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.     

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.     

Copper‐Promoted Site‐Selective Acyloxylation of Unactivated C(sp3)H Bonds

The site‐selective acyloxylation of aliphatic amides was achieved via a copper‐promoted C(sp³)? H bond functionalization process directed by a bidentate ligand. The reaction showed a great preference for activating C? H bonds of β‐methyl groups over those of γ‐methyl and unactivated methylene groups.     

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.     

Cu‐Catalyzed Intramolecular Amidation of Unactivated C(sp3)−H Bonds To Synthesize N‐Substituted Indolines

A copper‐catalyzed intramolecular amidation of unactivated C(sp³)?H bonds to construct indoline derivatives has been developed. Such an amidation proceeded well at primary C?H bonds preferred to secondary C?H bonds. The transformation owned a broad substrate scope. The corresponding indolines were obtained in good to excellent yields. N‐Formal and other carbonyl groups were suitable and were easily deprotected and transformed into methyl or long‐chained alkyl groups. Preliminary mechanistic studies suggested a radical pathway.     

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‐Catalyzed Dicarbofunctionalization of Unactivated Olefins

Transition metal (TM)‐catalyzed difunctionalization of unactivated olefins with two carbon‐based entities is a powerful method to construct complex molecular architectures rapidly from simple and readily available feedstock chemicals. While dicarbofunctionalization of unactivated olefins has a long history typically with the use of either carbon monoxide to intercept C(sp³)‐[M] (alkyl‐TM) species or substrates lacking in β‐hydrogen (β‐Hs), development of this class of reaction still remains seriously limited due to complications of β‐H elimination arising from the in situ‐generated C(sp³)‐[M] intermediates. Over the years, different approaches have been harnessed to suppress β‐H elimination, which have led to the development of various types of olefin dicarbofunctionalization reactions even in substrates that generate C(sp³)‐[M] intermediates bearing β‐Hs with a wide range of electrophiles and nucleophiles. In this review, these developments will be discussed both through the lens of historical perspectives as well as the strategies scrutinized over the years to address the issue of β‐H elimination. However, this review article by no means is designed to be exhaustive in the field, and is merely presented to provide the readers an overview of the key reaction developments.     

Microtubing‐Reactor‐Assisted Aliphatic C−H Functionalization with HCl as a Hydrogen‐Atom‐Transfer Catalyst Precursor in Conjunction with an Organic Photoredox Catalyst

Chlorine radical, which is classically generated by the homolysis of Cl₂ under UV irradiation, can abstract a hydrogen atom from an unactivated C(sp³)?H bond. We herein demonstrate the use of HCl as an effective hydrogen‐atom‐transfer catalyst precursor activated by an organic acridinium photoredox catalyst under visible‐light irradiation for C?H alkylation and allylation. The key to success relied on the utilization of microtubing reactors to maintain the volatile HCl catalyst. This photomediated chlorine‐based C?H activation protocol is effective for a variety of unactivated C(sp³)?H bond patterns, even with primary C(sp³)?H bonds, as in ethane. The merit of this strategy is illustrated by rapid access to several pharmaceutical drugs from abundant unfunctionalized alkane feedstocks.     

Sulfonamide‐Promoted Palladium(II)‐Catalyzed Alkylation of Unactivated Methylene C(sp3)H Bonds with Alkyl Iodides

The alkylation of unactivated β‐methylene C(sp³)? H bonds of α‐amino acid substrates with a broad range of alkyl iodides using Pd(OAc)₂ as the catalyst is described. The addition of NaOCN and 4‐Cl‐C₆H₄SO₂NH₂ was found to be crucial for the success of this transformation. The reaction is compatible with a diverse array of functional groups and proceeds with high diastereoselectivity. Furthermore, various β,β‐hetero‐dialkyl‐ and β‐alkyl‐β‐aryl‐α‐amino acids were prepared by sequential C(sp³)? H functionalization of an alanine‐derived substrate, thus providing a versatile strategy for the stereoselective synthesis of unnatural β‐disubstituted α‐amino acids.     

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.     

Synthesis of β‐Lactams by Palladium(0)‐Catalyzed C(sp3)−H Carbamoylation

A general and user‐friendly synthesis of β‐lactams is reported that makes use of Pd⁰‐catalyzed carbamoylation of C(sp³)−H bonds, and operates under stoichiometric carbon monoxide in a two‐chamber reactor. This reaction is compatible with a range of primary, secondary and activated tertiary C−H bonds, in contrast to previous methods based on C(sp³)−H activation. In addition, the feasibility of an enantioselective version using a chiral phosphonite ligand is demonstrated. Finally, this method can be employed to synthesize valuable enantiopure free β‐lactams and β‐amino acids.     

Palladium‐Catalyzed Arylation of Unactivated γ‐Methylene C(sp3)H and δ‐CH Bonds with an Oxazoline‐Carboxylate Auxiliary

A palladium‐catalyzed arylation of unactivated γ‐methylene C(sp³)?H and remote δ‐C?H bonds by using an oxazoline‐carboxylate directing group has been developed. Arylation occurs with a broad substrate scope and high tolerance of functional groups (i.e., halogen, nitro, cyano, ether, trifluoromethyl, amine, and ester). The oxazoline‐type auxiliary can be removed under acidic conditions.     

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.     

Practical Synthesis of anti‐β‐Hydroxy‐α‐Amino Acids by PdII‐Catalyzed Sequential C(sp3)H Functionalization

An improved and practical procedure for the stereoselective synthesis of anti‐β‐hydroxy‐α‐amino acids (anti‐βhAAs), by palladium‐catalyzed sequential C(sp³)?H functionalization directed by 8‐aminoquinoline auxiliary, is described. followed by a previously established monoarylation and/or alkylation of the β‐methyl C(sp³)?H of alanine derivative, β‐acetoxylation of both alkylic and benzylic methylene C(sp³)?H bonds affords various anti‐β‐hydroxy‐α‐amino acid derivatives. As an example, the synthesis of β‐mercapto‐α‐amino acids, which are highly important to the extension of native chemical ligation chemistry beyond cysteine, is described. The synthetic potential of this protocol is further demonstrated by the synthesis of diverse β‐branched α‐amino acids. The observed diastereoselectivities are strongly influenced by electronic effects of aromatic AAs and steric effects of the linear side‐chain AAs, which could be explained by the competition of intramolecular C?OAc bond reductive elimination from Pd^IV intermediates vs. intermolecular attack by an external nucleophile (AcO^?) in an S_N2‐type process.     

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.     

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.     

Nickel‐Catalyzed Alkoxy–Alkyl Interconversion with Alkylborane Reagents through C−O Bond Activation of Aryl and Enol Ethers

A nickel‐catalyzed alkylation of polycyclic aromatic methyl ethers as well as methyl enol ethers with B‐alkyl 9‐BBN and trialkylborane reagents that involves the cleavage of stable C(sp²)?OMe bonds is described. The transformation has a wide substrate scope and good chemoselectivity profile while proceeding under mild reaction conditions; it provides a versatile way to form C(sp²)?C(sp³) bonds that does not suffer from β‐hydride elimination. Furthermore, a selective and sequential alkylation process by cleavage of inert C?O bonds is presented to demonstrate the advantage of this method.     

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.     

Surface oxidation process of a diamond‐like carbon film analyzed by difference X‐ray photoelectron spectroscopy

Difference X‐ray photoelectron spectroscopy (D‐XPS) revealed the surface oxidation process of a diamond‐like carbon (DLC) film. Evaluation of surface functional groups on DLC solely by the C 1s spectrum is difficult because the spectrum is broad and has a secondary asymmetric lineshape. D‐XPS clarified the subtle but critical changes at the DLC surface caused by wet oxidation. The hydroxyl (C―OH) group was dominant at the oxidized surface. Further oxidized carbonyl (C?O) and carboxyl (including carboxylate) (COO) groups were also obtained; however, the oxidation of C?O to COO was suppressed to some extent because the reaction required C―C bond cleavage. Wet oxidation cleaved the aliphatic hydrogenated and non‐hydrogenated sp² carbon bonds (C―H sp² and C―C sp²) to create a pair of C―OH and hydrogenated sp³ carbon (C―H sp³) bonds. The reaction yield for C―H sp² was superior at the surface, suggesting that the DLC film was hydrogen rich at the surface. Oxidation of aromatic sp² rings or polycyclic aromatic hydrocarbons such as nanographite to phenols did not occur because of their resonance stabilization with electron delocalization. Non‐hydrogenated sp³ carbon (C―C sp³) bonds were not affected by oxidation, suggesting that these bonds are chemically inert. Copyright © 2014 John Wiley & Sons, Ltd.