Remote Radical Desaturation of Unactivated C−H Bonds in Amides

Desaturation of inert aliphatic C−H bonds in alkanes to form the corresponding alkenes is challenging. In this communication, a new and practical strategy for remote site-selective desaturation of amides via radical chemistry is reported. The readily installed N-allylsulfonylamide moiety serves as an N radical precursor. Intramolecular 1,5-hydrogen atom transfer from an inert C−H bond to the N-radical generates a translocated C-radical which is subsequently oxidized and deprotonated to give the corresponding alkene. The commercially available methanesulfonyl chloride is used as reagent and a Cu/Ag-couple as oxidant. The remote desaturation is realized on different types of unactivated sp³-C−H bonds. The potential synthetic utility of this method is further demonstrated by the dehydrogenation of natural product derivatives and drugs.     

Enantioselective Borylation of Aromatic C−H Bonds with Chiral Dinitrogen Ligands

The borylation of C−H bonds catalyzed by transition metals has been investigated extensively in the past two decades, but no iridium-catalyzed enantioselective borylation of C−H bonds has been reported. We report a set of iridium-catalyzed enantioselective borylations of aromatic C−H bonds. This reaction relies on a set of newly developed chiral quinolyl oxazoline ligands. This process proceeds under mild conditions with good to excellent enantioselectivity, and the borylated products can be converted to enantioenriched derivatives containing new C−O, C−C, C−Cl, or C−Br bonds.     

Enantioconvergent Palladium-Catalyzed Alkylation of Tertiary Allylic C−H Bonds

Enantioconvergent catalysis enables the conversion of racemic molecules into a single enantiomer in perfect yield and is considered an ideal approach for asymmetric synthesis. Despite remarkable advances in this field, enantioconvergent transformations of inert tertiary C−H bonds remain largely unexplored due to the high bond dissociation energy and the surrounding steric repulsion that pose unparalleled constraints on bond cleavage and formation. Here, we report an enantioconvergent Pd-catalyzed alkylation of racemic tertiary allylic C−H bonds of α-alkenes, providing a unique approach to access a broad range of enantioenriched γ,δ-unsaturated carbonyl compounds featuring quaternary carbon stereocenters. Mechanistic studies reveal that a stereoablative event occurs through the rate-limiting cleavage of tertiary allylic C−H bonds to generate σ-allyl-Pd species, and the achieved E/Z-selectivity of σ-allyl-Pd species effectively regulates the diastereoselectivity via a nucleophile coordination-enabled S_N2′-allylation pathway.     

Rationalizing the AlI-Promoted Oxidative Addition of C−C Versus C−H Bonds in Arenes

The factors controlling the oxidative addition of C−C and C−H bonds in arenes mediated by Al^I have been computationally explored by means of Density Functional Theory calculations. To this end, we compared the processes involving benzene, naphthalene and anthracene which are promoted by a recently prepared anionic Al^I-carbenoid. It is found that this species exhibits a strong tendency to oxidatively activate C−H bonds over C−C bonds, with the notable exception of benzene, where the C−C bond activation is feasible but only under kinetic control reaction conditions. State-of-the-art computational methods based on the combination of the Activation Strain Model of reactivity and the Energy Decomposition Analysis have been used to rationalize the competition between both bond activation reactions as well as to quantitatively analyze in detail the ultimate factors controlling these transformations.     

IrIII-Catalyzed Selective ortho-Monoiodination of Benzoic Acids with Unbiased C−H Bonds

An iridium-catalyzed selective ortho-monoiodination of benzoic acids with two equivalent C−H bonds is presented. A wide range of electron-rich and electron-poor substrates undergo the reaction under mild conditions, with >20:1 mono/di selectivity. Importantly, the C−H iodination occurs selectively ortho to the carboxylic acid moiety in substrates bearing competing coordinating directing groups. The reaction is performed at room temperature and no inert atmosphere or exclusion of moisture is required. Mechanistic investigations revealed a substrate-dependent reversible C−H activation/protodemetalation step, a substrate-dependent turnover-limiting step, and the crucial role of the Ag^I additive in the deactivation of the iodination product towards further reaction.     

Scalable Photoelectrochemical Dehydrogenative Cross-Coupling of Heteroarenes with Aliphatic C−H Bonds

Heteroarenes are structural motifs found in many bioactive compounds and functional materials. Dehydrogenative cross-coupling of heteroarenes with aliphatic C−H bonds provides straightforward access to functionalized heteroarenes from readily available materials. Established methods employ stoichiometric chemical oxidants under conditions of heating or light irradiation. By merging electrochemistry and photochemistry, we have achieved efficient photoelectrochemical dehydrogenative cross-coupling of heteroarenes and C(sp³)−H donors through H₂ evolution, without the addition of metal catalysts or chemical oxidants. Mechanistically, the C(sp³)−H donor is converted to a nucleophilic carbon radical through H-atom transfer with chlorine atom, which is produced by light irradiation of anodically generated Cl₂ from Cl⁻. The carbon radical then undergoes radical substitution to the heteroarene to afford alkylated heteroarene products.     

Sulfonate N-Heterocyclic Carbene–Copper Complexes: Uniquely Effective Catalysts for Enantioselective Synthesis of C−C,C−B,C−H,and C−Si Bonds

A copper-based complex that contains a sulfonate N-heterocyclic carbene ligand was first reported 15 years ago. Since then, these organometallic entities have proven to be uniquely effective in catalyzing an assortment of enantioselective transformations, including allylic substitutions, conjugate additions, proto-boryl additions to alkenes, boryl and silyl substitutions, hydride-allyl additions to alkenyl boronates, and additions of boron-containing allyl moieties to N-H ketimines. In this review article, we detail the shortcomings in the state-of-the-art that fueled the development of this air stable ligand class, members of which can be prepared on multigram scale. For each reaction type, when relevant, the prior art at the time of the advance involving sulfonate NHC-Cu catalysts and/or subsequent key developments are briefly analyzed, and the relevance of the advance to efficient and enantioselective total or formal synthesis of biologically active molecules is underscored. Mechanistic analysis of the structural attributes of sulfonate NHC-Cu catalysts that are responsible for their ability to facilitate transformations with high efficiency as well as regio- and enantioselectivity are detailed. This review contains several formerly undisclosed methodological advances and mechanistic analyses, the latter of which constitute a revision of previously reported proposals.     

Calcium Hydride Cation Dimer Catalyzed Hydrogenation of Unactivated 1-Alkenes and H2 Isotope Exchange: Competitive Ca−H−Ca Bridges and Terminal Ca−H Bonds

Recently, it was shown that the double Ca−H−Ca bridged calcium hydride cation dimer complex [LCaH₂CaL]²⁺ (macrocyclic ligand L=NNNN-tetradentate Me₄TACD) exhibited remarkable activity in catalyzing the hydrogenation of unactivated 1-alkenes as well as the H₂ isotope exchange under mild conditions, tentatively via the terminal Ca−H bond of cation monomer LCaH⁺. In this DFT mechanistic work, a novel substrate-dependent catalytic mechanism is disclosed involving cooperative Ca−H−Ca bridges for H₂ isotope exchange, competitive Ca−H−Ca bridges and terminal Ca−H bonds for anti-Markovnikov addition of unactivated 1-alkenes, and terminal Ca−H bonds for Markovnikov addition of conjugation-activated styrene. THF-coordination plays a key role in favoring the anti-Markovnikov addition while strong cation-π interactions direct the Markovnikov addition to terminal Ca−H bonds.     

Activation and Deactivation of Benzylic C−H Bonds Guided by Stereoelectronic Effects in Hydrogen Atom Transfer from Amides and Amines to Alkoxyl Radicals

Kinetic and product studies on the reactions of tert-alkoxyl radicals with secondary and tertiary alkanamides bearing benzylic α-C−H bonds, isoindoline, tetrahydroisoquinoline and the corresponding N-acetyl derivatives were carried out. Product studies on the reactions with the tert-butoxyl radical (tBuO⋅) point toward exclusive HAT from the benzylic α-C−H bonds. Comparison of the k_H values measured for reaction with the cumyloxyl radical (CumO⋅) with those obtained previously for the corresponding reactions of N-alkyl- and N,N-dialkylalkanamides, are indicative of a lack of benzylic activation and the operation of steric and stereoelectronic effects. Compared to N-methyl and N-ethyl groups, the presence of N-benzyl groups increases the barrier required to reach the optimal conformation for HAT, where the α-C−H bond to be cleaved is perpendicular to the plane of the amide, precluding concurrent overlap with the phenyl π-system. When the benzylic α-C−H bonds are in a conformation that allows for optimal overlap with both the phenyl π-system and the amide π-system or amine nitrogen lone pair, as in the isoindoline and tetrahydroisoquinoline derivatives, increases in k_H that exceed 2-orders of magnitude were observed, highlighting the strong contribution provided by stereoelectronic activation to these HAT processes.     

Synthesis of Tetraarylethene Luminogens by C−H Vinylation of Aromatic Compounds with Triazenes

Tetraarylethenes are obtained by acid-induced coupling of vinyl triazenes with aromatic compounds. This new C−H activation route for the synthesis of aggregation-induced emission luminogens is simple, fast, and versatile. It allows the direct grafting of triarylethenyl groups onto a variety of aromatic compounds, including heterocycles, supramolecular hosts, biologically relevant molecules, and commercial polymers.     

Direct Perfluoroalkylation of C−H Bonds in (Hetero)arenes

Perfluoroalkylated (hetero)arenes represent an extremely important family of molecules commonly utilized in many areas such as medicinal chemistry, agrochemistry and material sciences. Due to their unique properties, they have attracted significant interest from synthetic chemists and various methods have been developed for their synthesis. Among them, the direct perfluoroalkylation of C(sp²)−H bonds in (hetero)arenes is one of the most attractive and straightforward ones, provided that it proceeds with high levels of regioselectivity. In this review article, a comprehensive overview of advances in this field is presented, with a special focus on the reaction mechanisms involved in these transformations and their regioselectivity. All methods available have been classified according to the nature of the perfluoroalkyl chain introduced, trifluoromethylation reactions being overviewed in a separate section, and to the nature of the reagents/catalysts required.     

Rhodium-Catalyzed Copper-Assisted Intermolecular Domino C−H Annulation of 1,3-Diynes with Picolinamides: Access to Pentacyclic π-Extended Systems

A new mode of reactivity of 1,3-diynes in rhodium-catalyzed oxidative annulation reactions has enabled the rapid assembly of extended π systems from readily available picolinamide derivatives. The process involves a double C−H bond activation and the iterative annulation of two 1,3-diyne units, with each alkyne moiety engaged in an orchestrated insertion sequence with high regiocontrol, leading to the formation of five new C−C bonds and the construction of four fused rings in a single operation. Either isoquinoline-1-carboxamides or fused polycyclic systems can be accessed by a switch in the regioselectivity of the second diyne insertion depending on the reaction conditions. DFT theoretical calculations have elucidated that the cooperative participation of both rhodium and copper in substrate activation, favored in the presence of excess of the copper(II) salt, is key to such a reversal of regioselectivity and subsequent multiple cyclization leading to fused polycyclic products. The role of copper was found to be essential in assisting both multiple insertion and rhodium-walking sequences, with the implication of intermediates with a Rh−Cu bond (2.60 Å).     

A Spiro Phosphamide Catalyzed Enantioselective Proton Transfer of Ylides in a Free Carbene Insertion into N−H Bonds

Free carbene readily causes multiple side reactions due to its high energy, thus its asymmetric transformation is very difficult. We present here our findings of high-pK_a Brønsted acid catalysts that enable free carbene insertion into N−H bonds of amines to prepare chiral α-amino acid derivatives with high enantioselectivity. Under irradiation with visible light, diazo compounds produce high-energy free carbenes that are captured by amines to form free ylide intermediates, and then the newly designed high-pK_a Brønsted acids, chiral spiro phosphamides, promote the proton transfer of ylides to afford the products. Computational and kinetic studies uncover the principle for the rational design of proton-transfer catalysts and explain how the catalysts accelerate this transformation and provide stereocontrol.     

Direct Trifluoromethylselenolation and Fluoroalkylselenolation of C−H Bonds: Recent Advances in Reagents Development and Reactions

Due to their high lipophilicity and strong electron-withdrawing property, more and more attention has been paid to introducing trifluoromethylseleno and fluoroalkylseleno moieties into organic molecules. In this short review, we categorize the synthesis of compounds that combine selenium and fluorinated moieties into two main types: trifluoromethylselenolation (CF₃Se) and fluoroalkylselenolation (R_fSe, except CF₃Se). This review aims to provide a summary of the recent advances in direct C−H trifluoromethylselenolation and fluoroalkylselenolation from the synthesis of trifluoromethylselenolation and fluoroalkylselenolation reagents to their application. Based on the method of how the R_fSe group was introduced, the main content is divided into three parts: transition-metal-free reactions, transition-metal-mediated/catalyzed reactions and photo-catalyzed reactions. The general substrate scope, mechanism and limitations would also be discussed so that we hope the review will serve as an inspiration for further research in this appealing research field.     

Electrochemical Enabled Cascade Phosphorylation of N−H/O−H/S−H Bonds with P−H Compounds: An Efficient Access to P(O)-X Bonds

An electrochemical three component cascade phosphorylation reaction of various heteroatoms-containing nucleophiles including carbazoles, indoles, phenols, alcohols, and thiols with Ph₂PH has been established. Electricity is used as the “traceless” oxidant and water and air are utilized as the “green” oxygen source. All kinds of structurally diverse organophosphorus compounds with P(O)-N/P(O)-O/P(O)-S bonds are assembled in moderate to excellent yields (three categories of phosphorylation products, 50 examples, up to 97 % yield). A tentative free radical course is put forward to rationalize the reaction procedure.     

Intermediates of N-Heterocyclic Carbene (NHC) Dimerization Probed in the Gas Phase by Ion Mobility Mass Spectrometry: C−H⋅⋅⋅:C Hydrogen Bonding Versus Covalent Dimer Formation

N-Heterocyclic carbenes (NHCs, :C ) can interact with azolium salts ( C−H⁺ ) by either forming a hydrogen-bonded aggregate ( CHC⁺ ) or a covalent C−C bond ( CCH⁺ ). In this study, the intramolecular NHC–azolium salt interactions of aromatic imidazolin-2-ylidenes and saturated imidazolidin-2-ylidenes have been investigated in the gas phase by traveling wave ion mobility mass spectrometry (TW IMS) and DFT calculations. The TW IMS experiments provided evidence for the formation of these important intermediates in the gas phase, and they identified the predominant aggregation mode (hydrogen bond vs. covalent C−C) as a function of the nature of the interacting carbene–azolium pairs.     

Iridium-Catalyzed Enantioselective Hydroarylation of Alkenes through C−H bond Activation: Experiment and Computation

A new catalytic enantioselective hydroarylation of unactivated olefins is developed that provides rapid access to functionalized chiral dihydrobenzofurans with good yields and excellent enantioselectivities. Simple aromatic ketones or amides act as a directing group allowing the regioselective reaction at the more hindered ortho position. Tertiary benzylic stereocenters are obtained directly under mild reaction conditions and with complete atom economy from readily available starting materials.     

Low-Spin and High-Spin Perferryl Intermediates in Non-Heme Iron Catalyzed Oxidations of Aliphatic C−H Groups

The selectivity patterns of iron catalysts of the Fe(PDP) family in aliphatic C−H oxidation with H₂O₂ have been studied (PDP=N,N′-bis(pyridine-2-ylmethyl)-2,2′-bipyrrolidine). Cyclohexane, adamantane, 1-bromo-3,7-dimethyloctane, 3,7-dimethyloctyl acetate, (−)-acetoxy-p-menthane, and cis-1,2-dimethylcyclohexane were used as substrates. The studied catalyst systems generate low-spin (S=1/2) oxoiron(V) intermediates or high-spin (S=3/2) oxoiron(V) intermediates, depending on the electron-donating ability of remote substituents at the pyridine rings. The low-spin perferryl intermediates demonstrate lower stability and higher reactivity toward aliphatic C−H groups of cyclohexane than their high-spin congeners, according to the measured self-decay and second-order rate constants k₁ and k₂. Unexpectedly, there appears to be no uniform correlation between the spin state of the oxoiron(V) intermediates, and the chemo- and regioselectivity of the corresponding catalyst systems in the oxidation of the considered substrates. This contrasts with the asymmetric epoxidations by the same catalyst systems, in which case the epoxidation enantioselectivity increases when passing from the systems featuring the more reactive low-spin perferryl intermediates to those with their less reactive high-spin congeners.     

C−H Activation of Unbiased C(sp3)−H Bonds: Gold(I)-Catalyzed Cycloisomerization of 1-Bromoalkynes**

Selective functionalization of non-activated C(sp³)−H bonds is a major challenge in chemistry, so functional groups are often used to enhance reactivity. Here, we present a gold(I)-catalyzed C(sp³)−H activation of 1-bromoalkynes without any sort of electronic, or conformational bias. The reaction proceeds regiospecifically and stereospecifically to the corresponding bromocyclopentene derivatives. The latter can be readily modified, comprising an excellent library of diverse 3D scaffolds for medicinal chemistry. In addition, a mechanistic study has shown that the reaction proceeds via a so far unknown mechanism: a concerted [1,5]-H shift / C−C bond formation involving a gold-stabilized vinylcation-like transition state.     

Enantioselective Synthesis of N−N Biaryl Atropisomers through Iridium(I)-Catalyzed C−H Alkylation with Acrylates

Enantioselective synthesis of N−N biaryl atropisomers is an emerging area but remains underexplored. The development of efficient synthesis of N−N biaryl atropisomers is in great demand. Herein, the construction of N−N biaryl atropisomers through iridium-catalyzed asymmetric C−H alkylation is reported for the first time. In the presence of readily available Ir precursor and Xyl-BINAP, a variety of axially chiral molecules based on indole-pyrrole skeleton were obtained in good yields (up to 98 %) with excellent enantioselectivity (up to 99 % ee). In addition, N−N bispyrrole atropisomers could also be synthesized in excellent yields and enantioselectivity. This method features perfect atom economy, wide substrate scope, and multifunctionalized products allowing diverse transformations.