Cobalt‐Catalyzed Cross‐Dehydrogenative C(sp2)−C(sp3) Coupling of Oxazole/Thiazole with Ether or Cycloalkane

Direct C5‐alkylation of oxazole/thiazole with ether or cycloalkane has been achieved through a cobalt‐catalyzed cross‐dehydrogenative coupling (CDC) process in moderate to good yields. This transformation represents the first C(sp²)−C(sp³) cross‐coupling at the C5‐position of the oxazole/thiazole via double C−H bond cleavages. Various functional groups on oxazole/thiazole substrates, as well as water and air, are well‐tolerated with this concise and practical protocol, constituting straightforward access to heterocycles with great medicinal significance. A preliminary mechanism involving a radical process has also been proposed.     

Directing‐Group‐mediated C−H‐Alkynylations

C?C triple bonds are amongst the most versatile functional groups in synthetic chemistry. Complementary to the Sonogashira coupling the direct metal‐catalyzed alkynylation of C?H bonds has emerged as a highly promising approach in recent years. To guarantee a high regioselectivity suitable directing groups (DGs) are necessary to guide the transition metal (TM) into the right place. In this Focus Review we present the current developments in DG‐mediated C(sp²)?H and C(sp³)?H modifications with terminal alkynes under oxidative conditions and with electrophilic alkynylation reagents. We will discuss further modifications of the alkyne, in particular subsequent cyclizations to carbo‐ and heterocycles and modifications of the DG in the presence of the alkyne.     

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.     

2,4‐Dinitrophenol‐Catalyzed α‐C(sp3)−H and C(sp)−H Bond Functionalization of Cyclic Amines and Alkynes: Highly Regio‐/Diastereoselective Synthesis of α‐Alkynyl‐3‐Amino‐2‐Oxindoles

A transition‐metal‐ and oxidant‐free DNP (2,4‐dinitrophenol)‐catalyzed atom‐economical regio‐ and diastereoselective synthesis of monofunctionalized α‐alkynyl‐3‐amino‐2‐oxindole derivatives by C?H bond functionalization of cyclic amines and alkynes with indoline‐2,3‐diones has been developed. This cascade event sequentially involves the reductive amination of indoline‐2,3‐dione by imine formation and cross coupling between C(sp³)?H and C(sp)?H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α‐alkynyl‐3‐amino‐2‐oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP‐catalyzed metal‐free direct C(sp³)?H and C(sp)?H bond functionalization providing biologically active α‐alkynyl‐3‐amino‐2‐oxindole scaffolds.     

Synthesis of meta‐Terphenyl‐2,2′′‐diols by Anodic C−C Cross‐Coupling Reactions

The anodic C?C cross‐coupling reaction is a versatile synthetic approach to symmetric and non‐symmetric biphenols and arylated phenols. We herein present a metal‐free electrosynthetic method that provides access to symmetric and non‐symmetric meta‐terphenyl‐2,2′′‐diols in good yields and high selectivity. Symmetric derivatives can be obtained by direct electrolysis in an undivided cell. The synthesis of non‐symmetric meta‐terphenyl‐2,2′′‐diols required two electrochemical steps. The reactions are easy to conduct and scalable. The method also features a broad substrate scope, and a large variety of functional groups are tolerated. The target molecules may serve as [OCO]^3? pincer ligands.     

Ligand‐Enabled β‐Methylene C(sp3)−H Arylation of Masked Aliphatic Alcohols

Despite recent advances, reactivity and site‐selectivity remain significant obstacles for the practical application of C(sp³)?H bond functionalization methods. Here, we describe a system that combines a salicylic‐aldehyde‐derived L,X‐type directing group with an electron‐deficient 2‐pyridone ligand to enable the β‐methylene C(sp³)?H arylation of aliphatic alcohols, which has not been possible previously. Notably, this protocol is compatible with heterocycles embedded in both alcohol substrates and aryl coupling partners. A site‐ and stereo‐specific annulation of dihydrocholesterol and the synthesis of a key intermediate of englitazone illustrate the practicality of this method.     

Metal‐ and Oxidant‐Free Alkenyl C−H/Aromatic C−H Cross‐Coupling Using Electrochemically Generated Iodosulfonium Ions

A three‐step transformation consisting of 1) addition of electrochemically generated iodosulfonium ions to vinylarenes to give (1‐aryl‐2‐iodoethoxy)sulfonium ions, 2) nucleophilic substitution by subsequently added aromatic compounds to give 1,1‐diaryl‐2‐iodoethane, and 3) elimination of HI with a base to give 1,1‐diarylethenes was developed. The transformation serves as a powerful metal‐ and chemical‐oxidant‐free method for alkenyl C?H/aromatic C?H cross‐coupling.     

Ru‐Catalyzed Dehydrogenative C−O Bond Formation with Anilines and Phenols

The Ru catalyzed cross‐dehydrogenative C?O bond formation between anilines and phenols is described and discussed. The exclusive C?O versus C?N bond‐formation selectivity, moreover in the absence of chelating–assisting directing groups and while leaving the N?H position untouched, is a remarkable feature of this metal‐catalyzed radical cross‐dehydrogenative coupling.     

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.     

Regio‐ and Stereoselective Thianthrenation of Olefins To Access Versatile Alkenyl Electrophiles

Herein, we report a regioselective alkenyl electrophile synthesis from unactivated olefins that is based on a direct and regioselective C?H thianthrenation reaction. The selectivity is proposed to arise from an unusual inverse‐electron‐demand hetero‐Diels–Alder reaction. The alkenyl sulfonium salts can serve as electrophiles in palladium‐ and ruthenium‐catalyzed cross‐coupling reactions to make alkenyl C?C, C?Cl, C?Br, and C?SCF₃ bonds with stereoretention.     

Recent Progress in Application of Graphene Supported Metal Nanoparticles in C−C and C−X Coupling Reactions

The carbon‐carbon and carbon‐heteroatom bonds catalytic formation is among the most significant reactions in organic synthesis which extensively applied for synthesis of natural products, heterocycles, dendrimers, biologically active molecules and useful compounds. This review provides the latest advances in the preparation of graphene supported metal nanoparticles and their application in the catalytic formation of both carbon‐carbon (C−C) and carbon‐heteroatom (C−X) bonds including the Suzuki, Heck, Hiyama, Ullmann, Buchwald and Sonogashira coupling reactions. Numerous examples are given concerning the use of these catalysts in C−C and C−X coupling reactions along with the reliable and simple preparation methods of these catalysts, their characterization and catalytic properties and also the recycling possibilities.     

Regioselective Acceptorless Dehydrogenative Coupling of N‐Heterocycles toward Functionalized Quinolines,Phenanthrolines, and Indoles

A new strategy has been developed for the oxidant‐ and base‐free dehydrogenative coupling of N‐heterocycles at mild conditions. Under the action of an iridium catalyst, N‐heterocycles undergo multiple sp³ C? H activation steps, generating a nucleophilic enamine that reacts in situ with various electrophiles to give highly functionalized products. The dehydrogenative coupling can be cascaded with Friedel–Crafts addition, resulting in a double functionalization of the N‐heterocycles.     

Formation of C(sp3)–C(sp3) Bonds through Nickel‐Catalyzed Decarboxylative Olefin Hydroalkylation Reactions

Olefins and carboxylic acids are among the most important feedstock compounds. They are commonly found in natural products and drug molecules. We report a new reaction of nickel‐catalyzed decarboxylative olefin hydroalkylation, which provides a novel practical strategy for the construction of C(sp³)?C(sp³) bonds. This reaction can tolerate a variety of synthetically relevant functional groups and shows good chemo‐ and regioselectivity. It enables cross‐coupling of complex organic molecules containing olefin groups and carboxylic acid groups in a convergent fashion.     

Electrochemical Oxidative C−H Amination of Phenols: Access to Triarylamine Derivatives

Dehydrogenative C?H/N?H cross‐coupling serves as one of the most straightforward and atom‐economical approaches for C?N bond formation. In this work, an electrochemical reaction protocol has been developed for the oxidative C?H amination of unprotected phenols under undivided electrolytic conditions. Neither metal catalysts nor chemical oxidants are needed to facilitate the dehydrogenation process. A series of triarylamine derivatives could be obtained with good functional‐group tolerance. The electrolysis is scalable and can be performed at ambient conditions.     

Pd/C as a Catalyst for Completely Regioselective CH Functionalization of Thiophenes under Mild Conditions

The completely C3‐selective arylation of thiophenes and benzo[b]thiophenes was achieved by using Pd/C as a heterogeneous catalyst without ligands or additives under mild reaction conditions. The practicability of this transformation is demonstrated by notable functional group tolerance and the insensitivity of the reaction to H₂O and air. This method is also applicable to nitrogen‐ and oxygen‐containing heterocycles, yielding the corresponding C2‐arylated products. Three‐phase tests along with Hg‐poisoning and hot‐filtration tests suggest that the catalytically active species is heterogeneous in nature.     

Electrochemical C−H Amination by Cobalt Catalysis in a Renewable Solvent

Syntheses of substituted anilines primarily rely on palladium‐catalyzed coupling chemistry with prefunctionalized aryl electrophiles. While oxidative aminations have emerged as powerful alternatives, they largely produce undesired metal‐containing by‐products in stoichiometric quantities. In contrast, described herein is the unprecedented electrochemical C?H amination by cobalt‐catalyzed C?H activation. The environmentally benign electrocatalysis avoids stoichiometric metal oxidants, can be conducted under ambient air, and employs a biomass‐derived, renewable solvent for sustainable aminations in an atom‐ and step‐economical manner with H₂ as the sole byproduct.     

Scalable Photoelectrochemical Dehydrogenative Cross‐Coupling of Heteroarenes with Aliphatic C−H Bonds

Heteroarenes are structural motifs found in many bioactive compounds and functional materials. Dehydrogenative cross‐coupling of heteroarenes with aliphatic C?H bonds provides straightforward access to functionalized heteroarenes from readily available materials. Established methods employ stoichiometric chemical oxidants under conditions of heating or light irradiation. By merging electrochemistry and photochemistry, we have achieved efficient photoelectrochemical dehydrogenative cross‐coupling of heteroarenes and C(sp³)?H donors through H₂ evolution, without the addition of metal catalysts or chemical oxidants. Mechanistically, the C(sp³)?H donor is converted to a nucleophilic carbon radical through H‐atom transfer with chlorine atom, which is produced by light irradiation of anodically generated Cl₂ from Cl^?. The carbon radical then undergoes radical substitution to the heteroarene to afford alkylated heteroarene products.     

Rhodium(III)‐Catalyzed Enantio‐ and Diastereoselective C−H Cyclopropylation of N‐Phenoxylsulfonamides: Combined Experimental and Computational Studies

Cyclopropane rings are a prominent structural motif in biologically active molecules. Enantio‐ and diastereoselective construction of cyclopropanes through C?H activation of arenes and coupling with readily available cyclopropenes is highly appealing but remains a challenge. A dual directing‐group‐assisted C?H activation strategy was used to realize mild and redox‐neutral Rh^III‐catalyzed C?H activation and cyclopropylation of N‐phenoxylsulfonamides in a highly enantioselective, diastereoselective, and regioselective fashion with cyclopropenyl secondary alcohols as a cyclopropylating reagent. Synthetic applications are demonstrated to highlight the potential of the developed method. Integrated experimental and computational mechanistic studies revealed that the reaction proceeds via a Rh^V nitrenoid intermediate, and Noyori‐type outer sphere concerted proton‐hydride transfer from the secondary alcohol to the Rh=N bond produces the observed trans selectivity.     

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).     

Rhodium(III)‐Catalyzed ortho Alkenylation of N‐Phenoxyacetamides with N‐Tosylhydrazones or Diazoesters through CH Activation

A coupling reaction of N‐phenoxyacetamides with N‐tosylhydrazones or diazoesters through Rh^III‐catalyzed C? H activation is reported. In this reaction, ortho‐alkenyl phenols were obtained in good yields and with excellent regio‐ and stereoselectivity. Rh–carbene migratory insertion is proposed as the key step in the reaction mechanism.