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.     

Decarboxylative C(sp3)−O Cross‐Coupling

Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp³)?O cross‐coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp²)?O cross‐coupling and S_N2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp³)?O coupling of alkyl N‐hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional‐group tolerance to existing methods was demonstrated.     

Direct Trifluoromethylthiolation and Perfluoroalkylthiolation of C(sp2)?H Bonds with CF3SO2Na and RfSO2Na

A new method for CF₃SO₂Na‐based direct trifluoromethylthiolation of C(sp²) H bonds has been developed. CF₃SSCF₃ is generated in situ from cheap and easy‐to‐handle CF₃SO₂Na, and in the presence of CuCl can be used for electrophilic trifluoromethylthiolation of indoles, pyrroles, and enamines. The method has been extended to perfluoroalkylthiolation reactions using R_fSO₂Na.     

Direct Trifluoromethylthiolation and Perfluoroalkylthiolation of C(sp2)H Bonds with CF3SO2Na and RfSO2Na

A new method for CF₃SO₂Na‐based direct trifluoromethylthiolation of C(sp²)? H bonds has been developed. CF₃SSCF₃ is generated in situ from cheap and easy‐to‐handle CF₃SO₂Na, and in the presence of CuCl can be used for electrophilic trifluoromethylthiolation of indoles, pyrroles, and enamines. The method has been extended to perfluoroalkylthiolation reactions using R_fSO₂Na.     

Visible‐Light‐Driven Palladium‐Catalyzed Radical Alkylation of C−H Bonds with Unactivated Alkyl Bromides

Reported herein is a novel visible‐light photoredox system with Pd(PPh₃)₄ as the sole catalyst for the realization of the first direct cross‐coupling of C(sp³)−H bonds in N‐aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra‐ and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp³)−C(sp³) and C(sp²)−C(sp³) bonds in moderate to excellent yields. These redox‐neutral reactions feature broad substrate scope (>60 examples), good functional‐group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible‐light photocatalyst and radicals are involved in the process.     

Copper‐Catalyzed C(sp3)−H Amidation: Sterically Driven Primary and Secondary C−H Site‐Selectivity

Undirected C(sp³)?H functionalization reactions often follow site‐selectivity patterns that mirror the corresponding C?H bond dissociation energies (BDEs). This often results in the functionalization of weaker tertiary C?H bonds in the presence of stronger secondary and primary bonds. An important, contemporary challenge is the development of catalyst systems capable of selectively functionalizing stronger primary and secondary C?H bonds over tertiary and benzylic C?H sites. Herein, we report a Cu catalyst that exhibits a high degree of primary and secondary over tertiary C?H bond selectivity in the amidation of linear and cyclic hydrocarbons with aroyl azides ArC(O)N₃. Mechanistic and DFT studies indicate that C?H amidation involves H‐atom abstraction from R‐H substrates by nitrene intermediates [Cu](κ²‐N,O‐NC(O)Ar) to provide carbon‐based radicals R^. and copper(II)amide intermediates [Cu^II]‐NHC(O)Ar that subsequently capture radicals R^. to form products R‐NHC(O)Ar. These studies reveal important catalyst features required to achieve primary and secondary C?H amidation selectivity in the absence of directing groups.     

Fe3O4@SiO2‐copper sucrose xanthate as a green nanocatalyst for N‐, O‐ and S‐arylation

Formation of C(sp²)–X bonds was carried out using a Fe₃O₄@SiO₂‐copper(I) sucrose xanthate nanoparticle catalyst with the aid of the copper(I) xanthate moiety in the catalyst which was prepared from the reaction between sucrose and carbon disulfide through an alkaline medium via the traditional Zeise approach. Various techniques were employed for the characterization of these novel nanoparticles. Three sorts of heteroatoms, N, O and S, successfully underwent heteroatom arylation to produce secondary or tertiary amines, ethers and thioethers, respectively.     

Mechanistic Insights into the Ni‐Catalyzed Reductive Carboxylation of C−O Bonds in Aromatic Esters with CO2: Understanding Remarkable Ligand and Traceless‐Directing‐Group Effects

The mechanism of the Ni⁰‐catalyzed reductive carboxylation reaction of C(sp²)?O and C(sp³)?O bonds in aromatic esters with CO₂ to access valuable carboxylic acids was comprehensively studied by using DFT calculations. Computational results revealed that this transformation was composed of several key steps: C?O bond cleavage, reductive elimination, and/or CO₂ insertion. Of these steps, C?O bond cleavage was found to be rate‐determining, and it occurred through either oxidative addition to form a Ni^II intermediate, or a radical pathway that involved a bimetallic species to generate two Ni^I species through homolytic dissociation of the C?O bond. DFT calculations revealed that the oxidative addition step was preferred in the reductive carboxylation reactions of C(sp²)?O and C(sp³)?O bonds in substrates with extended π systems. In contrast, oxidative addition was highly disfavored when traceless directing groups were involved in the reductive coupling of substrates without extended π systems. In such cases, the presence of traceless directing groups allowed for docking of a second Ni⁰ catalyst, and the reactions proceed through a bimetallic radical pathway, rather than through concerted oxidative addition, to afford two Ni^I species both kinetically and thermodynamically. These theoretical mechanistic insights into the reductive carboxylation reactions of C?O bonds were also employed to investigate several experimentally observed phenomena, including ligand‐dependent reactivity and site‐selectivity.     

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.     

N‐Heterocyclic Carbene Iron(III) Porphyrin‐Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides

Metal‐catalyzed intramolecular C?H amination of alkyl azides constitutes an appealing approach to alicyclic amines; challenges remain in broadening substrate scope, enhancing regioselectivity, and applying the method to natural product synthesis. Herein we report an iron(III) porphyrin bearing axial N‐heterocyclic carbene ligands which catalyzes the intramolecular C(sp³)–H amination of a wide variety of alkyl azides under microwave‐assisted and thermal conditions, resulting in selective amination of tertiary, benzylic, allylic, secondary, and primary C?H bonds with up to 95 % yield. 14 out of 17 substrates were cyclized selectively at C4 to give pyrrolidines. The regioselectivity at C4 or C5 could be tuned by modifying the reactivity of the C5–H bond. Mechanistic studies revealed a concerted or a fast re‐bound mechanism for the amination reaction. The reaction has been applied to the syntheses of tropane, nicotine, cis‐octahydroindole, and leelamine derivatives.     

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.     

Direct Trifluoromethylthiolation of Unactivated C(sp3)H Using Silver(I) Trifluoromethanethiolate and Potassium Persulfate

A practical and efficient method for the direct trifluoromethylthiolation of unactivated C(sp³)? H bonds by AgSCF₃/K₂S₂O₈ under mild conditions is described. The reaction has a good functional‐group tolerance and good selectivity. Initial mechanistic investigations indicate that the reaction may involve a radical process in which K₂S₂O₈ plays key roles in both the activation of the C(sp³)? H bond and the oxidation of AgSCF₃.     

Carbene–Transition Metal Complexes Formed by Double C?H Bond Activation

The activation of a single sp³ C? H bond of alkanes and their derivatives by electron‐rich transition metal complexes has been a topic of interest since the landmark work by Bergman and Graham in 1982. Ten years later, it was shown that compounds of 5d elements, such as osmium and iridium, even enable a double α‐C? H bond activation of alkane or cycloalkane derivatives containing an OR or NR₂ functional group, thus opening up a new route to obtain Fischer‐type transition metal carbene complexes. Subsequent work focused in particular on the conversion of methyl alkyl and methyl aryl ethers into bound oxocarbenes and also of dimethyl amines to bound aminocarbenes. In the context of this work, it was recently shown that square‐planar oxocarbene–iridium(I) complexes prepared in this way exhibit an unusual mode of reactivity: They react with CO₂, CS₂, COS, PhNCO, and PhNCS by an atom‐ or group‐transfer metathesis, which has no precedent. Organic azides RN₃ and N₂O behave similarly. Recent results confirm that this novel type of metathesis can be made catalytic, thus offering a novel possibility for C? H bond functionalization.     

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.     

Direct Trifluoromethylthiolation of Unactivated C(sp3)?H Using Silver(I) Trifluoromethanethiolate and Potassium Persulfate

A practical and efficient method for the direct trifluoromethylthiolation of unactivated C(sp³) H bonds by AgSCF₃/K₂S₂O₈ under mild conditions is described. The reaction has a good functional‐group tolerance and good selectivity. Initial mechanistic investigations indicate that the reaction may involve a radical process in which K₂S₂O₈ plays key roles in both the activation of the C(sp³) H bond and the oxidation of AgSCF₃.     

Direct C(sp2)C(sp3) Cross‐Coupling of Diaryl Zinc Reagents with Benzylic,Primary, Secondary,and Tertiary Alkyl Halides

The direct C(sp²)? C(sp³) cross‐coupling of diaryl zinc reagents with benzylic, primary, secondary, and tertiary alkyl halides proceeded in the absence of coordinating ethereal solvents at ambient temperature without the addition of a catalyst. The C(sp²)? C(sp³) cross‐coupling showed excellent functional‐group tolerance, and products were isolated in high yields, generally without the requirement for purification by chromatography. This process represents an expedient, operationally simple method for the construction of new C(sp²)? C(sp³) bonds.     

Catalytic Reduction of Cyclic Ethers with Hydrosilanes

Catalytic reductive transformations of ethers as a synthetic building block are an important class of chemical reactions because a range of essential chemical feedstocks and fuels in contemporary life can be prepared through the key step of ethereal C?O bond cleavage of cellulosic biomass. Although conventional stoichiometric and catalytic methods for sp²‐ and sp³‐C?O bond cleavage of linear ethers and alcohols with hydrosilanes are well established, silylative ring opening of cyclic ethers has been less highlighted in this context. This review outlines catalytic systems for the silylative reduction of a range of cyclic ethers, including epoxides and sugars, leading to the corresponding alcohols and/or hydrocarbons. The chemical reactivity and selectivity of these ring‐opening catalytic processes are discussed with respect to the type of substrates; the representative catalytic working modes are also described.     

Direct C(sp2)?C(sp3) Cross‐Coupling of Diaryl Zinc Reagents with Benzylic,Primary, Secondary,and Tertiary Alkyl Halides

The direct C(sp²) C(sp³) cross‐coupling of diaryl zinc reagents with benzylic, primary, secondary, and tertiary alkyl halides proceeded in the absence of coordinating ethereal solvents at ambient temperature without the addition of a catalyst. The C(sp²) C(sp³) cross‐coupling showed excellent functional‐group tolerance, and products were isolated in high yields, generally without the requirement for purification by chromatography. This process represents an expedient, operationally simple method for the construction of new C(sp²) C(sp³) bonds.     

Oxydifluoromethylation of Alkenes by Photoredox Catalysis: Simple Synthesis of CF2H‐Containing Alcohols

We have developed a novel and simple protocol for the direct incorporation of a difluoromethyl (CF₂H) group into alkenes by visible‐light‐driven photoredox catalysis. The use of fac‐[Ir(ppy)₃] (ppy=2‐pyridylphenyl) photocatalyst and shelf‐stable Hu's reagent, N‐tosyl‐S‐difluoromethyl‐S‐phenylsulfoximine, as a CF₂H source is the key to success. The well‐designed photoredox system achieves synthesis of not only β‐CF₂H‐substituted alcohols but also ethers and an ester from alkenes through solvolytic processes. The present method allows a single‐step and regioselective formation of C(sp³)–CF₂H and C(sp³)?O bonds from C=C moiety in alkenes, such as hydroxydifluoromethylation, regardless of terminal or internal alkenes. Moreover, this methodology tolerates a variety of functional groups.     

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.