthesis, availability, and excellent functional‐group tolerance of organozinc reagents, this strategy provides a new platform for amide N?C bond/organozinc cross‐coupling under mild conditions.     

Sequential Barium‐Catalysed N−H/H−Si Dehydrogenative Cross‐Couplings: Cyclodisilazanes versus Linear Oligosilazanes

Starting from Ph₃SiH, the barium precatalyst Ba[CH(SiMe₃)₂]₂?(THF)₃ was used to produce the disilazane Ph₃SiN(Bn)SiPh₂NHBn ( 4 ) by sequential N?H/H?Si dehydrogenative couplings with BnNH₂ and Ph₂SiH₂. Substrate scope was extended to other amines and hydrosilanes. This smooth protocol gives quantitative yields and full chemoselectivity. Compound 4 and the intermediates Ph₃SiNHBn and Ph₃SiN(Bn)SiHPh₂ were structurally characterised. Further attempts at chain extension by dehydrocoupling of Ph₂SiH₂ with 4 instead resulted in cyclisation of this compound, forming the cyclodisilazane c‐(Ph₂Si‐NBn)₂ ( 5 ) which was crystallographically authenticated. The ring‐closure mechanism leading to 5 upon release of C₆H₆ was determined by complementary experimental and theoretical (DFT) investigations. Ba[CH(SiMe₃)₂]₂?(THF)₃ and 4 react to afford the reactive Ba{N(Bn)SiPh₂N(Bn)SiPh₃}₂, which was characterised in situ by NMR spectroscopy. Next, in a stepwise process, intramolecular nucleophilic attack of the metal‐bound amide on the terminal silicon atom generates a five‐coordinate silicate. It is followed by turnover‐limiting β‐C₆H₅ transfer to barium; this releases 5 and forms a transient [Ba]?Ph species, which undergoes aminolysis to regenerate [Ba]?N(Bn)SiPh₂N(Bn)SiPh₃. DFT computations reveal that the irreversible production of 5 through such a stepwise ring‐closure mechanism is much more kinetically facile (ΔG^≠=26.2 kcal mol^?1) than an alternative σ‐metathesis pathway (ΔG^≠=48.2 kcal mol^?1).     

Reagent‐ and Metal‐Free Anodic C−C Cross‐Coupling of Aniline Derivatives

The dehydrogenative cross‐coupling of aniline derivatives to 2,2′‐diaminobiaryls is reported. The oxidation is carried out electrochemically, which avoids the use of metals and reagents. A large variety of biphenyldiamines were thus prepared. The best results were obtained when glassy carbon was used as the anode material. The electrosynthetic reaction is easily performed in an undivided cell at slightly elevated temperature. In addition, common amine protecting groups based on carboxylic acids were employed that can be selectively removed under mild conditions after the cross‐coupling, which provides quick and efficient access to important building blocks featuring free amine moieties.     

Synthesis of Biaryls through Nickel‐Catalyzed Suzuki–Miyaura Coupling of Amides by Carbon–Nitrogen Bond Cleavage

The first Ni‐catalyzed Suzuki–Miyaura coupling of amides for the synthesis of widely occurring biaryl compounds through N?C amide bond activation is reported. The reaction tolerates a wide range of electron‐withdrawing, electron‐neutral, and electron‐donating substituents on both coupling partners. The reaction constitutes the first example of the Ni‐catalyzed generation of aryl electrophiles from bench‐stable amides with potential applications for a broad range of organometallic reactions.     

Product Control using Substrate Design: Ruthenium‐Catalysed Oxidative C−H Olefinations of Cyclic Weinreb Amides

A new class of Weinreb amides has been developed as directing groups for the ruthenium‐catalysed regioselective oxidative C?H olefination. The new Weinreb amides successfully inhibit the N?O bond reductive cleavage usually associated with the cationic ruthenium system, thereby keeping intact the synthetic utility of Weinreb amides. Mechanistic studies reveal interesting aspects of the directing group capabilities of Weinreb amides when compared to simple amides of similar structures.     

General Olefin Synthesis by the Palladium‐Catalyzed Heck Reaction of Amides: Sterically Controlled Chemoselective NC Activation

Metal‐catalyzed reactions of amides proceeding via metal insertion into the N? CO bond are severely underdeveloped due to resonance stabilization of the amide bond. Herein we report the first Heck reaction of amides proceeding via highly chemoselective N? CO cleavage catalyzed by Pd⁰ utilizing amide bond ground‐state destabilization. Conceptually, this transformation provides access to a myriad of metal‐catalyzed transformations of amides via metal insertion/decarbonylation.     

Carboxylate‐Assisted Iridium‐Catalyzed C−H Amination of Arenes with Biologically Relevant Alkyl Azides

An iridium‐catalyzed C?H amination of arenes with a wide substrate scope is reported. Benzamides with electron‐donating and ‐withdrawing groups and linear, branched, and cyclic alkyl azides are all applicable. Cesium carboxylate is crucial for both reactivity and regioselectivity of the reactions. Many biologically relevant molecules, such as amino acid, peptide, steroid, sugar, and thymidine derivatives can be introduced to arenes with high yields and 100 % chiral retention.     

Selective Methylation of Arenes: A Radical C−H Functionalization/Cross‐Coupling Sequence

A selective, nonchelation‐assisted methylation of arenes has been developed. The overall transformation, which combines a C?H functionalization reaction with a nickel‐catalyzed cross‐coupling, offers rapid access to methylated arenes with high para selectivity. The reaction is amenable to late‐stage methylation of small‐molecule pharmaceuticals.     

Decarboxylative C(sp3)−O Cross‐Coupling

Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp³)?O cross‐coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp²)?O cross‐coupling and S_N2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp³)?O coupling of alkyl N‐hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional‐group tolerance to existing methods was demonstrated.     

Lewis Acid Assisted Nickel‐Catalyzed Cross‐Coupling of Aryl Methyl Ethers by C−O Bond‐Cleaving Alkylation: Prevention of Undesired β‐Hydride Elimination

In the presence of trialkylaluminum reagents, diverse aryl methyl ethers can be transformed into valuable products by C?O bond‐cleaving alkylation, for the first time without the limiting β‐hydride elimination. This new nickel‐catalyzed dealkoxylative alkylation method enables powerful orthogonal synthetic strategies for the transformation of a variety of naturally occurring and easily accessible anisole derivatives. The directing and/or activating properties of aromatic methoxy groups are utilized first, before they are replaced by alkyl chains in a subsequent coupling process.     

Electrochemical Oxidative C−H/N−H Coupling between γ‐Lactams and Anilines

A mild method for the direct C?H/N?H coupling between γ‐lactams and anilines through electrochemical oxidation has been developed. The protocol proceeded smoothly without metal catalysts at room temperature to afford γ‐substituted γ‐lactams in good yields. It has been revealed that the quasi‐divided cell which provided high current density on the anode was crucial for this reaction.     

Rhodium‐Catalyzed Regioselective C7‐Olefination of Indazoles Using an N‐Amide Directing Group

A rhodium‐catalyzed regioselective C−H olefination of indazole is described. This protocol relies on the use of an efficient and removable N ,N ‐diisopropylcarbamoyl directing group, which offers facile access to C7‐olefinated indazoles with high regioselectivity, ample substrate scope and broad functional group tolerance.     

Oxidative C−H/C−H Cross‐Coupling Reactions between N‐Acylanilines and Benzamides Enabled by a Cp*‐Free RhCl3/TFA Catalytic System

By making use of a dual‐chelation‐assisted strategy, a completely regiocontrolled oxidative C?H/C?H cross‐coupling reaction between an N‐acylaniline and a benzamide has been accomplished for the first time. This process constitutes a step‐economic and highly efficient pathway to 2‐amino‐2′‐carboxybiaryl scaffolds from readily available substrates. A Cp*‐free RhCl₃/TFA catalytic system was developed to replace the [Cp*RhCl₂]₂/AgSbF₆ system generally used in oxidative C?H/C?H cross‐coupling reactions between two (hetero)arenes (Cp*=pentamethylcyclopentadienyl, TFA=trifluoroacetic acid). The RhCl₃/TFA system avoids the use of the expensive Cp* ligand and AgSbF₆. As an illustrative example, the procedure developed herein greatly streamlines the total synthesis of the naturally occurring benzo[c]phenanthridine alkaloid oxynitidine, which was accomplished in excellent overall yield.