Copper‐Catalyzed Intramolecular C(sp3)?H and C(sp2)?H Amidation by Oxidative Cyclization

The first copper‐catalyzed intramolecular C(sp³) H and C(sp²) H oxidative amidation has been developed. Using a Cu(OAc)₂ catalyst and an Ag₂CO₃ oxidant in dichloroethane solvent, C(sp³) H amidation proceeded at a terminal methyl group, as well as at the internal benzylic position of an alkyl chain. This reaction has a broad substrate scope, and various β‐lactams were obtained in excellent yield, even on gram scale. Use of CuCl₂ and Ag₂CO₃ under an O₂ atmosphere in dimethyl sulfoxide, however, leads to 2‐indolinone selectively by C(sp²) H amidation. Kinetic isotope effect (KIE) studies indicated that C H bond activation is the rate‐determining step. The 5‐methoxyquinolyl directing group could be removed by oxidation.     

Rhodium(I)‐Catalyzed Sequential C(sp)?C(sp3) and C(sp3)?C(sp3) Bond Formation through Migratory Carbene Insertion

A Rh^I‐catalyzed three‐component reaction of tert‐propargyl alcohol, diazoester, and alkyl halide has been developed. This reaction can be considered as a carbene‐involving sequential alkyl and alkynyl coupling, in which C(sp) C(sp³) and C(sp³) C(sp³) bonds are built successively on the carbenic carbon atom. The Rh^I‐carbene migratory insertion of an alkynyl moiety and subsequent alkylation are proposed to account for the two separate C C bond formations. This reaction provides an efficient and tunable method for the construction of all‐carbon quaternary center.     

Asymmetric C(sp2)?H Activation

A “niche” topic in the past decade, the asymmetric C? H bond activation has been attracting growing interest over the last few years. Particularly significant advances have been achieved in the field of direct, stereoselective transformations of C(sp²)? H bonds. This Concept article intends to showcase different types of asymmetric C(sp²)? H bond activation reactions, emphasising both the nature of the stereo‐discriminating step and the variability of valuable scaffolds that could be rapidly constructed by means of such strategies.     

Catalytic Functionalization of C(sp2)?H and C(sp3)?H Bonds by Using Bidentate Directing Groups

C? H bonds are ubiquitous in organic compounds. It would, therefore, appear that direct functionalization of substrates by activation of C? H bonds would eliminate the multiple steps and limitations associated with the preparation of functionalized starting materials. Regioselectivity is an important issue because organic molecules can contain a wide variety of C? H bonds. The use of a directing group can largely overcome the issue of regiocontrol by allowing the catalyst to come into proximity with the targeted C? H bonds. A wide variety of functional groups have been evaluated for use as directing groups in the transformation of C? H bonds. In 2005, Daugulis reported the arylation of unactivated C(sp³)? H bonds by using 8‐aminoquinoline and picolinamide as bidentate directing groups, with Pd(OAc)₂ as the catalyst. Encouraged by these promising results, a number of transformations of C? H bonds have since been developed by using systems based on bidentate directing groups. In this Review, recent advances in this area are discussed.     

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.     

Asymmetric Organocatalytic Direct C(sp2)?H/C(sp3)?H Oxidative Cross‐Coupling by Chiral Iodine Reagents

An asymmetric organocatalytic direct C H/C H oxidative coupling reaction of N¹,N³‐diphenylmalonamides has been well established by using chiral organoiodine compounds as catalysts, wherein four C H bonds were stereoselectively functionalized to give structurally diverse spirooxindoles with high levels of enantioselectivity. More importantly, the findings indicated that chiral hypervalent organoiodine reagents can serve as alternative catalysts for the creation of enantioselective functionalization of inactive C H bonds.     

Rhodium(III)‐Catalyzed Amidation of Unactivated C(sp3)?H Bonds

Nitrogenation by direct functionalization of C H bonds represents an important strategy for constructing C N bonds. Rhodium(III)‐catalyzed direct amidation of unactivated C(sp³) H bonds is rare, especially under mild reaction conditions. Herein, a broad scope of C(sp³) H bonds are amidated under rhodium catalysis in high efficiency using 3‐substituted 1,4,2‐dioxazol‐5‐ones as the amide source. The protocol broadens the scope of rhodium(III)‐catalyzed C(sp³) H activation chemistry, and is applicable to the late‐stage functionalization of natural products.     

Rhodium(III)‐Catalyzed Amidation of Unactivated C(sp3)?H Bonds

Nitrogenation by direct functionalization of C H bonds represents an important strategy for constructing C N bonds. Rhodium(III)‐catalyzed direct amidation of unactivated C(sp³) H bonds is rare, especially under mild reaction conditions. Herein, a broad scope of C(sp³) H bonds are amidated under rhodium catalysis in high efficiency using 3‐substituted 1,4,2‐dioxazol‐5‐ones as the amide source. The protocol broadens the scope of rhodium(III)‐catalyzed C(sp³) H activation chemistry, and is applicable to the late‐stage functionalization of natural products.     

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.     

Benzylic C(sp3)?H Perfluoroalkylation of Six‐Membered Heteroaromatic Compounds

Successful benzylic C(sp³) H trifluoromethylation, pentafluoroethylation, and heptafluoropropylation of six‐membered heteroaromatic compounds were achieved as the first examples of a practical benzylic C(sp³) H perfluoroalkylation. In these reactions, BF₂C_nF_2n+1 (n=1–3) functioned as both a Lewis acid to activate the benzylic position and a C_nF_2n+1 (n=1–3) source. The perfluoroalkylation proceeded at both terminal and internal positions of the alkyl chains. Perfluoroalkylated products were obtained in moderate to excellent yields, even on gram scale, and in a sequential procedure without isolation of the intermediates. By using this method, trifluoromethylation of a bioactive compound, as well as introduction of a CF₃ group into a bioactive molecular skeleton, proceeded regioselectively.     

Gold‐Catalyzed C(sp3)?H/C(sp)?H Coupling/Cyclization/Oxidative Alkynylation Sequence: A Powerful Strategy for the Synthesis of 3‐Alkynyl Polysubstituted Furans

In sharp contrast to the gold‐catalyzed reactions of alkynes/allenes with nucleophiles, gold‐catalyzed oxidative cross‐couplings and especially C H/C H cross‐coupling have been under represented. By taking advantage of the unique redox property and carbophilic π acidity of gold, this work realizes the first gold‐catalyzed direct C(sp³) H alkynylation of 1,3‐dicarbonyl compounds with terminal alkynes under mild reaction conditions, with subsequent cyclization and in situ oxidative alkynylation. A variety of terminal alkynes including aryl, heteroaryl, alkenyl, alkynyl, alkyl, and cyclopropyl alkynes all successfully participate in the domino reaction. The protocol offers a simple and region‐defined approach to 3‐alkynyl polysubstituted furans.     

Redox‐Neutral Rhodium‐Catalyzed C?H Functionalization of Arylamine N‐Oxides with Diazo Compounds: Primary C(sp3)?H/C(sp2)?H Activation and Oxygen‐Atom Transfer

An unprecedented rhodium(III)‐catalyzed regioselective redox‐neutral annulation reaction of 1‐naphthylamine N‐oxides with diazo compounds was developed to afford various biologically important 1H‐benzo[g]indolines. This coupling reaction proceeds under mild reaction conditions and does not require external oxidants. The only by‐products are dinitrogen and water. More significantly, this reaction represents the first example of dual functiaonalization of unactivated a primary C(sp³) H bond and C(sp²) H bond with diazocarbonyl compounds. DFT calculations revealed that an intermediate iminium is most likely involved in the catalytic cycle. Moreover, a rhodium(III)‐catalyzed coupling of readily available tertiary aniline N‐oxides with α‐diazomalonates was also developed under external oxidant‐free conditions to access various aminomandelic acid derivatives by an O‐atom‐transfer reaction.     

Rhodium(III)‐Catalyzed Alkenylation Reactions of 8‐Methylquinolines with Alkynes by C(sp3)?H Activation

The alkenylation reactions of 8‐methylquinolines with alkynes, catalyzed by [{Cp*RhCl₂}₂], proceeds efficiently to give 8‐allylquinolines in good yields by C(sp³) H bond activation. These reactions are highly regio‐ and stereoselective. A catalytically competent five‐membered rhodacycle has been structurally characterized, thus revealing a key intermediate in the catalytic cycle.     

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.     

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.     

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.     

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.     

Functionalization of Organic Molecules by Transition‐Metal‐Catalyzed C(sp3)?H Activation

Transition‐metal‐catalyzed C? H activation has recently emerged as a powerful tool for the functionalization of organic molecules. While many efforts have focused on the functionalization of arenes and heteroarenes by this strategy in the past two decades, much less research has been devoted to the activation of non‐acidic C? H bonds of alkyl groups. This Minireview highlights recent work in this area, with a particular emphasis on synthetically useful methods.