Transition‐metal‐catalyzed Chelation‐assisted C–H Functionalization of Aromatic Substrates

In the past decade, transition‐metal‐catalyzed C–H activations have been very popular in the research field of organometallic chemistry, and have been considered as efficient and convenient strategies to afford complex natural products, functional advanced materials, fluorescent compounds, and pharmaceutical compounds. In this account, we begin with a brief introduction to the development of transition‐metal‐catalyzed C–H activation, especially the development of transition‐metal‐catalyzed chelation‐assisted C–H activation. Then, a more detailed discussion is directed towards our recent studies on the transition‐metal‐catalyzed chelation‐assisted oxidative C–H/C–H functionalization of aromatic substrates bearing directing functional groups.     

Synthesis of Phenolic Compounds via Palladium Catalyzed C−H Functionalization of Arenes

Phenol and its derivatives are extremely useful compounds in organic synthesis, medicinal chemistry and material sciences. The synthesis of phenols involving selective construction of the C?O bond at a C?H bond of arenes using transition‐metal catalysis represents the most appealing strategy. Indeed, active research is currently going on for the synthesis of valuable phenolic compounds using a transition‐metal‐catalyzed C?H functionalization strategy. This short review summarizes recent advances on palladium‐catalyzed C?O bond forming reactions that enable direct access to phenolic compounds. These catalytic reactions proceed either via C?H esterification with trifluoroacetic acid/trifluoroacetic anhydride followed by in situ hydrolysis of the ester or via direct C?H hydroxylation. A brief analysis of substrate scope and limitation, reaction mechanism as well as synthetic utility of these reactions has been included.     

Palladium‐Catalyzed/Norbornene‐Mediated CH Activation/ N‐Tosylhydrazone Insertion Reaction: A Route to Highly Functionalized Vinylarenes

A straightforward method for the synthesis of highly functionalized vinylarenes through palladium‐catalyzed, norbornene‐mediated C?H activation/carbene migratory insertion is described. Extension to a one‐pot procedure is also developed. Furthermore, this method can also be used to generate polysubstituted bicyclic molecules. The reaction proceeds under mild conditions to give the products in satisfactory yields using readily available starting materials. This is a Catellani–Lautens reaction that incorporates different types of coupling partners. Additionally, this reaction is the first to demonstrate the possibility of combining Pd‐catalyzed insertion of diazo compounds and Pd‐catalyzed C?H activation.     

Iridium‐Catalyzed Intermolecular Dehydrogenative Silylation of Polycyclic Aromatic Compounds without Directing Groups

This study describes the iridium‐catalyzed intermolecular dehydrogenative silylation of C(sp²)?H bonds of polycyclic aromatic compounds without directing groups. The reaction produced various arylsilanes through both Si?H and C?H bond activation, with hydrogen as the sole byproduct. Reactivity was affected by the electronic nature of the aromatic compounds, and silylation of electron‐deficient and polycyclic aromatic compounds proceeded efficiently. Site‐selectivity was controlled predominantly by steric factors. Therefore, the current functionalization proceeded with opposite chemo‐ and site‐selectivity compared to that observed for general electrophilic functionalization of aromatic compounds.     

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.     

Triazole‐Assisted Ruthenium‐Catalyzed CH Arylation of Aromatic Amides

Site‐selective ruthenium(II)‐catalyzed direct arylation of amides was achieved through C?H cleavages with modular auxiliaries, derived from easily accessible 1,2,3‐triazoles. The triazolyldimethylmethyl (TAM) bidentate directing group was prepared in a highly modular fashion through copper(I)‐catalyzed 1,3‐dipolar cycloaddition and allowed for ruthenium‐catalyzed C?H arylations on arenes and heteroarenes, as well as alkenes, by using easy‐to‐handle aryl bromides as the arylating reagents. The triazole‐assisted C?H activation strategy was found to be widely applicable, to occur under mild reaction conditions, and the catalytic system was tolerant of important electrophilic functionalities. Notably, the flexible triazole‐based auxiliary proved to be a more potent directing group for the optimized ruthenium(II)‐catalyzed direct arylations, compared with pyridyl‐substituted amides or substrates derived from 8‐aminoquinoline.     

Electrochemical Access to Aza‐Polycyclic Aromatic Hydrocarbons: Rhoda‐Electrocatalyzed Domino Alkyne Annulations

Nitrogen‐doped polycyclic aromatic hydrocarbons (aza‐PAHs) have found broad applications in material sciences. Herein, a modular electrochemical synthesis of aza‐PAHs was developed via a rhodium‐catalyzed cascade C?H activation and alkyne annulation. A multifunctional O‐methylamidoxime enabled the high chemo‐ and regioselectivity. The isolation of two key rhodacyclic intermediates made it possible to delineate the exact order of three C?H activation steps. In addition, the metalla‐electrocatalyzed multiple C?H transformation is characterized by unique functional group tolerance, including highly reactive iodo and azido groups.     

Asymmetric Total Syntheses of Di‐ and Sesquiterpenoids by Catalytic C−C Activation of Cyclopentanones

To show the synthetic utility of the catalytic C?C activation of less strained substrates, described here are the collective and concise syntheses of the natural products (?)‐microthecaline A, (?)‐leubehanol, (+)‐pseudopteroxazole, (+)‐seco‐pseudopteroxazole, pseudopterosin A–F and G—J aglycones, and (+)‐heritonin. The key step in these syntheses involve a Rh‐catalyzed C?C/C?H activation cascade of 3‐arylcyclopentanones, which provides a rapid and enantioselective route to access the polysubstituted tetrahydronaphthalene cores presented in these natural products. Other important features include 1) the direct C?H amination of the tetralone substrate in the synthesis of (?)‐microthecaline A, 2) the use of phosphoric acid to enhance efficiency and regioselectivity for problematic cyclopentanone substrates in the C?C activation reactions, and 3) the direct conversion of serrulatane into amphilectane diterpenes by an allylic cyclodehydrogenation coupling.     

Transition‐Metal‐Mediated Cleavage of C−C Bonds in Aromatic Rings

Metal‐mediated cleavage of aromatic C?C bonds has a range of potential synthetic applications: from direct coal liquefaction to synthesis of natural products. However, in contrast to the activation of aromatic C?H bonds, which has already been widely studied and exploited in diverse set of functionalization reactions, cleavage of aromatic C?C bonds remains Terra incognita. This Minireview summarizes the recent progress in this field and outlines key challenges to be overcome to develop synthetic methods based on this fundamental organometallic transformation.     

Silver(I)‐Catalyzed Tandem 1,3‐Acyloxy Migration/Mannich‐type Addition/Elimination of the Sulfonyl Group of N‐Sulfonylhydrazone‐propargylic Esters to 5,6‐Dihydropyridazin‐4‐one Derivatives

The addition of nucleophiles to C?N bonds offers a highly efficient synthetic strategy for accessing nitrogen‐containing molecules. 1 Among the well‐developed addition reactions, such as the highly efficient Mannich reaction, various C? H bond‐activated compounds including carboxylic acid derivatives, nitroalkanes, and terminal alkynes have been applied as nucleophiles to achieve different classes of amines. 2 However, employing new nucleophiles without activated C? H bonds, such as internal alkynes and allenic esters are limited when using metal catalysts. 3 Herein, we wish to report a new addition of allenic esters to C?N bonds initiated by a silver‐catalyzed 1,3‐migration of propargylic esters.     

Diastereoselective [3+2] Annulation of Aromatic/Vinylic Amides with Bicyclic Alkenes through Cobalt‐Catalyzed C−H Activation and Intramolecular Nucleophilic Addition

A highly diastereoselective method for the synthesis of dihydroepoxybenzofluorenone derivatives from aromatic/vinylic amides and bicyclic alkenes is described. This new transformation proceeds through cobalt‐catalyzed C?H activation and intramolecular nucleophilic addition to the amide functional group. Transition‐metal‐catalyzed C?H activation reactions of secondary amides with alkenes usually lead to [4+2] or [4+1] annulation; to the best of our knowledge, this is the first time that a [3+2] cycloaddition is described in this context. The reaction proceeds under mild conditions and tolerates a wide range of functional groups. Mechanistic studies imply that the C?H bond cleavage may be the rate‐limiting step.     

Recent Advancements in Transition‐Metal‐Catalyzed One‐Pot Twofold Unsymmetrical Difunctionalization of Arenes

Transition‐metal‐catalyzed direct C?H bond activation reactions have been embraced as a powerful synthetic tool to access diverse functionalized arenes. However, site‐selective incorporation of multiple distinct functionalities in an arene has always been a formidable challenge. Recent efforts from the synthetic community have disclosed a few dynamic synthetic approaches to fabricate multifunctionalized arenes in one‐pot using a single catalytic system. These reports manifested the immense potential of such approaches to expedite contemporary organic synthesis towards building molecular complexity. In this minireview, we have illustrated the recent progress in this area, highlighting the contribution from several synthetic chemists including our group.     

Ruthenium(II)‐Catalyzed CH Functionalizations with Allenes: Versatile Allenylations and Allylations

Ruthenium(II)‐catalyzed direct C?H functionalization of aromatic compounds with allenes was achieved under exceedingly mild reaction conditions to yield trisubstituted allenes. The reactions of N‐methoxybenzamides proceeded smoothly in an isohypsic fashion at ambient temperature with high chemo‐ and regioselectivity, thereby providing a versatile means of accessing trisubstituted allenes. Detailed mechanistic studies were suggestive of a kinetically relevant C?H metalation step, which occurs by the assistance of a carboxylate moiety; this also set the stage for unprecedented C?H allylations with removable directing groups in a step‐economical fashion.     

Manganese‐Catalyzed Dehydrogenative [4+2] Annulation of NH Imines and Alkynes by CH/NH Activation

Described herein is a manganese‐catalyzed dehydrogenative [4+2] annulation of N? H imines and alkynes, a reaction providing highly atom‐economical access to diverse isoquinolines. This transformation represents the first example of manganese‐catalyzed C? H activation of imines; the stoichiometric variant of the cyclomanganation was reported in 1971. The redox neutral reaction produces H₂ as the major byproduct and eliminates the need for any oxidants, external ligands, or additives, thus standing out from known isoquinoline synthesis by transition‐metal‐catalyzed C? H activation. Mechanistic studies revealed the five‐membered manganacycle and manganese hydride species as key reaction intermediates in the catalytic cycle.     

Aromatic Homologation by Non‐Chelate‐Assisted RhIII‐Catalyzed CH Functionalization of Arenes with Alkynes

Larger condensed arenes are of interest owing to their electro‐ and photochemical properties. An efficient synthesis is the catalyzed aromatic annulation of a smaller arene with two alkyne molecules. Besides difunctionalized starting materials, directed C? H functionalization can be used for such aromatic homologation. However, thus far the requirement of either pre‐functionalized substrates or suitable directing groups were limiting this approach. Herein, we describe a rhodium(III)‐catalyzed method allowing the use of completely unbiased arenes and internal alkynes. The reaction works best with copper(II) 2‐ethylhexanoate and decabromodiphenyl ether as the oxidant combination. This aromatic annulation tolerates a variety of functional groups and delivers homologated condensed arenes. Aside from simple benzenes, naphthalenes and higher condensed arenes provide access to highly substituted and highly soluble acenes structures having important electronic and photophysical properties.     

Rhodium‐Catalyzed PIII‐Directed ortho‐C−H Borylation of Arylphosphines

Transition‐metal‐mediated metalation of an aromatic C?H bond that is adjacent to a tertiary phosphine group in arylphosphines via a four‐membered chelate ring was first discovered in 1968. Herein, we overcome a long‐standing problem with the ortho‐C?H activation of arylphosphines in a catalytic fashion. In particular, we developed a rhodium‐catalyzed ortho‐selective C?H borylation of various commercially available arylphosphines with B₂pin₂ through P^III‐chelation‐assisted C?H activation. This discovery is suggestive of a generic platform that could enable the late‐stage modification of readily accessible arylphosphines.     

Synthesis of Indoles Using Visible Light: Photoredox Catalysis for Palladium‐Catalyzed CH Activation

A combined palladium‐ and photoredox‐catalyzed C? H olefination enables the synthesis of indoles. By using visible light, the direct C? H activation of aromatic enamines can be achieved and a variety of indole derivatives can be obtained in good yields under mild reaction conditions.     

HFIP‐Assisted C−H Functionalization by Cp*CoIII: Access to Key Reactive Cobaltacycles and Implication in Catalysis

Described here is a synthetic approach to access two of the most widely invoked cationic cobaltacycles in Cp*Co^III‐catalyzed C?H functionalization reactions by C?H activation. The unique stabilizing capability of MeCN was used to surmount the previously proposed reversible nature of the C?H metalation step. Moreover, it is revealed the boosting effect of 1,1,1,3,3,3‐hexafluoroisopropanol in the metalation step and in the reaction between N‐pyrimidinylindole and diphenylacetylene under catalytic conditions.     

Isoindolinone Synthesis via One-Pot Type Transition Metal Catalyzed C−C Bond Forming Reactions

Isoindolinone structure is an important privileged scaffold found in a large variety of naturally occurring as well as synthetic, biologically and pharmaceutically active compounds. Owing to its crucial role in a number of applications, the synthetic methodologies for accessing this heterocyclic skeleton have received significant attention during the past decade. In general, the synthetic strategies can be divided into two categories: First, direct utilization of phthalimides or phthalimidines as starting materials for the synthesis of isoindolinones; and second, construction of the lactam and/or aromatic rings by different catalytic methods, including C−H activation, cross-coupling, carbonylation, condensation, addition and formal cycloaddition reactions. Especially in the last mentioned, utilization of transition metal catalysts provides access to a broad range of substituted isoindolinones. Herein, the recent advances (2010–2020) in transition metal catalyzed synthetic methodologies via formation of new C−C bonds for isoindolinones are reviewed.     

Catalytic Behavior of Mono‐N‐Protected Amino‐Acid Ligands in Ligand‐Accelerated C−H Activation by Palladium(II)

Mono‐N‐protected amino acids (MPAAs) are increasingly common ligands in Pd‐catalyzed C?H functionalization reactions. Previous studies have shown how these ligands accelerate catalytic turnover by facilitating the C?H activation step. Here, it is shown that MPAA ligands exhibit a second property commonly associated with ligand‐accelerated catalysis: the ability to support catalytic turnover at substoichiometric ligand‐to‐metal ratios. This catalytic role of the MPAA ligand is characterized in stoichiometric C?H activation and catalytic C?H functionalization reactions. Palladacycle formation with substrates bearing carboxylate and pyridine directing groups exhibit a 50–100‐fold increase in rate when only 0.05 equivalents of MPAA are present relative to Pd^II. These and other mechanistic data indicate that facile exchange between MPAAs and anionic ligands coordinated to Pd^II enables a single MPAA to support C?H activation at multiple Pd^II centers.