Iridium‐Catalyzed β‐Alkynylation of Aliphatic Oximes as Masked Carbonyl Compounds and Alcohols

An Ir‐catalyzed C(sp³)?H alkynylation of aliphatic ketones, aldehydes, and alcohols was achieved by using the corresponding oxime derivatives and a Ir^III catalyst. This general reaction is selective towards primary C(sp³)?H bonds and can be used for the late‐stage C?H alkynylation of complex molecules.     

Amidyl Radical Directed Remote Allylation of Unactivated sp3 C−H Bonds by Organic Photoredox Catalysis

The development of visible‐light‐mediated allylation of unactivated sp³ C?H bonds is reported. The remote allylation was directed by the amidyl radical, which was generated by photocatalytic fragmentation of a pre‐functionalized amide precursor. Both aromatic and aliphatic amide derivatives could successfully deliver the remote C?H allylation products in good yields. A variety of electron deficient allyl sulfone systems could be used as δ‐carbon radical acceptor.     

PdII‐Catalyzed Enantioselective C(sp3)–H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group

The use of chiral transient directing groups (TDGs) is a promising approach for developing Pd^II‐catalyzed enantioselective C(sp³)?H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C?H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to Pd^II centers, which can result in a mixture of reactive complexes. We report a Pd^II‐catalyzed enantioselective β‐C(sp³)?H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono‐substituted cyclobutane through sequential C?H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron‐deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.     

A Planar‐Chiral Rhodium(III) Catalyst with a Sterically Demanding Cyclopentadienyl Ligand and Its Application in the Enantioselective Synthesis of Dihydroisoquinolones

The rapid development of enantioselective C?H activation reactions has created a demand for new types of catalysts. Herein, we report the synthesis of a novel planar‐chiral rhodium catalyst [(C₅H₂^tBu₂CH₂^tBu)RhI₂]₂ in two steps from commercially available [(cod)RhCl]₂ and tert‐butylacetylene. Pure enantiomers of the catalyst were obtained through separation of its diastereomeric adducts with natural (S)‐proline. The catalyst promoted enantioselective reactions of aryl hydroxamic acids with strained alkenes to give dihydroisoquinolones in high yields (up to 97 %) and with good stereoselectivity (up to 95 % ee).     

Iron(II)‐Catalyzed Site‐Selective Functionalization of Unactivated C(sp3)−H Bonds Guided by Alkoxyl Radicals

An alkoxyl radical guided strategy for site‐selective functionalization of unactivated methylene and methine C?H bonds enabled by an Fe^II‐catalyzed redox process is described. The mild, expeditious, and modular protocol allows efficient remote aliphatic fluorination, chlorination, amination, and alkynylation of structurally and electronically varied primary, secondary, and tertiary hydroperoxides with excellent functional‐group tolerance. The application for one‐pot 1,4‐hydroxyl functionalization of non‐oxygenated alkane substrates initiated by aerobic C?H oxygenation is also demonstrated.     

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.     

Oxidative Olefination of Anilides with Unactivated Alkenes Catalyzed by an (Electron‐Deficient η5‐Cyclopentadienyl)Rhodium(III) Complex Under Ambient Conditions

The oxidative olefination of sp² C?H bonds of anilides with both activated and unactivated alkenes using an (electron‐deficient η⁵‐cyclopentadienyl)rhodium(III) complex is reported. In contrast to reactions using this electron‐deficient rhodium(III) catalyst, [Cp*RhCl₂]₂ showed no activity against olefination with unactivated alkenes. In addition, the deuterium kinetic isotope effect (DKIE) study revealed that the C?H bond cleavage step is thought to be the turnover‐limiting step.     

Iridium(III)‐Catalyzed Intermolecular C(sp3)−H Insertion Reaction of Quinoid Carbene: A Radical Mechanism

Described herein is an Ir^III/porphyrin‐catalyzed intermolecular C(sp³)?H insertion reaction of a quinoid carbene (QC). The reaction was designed by harnessing the hydrogen‐atom transfer (HAT) reactivity of a metal‐QC species with aliphatic substrates followed by a radical rebound process to afford C?H arylation products. This methodology is efficient for the arylation of activated hydrocarbons such as 1,4‐cyclohexadienes (down to 40 min reaction time, up to 99 % yield, up to 1.0 g scale). It features unique regioselectivity, which is mainly governed by steric effects, as the insertion into primary C?H bonds is favored over secondary and/or tertiary C?H bonds in the substituted cyclohexene substrates. Mechanistic studies revealed a radical mechanism for the reaction.     

Overriding Intrinsic Reactivity in Aliphatic C−H Oxidation: Preferential C3/C4 Oxidation of Aliphatic Ammonium Substrates

The site‐selective C?H oxidation of unactivated positions in aliphatic ammonium chains poses a tremendous synthetic challenge, for which a solution has not yet been found. Here, we report the preferential oxidation of the strongly deactivated C3/C4 positions of aliphatic ammonium substrates by employing a novel supramolecular catalyst. This chimeric catalyst was synthesized by linking the well‐explored catalytic moiety Fe(pdp) to an alkyl ammonium binding molecular tweezer. The results highlight the vast potential of overriding the intrinsic reactivity in chemical reactions by guiding catalysis using supramolecular host structures that enable a precise orientation of the substrates.     

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.     

Aliphatic Radical Relay Heck Reaction at Unactivated C(sp3)−H Sites of Alcohols

The Mizoroki–Heck reaction is one of the most efficient methods for alkenylation of aryl, vinyl, and alkyl halides. Given its innate nature, this protocol requires the employment of compounds possessing a halogen atom at the site of functionalization. However, the accessibility of organic molecules possessing a halogen atom at a particular site in aliphatic systems is extremely limited. Thus, a protocol that allows a Heck reaction to occur at a specific nonfunctionalized C(sp³)?H site is desirable. Reported here is a radical relay Heck reaction which allows selective remote alkenylation of aliphatic alcohols at unactivated β‐, γ‐, and δ‐C(sp³)?H sites. The use of an easily installed/removed Si‐based auxiliary enables selective I‐atom/radical translocation events at remote C?H sites followed by the Heck reaction. Notably, the reaction proceeds smoothly under mild visible‐light‐mediated conditions at room temperature, producing highly modifiable and valuable alkenol products from readily available alcohols feedstocks.     

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.     

Nickel‐Catalyzed Insertion of Alkynes and Electron‐Deficient Olefins into Unactivated sp3 CH Bonds

Insertion of unsaturated systems such as alkynes and olefins into unactivated sp³ C?H bonds remains an unexplored problem. We herein address this issue by successfully incorporating a wide variety of functionalized alkynes and electron‐deficient olefins into the unactivated sp³ C?H bond of pivalic acid derivatives with excellent syn‐ and linear‐ selectivity. A strongly chelating 8‐aminoquinoline directing group proved beneficial for these insertion reactions, while an air‐stable and inexpensive Ni^II salt has been employed as the active catalyst.     

Palladium(0)/PAr3‐Catalyzed Intermolecular Amination of C(sp3)H Bonds: Synthesis of β‐Amino Acids

An intermolecular C(sp³)? H amination using a Pd⁰/PAr₃ catalyst was developed. The reaction begins with oxidative addition of R₂N? OBz to a Pd⁰/PAr₃ catalyst and subsequent cleavage of a C(sp³)? H bond by the generated Pd? NR₂ intermediate. The catalytic cycle proceeds without the need for external oxidants in a similar manner to the extensively studied palladium(0)‐catalyzed C? H arylation reactions. The electron‐deficient triarylphosphine ligand is crucial for this C(sp³)? H amination reaction to occur.     

Axial Ligand and Spin‐State Influence on the Formation and Reactivity of Hydroperoxo–Iron(III) Porphyrin Complexes

The present study focuses on the formation and reactivity of hydroperoxo–iron(III) porphyrin complexes formed in the [Fe^III(tpfpp)X]/H₂O₂/HOO^? system (TPFPP=5,10,15,20‐tetrakis(pentafluorophenyl)‐21H,23H‐porphyrin; X=Cl^? or CF₃SO₃^?) in acetonitrile under basic conditions at ?15 °C. Depending on the selected reaction conditions and the active form of the catalyst, the formation of high‐spin [Fe^III(tpfpp)(OOH)] and low‐spin [Fe^III(tpfpp)(OH)(OOH)] could be observed with the application of a low‐temperature rapid‐scan UV/Vis spectroscopic technique. Axial ligation and the spin state of the iron(III) center control the mode of O? O bond cleavage in the corresponding hydroperoxo porphyrin species. A mechanistic changeover from homo‐ to heterolytic O? O bond cleavage is observed for high‐ [Fe^III(tpfpp)(OOH)] and low‐spin [Fe^III(tpfpp)(OH)(OOH)] complexes, respectively. In contrast to other iron(III) hydroperoxo complexes with electron‐rich porphyrin ligands, electron‐deficient [Fe^III(tpfpp)(OH)(OOH)] was stable under relatively mild conditions and could therefore be investigated directly in the oxygenation reactions of selected organic substrates. The very low reactivity of [Fe^III(tpfpp)(OH)(OOH)] towards organic substrates implied that the ferric hydroperoxo intermediate must be a very sluggish oxidant compared with the iron(IV)–oxo porphyrin π‐cation radical intermediate in the catalytic oxygenation reactions of cytochrome P450.     

Synthesis of Extended π‐Systems through C–H Activation

Activation of aromatic C? H bonds by a transition metal catalyst has received significant attention in the synthetic chemistry community. In recent years, rapid and site‐selective extension of π‐electron systems by C–H activation has emerged as an ideal methodology for preparing organic materials with extended π‐systems. This Review focuses on recently reported π‐extending C–H activation reactions directed toward new optoelectronic conjugated materials.     

Catalytic Synthesis of 8‐Membered Ring Compounds via Cobalt(III)‐Carbene Radicals

The metalloradical activation of o‐aryl aldehydes with tosylhydrazide and a cobalt(II) porphyrin catalyst produces cobalt(III)‐carbene radical intermediates, providing a new and powerful strategy for the synthesis of medium‐sized ring structures. Herein we make use of the intrinsic radical‐type reactivity of cobalt(III)‐carbene radical intermediates in the [Co^II(TPP)]‐catalyzed (TPP=tetraphenylporphyrin) synthesis of two types of 8‐membered ring compounds; novel dibenzocyclooctenes and unprecedented monobenzocyclooctadienes. The method was successfully applied to afford a variety of 8‐membered ring compounds in good yields and with excellent substituent tolerance. Density functional theory (DFT) calculations and experimental results suggest that the reactions proceed via hydrogen atom transfer from the bis‐allylic/benzallylic C?H bond to the carbene radical, followed by two divergent processes for ring‐closure to the two different types of 8‐membered ring products. While the dibenzocyclooctenes are most likely formed by dissociation of o‐quinodimethanes (o‐QDMs) which undergo a non‐catalyzed 8π‐cyclization, DFT calculations suggest that ring‐closure to the monobenzocyclooctadienes involves a radical‐rebound step in the coordination sphere of cobalt. The latter mechanism implies that unprecedented enantioselective ring‐closure reactions to chiral monobenzocyclooctadienes should be possible, as was confirmed for reactions mediated by a chiral cobalt‐porphyrin catalyst.     

Eosin Y as a Direct Hydrogen‐Atom Transfer Photocatalyst for the Functionalization of C−H Bonds

Eosin Y, a well‐known economical alternative to metal catalysts in visible‐light‐driven single‐electron transfer‐based organic transformations, can behave as an effective direct hydrogen‐atom transfer catalyst for C?H activation. Using the alkylation of C?H bonds with electron‐deficient alkenes as a model study revealed an extremely broad substrate scope, enabling easy access to a variety of important synthons. This eosin Y‐based photocatalytic hydrogen‐atom transfer strategy is promising for diverse functionalization of a wide range of native C?H bonds in a green and sustainable manner.     

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.     

Bifunctional Heterogeneous Catalysis of Silica–Alumina‐Supported Tertiary Amines with Controlled Acid–Base Interactions for Efficient 1,4‐Addition Reactions

We report the first tunable bifunctional surface of silica–alumina‐supported tertiary amines (SA–NEt₂) active for catalytic 1,4‐addition reactions of nitroalkanes and thiols to electron‐deficient alkenes. The 1,4‐addition reaction of nitroalkanes to electron‐deficient alkenes is one of the most useful carbon–carbon bond‐forming reactions and applicable toward a wide range of organic syntheses. The reaction between nitroethane and methyl vinyl ketone scarcely proceeded with either SA or homogeneous amines, and a mixture of SA and amines showed very low catalytic activity. In addition, undesirable side reactions occurred in the case of a strong base like sodium ethoxide employed as a catalytic reagent. Only the present SA‐supported amine (SA–NEt₂) catalyst enabled selective formation of a double‐alkylated product without promotions of side reactions such as an intramolecular cyclization reaction. The heterogeneous SA–NEt₂ catalyst was easily recovered from the reaction mixture by simple filtration and reusable with retention of its catalytic activity and selectivity. Furthermore, the SA–NEt₂ catalyst system was applicable to the addition reaction of other nitroalkanes and thiols to various electron‐deficient alkenes. The solid‐state magic‐angle spinning (MAS) NMR spectroscopic analyses, including variable‐contact‐time ¹³C cross‐polarization (CP)/MAS NMR spectroscopy, revealed that acid–base interactions between surface acid sites and immobilized amines can be controlled by pretreatment of SA at different temperatures. The catalytic activities for these addition reactions were strongly affected by the surface acid–base interactions.