Cobalt‐Catalyzed Tandem C−H Activation/C−C Cleavage/C−H Cyclization of Aromatic Amides with Alkylidenecyclopropanes

A cobalt‐catalyzed chelation‐assisted tandem C?H activation/C?C cleavage/C?H cyclization of aromatic amides with alkylidenecyclopropanes is reported. This process allows the sequential formation of two C?C bonds, which is in sharp contrast to previous reports on using rhodium catalysts for the formation of C?N bonds. Here the inexpensive catalyst system exhibits good functional‐group compatibility and relatively broad substrate scope. The desired products can be easily transformed into polycyclic lactones with m‐CPBA. Mechanistic studies revealed that the tandem reaction proceeds through a C?H cobaltation, β‐carbon elimination, and intramolecular C?H cobaltation sequence.     

Cobalt‐Catalyzed Oxidative C−H/C−H Cross‐Coupling between Two Heteroarenes

The first example of cobalt‐catalyzed oxidative C?H/C?H cross‐coupling between two heteroarenes is reported, which exhibits a broad substrate scope and a high tolerance level for sensitive functional groups. When the amount of Co(OAc)₂?4 H₂O is reduced from 6.0 to 0.5 mol %, an excellent yield is still obtained at an elevated temperature with a prolonged reaction time. The method can be extended to the reaction between an arene and a heteroarene. It is worth noting that the Ag₂CO₃ oxidant is renewable. Preliminary mechanistic studies by radical trapping experiments, hydrogen/deuterium exchange experiments, kinetic isotope effect, electron paramagnetic resonance (EPR), and high resolution mass spectrometry (HRMS) suggest that a single electron transfer (SET) pathway is operative, which is distinctly different from the dual C?H bond activation pathway that the well‐described oxidative C?H/C?H cross‐coupling reactions between two heteroarenes typically undergo.     

Electrochemical C−H/N−H Activation by Water‐Tolerant Cobalt Catalysis at Room Temperature

Electrochemistry enabled C?H/N?H functionalizations at room temperature by external oxidant‐free cobalt catalysis. Thus, the sustainable cobalt electrocatalysis manifold proceeds with excellent levels of chemoselectivity and positional selectivity, and with ample scope, thus allowing electrochemical C?H activation under exceedingly mild reaction conditions at room temperature in water.     

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.     

Insights into Cobalta(III/IV/II)‐Electrocatalysis: Oxidation‐Induced Reductive Elimination for Twofold C−H Activation

The merger of cobalt‐catalyzed C?H activation and electrosynthesis provides new avenues for resource‐economical molecular syntheses, unfortunately their reaction mechanisms remain poorly understood. Herein, we report the identification and full characterization of electrochemically generated high‐valent cobalt(III/IV) complexes as crucial intermediates in electrochemical cobalt‐catalyzed C?H oxygenations. Detailed mechanistic studies provided support for an oxidatively‐induced reductive elimination via highly‐reactive cobalt(IV) intermediates. These key insights set the stage for unprecedented cobaltaelectro two‐fold C?H/C?H activation.     

1,4‐Iron Migration for Expedient Allene Annulations through Iron‐Catalyzed C−H/N−H/C−O/C−H Functionalizations

C?H activation bears great potential for enabling sustainable molecular syntheses in a step‐ and atom‐economical manner, with major advances having been realized with precious 4d and 5d transition metals. In contrast, we employed earth abundant, nontoxic iron catalysts for versatile allene annulations through a unique C?H/N?H/C?O/C?H functionalization sequence. The powerful iron catalysis occurred under external‐oxidant‐free conditions even at room temperature, while detailed mechanistic studies revealed an unprecedented 1,4‐iron migration regime for facile C?H activations.     

Cobalt‐Catalyzed Oxidase C−H/N−H Alkyne Annulation: Mechanistic Insights and Access to Anticancer Agents

Cp*‐free cobalt‐catalyzed alkyne annulations by C?H/N?H functionalizations were accomplished with molecular O₂ as the sole oxidant. The user‐friendly oxidase strategy proved viable with various internal and terminal alkynes through kinetically relevant C?H cobaltation, providing among others step‐economical access to the anticancer topoisomerase‐I inhibitor 21,22‐dimethoxyrosettacin. DFT calculations suggest that electronic effects control the regioselectivity of the alkyne insertion step.     

Cobalt(III)‐Catalyzed Intramolecular Cross‐Dehydrogenative C−H/X−H Coupling: Efficient Synthesis of Indoles and Benzofurans

An efficient cobalt(III)‐catalyzed intramolecular cross‐dehydrogenative C?H/N?H coupling of ortho‐alkenylanilines has been developed utilizing O₂ as a terminal oxidant. The developed reaction tolerates various reactive functional groups and allows the synthesis of diverse indole derivatives in good to excellent yields. The method was successfully extended to the synthesis of benzofurans through the intramolecular cross‐dehydrogenative C?H/O?H coupling of ortho‐alkenylphenols.     

Overcoming the Limitations of C−H Activation with Strongly Coordinating N‐Heterocycles by Cobalt Catalysis

Strongly coordinating nitrogen heterocycles, including pyrimidines, oxazolines, pyrazoles, and pyridines, were fully tolerated in cobalt‐catalyzed C?H amidations by imidate assistance. Structurally complex quinazolines are thus accessible in a step‐economic manner. Our findings also establish the relative powers of directing groups in cobalt(III)‐catalyzed C?H functionalization for the first time.     

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.     

Catalyst‐Dependent Chemoselective Formal Insertion of Diazo Compounds into C−C or C−H Bonds of 1,3‐Dicarbonyl Compounds

A catalyst‐dependent chemoselective one‐carbon insertion of diazo compounds into the C?C or C?H bonds of 1,3‐dicarbonyl species is reported. In the presence of silver(I) triflate, diazo insertion into the C(=O)?C bond of the 1,3‐dicarbonyl substrate leads to a 1,4‐dicarbonyl product containing an all‐carbon α‐quaternary center. This reaction constitutes the first example of an insertion of diazo‐derived carbenoids into acyclic C?C bonds. When instead scandium(III) triflate was applied as the catalyst, the reaction pathway switched to formal C?H insertion, affording 2‐alkylated 1,3‐dicarbonyl products. Different reaction pathways are proposed to account for this powerful catalyst‐dependent chemoselectivity.     

Electrooxidative Rhodium‐Catalyzed C−H/C−H Activation: Electricity as Oxidant for Cross‐Dehydrogenative Alkenylation

Rhodium(III) catalysis has enabled a plethora of oxidative C?H functionalizations, which predominantly employ stoichiometric amounts of toxic and/or expensive metal oxidants. In contrast, we herein describe the first electrochemical rhodium‐catalyzed C?H activation that avoids hazardous chemical oxidants. Environmentally benign twofold C?H/C?H functionalizations were accomplished with weakly coordinating benzoic acids and benzamides, employing electricity as the terminal oxidant and generating H₂ as the sole byproduct.     

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.     

Site‐Selective Remote Radical C−H Functionalization of Unactivated C−H Bonds in Amides Using Sulfone Reagents

A general and practical strategy for remote site‐selective functionalization of unactivated aliphatic C?H bonds in various amides by radical chemistry is introduced. C?H bond functionalization is achieved by using the readily installed N‐allylsulfonyl moiety as an N‐radical precursor. The in situ generated N‐radical engages in intramolecular 1,5‐hydrogen atom transfer to generate a translocated C radical which is subsequently trapped with various sulfone reagents to afford the corresponding C?H functionalized amides. The generality of the approach is documented by the successful remote C?N₃, C?Cl, C?Br, C?SCF₃, C?SPh, and C?C bond formation. Unactivated tertiary and secondary C?H bonds, as well as activated primary C?H bonds, can be readily functionalized by this method.     

Cu/Fe Catalyzed Intermolecular Oxidative Amination of Benzylic C−H Bonds

We report a Cu/Fe co‐catalyzed Ritter‐type C?H activation/amination reaction that allows efficient and selective intermolecular functionalization of benzylic C?H bonds. This new reaction is featured by simple reaction conditions, readily available reagents and general substrate scope, allowing facile synthesis of biologically interesting nitrogen containing heterocycles. The Cu and Fe salts were found to play distinct roles in this cooperative catalysis.     

Copper Catalyzed C−H Activation

Activation of C?H bonds and their application in cross coupling chemistry has received a wider interest in recent years. The conventional strategy in cross coupling reaction involves the pre‐functionalization step of coupling reactants such as organic halides, pseudo‐halides and organometallic reagents. The C?H activation facilitates a simple and straight forward approach devoid of pre‐functionalization step. This approach also addresses the environmental and economical issues involved in several chemical reactions. In this account, we have reported C?H bond activation of small organic molecules, for example, formamide C?H bond can be activated and coupled with β‐dicarbonyl or 2‐carbonyl substituted phenols under oxidative conditions to yield carbamates using inexpensive copper catalysts. Phenyl carbamates were successfully synthesized in moderate to good yields by cross dehydrogenative coupling (CDC) of phenols with formamides using copper catalysts in presence of a ligand. We have also prepared unsymmetrical urea derivatives by oxidative cross coupling of formamides with amines using copper catalysts. Synthesis of N,N‐dimethyl substituted amides, 5‐substituted‐γ‐lactams and α‐acyloxy ethers was carried out from carboxylic acids using recyclable CuO nanoparticles. Copper nanoparticles afforded N‐aryl‐γ‐amino‐γ‐lactams by oxidative coupling of aromatic amines with 2‐pyrrolidinone. Reusable transition metal HT‐derived oxide catalyst was used for the synthesis of N,N‐dimethyl substituted amides by the oxidative cross‐coupling of carboxylic acids and substituted benzaldehydes. Overview of our work in this area is summarized.     

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.     

Diastereoselective [3+2] Annulation of Aromatic/Vinylic Amides with Bicyclic Alkenes through Cobalt‐Catalyzed C−H Activation and Intramolecular Nucleophilic Addition

A highly diastereoselective method for the synthesis of dihydroepoxybenzofluorenone derivatives from aromatic/vinylic amides and bicyclic alkenes is described. This new transformation proceeds through cobalt‐catalyzed C?H activation and intramolecular nucleophilic addition to the amide functional group. Transition‐metal‐catalyzed C?H activation reactions of secondary amides with alkenes usually lead to [4+2] or [4+1] annulation; to the best of our knowledge, this is the first time that a [3+2] cycloaddition is described in this context. The reaction proceeds under mild conditions and tolerates a wide range of functional groups. Mechanistic studies imply that the C?H bond cleavage may be the rate‐limiting step.     

Chemically Non‐Innocent Cyclic (Alkyl)(Amino)Carbenes: Ligand Rearrangement,C−H and C−F Bond Activation

A cyclic (alkyl)(amino)carbene (CAAC) was found to undergo unprecedented rearrangements and transformations of its core structure in the presence of Group 1 and 2 metals. Although the carbene was also found to be prone to intramolecular C?H activation, it was competent for intermolecular activation of a variety of sp‐, sp²‐, and sp³‐hybridized C?H bonds. Double C?F activation of hexafluorobenzene was also observed in this work. These processes all hold relevance to the role of these carbenes in catalysis, as well as to their use in the synthesis of new and unusual main group or transition metal complexes.     

RhI‐Catalyzed Intramolecular Carbonylative C−H/C−I Coupling of 2‐Iodobiphenyls Using Furfural as a Carbonyl Source

Synthesis of fluoren‐9‐ones by a Rh‐catalyzed intramolecular C?H/C?I carbonylative coupling of 2‐iodobiphenyls using furfural as a carbonyl source is presented. The findings indicate that the rate‐determining step is not a C?H bond cleavage but, rather, the oxidative addition of the C?I bond to a Rh^I center.