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.     

Monofluoroalkenylation of Dimethylamino Compounds through Radical–Radical Cross‐Coupling

An unprecedented and challenging radical–radical cross‐coupling of α‐aminoalkyl radicals with monofluoroalkenyl radicals derived from gem‐difluoroalkenes was achieved. This first example of tandem C(sp³)?H and C(sp²)?F bond functionalization through visible‐light photoredox catalysis offers a facile and flexible access to privileged tetrasubstituted monofluoroalkenes under very mild reaction conditions. The striking features of this redox‐neutral method in terms of scope, functional‐group tolerance, and regioselectivity are illustrated by the late‐stage fluoroalkenylation of complex molecular architectures such as bioactive (+)‐diltiazem, rosiglitazone, dihydroartemisinin, oleanic acid, and androsterone derivatives, which represent important new α‐amino C?H monofluoroalkenylations.     

Rhodium(III)‐Catalyzed Redox‐Neutral Coupling of α‐Trifluoromethylacrylic Acid with Benzamides through Directed C−H Bond Cleavage

A rhodium(III)‐catalyzed redox‐neutral coupling of α‐trifluoromethylacrylic acid with bezamides proceeds smoothly accompanied by amide‐directed C?H bond cleavage to produce β‐[2‐(aminocarbonyl)phenyl]‐α‐trifluoromethylpropanoic acid derivatives. One of the products can be transformed to a trifluoromethyl substituted heterocyclic compound. In addition, the redox‐neutral coupling of α‐trifluoromethylacrylic acid with related aromatic substrates possessing a nitrogen‐containing directing group can also be conducted under similar conditions.     

Structures of Highly Twisted Amides Relevant to Amide N−C Cross‐Coupling: Evidence for Ground‐State Amide Destabilization

Herein, we show that acyclic amides that have recently enabled a series of elusive transition‐metal‐catalyzed N?C activation/cross‐coupling reactions are highly twisted around the N?C(O) axis by a new destabilization mechanism of the amide bond. A unique effect of the N‐glutarimide substituent, leading to uniformly high twist (ca. 90°) irrespective of the steric effect at the carbon side of the amide bond has been found. This represents the first example of a twisted amide that does not bear significant steric hindrance at the α‐carbon atom. The ¹⁵N NMR data show linear correlations between electron density at nitrogen and amide bond twist. This study strongly supports the concept of amide bond ground‐state twist as a blueprint for activation of amides toward N?C bond cleavage. The new mechanism offers considerable opportunities for organic synthesis and biological processes involving non‐planar amide bonds.     

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.     

Remote C−H Activation of Quinolines through Copper‐Catalyzed Radical Cross‐Coupling

Achieving site selectivity in carbon–hydrogen (C?H) functionalization reactions is a formidable challenge in organic chemistry. Herein, we report a novel approach to activating remote C?H bonds at the C5 position of 8‐aminoquinoline through copper‐catalyzed sulfonylation under mild conditions. Our strategy shows high conversion efficiency, a broad substrate scope, and good toleration with different functional groups. Furthermore, our mechanistic investigations suggest that a single‐electron‐transfer process plays a vital role in generating sulfonyl radicals and subsequently initiating C?S cross‐coupling. Importantly, our copper‐catalyzed remote functionalization protocol can be expanded for the construction of a variety of chemical bonds, including C?O, C?Br, C?N, C?C, and C?I. These findings provide a fundamental insight into the activation of remote C?H bonds, while offering new possibilities for rational design of drug molecules and optoelectronic materials requiring specific modification of functional groups.     

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.     

Oxidative Coupling via Organocopper Compounds

The type of reaction described here, which achieved preparative importance before the turn of the century in the form of the Glaser reaction, has found new applications in recent years: Syntheses of 1,3-dienes, 2,3,6,7-tetraaza-1,3,5,7-tetraenes, 2,3-diaza-1,3-dienes, hydrazine derivatives, bis(heteroallyl) compounds, hetarenes, polyhetarenes, cyclopolyarenes, protophanes, phanes, and heteraprotophanes. The reaction, which consists in the metalation of the starting substance followed by oxidative coupling of the metal derivative, merits special preparative interest when several successive coupling processes are possible (e. g. polyyne, polyarene, cyclopolyarene, and protophane syntheses). The main factors limiting its applicability are the high thermal stability of some organic copper compounds and the disproportionation of the ligands that frequently occurs as a competing reaction. Selective asymmetric linkages are not generally possible by this method.     

Nucleophilic and Electrophilic Activation of Non‐Heteroaromatic Amides in Atom‐Economical Asymmetric Catalysis

Recent advances in catalytic asymmetric carbon–carbon bond‐forming reactions of non‐heteroaromatic amide substrates are highlighted. Among carbonyl compounds, amides have received limited attention in catalytic asymmetric transformations mainly owing to their lower reactivity. Amides are reluctant to form enolates for nucleophilic addition, and α,β‐unsaturated amides exhibit diminished electrophilicity at the β‐carbon. Recent advances in asymmetric catalysis rendered these amides amenable to enantioselective reactions with perfect atom economy, producing synthetically useful chiral building blocks. This Minireview summarizes recent developments in the field.     

Shedding Light on the Diverse Reactivity of NacNacAl with N‐Heterocycles

The aluminum(I) compound NacNacAl (NacNac=[ArNC(Me)CHC(Me)NAr]^?, Ar=2,6‐iPr₂C₆H₃, 1 ) shows diverse and substrate‐controlled reactivity in reactions with N‐heterocycles. 4‐Dimethylaminopyridine (DMAP), a basic substrate in which the 4‐position is blocked, induces rearrangement of NacNacAl by shifting a hydrogen atom from the methyl group of the NacNac backbone to the aluminum center. In contrast, C?H activation of the methyl group of 4‐picoline takes place to produce a species with a reactive terminal methylene. Reaction of 1 with 3,5‐lutidine results in the first example of an uncatalyzed, room‐temperature cleavage of an sp² C?H bond (in the 4‐position) by an Al^I species. Another reactivity mode was observed for quinoline, which undergoes 2,2′‐coupling. Finally, the reaction of 1 with phthalazine produces the product of N?N bond cleavage.     

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.     

Copper‐Catalyzed Reductive N‐Alkylation of Amides with N‐Tosylhydrazones Derived from Ketones

A CuI‐catalyzed reductive coupling of ketone‐derived N‐tosylhydrazones with amides is presented. Under the optimized conditions, an array of N‐tosylhydrazones derived from aryl–alkyl and diaryl ketones could couple effectively with a wide variety of (hetero)aryl as well as aliphatic amides to afford the N‐alkylated amides in high yields. The method represents the very few examples for reliably accessing secondary and tertiary amides through a reductive N‐alkylation protocol.     

Transition Metal Catalyzed Coupling Reactions under C−H Activation

C−C coupling by transition metal catalyzed C−H activation has developed into a diverse area of research. The applicable catalysts are manifold, and the variety of products obtained range from basic chemicals to pharmaceuticals and building blocks for carbon networks. One reaction, in which several C−C bonds are formed under C−H activation of a methyl group, is the conversion of ortho-iodoanisole according to Equation (1).     

Regioselective Synthesis of Quinazolinone‐/Phenanthridine‐Fused Heteropolycycles by Pd‐Catalyzed Direct Intramolecular Aerobic Oxidative C−H Amination from Aromatic Strained Amides

A new route for the expedient synthesis of specific regioisomer of quinazolinone‐ and phenanthridine‐fused heterocycles through a palladium‐catalyzed regioselective intramolecular oxidative C?H amination from cyclic strained amides of aromatic amido–amidine systems (quinazolinones) has been developed. The amine functionalization of an aromatic C?H bond from a strained amide nitrogen involved in aromaticity has been a challenging work so far. The fusion of two heterocyclic cores, quinazolinone and phenanthridine, can occur in two different ways (linear and angular), but under the conditions reported here, only linear type isomer is exclusively produced. This approach provides a variety of substituted quinazolinone‐ and phenanthridine‐fused derivatives in moderate to excellent yields. Moreover, such fused molecules show excellent fluorescent properties and have great potential to be a new type of fluorophores for the use in medicinal and material science.     

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.