Selective Functionalization of Aromatic C(sp2)−H Bonds in the Presence of Benzylic C(sp3)−H Bonds by Electron‐Deficient Carbenoids Generated from 4‐Acyl‐1‐Sulfonyl‐1,2,3‐Triazoles

A rhodium(II)‐catalyzed reaction of newly prepared 4‐acyl‐1‐sulfonyl‐1,2,3‐triazoles with benzene, and its derivatives, is investigated. Acceptor/acceptor carbenoids generated from 4‐acyltriazoles undergo selective insertion at aromatic C(sp²)−H bonds in the presence of benzylic C(sp³)−H bonds to produce N ‐sulfonylenaminones.     

Thioamide‐Directed Cobalt(III)‐Catalyzed Selective Amidation of C(sp3)−H Bonds

A mild, oxidant‐free, and selective Cp*Co^III‐catalyzed amidation of thioamides with robust dioxazolone amidating agents via C(sp³)−H bond activation to generate the desired amidated products is reported. The method is efficient and allows for the C−H amidation of a wide range of functionalized thioamides with aryl‐, heteroaryl‐, and alkyl‐substituted dioxazolones under the Cp*Co^III‐catalyzed conditions. The observed regioselectivity towards primary C(sp³)−H activation is supported by computational studies and the cyclometalation is proposed to proceed by means of an external carboxylate‐assisted concerted metalation/deprotonation mechanism. The reported method is a rare example of the use of a directing group other than the commonly used pyridine and quinolone classes for Cp*Co^III‐catalyzed C(sp³)−H functionalization and the first to exploit thioamides.     

Mechanism of Nickel(II)‐Catalyzed Oxidative C(sp2)−H/C(sp3)−H Coupling of Benzamides and Toluene Derivatives

The Ni‐catalyzed C(sp²)?H/C(sp³)?H coupling of benzamides with toluene derivatives was recently successfully achieved with mild oxidant iC₃F₇I. Herein, we employ density functional theory (DFT) methods to resolve the mechanistic controversies. Two previously proposed mechanisms are excluded, and our proposed mechanism involving iodine‐atom transfer (IAT) between iC₃F₇I and the Ni^II intermediate was found to be more feasible. With this mechanism, the presence of a carbon radical is consistent with the experimental observation that (2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl (TEMPO) completely quenches the reaction. Meanwhile, the hydrogen‐atom abstraction of toluene is irreversible and the activation of the C(sp²)?H bond of benzamides is reversible. Both of these conclusions are in good agreement with Chatani's deuterium‐labeling experiments.     

Palladium‐Catalyzed Alkylation with Alkyl Halides by C(sp3)−H Activation

Utilizing halogens as traceless directing goups represents an attractive strategy for C−H functionalization. A two C−H alkylation system, initiated by the oxidative addition of organohalides to Pd⁰, has been developed. The first reaction involves an intermolecular alkylation of palladacycles to form C(sp³)−C(sp²) bonds followed by C(sp²)−H activation/cyclization to deliver alkylated benzocyclobutenes as the final products. In the second reaction, two C−C bonds are formed by the reaction of palladacycles with CH₂Br₂, and provides a facile and efficient method for the synthesis of indanes. The alkylated benzocyclobutene products can be transformed into tricyclic hyrocarbons, and the indane derivatives are essential structural motifs in bioactive and odorant molecules.     

Silver‐Catalyzed Oxidative C(sp3)−P Bond Formation through C−C and P−H Bond Cleavage

The silver‐catalyzed oxidative C(sp³)−H/P−H cross‐coupling of 1,3‐dicarbonyl compounds with H‐phosphonates, followed by a chemo‐ and regioselective C(sp³)−C(CO) bond‐cleavage step, provided heavily functionalized β‐ketophosphonates. This novel method based on a readily available reaction system exhibits wide scope, high functional‐group tolerance, and exclusive selectivity.     

Copper‐Catalyzed Bromination of C(sp3)−H Bonds Distal to Functional Groups

Selective bromination of γ‐methylene C(sp³)−H bonds of aliphatic amides and δ‐methylene C(sp³)−H bonds of nosyl‐protected alkyl amines are developed using NBS as the brominating reagent and catalytic amount of Cu^II/phenanthroline complexes as the catalyst. Aryl and benzylic C−H bonds at other locations remain intact during this directed radical abstraction reaction.     

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.     

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.     

Ligand‐Enabled Alkynylation of C(sp3)−H Bonds with Palladium(II) Catalysts

The palladium(II)‐catalyzed β‐ and γ‐alkynylation of amide C(sp³)−H bonds is enabled by pyridine‐based ligands. This alkynylation reaction is compatible with substrates containing α‐tertiary or α‐quaternary carbon centers. The β‐methylene C(sp³)−H bonds of various carbocyclic rings were also successfully alkynylated.     

Copper‐Catalyzed Remote C(sp3)−H Trifluoromethylation of Carboxamides and Sulfonamides

Reported herein is an unprecedented protocol for trifluoromethylation of unactivated aliphatic C(sp³)?H bonds. With Cu(OTf)₂ as the catalyst, the reaction of N‐fluoro‐substituted carboxamides (or sulfonamides) with Zn(CF₃)₂ complexes provides the corresponding δ‐trifluoromethylated carboxamides (or sulfonamides) in satisfactory yields under mild reaction conditions. A radical mechanism involving 1,5‐hydrogen atom transfer of N‐radicals followed by CF₃‐transfer from Cu^II?CF₃ complexes to the thus formed alkyl radicals is proposed.     

Cobalt‐Catalyzed Cross‐Dehydrogenative C(sp2)−C(sp3) Coupling of Oxazole/Thiazole with Ether or Cycloalkane

Direct C5‐alkylation of oxazole/thiazole with ether or cycloalkane has been achieved through a cobalt‐catalyzed cross‐dehydrogenative coupling (CDC) process in moderate to good yields. This transformation represents the first C(sp²)−C(sp³) cross‐coupling at the C5‐position of the oxazole/thiazole via double C−H bond cleavages. Various functional groups on oxazole/thiazole substrates, as well as water and air, are well‐tolerated with this concise and practical protocol, constituting straightforward access to heterocycles with great medicinal significance. A preliminary mechanism involving a radical process has also been proposed.     

Ligand‐Promoted C(sp3)−H Olefination en Route to Multi‐functionalized Pyrazoles

A Pd‐catalyzed/N‐heterocycle‐directed C(sp³)?H olefination has been developed. The monoprotected amino acid ligand (MPAA) is found to significantly promote Pd‐catalyzed C(sp³)?H olefination for the first time. Cu(OAc)₂ instead of Ag⁺ salts are used as the terminal oxidant. This reaction provides a useful method for the synthesis of alkylated pyrazoles.     

Stapled Peptides by Late‐Stage C(sp3)−H Activation

Despite the importance of stapled peptides for drug discovery, only few practical processes to prepare cross‐linked peptides have been described; thus the structural diversity of available staple motifs is currently limited. At the same time, C−H activation has emerged as an efficient approach to functionalize complex molecules. Although there are many reports on the C−H functionalization of amino acids, examples of post‐synthetic peptide C−H modification are rare and comprise almost only C(sp²)−H activation. Herein, we report the development of a palladium‐catalyzed late‐stage C(sp³)−H activation method for peptide stapling, affording an unprecedented hydrocarbon cross‐link. This method was first employed to prepare a library of stapled peptides in solution. The compatibility with various amino acids as well as the influence of the size (i ,i +3 and i ,i +4) and length of the staple were investigated. Finally, a simple solid‐phase procedure was also established.     

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.     

Synthesis of Bicyclo[n.1.0]alkanes by a Cobalt‐Catalyzed Multiple C(sp3)−H Activation Strategy

A cobalt‐catalyzed dual C(sp³)−H activation strategy has been developed and it provides a novel strategy for the synthesis of bicyclo[4.1.0]heptanes and bicyclo[3.1.0]hexanes. A key to the success of this reaction is the conformation‐induced methylene C(sp³)−H activation of the resulting cobaltabicyclo[4.n.1] intermediate. In addition, the synthesis of bicyclo[3.1.0]hexane from pivalamide, by a triple C(sp³)−H activation, has also been demonstrated.     

Copper(I)‐Catalyzed Chemoselective Coupling of Cyclopropanols with Diazoesters: Ring‐Opening C−C Bond Formations

Reported herein is an exceptional chemoselective ring‐opening/C(sp³)−C(sp³) bond formation in the copper(I)‐catalyzed reaction of cyclopropanols with diazo esters. The conventional O−H insertion product is essentially suppressed by judicious choice of reaction conditions. DFT calculations provide insights into the reaction mechanism and the rationale for this unusual chemoselectivity.     

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.     

Rhodium(II)‐ or Copper(I)‐Catalyzed Formal Intramolecular Carbene Insertion into Vinylic C(sp2)−H Bonds: Access to Substituted 1H‐Indenes

A rhodium(II)‐ or copper(I)‐catalyzed formal intramolecular carbene insertion into vinylic C(sp²)−H bonds is reported herein. This method provides straightforward access to 1H ‐indenes with high efficiency and excellent functional‐group compatibility. Mechanistically, the reaction is proposed to involve the following sequence: metal carbene formation, intramolecular nucleophilic addition of the double bond to the electron‐deficient carbene carbon atom, dearomatization, and finally a 1,5‐H shift.     

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‐Catalyzed Intramolecular Carbene Insertion into C(sp3)−H Bonds

A palladium‐catalyzed carbene insertion into C(sp³)?H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd⁰ and Pd^II, is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium‐catalyzed C(sp³)?C(sp³) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp³)?H bond functionalization reaction involves an unprecedented concerted metalation–deprotonation step.