Combinatorial Ligand Assisted Simultaneous Control of Axial and Central Chirality in Highly Stereoselective C−H Allylation

The significance of stereoselective C−H bond functionalization thrives on its direct application potential to pharmaceuticals or complex chiral molecule synthesis. Complication arises when there are multiple stereogenic elements such as a center and an axis of chirality to control. Over the years cooperative assistance of multiple chiral ligands has been applied to control only chiral centers. In this work, we harness the essence of cooperative ligand approach to control two different stereogenic elements in the same molecule by atroposelective allylation to synthesize axially chiral biaryls from its racemic precursor. The crucial roles played by chiral phosphoric acid and chiral amino acid ligand in concert helped us to obtain one major stereoisomer out of four distinct possibilities.     

Ruthenium(II)-Catalyzed Asymmetric Inert C−H Bond Activation Assisted by a Chiral Transient Directing Group

A ruthenium(II)-catalyzed asymmetric intramolecular hydroarylation assisted by a chiral transient directing group has been developed. A series of 2,3-dihydrobenzofurans bearing chiral all-carbon quaternary stereocenters have been prepared in remarkably high yields (up to 98 %) and enantioselectivities (up to >99 % ee). By this methodology, a novel asymmetric total synthesis of CB2 receptor agonist MDA7 has been successfully developed.     

Introducing the Chiral Transient Directing Group Strategy to Rhodium(III)-Catalyzed Asymmetric C−H Activation

The chiral transient directing group (TDG) strategy has been successfully introduced to the rhodium(III)-catalyzed asymmetric C−H activation. In the presence of a catalytic amount of a chiral amine and an achiral rhodium catalyst, various chiral phthalides were synthesized from simple aldehydes with high chemoselectivity, regioselectivity, and enantioselectivity (53 examples, up to 73 % yield and >99 % ee). It is noteworthy that the chiral induction model is different from the previously reported chiral TDG system using amino acid derivatives and palladium salts. The imino group generated in situ from chiral amine and aldehyde acts as the monodentate TDG to promote the C−H activation, stereoselectively generating the chiral rhodacycle bearing a chiral metal center. Moreover, the stereogenic center of the product is created and stereocontrolled during the Grignard-type addition of the C−Rh bond to aldehyde, rather than during the C−H activation step.     

Controlling Metal-Oxide Reducibility for Efficient C−H Bond Activation in Hydrocarbons

Knowing the structure of catalytically active species/phases and providing methods for their purposeful generation are two prerequisites for the design of catalysts with desired performance. Herein, we introduce a simple method for precise preparation of supported/bulk catalysts. It utilizes the ability of metal oxides to dissolve and to simultaneously precipitate during their treatment in an aqueous ammonia solution. Applying this method for a conventional VO_x−Al₂O₃ catalyst, the concentration of coordinatively unsaturated Al sites was tuned simply by changing the pH value of the solution. These sites affect the strength of V−O−Al bonds of isolated VO_x species and thus the reducibility of the latter. This method is also applicable for controlling the reducibility of bulk catalysts as demonstrated for a CeO₂−ZrO₂−Al₂O₃ system. The application potential of the developed catalysts was confirmed in the oxidative dehydrogenation of ethylbenzene to styrene with CO₂ and in the non-oxidative propane dehydrogenation to propene. Our approach is extendable to the preparation of any metal oxide catalysts dissolvable in an ammonia solution.     

Palladium-Catalyzed Atroposelective Kinetic C−H Olefination and Allylation for the Synthesis of C−B Axial Chirality

The direct C−H functionalization of 1,2-benzazaborines, especially asymmetric version, remains a great challenge. Here we report a palladium-catalyzed enantioselective C−H olefination and allylation reactions of 1,2-benzazaborines. This asymmetric approach is a kinetic resolution (KR), providing various C−B axially chiral 2-aryl-1,2-benzazaborines and 3-substituted 2-aryl-1,2-benzazaborines in generally high yields with excellent enantioselectivities (selectivity (S) factor up to 354). The synthetic potential of this reaction is showcased by late-stage modification of complex molecules, scale-up reaction, and applications.     

C−N Axial Chiral Hypervalent Iodine Reagents: Catalytic Stereoselective α-Oxytosylation of Ketones

A simple synthesis of a library of novel C−N axially chiral iodoarenes is achieved in a three-step synthesis from commercially available aniline derivatives. C−N axial chiral iodine reagents are rarely investigated in the hypervalent iodine arena. The potential of the novel chiral iodoarenes as organocatalysts for stereoselective oxidative transformations is assessed using the well explored, but challenging stereoselective α-oxytosylation of ketones. All investigated reagents catalyse the stereoselective oxidation of propiophenone to the corresponding chiral α-oxytosylated products with good stereochemical control. Using the optimised reaction conditions a wide range of products was obtained in generally good to excellent yields and with good enantioselectivities.     

Reactivity Control of CH Bond Activation over Vanadium-Silver Bimetallic Oxide Cluster Cations

Vanadium-silver bimetallic oxide cluster ions (V(x) Ag(y) O(z) (+) ; x=1-4, y=1-4, z=3-11) are produced by laser ablation and reacted with ethane in a fast-flow reactor. A reflectron time of flight (Re-TOF) mass spectrometer is used to detect the cluster distribution before and after the reactions. Hydrogen atom abstraction (HAA) reactions are identified over VAgO(3) (+) , V(2) Ag(2) O(6) (+) , V(2) Ag(4) O(7) (+) , V(3) AgO(8) (+) , V(3) Ag(3) O(9) (+) , and V(4) Ag(2) O(11) (+) ions, in which the oxygen-centered radicals terminally bonded on V atoms are active sites for the facile HAA reactions. DFT calculations are performed to study the structures, bonding, and reactivity. The reaction mechanisms of V(2) Ag(2) O(6) (+) +C(2) H(6) are also given. The doped Ag atoms with a valence state of +1 are highly dispersed at the periphery of the V(x) Ag(y) O(z) (+) cluster ions. The reactivity can be well-tuned gradually by controlling the number of Ag atoms. The steric protection due to the peripherally bonded Ag atoms greatly enhances the selectivity of the V-Ag bimetallic oxide clusters with respect to the corresponding pure vanadium oxide systems.     

PdII-Catalyzed Enantioselective C(sp3)–H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group

The use of chiral transient directing groups (TDGs) is a promising approach for developing Pd^II-catalyzed enantioselective C(sp³)−H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C−H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to Pd^II centers, which can result in a mixture of reactive complexes. We report a Pd^II-catalyzed enantioselective β-C(sp³)−H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono-substituted cyclobutane through sequential C−H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron-deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.     

Chiral Aluminum Complex Controls Enantioselective Nickel-Catalyzed Synthesis of Indenes: C−CN Bond Activation

A chiral aluminum complex controlled, enantioselective nickel-catalyzed domino reaction of aryl nitriles and alkynes proceeding by C−CN bond activation was developed. The reaction provides various indenes, bearing chiral all-carbon quaternary centers, under mild reaction conditions in yields of 32 to 91 % and ee values within the 73–98 % range. The reaction mechanism and aspects of stereocontrol were investigated by DFT calculations.     

Stereoselective Synthesis of Tetrasubstituted Alkenes via a Cp*CoIII-Catalyzed C−H Alkenylation/Directing Group Migration Sequence

A highly atom economical and stereoselective synthesis of tetrasubstituted α,β-unsaturated amides was achieved by a Cp*Co^III-catalyzed C−H alkenylation/directing group migration sequence. A carbamoyl directing group, which is typically removed after C−H functionalization, worked as an internal acylating agent and migrated onto the alkene moiety of the product. The directing group migration was realized with the Cp*Co^III catalyst, while a related Cp*Rh^III catalyst did not promote the migration process. The product was further converted into two types of tricyclic compounds, one of which had fluorescent properties.     

Catalytic C−C/C−H Bond Activation Relay for Synthesis of Fluorescent Naphthoquinolizinium Salts

Herein, we report the design and synthesis of a series of novel cationic nitrogen-embedded polyaromatic hydrocarbons with a planar geometry. The synthetic pathway is based on catalytic C−C/C−H bond activation relay that enabled preparation of regioselectively 5,6,10,11-tetrasubstituted naphtho[2,1,8-ija]quinolizinium salts bearing various types of substituents. Single-crystal X-ray analyses of selected compounds confirmed planarity of the quinolizinium core. Most of the prepared compounds exhibited strong fluorescence (Φ_s up to >99 %) ranging from 420–600 nm depending on the substitution pattern. According to DFT calculations LUMO is always distributed over the quinolizinium framework regardless of the attached substituents, whereas delocalization of HOMO is related to the substitution pattern. Electrochemical measurements show irreversible reduction of all compounds, which is supported by the calculated location of LUMO orbitals.     

Design of Chiral NHC-Carboxylates as Potential Ligands for Pd-Catalyzed Enantioselective C−H Activation

Despite numerous efforts, the synthesis of scalemic carbo- and heterocycles through Pd⁰-catalyzed C(sp³)−H activation employing chiral ancillary ligands or chiral bases is still limited. Inspired by the recently reported outstanding performance of IBiox-type NHC ligands and bifunctional ligands in similar transformations, a new class of bifunctional NHC-ligands bearing a pendant carboxylate group was designed. A library of 10 imidazolium-carboxylic acids was obtained in five to six steps from enantiopure l -tert-leucinol. In addition, four well-defined Pd(DMBPA)-NHC palladacycles were synthesized in good to excellent yields from the corresponding imidazolium precursors. These complexes were tested in a prototypical C(sp³)−H arylation reaction, and the most active one afforded the indoline product in low yield but significant enantioselectivity. These new bifunctional NHCs could find broader applications in catalytic enantioselective transformations occurring under milder conditions.     

Synthesis of Axially Chiral Styrenes through Pd-Catalyzed Asymmetric C−H Olefination Enabled by an Amino Amide Transient Directing Group

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through Pd^II-catalyzed atroposelective C−H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in Co^III-catalyzed enantioselective C(sp³)−H amidation of thioamide. Mechanistic studies suggest that C−H cleavage is the enantioselectivity-determining step.     

A Fujiwara-Moritani-Type Alkenylation Using a Traceless Directing Group Strategy: A Rare Example of C−C Bond Formation towards the C2-Carbon of Terminal Alkenes

Herein we report, a rhodium-catalyzed Fujiwara-Moritani-type reaction of unactivated terminal alkenes and benzoic acid derivatives bearing electron donating residues under mild conditions. The acid functionality acts as a traceless directing group delivering products alkenylated in meta-position to the electron donating substituent in contrast to the usually obtained ortho- and para-substitution in Friedel-Crafts-type reactions. Remarkably, the new C−C bond is formed to the C2 of the terminal olefin, in contrast to similar reported transformations. Initially formed mixtures of exo- and endo-double bond isomers can be efficiently isomerized to the more stable endo-products.     

RhIII-Catalyzed C−H Activation of Aryl Hydroxamates for the Synthesis of Isoindolinones

Rh^III-catalyzed C−H functionalization reaction yielding isoindolinones from aryl hydroxamates and ortho-substituted styrenes is reported. The reaction proceeds smoothly under mild conditions at room temperature, and tolerates a range of functional groups. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the presence of an ortho-substituent embedded in the styrene. The resulting isoindolinones are valuable building blocks for the synthesis of bioactive compounds. They provide easy access to the natural-product-like compounds, isoindolobenzazepines, in a one-pot two-step reaction. Selected isoindolinones inhibited Hedgehog (Hh)-dependent differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts.     

Structural Basis for Copper–Oxygen Mediated C−H Bond Activation by the Formylglycine-Generating Enzyme

The formylglycine-generating enzyme (FGE) is a unique copper protein that catalyzes oxygen-dependent C−H activation. We describe 1.66 Å- and 1.28 Å-resolution crystal structures of FGE from Thermomonospora curvata in complex with either Ag^I or Cd^II providing definitive evidence for a high-affinity metal-binding site in this enzyme. The structures reveal a bis-cysteine linear coordination of the monovalent metal, and tetrahedral coordination of the bivalent metal. Similar coordination changes may occur in the active enzyme as a result of Cu^I/II redox cycling. Complexation of copper atoms by two cysteine residues is common among copper-trafficking proteins, but is unprecedented for redox-active copper enzymes or synthetic copper catalysts.     

Metalated Porous Phenanthroline-Based Polymers as Efficient Heterogeneous Catalysts for Regioselective C−H Activation of Heteroarenes

Direct C−H bond activation of heterocycles as a step-economical and environmentally friendly approach to build the heterobiaryls motifs is highly attractive, but it still has a challenge to design and prepare a cheap and regioselective heterogeneous catalyst. To tackle this challenge, we have introduced Ni species into a porous phenanthroline-based organic polymer donated as POP-Phen@Ni. This heterogeneous catalyst shows excellent catalytic performances in regioselective C−H activation of heterocycles, even better than those of the corresponding homogenous catalyst. H/D exchange experiments show that the lithium bis(trimethylsilyl)amide (LiHMDS), a base added in the reaction, play a very important role during the reaction processes. We believe that this heterogeneous catalyst would open a new door for design of heterogeneous catalysts to efficiently catalyze the regioselective C−H activation of heterocycles.     

The Role of Sulphonamides and N-Sulphonyl Ketimines/Aldimines as Directing Groups in the Field of C−H Activation

Sulphonamides and N-sulphonyl ketimines/aldimines have turned out to be versatile motifs in the field of synthetic and medicinal chemistry. The field of C−H activation/functionalization flourished remarkably due to their synthetic applicability and directing group plays a remarkable role to achieve regioselectivity in these reactions. The current review summarizes recent tactics by utilizing sulphonamides and N-sulphonyl ketimines/aldimines as directing groups for C−H activation or functionalization. As a directing group, they also facilitate site selectivity and late-stage functionalization of drug molecules in order to construct complex scaffolds of therapeutic importance by C−H activation.     

Continued Progress towards Efficient Functionalization of Natural and Non-natural Targets under Mild Conditions: Oxygenation by C−H Bond Activation with Dioxirane

The successful isolation and characterization of a dioxirane species in 1988 opened up one of the most attractive methods for the efficient oxidation of simple and/or structurally complex molecules. Dioxirane today rank among the most powerful tools in organic chemistry, with numerous applications in commercially important processes. They were quickly recognized as efficient oxygen transfer agents, especially for epoxidations and for a wide range of O-insertion reactions into C−H bonds. Dioxirane possess catalytic activity and appear as highly (chemo-, regio-, and stereo-) selective oxidants, despite their reactivity under mild and strictly neutral conditions being controlled by a combination of steric and electronic factors. In this review, we discuss some of the most recent and significant developments in the selective homogeneous and heterogeneous oxyfunctionalization of non-activated C−H bonds in hydrocarbons of natural and non-natural targets by using isolated dioxirane or, more generally, by using the ketones (i.e., the dioxirane precursors) as organocatalysts.     

Cross-Dehydrogenative Coupling Polymerization via C−H Activation for the Synthesis of Conjugated Polymers

Owing to their versatile (opto)electronic properties, conjugated polymers have found application in several organic electronic devices. Cross-coupling reactions such as Stille, Suzuki, Kumada couplings, and direct arylation reactions have proved to be effective for their synthesis. More atom-efficient oxidative direct arylation polymerization has also been reported for making homopolymers. However, growing interest toward donor-acceptor polymers has led to the recent emergence of cross-dehydrogenative coupling (CDC) polymerization to synthesize alternating copolymers without any prefunctionalization of monomers. Metal-catalyzed cross-coupling of two simple arenes via double C−H activation, or of an arene with an alkene via oxidative Heck-type reaction have been used so far for CDC polymerization. In this article, we discuss the development of CDC polymerization protocols along with the relevant small molecule CDC reactions for an improved understanding of these reactions.