Intermolecular Amination of Unactivated C(sp3)−H Bonds with Cyclic Alkylamines: Formation of C(sp3)−N Bonds through Copper/Oxygen‐Mediated C(sp3)−H/N−H Activation

The first example of intermolecular amination of unactivated C(sp³)?H bonds by cyclic alkylamines mediated by Cu(OAc)₂/O₂ is reported. This method avoids the use of benzoyloxyamines as the aminating reagent, which are normally prepared from alkylamines in extra steps. A variety of unnatural β^{2, 2}‐amino acid analogues are synthesized by this simple and efficient procedure. This approach offers a solution to the previous unmet challenge of C(sp³)?H/N?H activation for the formation of C(sp³)?N bonds.     

Easily Accessible Auxiliary for Palladium‐Catalyzed Intramolecular Amination of C(sp2)H and C(sp3)H Bonds at δ‐ and ε‐Positions

An easily synthesized and accessible N,O‐bidentate auxiliary has been developed for selective C? H activation under palladium catalysis. The novel auxiliary showed its first powerful application in C? H functionalization of remote positions. Both C(sp²)? H and C(sp³)? H bonds at δ‐ and ε‐positions were effectively activated, thus giving tetrahydroquinolines, benzomorpholines, pyrrolidines, and indolines in moderate to excellent yields by palladium‐catalyzed intramolecular C? H amination.     

PdII‐Catalyzed Intermolecular Amination of Unactivated C(sp3)H Bonds

Pd^II‐catalyzed intermolecular amination of unactivated C(sp³)?H bonds has been successfully developed for the first time. This method provides a new way to achieve the challenging intermolecular amination of unactivated C(sp³)?H bonds, producing a variety of unnatural β²‐amino carboxylic acid analogues. This C(sp³)?H amination protocol is demonstrated with a broad substrate scope, good functional‐group tolerance, and chemoselectivity. It is operated without use of phosphine ligand or external oxidant.     

Regioselective Vinylation of Remote Unactivated C(sp3)−H Bonds: Access to Complex Fluoroalkylated Alkenes

Regioselective incorporation of a particular functional group into aliphatic sites by direct activation of unreactive C?H bonds is of great synthetic value. Despite advances in radical‐mediated functionalization of C(sp³)?H bonds by a hydrogen‐atom transfer process, the site‐selective vinylation of remote C(sp³)?H bonds still remains underexplored. Reported herein is a new protocol for the regioselective vinylation of unactivated C(sp³)?H bonds. The remote C(sp³)?H activation is promoted by a C‐centered radical instead of the commonly used N and O radicals. The reaction possesses high product diversity and synthetic efficiency, furnishing a plethora of synthetically valuable E alkenes bearing tri‐/di‐/mono‐fluoromethyl and perfluoroalkyl groups.     

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.     

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.     

Chemoselective Amination of Propargylic C(sp3)H Bonds by Cobalt(II)‐Based Metalloradical Catalysis

Highly chemoselective intramolecular amination of propargylic C(sp³)? H bonds has been demonstrated for N‐bishomopropargylic sulfamoyl azides through cobalt(II)‐based metalloradical catalysis. Supported by D_2h‐symmetric amidoporphyrin ligand 3,5‐Di^tBu‐IbuPhyrin, the cobalt(II)‐catalyzed C? H amination proceeds effectively under neutral and nonoxidative conditions without the need of any additives, and generates N₂ as the only byproduct. The metalloradical amination is suitable for both secondary and tertiary propargylic C? H substrates with an unusually high degree of functional‐group tolerance, thus providing a direct method for high‐yielding synthesis of functionalized propargylamine derivatives.     

Redox‐Neutral Coupling between Two C(sp3)−H Bonds Enabled by 1,4‐Palladium Shift for the Synthesis of Fused Heterocycles

The intramolecular coupling of two C(sp³)?H bonds to forge a C(sp³)?C(sp³) bond is enabled by 1,4‐Pd shift from a trisubstituted aryl bromide. Contrary to most C(sp³)?C(sp³) cross‐dehydrogenative couplings, this reaction operates under redox‐neutral conditions, with the C?Br bond acting as an internal oxidant. Furthermore, it allows the coupling between two moderately acidic primary or secondary C?H bonds, which are adjacent to an oxygen or nitrogen atom on one side, and benzylic or adjacent to a carbonyl group on the other side. A variety of valuable fused heterocycles were obtained from easily accessible ortho‐bromophenol and aniline precursors. The second C?H bond cleavage was successfully replaced with carbonyl insertion to generate other types of C(sp³)‐C(sp³) bonds.     

Triiodide‐Mediated δ‐Amination of Secondary C−H Bonds

The C_δ?H amination of unactivated, secondary C?H bonds to form a broad range of functionalized pyrrolidines has been developed by a triiodide (I₃^?)‐mediated strategy. By in situ 1) oxidation of sodium iodide and 2) sequestration of the transiently generated iodine (I₂) as I₃^?, this approach precludes undesired I₂‐mediated decomposition which can otherwise limit synthetic utility to only weak C(sp³)?H bonds. The mechanism of this triiodide‐mediated cyclization of unbiased, secondary C(sp³)?H bonds, by either thermal or photolytic initiation, is supported by NMR and UV/Vis data, as well as intercepted intermediates.     

Ligand‐Promoted Borylation of C(sp3)H Bonds with Palladium(II) Catalysts

A quinoline‐based ligand effectively promotes the palladium‐catalyzed borylation of C(sp³)? H bonds. Primary β‐C(sp³)? H bonds in carboxylic acid derivatives as well as secondary C(sp³)? H bonds in a variety of carbocyclic rings, including cyclopropanes, cyclobutanes, cyclopentanes, cyclohexanes, and cycloheptanes, can thus be borylated. This directed borylation method complements existing iridium(I)‐ and rhodium(I)‐catalyzed C? H borylation reactions in terms of scope and operational conditions.     

Dehydrogenative N‐Incorporation: A Direct Approach to Quinoxaline N‐Oxides under Mild Conditions

An efficient method for the synthesis of quinoxaline N‐oxides proceeds by the dehydrogenative N‐incorporation of simple imines by C(sp²)? H and C(sp³)? H bond functionalization. The overall transformation involves the cleavage of three C? H bonds. The reaction is easily handled and proceeds under mild conditions. Simple and readily available tert‐butyl nitrite (TBN) was employed as the NO source.     

Site‐Selective δ‐C(sp3)−H Alkylation of Amino Acids and Peptides with Maleimides via a Six‐Membered Palladacycle

The site‐selective functionalization of unactivated C(sp³)?H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site‐selective δ‐C(sp³)?H alkylation of amino acids and peptides with maleimides via a kinetically less favored six‐membered palladacycle in the presence of more accessible γ‐C(sp³)?H bonds. Experimental studies revealed that C?H bond cleavage occurs reversibly and preferentially at γ‐methyl over δ‐methyl C?H bonds while the subsequent alkylation proceeds exclusively at the six‐membered palladacycle that is generated by δ‐C?H activation. The selectivity can be explained by the Curtin–Hammett principle. The exceptional compatibility of this alkylation with various oligopeptides renders this procedure valuable for late‐stage peptide modifications. Notably, this process is also the first palladium(II)‐catalyzed Michael‐type alkylation reaction that proceeds through C(sp³)?H activation.     

Catalytic Enantioselective Methylene C(sp3)−H Amidation of 8‐Alkylquinolines Using a Cp*RhIII/Chiral Carboxylic Acid System

Catalytic enantioselective directed methylene C(sp³)?H amidation reactions of 8‐alkylquinolines using a Cp*Rh^III/chiral carboxylic acid (CCA) hybrid catalytic system are described. A binaphthyl‐based chiral carboxylic acid efficiently differentiates between the enantiotopic methylene C?H bonds, which leads to the formation of C?N bonds with good enantioselectivity.     

Distal γ‐C(sp3)−H Olefination of Ketone Derivatives and Free Carboxylic Acids

Reported herein is the distal γ‐C(sp³)?H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino‐acid directing group and using the ligand combination of a mono‐N‐protected amino acid (MPAA) and an electron‐deficient 2‐pyridone were critical for the γ‐C(sp³)?H olefination of ketone substrates. In addition, MPAAs enabled the γ‐C(sp³)?H olefination of free carboxylic acids to form diverse six‐membered lactones. Besides alkyl carboxylic acids, benzylic C(sp³)?H bonds also could be functionalized to form 3,4‐dihydroisocoumarin structures in a single step from 2‐methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ‐C(sp³)?H olefinated products.     

Palladium/Norbornene‐Catalyzed C−H Alkylation/Alkyne Insertion/Indole Dearomatization Domino Reaction: Assembly of Spiroindolenine‐Containing Pentacyclic Frameworks

Reported is a highly chemoselective intermolecular annulation of indole‐based biaryls with bromoalkyl alkynes by using palladium/norbornene (Pd/NBE) cooperative catalysis. This reaction is realized through a sequence of Catellani‐type C?H alkylation, alkyne insertion, and indole dearomatization, by forming two C(sp²)?C(sp³) and one C(sp²)?C(sp²) bonds in a single chemical operation, thus providing a diverse range of pentacyclic molecules, containing a spiroindolenine fragment, in good yields with excellent functional‐group tolerance. Preliminary mechanistic studies reveal that C?H bond cleavage is likely involved in the rate‐determining step, and the indole dearomatization might take place through an olefin coordination/insertion and β‐hydride elimination Heck‐type pathway.     

Cp*RhIII‐Catalyzed Arylation of C(sp3)H Bonds

The first Cp*Rh^III‐catalyzed arylation of unactivated C(sp³)? H bonds is presented. The unactivated primary C(sp³)? H bond of 2‐alkylpyridines can be activated by Rh^III and further reacts with triarylboroxines to efficiently build new C(sp³)? aryl bonds. The methodology also provides a facile and efficient synthesis of unsymmetrical triarylmethanes by Rh^III‐catalyzed C(sp³)? H arylation of diarylmethanes.     

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.     

Synergistic Activation of Amides and Hydrocarbons for Direct C(sp3)–H Acylation Enabled by Metallaphotoredox Catalysis

The utilizations of omnipresent, thermodynamically stable amides and aliphatic C(sp³)?H bonds for various functionalizations are ongoing challenges in catalysis. In particular, the direct coupling between the two functional groups has not been realized. Here, we report the synergistic activation of the two challenging bonds, the amide C?N and unactivated aliphatic C(sp³)?H, via metallaphotoredox catalysis to directly acylate aliphatic C?H bonds utilizing amides as stable and readily accessible acyl surrogates. N‐acylsuccinimides served as efficient acyl reagents for the streamlined synthesis of synthetically useful ketones from simple C(sp³)?H substrates. Detailed mechanistic investigations using both computational and experimental mechanistic studies were performed to construct a detailed and complete catalytic cycle. The origin of the superior reactivity of the N‐acylsuccinimides over other more reactive acyl sources such as acyl chlorides was found to be an uncommon reaction pathway which commences with C?H activation prior to oxidative addition of the acyl substrate.     

Copper(I)‐Catalyzed Alkylation of Polyfluoroarenes through Direct CH Bond Functionalization

The copper(I)‐catalyzed alkylation of electron‐deficient polyfluoroarenes with N‐tosylhydrazones and diazo compounds has been developed. This reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of C(sp²)? C(sp³) bonds with polyfluoroarenes through direct C? H bond functionalization. Mechanistically, copper(I) carbene formation and subsequent migratory insertion are proposed as the key steps in the reaction pathway.     

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.