Complementary Strategies for Directed C(sp3)−H Functionalization: A Comparison of Transition‐Metal‐Catalyzed Activation,Hydrogen Atom Transfer,and Carbene/Nitrene Transfer

The functionalization of C(sp³)?H bonds streamlines chemical synthesis by allowing the use of simple molecules and providing novel synthetic disconnections. Intensive recent efforts in the development of new reactions based on C?H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths and weaknesses of three main approaches: transition‐metal‐catalyzed C?H activation, 1,n‐hydrogen atom transfer, and transition‐metal‐catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp³)?H bonds. For each strategy, the scope, the reactivity of different C?H bonds, the position of the reacting C?H bonds relative to the directing group, and stereochemical outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C?H functionalization reactions and inspire future research in this area.     

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.     

Sulfilimines as Versatile Nitrene Transfer Reagents: Facile Access to Diverse Aza‐Heterocycles

We herein report the unprecedented synthesis of diverse biologically important aza‐heterocycles by employing sulfilimines as nitrene transfer reagents. This class of sulfur‐based aza‐ylides had not been successfully used for gold nitrene transfer before. This work contains an efficient generation of α‐imino gold carbenes by N?S cleavage of sulfilimines. These gold carbenes undergo C?H insertion, cyclopropanation, and nucleophilic attack to form indoles (44 examples), 3‐azabicyclo[3.1.0]hexan‐2‐imines (24 examples), and imidazoles (3 examples). Our study represents a unique gold‐catalyzed reaction between alkynes and sulfur ylides, and also includes the first aza‐heterocycle synthesis that proceeds by intermolecular nitrene transfer followed by cyclopropanation of the α‐imino gold carbenes. Moreover, an unexpected synthesis of 4‐acylquinolines (3 examples) from 2‐acylphenyl sulfilimines and propargylic silyl ether derivatives by a 1,2‐hydride shift onto the α‐imino gold carbene and a subsequent Mukaiyama aldol cyclization was discovered.     

Palladium‐Catalyzed Asymmetric C(sp3)−H Allylation of 2‐Alkylpyridines

The palladium‐catalyzed asymmetric side‐chain C(α)‐allylation of 2‐alkylpyridines, without using an external base, was developed. The high linear selectivities and enantioselectivities were achieved using new chiral diamidophosphite monodentate ligands. Given that the reaction conditions do not require an external base, this catalyst system enabled chemoselective C(α)‐allylation of 2‐alkylpyridines containing α‐carbonyl C?H bonds, which are more acidic than α‐pyridyl C?H bonds.     

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.     

C−H Bond Activation by an Imido Cobalt(III) and the Resulting Amido Cobalt(II) Complex

The 3d‐metal mediated nitrene transfer is under intense scrutiny due to its potential as an atom economic and ecologically benign way for the directed amination of (un)functionalised C?H bonds. Here we present the isolation and characterisation of a rare, trigonal imido cobalt(III) complex, which bears a rather long cobalt–imido bond. It can cleanly cleave strong C?H bonds with a bond dissociation energy of up to 92 kcal mol^?1 in an intermolecular fashion, unprecedented for imido cobalt complexes. This resulted in the amido cobalt(II) complex [Co(hmds)₂(NH^tBu)]^?. Kinetic studies on this reaction revealed an H atom transfer mechanism. Remarkably, the cobalt(II) amide itself is capable of mediating H atom abstraction or stepwise proton/electron transfer depending on the substrate. A cobalt‐mediated catalytic application for substrate dehydrogenation using an organo azide is presented.     

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.     

Anthranil: An Aminating Reagent Leading to Bifunctionality for Both C(sp3)−H and C(sp2)−H under Rhodium(III) Catalysis

Previous direct C?H nitrogenation suffered from simple amidation/amination with limited atom‐economy and is mostly limited to C(sp²)?H substrates. In this work, anthranil was designed as a novel bifunctional aminating reagent for both C(sp²)?H and C(sp³)?H bonds under rhodium(III) catalysis, thus affording a nucleophilic aniline tethered to an electrophilic carbonyl. A tridendate rhodium(III) complex has been isolated as the resting state of the catalyst, and DFT studies established the intermediacy of a nitrene species.     

Highly Stereoselective Cobalt(III)‐Catalyzed Three‐Component C−H Bond Addition Cascade

A highly stereoselective three‐component C(sp²)?H bond addition across alkene and polarized π‐bonds is reported for which Co^III catalysis was shown to be much more effective than Rh^III. The reaction proceeds at ambient temperature with both aryl and alkyl enones employed as efficient coupling partners. Moreover, the reaction exhibits extremely broad scope with respect to the aldehyde input; electron rich and poor aromatic, alkenyl, and branched and unbranched alkyl aldehydes all couple in good yield and with high diastereoselectivity. Multiple directing groups participate in this transformation, including pyrazole, pyridine, and imine functional groups. Both aromatic and alkenyl C(sp²)?H bonds undergo the three‐component addition cascade, and the alkenyl addition product can readily be converted into diastereomerically pure five‐membered lactones. Additionally, the first asymmetric reactions with Co^III‐catalyzed C?H functionalization are demonstrated with three‐component C?H bond addition cascades employing N‐tert‐butanesulfinyl imines. These examples represent the first transition metal catalyzed C?H bond additions to N‐tert‐butanesulfinyl imines, which are versatile and extensively used intermediates for the asymmetric synthesis of amines.     

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.     

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.     

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.     

Recent Trends in Copper‐Catalyzed C−H Amination Routes to Biologically Important Nitrogen Scaffolds

Nitrogen‐containing heterocycles have found remarkable applications in natural product research, material sciences, and pharmaceuticals. Although the synthesis of this interesting class of compounds attracted the interest of generations of organic chemists, simple and straightforward assembly methods based on transition‐metal catalysis have regularly been elusive. The recent advancements in the development of C?H functionalization have helped in accomplishing the synthesis of a variety of complex heterocycles from simple precursors. This Focus Review summarizes the recent advances in one particular field: the copper‐catalyzed C?N bond formation reactions via C?H bond functionalization to furnish a comprehensive range of nitrogen heterocycles. Applicability and synthetic feasibility of a particular reaction represent major requirements for the inclusion in this review.     

Rh(III)‐Catalyzed Denitrogenative [4+2] Annulation of Benzamides and 3‐Diazoindolin‐2‐imines: Expedient Access to Indolo[2,3‐c] isoquinolin‐5‐ones

An effective and pragmatic strategy for the synthesis of structurally diverse indolo[2,3‐c]isoquinolin‐5‐ones has been developed via a Rh(III)‐catalyzed C?H activation and [4+2] annulation reaction of N‐methoxybenzamides and 3‐diazoindolin‐2‐imines. The reaction involves the efficient formation of two new (one C?C and one C?N) bonds under operationally simple conditions and has the benefits of a broad substrate scope.     

A Light/Ketone/Copper System for Carboxylation of Allylic C−H Bonds of Alkenes with CO2

A photo‐induced carboxylation reaction of allylic C?H bonds of simple alkenes with CO₂ is prompted by means of a ketone and a copper complex. The unique carboxylation reaction proceeds through a sequence of an endergonic photoreaction of ketones with alkenes forming homoallyl alcohol intermediates and a thermal copper‐catalyzed allyl transfer reaction from the homoallyl alcohols to CO₂ through C?C bond cleavage.     

Oxidative Alkane C−H Alkoxycarbonylation

Directly utilizing a chemical feedstock to construct valuable compounds is an attractive prospect in organic synthesis. In particular, the combination of C(sp³)?H activation and oxidative carbonylation involving alkanes and CO gas is a promising and efficient method to synthesize carbonyl derivatives. However, due to the high C?H bond dissociation energy and low polarity of unactivated alkanes, the carbonylation of unactivated C(sp³)?H bonds still remains a great challenge. In this work, we introduce a palladium‐catalyzed radical oxidative alkoxycarbonylation of alkanes to prepare numerous alkyl carboxylates. Various alkanes and alcohols were compatible, generating the desired products in up to 94 % yield. Remarkably, ethane, a constituent of natural gas, could be employed as a substrate under the standard reaction conditions. Preliminary mechanistic studies revealed a probable palladium‐catalyzed radical process.     

C7‐Indole Amidations and Alkenylations by Ruthenium(II) Catalysis

C7?H‐functionalized indoles are ubiquitous structural units of biological and pharmaceutical compounds for numerous antiviral agents against SARS‐CoV or HIV‐1. Thus, achieving site‐selective functionalizations of the C7?H position of indoles, while discriminating among other bonds, is in high demand. Herein, we disclose site‐selective C7?H activations of indoles by ruthenium(II) biscarboxylate catalysis under mild conditions. Base‐assisted internal electrophilic‐type substitution C?H ruthenation by weak O‐coordination enabled the C7?H functionalization of indoles and offered a broad scope, including C?N and C?C bond formation. The versatile ruthenium‐catalyzed C7?H activations were characterized by gram‐scale syntheses and the traceless removal of the directing group, thus providing easy access to pharmaceutically relevant scaffolds. Detailed mechanistic studies through spectroscopic and spectrometric analyses shed light on the unique nature of the robust ruthenium catalysis for the functionalization of the C7?H position of indoles.     

Visible‐Light‐Enabled Ruthenium‐Catalyzed meta‐C−H Alkylation at Room Temperature

Visible‐light‐induced ruthenium catalysis has enabled remote C?H alkylations with excellent levels of position control under exceedingly mild conditions at room temperature. The metallaphotocatalysis occurred under exogenous‐photosensitizer‐free conditions and features an ample substrate scope. The robust nature of the photo‐induced mild meta‐C?H functionalization is reflected by the broad functional group tolerance, and the reaction can be carried out in an operationally simple manner, setting the stage for challenging secondary and tertiary meta‐C?H alkylations by ruthenaphotoredox catalysis.     

Visible‐Light‐Driven Photocatalytic Activation of Inert Sulfur Ylides for 3‐Acyl Oxindole Synthesis

Bicarbonyl‐substituted sulfur ylide is a useful, but inert reagent in organic synthesis. Usually, harsh reaction conditions are required for its transformation. For the first time, it was demonstrated that a new, visible‐light photoredox catalytic annulation of sulfur ylides under extremely mild conditions, permits the synthesis of oxindole derivatives in high selectivities and efficiencies. The key to its success is the photocatalytic single‐electron‐transfer (SET) oxidation of the inert amide and acyl‐stabilized sulfur ylides to reactive radical cations, which easily proceeds with intramolecular C?H functionalization to give the final products.     

Nucleophilic Iron Complexes in Proton‐Transfer Catalysis: An Iron‐Catalyzed Dimroth Cyclocondensation

The nucleophilic iron complex Bu₄N[Fe(CO)₃(NO)] (TBA[Fe]) is an active catalyst in C?H‐amination but also in proton‐transfer catalysis. Herein, we describe the successful use of this complex as a proton‐transfer catalyst in the cyclocondensation reaction between azides and ketones to the corresponding 1,2,3‐triazoles. Cross‐experiments indicate that the proton‐transfer catalysis is significantly faster than the nitrene‐transfer catalysis, which would lead to the C?H amination product. An example of a successful sequential Dimroth triazole–indoline synthesis to the corresponding triazole‐substituted indolines is presented.