Rhodium(III)-Catalyzed Enantio- and Diastereoselective C−H Cyclopropylation of N-Phenoxylsulfonamides: Combined Experimental and Computational Studies

Cyclopropane rings are a prominent structural motif in biologically active molecules. Enantio- and diastereoselective construction of cyclopropanes through C−H activation of arenes and coupling with readily available cyclopropenes is highly appealing but remains a challenge. A dual directing-group-assisted C−H activation strategy was used to realize mild and redox-neutral Rh^III-catalyzed C−H activation and cyclopropylation of N-phenoxylsulfonamides in a highly enantioselective, diastereoselective, and regioselective fashion with cyclopropenyl secondary alcohols as a cyclopropylating reagent. Synthetic applications are demonstrated to highlight the potential of the developed method. Integrated experimental and computational mechanistic studies revealed that the reaction proceeds via a Rh^V nitrenoid intermediate, and Noyori-type outer sphere concerted proton-hydride transfer from the secondary alcohol to the Rh=N bond produces the observed trans selectivity.     

Precise Functionalization of Remote C―H Bonds

Remote C-H bond functionalization of arenes with precise control is a recognized extraordinary challenge in organic synthesis. Recently, Yu and Houk et al. developed an elegant strategy to distinguish and functionalize remote C_sp²-H bonds of (hetero)arenes within one-bond distance by the interplay of a remote directing template and a transient norbornene-type mediator. A wide range of medicinally important benzoazines are well compatible with this method. The chemistry significantly expands the toolbox for site-selective functionalization of remote C_sp²-H bond of (hetero)arenes. This work has been published in Nature Chemistry in March, 2020.     

Site-Selective C−H Functionalization of Carbazoles

Carbazole alkaloids hold great potential in pharmaceutical and material sciences. However, the current approaches for C1 functionalization of carbazoles rely on the use of a pre-installed directing group, severely limiting their applicability and hindering their overall efficiency. Herein, we report for the first time the development of direct Pd-catalyzed C−H alkylation and acylation of carbazoles assisted by norbornene (NBE) as a transient directing mediator. Notably, the involvement of a six-membered palladacycle intermediate was suggested in this case, representing the first example of such intermediacy within the extensively studied Pd/norbornene reactions realm.     

meta-Selective C−H Functionalization of Pyridines

The pyridine moiety is an important core structure for a variety of drugs, agrochemicals, catalysts, and functional materials. Direct functionalization of C−H bonds in pyridines is a straightforward approach to access valuable substituted pyridines. Compared to the direct ortho- and para-functionalization, meta-selective pyridine C−H functionalization is far more challenging due to the inherent electronic properties of the pyridine entity. This review summarizes currently available methods for pyridine meta-C−H functionalization using a directing group, non-directed metalation, and temporary dearomatization strategies. Recent advances in ligand control and temporary dearomatization are highlighted. We analyze the advantages as well as limitations of current techniques and hope to inspire further developments in this important area.     

Palladium-Catalyzed C8-Arylation of Naphthalenes through C−H Activation: A Combined Experimental and Computational Study

Herein, a direct C8-arylation reaction of 1-amidonaphthalenes is described. By using diaryliodonium salts as arylating agents, the palladium-catalyzed C−H activation reaction showed perfect C8 regioselectivity and a wide functional group tolerance. In most cases, the desired polyaromatic compounds were isolated in good to excellent yields. To explain the observed regioselectivity, DFT calculations were performed and highlighted the crucial role of the amide directing group. Finally, the utility of this method is showcased by the synthesis of benzanthrone derivatives.     

Electrophotocatalytic Decarboxylative C−H Functionalization of Heteroarenes

Decarboxylative C−H functionalization reactions are highly attractive methods for forging carbon–carbon bonds considering their inherent step- and atom-economical features and the pervasiveness of carboxylic acids and C−H bonds. An ideal approach to achieve these dehydrogenative transformations is through hydrogen evolution without using any chemical oxidants. However, effective couplings by decarboxylative carbon–carbon bond formation with proton reduction remain an unsolved challenge. Herein, we report an electrophotocatalytic approach that merges organic electrochemistry with photocatalysis to achieve the efficient direct decarboxylative C−H alkylation and carbamoylation of heteroaromatic compounds through hydrogen evolution. This electrophotocatalytic method, which combines the high efficiency and selectivity of photocatalysis in promoting decarboxylation with the superiority of electrochemistry in effecting proton reduction, enables the efficient coupling of a wide range of heteroaromatic bases with a variety of carboxylic acids and oxamic acids. Advantageously, this method is scalable to decagram amounts, and applicable to the late-stage functionalization of drug molecules.     

Organocatalytic C−H Functionalization of Simple Alkanes

The direct functionalization of inert C(sp³)-H bonds to form carbon-carbon and carbon-heteroatom bonds offers vast potential for chemical synthesis and therefore receives increasing attention. At present, most successes come from strategies using metal catalysts/reagents or photo/electrochemical processes. The use of organocatalysis for this purpose remains scarce, especially when dealing with challenging C−H bonds such as those from simple alkanes. Here we disclose the first organocatalytic direct functionalization/acylation of inert C(sp³)-H bonds of completely unfunctionalized alkanes. Our approach involves N-heterocyclic carbene catalyst-mediated carbonyl radical intermediate generation and coupling with simple alkanes (through the corresponding alkyl radical intermediates generated via a hydrogen atom transfer process). Unreactive C−H bonds are widely present in fossil fuel feedstocks, commercially important organic polymers, and complex molecules such as natural products. Our present study shall inspire a new avenue for quick functionalization of these molecules under the light- and metal-free catalytic conditions.     

Chemical Upcycling of Polyolefins through C−H Functionalization

Polyolefins consist of abundant hydrophobic C−C and C−H bonds, and are considered as immensely potential untapped resources. Chemical upcycling offers a convenient and promising recycling strategy of polyolefins to produce newly-functionalized polymeric materials, and high-value added chemicals. The significant progress made in C−H functionalization reactions of alkane molecules provides new opportunities for improving polyolefin treatments. This review focuses on recent advancements in post-modification routes, specifically the introduction of C−C and C−X (X=O, N, S, halogens and etc.) bonds onto polyolefin chain backbones, as well as degradation models involving homogeneous C−H functionalization. By emphasizing these developments, we aim to highlight the potential of chemical upcycling for enhancing the treatment of polyolefins.     

C−H Functionalization and Allylic Amination for Post-Polymerization Modification of Polynorbornenes

Post-polymerization modification (PPM) via direct C−H functionalization is a powerful synthetic strategy to convert polymer feed-stocks into value-added products. We found that a metal-free, Se-catalyzed allylic C−H amination provided an efficient method for PPM of polynorbornenes (PNBs) produced via ring-opening metathesis polymerization. Inherent to the mechanism of the allylic amination, PPM on PNBs preserved the alkene functional groups along the polymer backbone, while also avoiding transposition of the double bonds. Amination using a series of aryl sulfonamides led to good control over the degree of functionalization, access to a range of functionalities, and tunable thermal properties from the resulting polymers.     

Functionality-Directed Regio- and Enantio-Selective Olefinic C−H Functionalization of Aryl Alkenes

Aryl alkenes represents one of the most widely occurring structural motif in countless drugs and natural products, and direct C−H functionalization of aryl alkenes provides atom- step efficient access toward valuable analogues. Among them, group-directed selective olefinic α- and β-C−H functionalization, bearing a directing group on the aromatic ring, has attracted remarkable attentions, including alkynylation, alkenylation, amino-carbonylation, cyanation, domino cyclization and so on. These transformations proceed by endo- and exo−C−H cyclometallation and provide aryl alkene derivatives in excellent site- stereo-selectivity. Enantio-selective α- and β- olefinic C−H functionalization were also covered to synthesis axially chiral styrenes.     

C−H Functionalization of Aldehydes and Ketones with Transient Directing Groups: Recent Developments

In order to directly functionalize C−H bonds of complex molecules and, in particular, to control the regioselectivity of the reaction, a wide range of directing groups has been used. However, these directing groups need to be installed and removed for further applications, which may limit the use of C−H activation in synthesis. Concerning aldehydes and ketones, a transient directing group strategy has recently emerged to overcome this drawback. The addition of an additive, in general an amine, allowed the in situ formation of the real directing group to achieve C−H activation. This review presents the latest developments in the field over the period 2020–2023.     

Late-stage C−H Functionalization of Tryptophan-Containing Peptides with Thianthrenium Salts: Conjugation and Ligation

Bioorthogonal late-stage diversification of structurally complex peptides bears enormous potential for drug discovery and molecular imaging, among other applications. Herein, we report on a palladium-catalyzed C−H arylation of tryptophan-containing peptides with readily accessible and modular arylthianthrenium salts. Under exceedingly mild reaction conditions, the late-stage diversification of structurally complex peptides was accomplished. The tunability and ease of preparation of arylthianthrenium salts allowed the expedient stitching of tryptophan-containing peptides with drug, natural product, and peptidic scaffolds by forging sterically congested biaryl linkages. The robustness of the palladium catalysis regime was reflected by the full tolerance of a plethora of sensitive and coordinating functional groups. Hence, our manifold enabled efficient access to highly decorated, labelled, conjugated, and ligated linear and cyclic peptides.     

Synthesis of Natural Products by C−H Functionalization of Heterocycless

Total synthesis is considered by many as the finest combination of art and science. During the last decades, several concepts were proposed for achieving the perfect vision of total synthesis, such as atom economy, step economy, or redox economy. In this context, C−H functionalization represents the most powerful platform that has emerged in the last years, empowering rapid synthesis of complex natural products and enabling diversification of bioactive scaffolds based on natural product architectures. In this review, we present an overview of the recent strategies towards the total synthesis of heterocyclic natural products enabled by C−H functionalization. Heterocycles represent the most common motifs in drug discovery and marketed drugs. The implementation of C−H functionalization of heterocycles enables novel tactics in the construction of core architectures, but also changes the logic design of retrosynthetic strategies and permits access to natural product scaffolds with novel and enhanced biological activities.     

Development of Catalytic Site-Selective C−H Oxidation

Direct C−H bond oxygenation is a strong and useful tool for the construction of oxygen functional groups. After Chen and White's pioneering works, various non-heme-type iron and manganese complexes were introduced, leading to strong development in this area. However, for this method to become a truly useful tool for synthetic organic chemistry, it is necessary to make further efforts to improve site-selectivity, and catalyst durability. Recently, we found that non-heme-type ruthenium complex cis- 1 presents efficient catalysis in C(sp³)−H oxygenation under acidic conditions. cis- 1 -catalysed C−H oxygenation can oxidize various substrates including highly complex natural compounds using hypervalent iodine reagents as a terminal oxidant. Moreover, the catalyst system can use almost stoichiometric water molecules as the oxygen source through reversible hydrolysis of PhI(OCOR)₂. It is a strong tool for producing isotopic-oxygen-labelled compounds. Moreover, the environmentally friendly hydrogen peroxide can be used as a terminal oxidant under acidic conditions.     

Formal γ−C−H Functionalization of Cyclobutyl Ketones: Synthesis of cis-1,3-Difunctionalized Cyclobutanes

1,3-Difunctionalized cyclobutanes are an emerging scaffold in medicinal chemistry that can confer beneficial pharmacological properties to small-molecule drug candidates. However, the diastereocontrolled synthesis of these compounds typically requires complicated synthetic routes, indicating a need for novel methods. Here, we report a sequential C−H/C−C functionalization strategy for the stereospecific synthesis of cis-γ-functionalized cyclobutyl ketones from readily available cyclobutyl aryl ketones. Specifically, a bicyclo[1.1.1]pentan-2-ol intermediate is generated from the parent cyclobutyl ketone via an optimized Norrish-Yang procedure. This intermediate then undergoes a ligand-enabled, palladium-catalyzed C−C cleavage/functionalization to produce valuable cis-γ-(hetero)arylated, alkenylated, and alkynylated cyclobutyl aryl ketones, the benzoyl moiety of which can subsequently be converted to a wide range of functional groups including amides and esters.     

Designed Iron Catalysts for Allylic C−H Functionalization of Propylene and Simple Olefins

Propylene gas is produced worldwide by steam cracking on million-metric-ton scale per year. It serves as a valuable starting material for π-bond functionalization but is rarely applied in transition metal-catalyzed allylic C−H functionalization for fine chemical synthesis. Herein, we report that a newly-developed cationic cyclopentadienyliron dicarbonyl complex allows for the conversion of propylene to its allylic C−C bond coupling products under catalytic conditions. This approach was also found applicable to the allylic functionalization of simple α-olefins with distinctive branched selectivity. Experimental and computational mechanistic studies supported the allylic deprotonation of the metal-coordinated alkene as the turnover-limiting step and led to insights into the multifaceted roles of the newly designed ligand in promoting allylic C−H functionalization with enhanced reactivity and stereoselectivity.     

Diastereoselective Double C−H Functionalization of Chiral Ferrocenes with Heteroaromatics

Diastereoselective double C−H heteroarylation of chiral ferrocenes provides valuable compounds with multiple functionalities using mild reaction conditions and simple reagents. Pd-Complexes with chiral mono-protected amino acids afforded corresponding heteroarylated ferrocenyl amines in good yields and high diastereomeric purities. In this way, a variety of indole, thiophene, pyrrole, or furan substituents were introduced to the ferrocene moiety. Furthermore, a range of relevant functional groups, for example ketone, ester, chloro, nitro, or silyl, are tolerated by this method. An alternative combination of amino acid and ferrocenyl amine configurations was leveraged to provide the complementary diastereomeric products. The products of C−H heteroarylation can be transformed into corresponding phosphines. Absolute configurations of CH-activation products were confirmed by the combination of X-ray crystallographic analysis and CD spectroscopy. ¹⁹F NMR kinetic study and DFT calculations provided insights into the reaction mechanism and reasons governing stereoinduction.     

Late-Stage Direct o-Alkenylation of Phenols by PdII-Catalyzed C−H Functionalization

o-Alkenylation of unprotected phenols has been developed by direct C−H functionalization catalyzed by Pd^II. This work features phenol group as a directing group and realizes highly site-selective C−H bond functionalization of phenols to achieve the corresponding products in moderate to excellent yields at 60 °C. The advantages of this reaction include unprecedented C−H functionalization using phenol as a directing group, high regioselectivity, good substrate scope, mild reaction conditions, and high efficiency. To the best of our knowledge, this is the first example of a regioselective C−H alkenylation of unprotected phenols utilizing phenolic hydroxyl group as a directing group. The alkenylation of unprotected tyrosine and intramolecular cyclization are also successfully carried out under this catalytic system in good yields. Furthermore, this novel method enables a late-stage modification of complex phenol-containing bioactive molecules toward a diversity-oriented drug discovery.     

Rational Development of a Metal-Free Bifunctional System for the C−H Activation of Methane: A Density Functional Theory Investigation

The activation or heterolytic splitting of methane, a challenging substrate usually restricted to transition metals, has so far proven elusive in experimental frustrated Lewis pair (FLP) chemistry. In this article, we demonstrate, using density functional theory (DFT), that 1-aza-9-boratriptycene is a conceptually simple intramolecular FLP for the activation of methane. Systematic comparison with other FLP systems allows to gain insight into their reactivity with methane. The thermodynamics and kinetics of methane activation are interpreted by referring to the analysis of the natural charges and by employing the distortion-interaction/activation strain (DIAS) model. These showed that the nature of the Lewis base influences the selectivity over the reaction pathway, with N Lewis bases favoring the deprotonation mechanism and P bases the hydride abstraction one. The lower barrier of activation for 1-aza-9-boratriptycene and the higher products stability are due to a better interaction energy than its counterparts, itself due to electrostatic interactions with the methane moiety, favorable orbital overlaps allowed by the side-attack, and space proximity between the B and N atoms.     

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.