Intermolecular 1,4‐Carboamination of Conjugated Dienes Enabled by Cp*RhIII‐Catalyzed C−H Activation

A protocol for the three‐component 1,4‐carboamination of dienes is described. Synthetically versatile Weinreb amides were coupled with 1,3‐dienes and readily available dioxazolones as the nitrogen source using [Cp*RhCl₂]₂‐catalyzed C?H activation to deliver the 1,4‐carboaminated products. This transformation proceeds under mild reaction conditions and affords the products with high levels of regio‐ and E‐selectivity. Mechanistic investigations suggest an intermediate Rh^III–allyl species is trapped by an electrophilic amidation reagent in a redox‐neutral fashion.     

Palladium‐Catalyzed C−H Alkynylation of Unactivated Alkenes

Palladium‐catalyzed regio‐ and diastereoselective C?H functionalization with bromoalkynes and electronically unbiased olefins is reported. The picolinamide directing group enables the formation of putative 5 and 6‐exo‐metallacycles as intermediates to afford monoalkynylated products in up to 91 % yield in a stereospecific fashion. The systematic study reveals that substrates with a wide range of substituents on the olefin and bromoalkyne coupling partners are tolerated. Chemoselective transformations were demonstrated for the obtained amides, olefins, and alkynes.     

Cooperative Lewis Acid/Cp*CoIII Catalyzed C−H Bond Activation for the Synthesis of Isoquinolin‐3‐ones

A facile route toward the synthesis of isoquinolin‐3‐ones through a cooperative B(C₆F₅)₃‐ and Cp*Co^III‐catalyzed C?H bond activation of imines with diazo compounds is presented. The inclusion of a catalytic amount of B(C₆F₅)₃ results in a highly efficient reaction, thus enabling unstable NH imines to serve as substrates.     

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).     

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.     

Mild C−H/C−C Activation by Z‐Selective Cobalt Catalysis

Cationic cobalt complexes enable unprecedented cobalt‐catalyzed C?H/C?C functionalizations with unique selectivity features. The versatile cobalt catalyst proved broadly applicable, enabled efficient C?H/C?C cleavage at room temperature, and delivered Z‐alkenes with excellent diastereocontrol.     

Enaminones as Synthons for a Directed C−H Functionalization: RhIII‐Catalyzed Synthesis of Naphthalenes

The use of enaminones as effective synthons for a directed C?H functionalization is reported. Proof‐of‐concept protocols have been developed for the Rh^III‐catalyzed synthesis of naphthalenes, based on the coupling of enaminones with either alkynes or α‐diazo‐β‐ketoesters. Two inherently reactive functionalities (hydroxy and aldehyde groups) are integrated into the newly formed cyclic framework and a broad range of substituents are tolerated, rendering target products readily available for further elaboration.     

Micellar Catalysis for Ruthenium(II)‐Catalyzed C−H Arylation: Weak‐Coordination‐Enabled C−H Activation in H2O

Chemoselective C?H arylations were accomplished through micellar catalysis by a versatile single‐component ruthenium catalyst. The strategy provided expedient access to C?H‐arylated ferrocenes with wide functional‐group tolerance and ample scope through weak chelation assistance. The sustainability of the C?H arylation was demonstrated by outstanding atom‐economy and recycling studies. Detailed computational studies provided support for a facile C?H activation through thioketone assistance.     

Copper‐Catalyzed N−F Bond Activation for Uniform Intramolecular C−H Amination Yielding Pyrrolidines and Piperidines

The dual function of the N?F bond as an effective oxidant and subsequent nitrogen source in intramolecular aliphatic C?H functionalization reactions is explored. Copper catalysis is demonstrated to exercise full regio‐ and chemoselectivity control, which opens new synthetic avenues to nitrogenated heterocycles with predictable ring sizes. For the first time, a uniform catalysis manifold has been identified for the construction of both pyrrolidine and piperidine cores. The individual steps of this new copper oxidation catalysis were elucidated by control experiments and computational studies, clarifying the singularity of the N?F function and characterizing the catalytic cycle to be based on a copper(I/II) manifold.     

C−H Bond Activation/Arylation Catalyzed by Arene–Ruthenium–Aniline Complexes in Water

Water‐soluble arene–ruthenium complexes coordinated with readily available aniline‐based ligands were successfully employed as highly active catalysts in the C?H bond activation and arylation of 2‐phenylpyridine with aryl halides in water. A variety of (hetero)aryl halides were also used for the ortho‐C?H bond arylation of 2‐phenylpyridine to afford the corresponding ortho‐ monoarylated products as major products in moderate to good yields. Our investigations, including time‐scaled NMR spectroscopy and mass spectrometry studies, evidenced that the coordinating aniline‐based ligands, having varying electronic and steric properties, had a significant influence on the catalytic activity of the resulting arene–ruthenium–aniline‐based complexes. Moreover, mass spectrometry identification of the cycloruthenated species, {(η⁶‐arene)Ru(κ²‐C,N‐phenylpyridine)}⁺, and several ligand‐coordinated cycloruthenated species, such as [(η⁶‐arene)Ru(4‐methylaniline)(κ²‐C,N‐phenylpyridine)]⁺, found during the reaction of 2‐phenylpyridine with the arene–ruthenium–aniline complexes further authenticated the crucial roles of these species in the observed highly active and tuned catalyst. At last, the structures of a few of the active catalysts were also confirmed by single‐crystal X‐ray diffraction studies.     

Manganese‐Catalyzed Redox‐Neutral C−H Olefination of Ketones with Unactivated Alkenes

Since 1987, stoichiometric cyclomanganation of ketones and subsequent reactions with olefins in the presence of either palladium salts or trimethylamine N‐oxide (Me₃N⁺O^?) have been reported, but the catalytic versions remain untouched so far. Herein, the first manganese‐catalyzed redox‐neutral C?H olefination of ketones with unactivated alkenes is described, and shows a distinct reactivity with its parent stoichimetric reactions. Remarkably, mechanistic experiments and DFT calculations uncovers a unique concerted bis‐metalation deprotonation (CBMD) mechanism of the Mn‐Zn‐enabled C?H bond activation.     

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.     

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.     

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.     

Rhodium‐Catalyzed Enantioselective Silylation of Cyclopropyl C−H Bonds

Hydrosilyl ethers, generated in situ by the dehydrogenative silylation of cyclopropylmethanols with diethylsilane, undergo asymmetric, intramolecular silylation of cyclopropyl C?H bonds in high yields and with high enantiomeric excesses in the presence of a rhodium catalyst derived from a rhodium precursor and the bisphosphine (S)‐DTBM‐SEGPHOS. The resulting enantioenriched oxasilolanes are suitable substrates for the Tamao–Fleming oxidation to form cyclopropanols with conservation of the ee value from the C?H silylation. Preliminary mechanistic data suggest that C?H cleavage is likely to be the turnover‐limiting and enantioselectivity‐determining step.     

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.     

Solvent‐Dependent Asymmetric Synthesis of Alkynyl and Monofluoroalkenyl Isoindolinones by CpRhIII‐Catalyzed C−H Activation

The asymmetric synthesis of alkynyl and monofluoroalkenyl isoindolinones from N‐methoxy benzamides and α,α‐difluoromethylene alkynes is enabled by C?H activation with a chiral CpRh^III catalyst. Remarkably, product formation is solvent‐dependent; alkynyl isoindolinones are afforded in MeOH (up to 86 % yield, 99.6 % ee) whereas monofluoroalkenyl isoindolinones are generated in ⁱPrCN (up to 98:2 Z/E, 93 % yield, 86 % ee). Mechanistic studies revealed chiral allene and E‐configured alkenyl rhodium species as reaction intermediates. The latter is transformed into the corresponding Z‐configured monofluoroalkene upon protonation in the ⁱPrCN system and into an alkyne by an unusual anti β‐F elimination in the MeOH system. Notably, kinetic resolution processes occur in this reaction. Despite the moderate enantiocontrol for the formation of the chiral allene, the Z‐monofluoroalkenyl isoindolinones and alkynyl isoindolinones were obtained in good enantiopurities by one or two sequential kinetic resolution processes.     

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.     

Copper‐Catalyzed Reaction Cascade of Thiophenol Hydroxylation and S‐Arylation through Disulfide‐Directed C−H Activation

Copper‐catalyzed thiophenol C?H activation is described. Through an initial attempt to conduct C‐arylation with arylboronic acid, a rather surprising sequential C?H activation and S‐arylation was discovered. Mechanistic investigation revealed the disulfide intermediate as the key component in directing C?H oxidation. The overall reaction proceeded under mild conditions with molecular oxygen as the oxidant. Discovery of disulfide as the directing group provides a potential new direction for catalytic C?H functionalization under mild conditions.