Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

Expanding the toolbox of C−H functionalization reactions applicable to the late-stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition-metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C−H bond. However, these high-energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C−H functionalization reactions with diazoacetate derivatives, furnishing sp²–sp³ coupled products with moderate-to-good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition-metal catalyst.     

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.     

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.     

Copper‐Catalyzed C(sp3)−H Amidation: Sterically Driven Primary and Secondary C−H Site‐Selectivity

Undirected C(sp³)?H functionalization reactions often follow site‐selectivity patterns that mirror the corresponding C?H bond dissociation energies (BDEs). This often results in the functionalization of weaker tertiary C?H bonds in the presence of stronger secondary and primary bonds. An important, contemporary challenge is the development of catalyst systems capable of selectively functionalizing stronger primary and secondary C?H bonds over tertiary and benzylic C?H sites. Herein, we report a Cu catalyst that exhibits a high degree of primary and secondary over tertiary C?H bond selectivity in the amidation of linear and cyclic hydrocarbons with aroyl azides ArC(O)N₃. Mechanistic and DFT studies indicate that C?H amidation involves H‐atom abstraction from R‐H substrates by nitrene intermediates [Cu](κ²‐N,O‐NC(O)Ar) to provide carbon‐based radicals R^. and copper(II)amide intermediates [Cu^II]‐NHC(O)Ar that subsequently capture radicals R^. to form products R‐NHC(O)Ar. These studies reveal important catalyst features required to achieve primary and secondary C?H amidation selectivity in the absence of directing groups.     

Access to β‐Lactams by Enantioselective Palladium(0)‐Catalyzed C(sp3)H Alkylation

β‐Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring‐opening reactions. Transition‐metal‐catalyzed C? H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd⁰‐catalyzed C? H functionalization for aryl–aryl couplings, related reactions involving the formation of saturated C(sp³)? C(sp³) bonds are elusive. Reported here is an asymmetric C? H functionalization approach to β‐lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp³)? C(sp³) and strain‐building reductive eliminations to for the four‐membered ring. In general, the β‐lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.     

Transition‐Metal‐Free Deconstructive Lactamization of Piperidines

One of the major challenges in organic synthesis is the activation or deconstructive functionalization of unreactive C(sp³)–C(sp³) bonds, which requires using transition or precious metal catalysts. We present here an alternative: the deconstructive lactamization of piperidines without using transition metal catalysts. To this end, we use 3‐alkoxyamino‐2‐piperidones, which were prepared from piperidines through a dual C(sp³)–H oxidation, as transitory intermediates. Experimental and theoretical studies confirm that this unprecedented lactamization occurs in a tandem manner involving an oxidative deamination of 3‐alkoxyamino‐2‐piperidones to 3‐keto‐2‐piperidones, followed by a regioselective Baeyer–Villiger oxidation to give N‐carboxyanhydride intermediates, which finally undergo a spontaneous and concerted decarboxylative intramolecular translactamization.     

Transition Metal‐Catalyzed Carbonylative CH Bond Functionalization of Arenes and C(sp3)H Bond of Alkanes

In this article, we present the progress made in the area of carbonylative C? H functionalization, with special emphasis on arenes and alkanes. The importance of directing group assistance and C? H functionalization using CO surrogates is also included. The budding development in the area of transition metal‐catalyzed C(sp³)? H activation makes us feel it necessary to file a summary on the past, as well as current, contributions and a prospective outlook on the transition metal‐catalyzed carbonylative transformation of C? H bonds, which is the focus of this review.     

Functionalization of C‐H Bonds by Photoredox Catalysis

Visible‐light photoredox catalysis has been successfully used in the functionalization of inert C?H bonds including C(sp²)‐H bonds of arenes and C(sp³)‐H bonds of aliphatic compounds over the past decade. These transformations are typically promoted by the process of single‐electron‐transfer (SET) between substrates and photo‐excited photocatalyst upon visible light irradiation (household bulbs or LEDs). Compared with other synthetic strategies, such as the transition‐metal catalysis and traditional radical reactions, visible‐light photoredox approach has distinct advantages in terms of operational simplicity and practicability. Versatile direct functionalization of inert C(sp²)‐H and C(sp³)‐H bonds including alkylation, trifluoromethylation, arylation and amidation, has been achieved using this practical strategy.     

Merging Photochemistry with Electrochemistry: Functional‐Group Tolerant Electrochemical Amination of C(sp3)−H Bonds

Direct amination of C(sp³)?H bonds is of broad interest in the realm of C?H functionalization because of the prevalence of nitrogen heterocycles and amines in pharmaceuticals and natural products. Reported here is a combined electrochemical/photochemical method for dehydrogenative C(sp³)?H/N?H coupling that exhibits good reactivity with both sp² and sp³ N?H bonds. The results show how use of iodide as an electrochemical mediator, in combination with light‐induced cleavage of intermediate N?I bonds, enables the electrochemical process to proceed at low electrode potentials. This approach significantly improves the functional‐group compatibility of electrochemical C?H amination, for example, tolerating electron‐rich aromatic groups that undergo deleterious side reactions in the presence of high electrode potentials.     

The Fluorination of C−H Bonds: Developments and Perspectives

This Review summarizes advances in fluorination by C(sp²)?H and C(sp³)?H activation. Transition‐metal‐catalyzed approaches championed by palladium have allowed the installation of a fluorine substituent at C(sp²) and C(sp³) sites, exploiting the reactivity of high‐oxidation‐state transition‐metal fluoride complexes combined with the use of directing groups (some transient) to control site and stereoselectivity. The large majority of known methods employ electrophilic fluorination reagents, but methods combining a nucleophilic fluoride source with an oxidant have appeared. External ligands have proven to be effective for C(sp³)?H fluorination directed by weakly coordinating auxiliaries, thereby enabling control over reactivity. Methods relying on the formation of radical intermediates are complementary to transition‐metal‐catalyzed processes as they allow for undirected C(sp³)?H fluorination. To date, radical C?H fluorinations mainly employ electrophilic N?F fluorination reagents but a unique Mn^III‐catalyzed oxidative C?H fluorination using fluoride has been developed. Overall, the field of late‐stage nucleophilic C?H fluorination has progressed much more slowly, a state of play explaining why C?H ¹⁸F‐fluorination is still in its infancy.     

Predictable Selectivity in Remote C−H Oxidation of Steroids: Analysis of Substrate Binding Mode

Predictability is a key requirement to encompass late‐stage C?H functionalization in synthetic routes. However, prediction (and control) of reaction selectivity is usually challenging, especially for complex substrate structures and elusive transformations such as remote C(sp³)?H oxidation, as it requires distinguishing a specific C?H bond from many others with similar reactivity. Developed here is a strategy for predictable, remote C?H oxidation that entails substrate binding to a supramolecular Mn or Fe catalyst followed by elucidation of the conformation of the host‐guest adduct by NMR analysis. These analyses indicate which remote C?H bonds are suitably oriented for the oxidation before carrying out the reaction, enabling prediction of site selectivity. This strategy was applied to late‐stage C(sp³)?H oxidation of amino‐steroids at C15 (or C16) positions, with a selectivity tunable by modification of catalyst chirality and metal.     

Nickel‐Catalyzed Site‐Selective Amidation of Unactivated C(sp3)H Bonds

Intramolecular dehydrogenative cyclization of aliphatic amides was achieved on unactivated sp³ carbon atoms by a nickel‐catalyzed C?H bond functionalization process with the assistance of a bidentate directing group. The reaction favors the C?H bonds of β‐methyl groups over the γ‐methyl or β‐methylene groups. Additionally, a predominant preference for the β‐methyl C?H bonds over the aromatic sp² C?H bonds was observed. Moreover, this process also allows for the effective functionalization of benzylic secondary sp³ C?H bonds.     

Synergistic Catalysis for the Umpolung Trifluoromethylthiolation of Tertiary Ethers

The first transition‐metal‐free, site‐specific umpolung trifluoromethylthiolation of tertiary alkyl ethers has been developed, achieving the challenging tertiary C(sp³)–SCF₃ coupling under redox‐neutral conditions. The synergism of organophotocatalyst 4CzIPN and BINOL‐based phosphorothiols can site‐selectively cleave tertiary sp³ C(sp³)–O ether bonds in complex molecules initiated by a polarity‐matching hydrogen‐atom‐transfer (HAT) event. The incorporation of several competing benzylic and methine C(sp³)?H bonds in alkyl ethers has little influence on the regioselectivity. Selective difluoromethylthiolation of C?O bonds has also been achieved. This represents not only an important step forward in trifluoromethylthiolation but also a promising means for site‐selective C?O bond functionalization of unsymmetrical tertiary alkyl ethers.     

Copper‐Catalyzed Site‐Selective Intramolecular Amidation of Unactivated C(sp3)H Bonds

The intramolecular dehydrogenative amidation of aliphatic amides, directed by a bidentate ligand, was developed using a copper‐catalyzed sp³ C? H bond functionalization process. The reaction favors predominantly the C? H bonds of β‐methyl groups over the unactivated methylene C? H bonds. Moreover, a preference for activating sp³ C? H bonds of β‐methyl groups, via a five‐membered ring intermediate, over the aromatic sp² C? H bonds was also observed in the cyclometalation step. Additionally, sp³ C? H bonds of unactivated secondary sp³ C? H bonds could be functionalized by favoring the ring carbon atoms over the linear carbon atoms.     

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.     

The Redox‐Neutral Approach to C?H Functionalization

The direct functionalization of C? H bonds is an attractive strategy in organic synthesis. Although several advances have been made in this area, the selective activation of inert sp³ C? H bonds remains a daunting challenge. Recently, a new type of sp³ C? H activation mode through internal hydride transfer has demonstrated the potential to activate remote sp³ C? H linkages in an atom‐economic manner. This Minireview attempts to classify recent advances in this area including the transition to non‐activated sp³ C? H bonds and asymmetric hydride transfers.     

Synthesis of Pyrrolophenanthridine Alkaloids Based on C(sp3)H and C(sp2)H Functionalization Reactions

Assoanine, pratosine, hippadine, and dehydroanhydrolycorine belong to the pyrrolophenanthridine family of alkaloids, which are isolated from plants of the Amaryllidaceae species. Structurally, these alkaloids are characterized by a tetracyclic skeleton that contains a biaryl moiety and an indole core, and compounds belonging to this class have received considerable interest from researchers in a number of fields because of their biological properties and the challenges associated with their synthesis. Herein, a strategy for the total synthesis of these alkaloids by using C? H activation chemistry is described. The tetracyclic skeleton was constructed in a stepwise manner by C(sp³)? H functionalization followed by a Catellani reaction, including C(sp²)? H functionalization. A one‐pot reaction involving both C(sp³)? H and C(sp²)? H functionalization was also attempted. This newly developed strategy is suitable for the facile preparation of various analogues because it uses simple starting materials and does not require protecting groups.     

Catalytic Approaches for the Direct Heterofunctionalization of Aliphatic Carboxylic Acids and Their Equivalents with Group 16 Elements

In contrast to traditional multistep synthesis, modern organic synthesis extensively depends on the direct functionalization of unactivated C?H bonds for the construction of various C?C and C‐heteroatom bonds in atom‐ and step‐economic manner. Common aliphatic substrates, e. g. carboxylic acids and their synthetic equivalents, are regiospecifically functionalized based on either a directed approach, in which the polar directing group assists to functionalize a specific C?H bond positioned at β‐ and γ‐carbon centers, or a non‐directed approach typically leading to α‐functionalization. While numerous reviews on catalytic C?H functionalization have appeared, a concise review on the direct C(sp³)?H heterofunctionalization of carboxylic acid synthons with Group 16 elements has been awaited. The recent advances on the direct oxy‐functionalization and chalcogenation of aliphatic carboxylic acid synthons enabled by transition metal, organo‐ and photocatalysts are described herein.     

Access to β‐Lactams by Enantioselective Palladium(0)‐Catalyzed C(sp3)?H Alkylation

β‐Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring‐opening reactions. Transition‐metal‐catalyzed C H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd⁰‐catalyzed C H functionalization for aryl–aryl couplings, related reactions involving the formation of saturated C(sp³) C(sp³) bonds are elusive. Reported here is an asymmetric C H functionalization approach to β‐lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp³) C(sp³) and strain‐building reductive eliminations to for the four‐membered ring. In general, the β‐lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.     

Iridium‐Catalyzed Intermolecular Dehydrogenative Silylation of Polycyclic Aromatic Compounds without Directing Groups

This study describes the iridium‐catalyzed intermolecular dehydrogenative silylation of C(sp²)?H bonds of polycyclic aromatic compounds without directing groups. The reaction produced various arylsilanes through both Si?H and C?H bond activation, with hydrogen as the sole byproduct. Reactivity was affected by the electronic nature of the aromatic compounds, and silylation of electron‐deficient and polycyclic aromatic compounds proceeded efficiently. Site‐selectivity was controlled predominantly by steric factors. Therefore, the current functionalization proceeded with opposite chemo‐ and site‐selectivity compared to that observed for general electrophilic functionalization of aromatic compounds.