Site‐Selective Alkoxylation of Benzylic C−H Bonds by Photoredox Catalysis

Methods that enable the direct C?H alkoxylation of complex organic molecules are significantly underdeveloped, particularly in comparison to analogous strategies for C?N and C?C bond formation. In particular, almost all methods for the incorporation of alcohols by C?H oxidation require the use of the alcohol component as a solvent or co‐solvent. This condition limits the practical scope of these reactions to simple, inexpensive alcohols. Reported here is a photocatalytic protocol for the functionalization of benzylic C?H bonds with a wide range of oxygen nucleophiles. This strategy merges the photoredox activation of arenes with copper(II)‐mediated oxidation of the resulting benzylic radicals, which enables the introduction of benzylic C?O bonds with high site selectivity, chemoselectivity, and functional‐group tolerance using only two equivalents of the alcohol coupling partner. This method enables the late‐stage introduction of complex alkoxy groups into bioactive molecules, providing a practical new tool with potential applications in synthesis and medicinal chemistry.     

Functionalization of C‐H Bonds by Photoredox Catalysis

Visible‐light photoredox catalysis has been successfully used in the functionalization of inert C?H bonds including C(sp²)‐H bonds of arenes and C(sp³)‐H bonds of aliphatic compounds over the past decade. These transformations are typically promoted by the process of single‐electron‐transfer (SET) between substrates and photo‐excited photocatalyst upon visible light irradiation (household bulbs or LEDs). Compared with other synthetic strategies, such as the transition‐metal catalysis and traditional radical reactions, visible‐light photoredox approach has distinct advantages in terms of operational simplicity and practicability. Versatile direct functionalization of inert C(sp²)‐H and C(sp³)‐H bonds including alkylation, trifluoromethylation, arylation and amidation, has been achieved using this practical strategy.     

Amine‐Catalyzed Direct Photoarylation of Unactivated Arenes

Constructing biaryls through direct aromatic C? H functionalization of unactivated arenes has become a popular topic in organic chemistry. Many efficient methods have been developed. In this Communication, a direct arylation of unactivated arenes with a broad range of aryl iodides is reported. This reaction proceeds through a new type of amine‐catalyzed single electron transfer initiated radical coupling procedure to form biaryls in high yields under UV irradiation at room temperature. Only 20 mol% of TMEDA is used as the catalyst. No other additives are required for this transformation, thus avoiding the use of toxic transition metal catalysts, strong bases, or large amounts of other organic additives. This greener protocol provides a new strategy to achieve direct aromatic C? H functionalization and offers a new example of cost‐effective and environmentally benign access to biaryls.     

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.     

CH Functionalization of Phenols Using Combined Ruthenium and Photoredox Catalysis: In Situ Generation of the Oxidant

A combination of ruthenium and photoredox catalysis allowed the ortho olefination of phenols. Using visible light, the direct C? H functionalization of o‐(2‐pyridyl)phenols occurred, and diverse phenol ethers were obtained in good yields. The regeneration of the ruthenium catalyst was accomplished by a photoredox‐catalyzed oxidative process.     

Pd‐Catalyzed C−H Alkylation of Arenes Using PyrDipSi,a Transformable and Removable Silicon‐Tethered Directing Group

An efficient Pd‐catalyzed ortho‐C?H alkylation reaction of arenes using a transformable and removable Si‐tethered pyridyldiisopropylsilyl (PyrDipSi) directing group has been developed. In addition, the PyrDipSi directing group allows for an efficient sequential double‐fold C?H alkylation/oxygenation of arenes to produce meta‐alkylated phenols. This directing group can easily be removed or converted into valuable functionalities, such as aryl, iodo, boronic ester, or phenol.     

Late‐Stage Functionalization of Biologically Active Heterocycles Through Photoredox Catalysis

The direct C? H functionalization of heterocycles has become an increasingly valuable tool in modern drug discovery. However, the introduction of small alkyl groups, such as methyl, by this method has not been realized in the context of complex molecule synthesis since existing methods rely on the use of strong oxidants and elevated temperatures to generate the requisite radical species. Herein, we report the use of stable organic peroxides activated by visible‐light photoredox catalysis to achieve the direct methyl‐, ethyl‐, and cyclopropylation of a variety of biologically active heterocycles. The simple protocol, mild reaction conditions, and unique tolerability of this method make it an important tool for drug discovery.     

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

Expanding the toolbox of C?H functionalization reactions applicable to the late‐stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition‐metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C?H bond. However, these high‐energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C?H functionalization reactions with diazoacetate derivatives, furnishing sp²–sp³ coupled products with moderate‐to‐good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition‐metal catalyst.     

Cobalt‐Catalyzed C?H Bond Functionalizations with Aryl and Alkyl Chlorides

Inexpensive cobalt catalysts derived from N‐heterocylic carbenes (NHC) allowed efficient catalytic C? H bond arylations on heteroaryl‐substituted arenes with widely available aryl chlorides, which set the stage for the preparation of sterically hindered tri‐ortho‐substituted biaryls. Likewise, challenging direct alkylations with β‐hydrogen‐containing primary and even secondary alkyl chlorides proceeded on pyridyl‐ and pyrimidyl‐substituted arenes and heteroarenes. The cobalt‐catalyzed C? H bond functionalizations occurred efficiently at ambient reaction temperature with excellent levels of site‐selectivities and ample scope. Mechanistic studies highlighted that electron‐deficient aryl chlorides reacted preferentially, while the arenes kinetic C? H bond acidity was found to largely govern their reactivity.     

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.     

Towards Ideal Synthesis: Alkenylation of Aryl CH Bonds by a Fujiwara–Moritani Reaction

An overview of recent progress in the Fujiwara–Moritani reaction, which is the palladium‐catalyzed oxidative coupling of arenes with olefins to afford alkenyl arenes, is described. It is emphasized that regioselectivity on aryl ortho‐ or meta‐C?H activation could be controlled very well in the presence of Pd, Rh, or Ru catalysts with the assistance of various chelation groups on aromatic rings in this coupling reaction. Catalytic alkenylation of aryl C?H bonds from simple arenes is also discussed, especially from electron‐deficient arenes. These advanced protocols would not only make the Fujiwara–Moritani reaction more useful and applicable in organic synthesis but also light the way for the further development of the functionalization of normal C?H bonds.     

Synthesis,Characterization, and Reactivity of a Hypervalent‐Iodine‐Based Nitrooxylating Reagent

Herein, the synthesis and characterization of a hypervalent‐iodine‐based reagent that enables a direct and selective nitrooxylation of enolizable C?H bonds to access a broad array of organic nitrate esters is reported. This compound is bench stable, easy‐to‐handle, and delivers the nitrooxy (‐ONO₂) group under mild reaction conditions. Activation of the reagent by Brønsted and Lewis acids was demonstrated in the synthesis of nitrooxylated β‐keto esters, 1,3‐diketones, and malonates, while its activity under photoredox catalysis was shown in the synthesis of nitrooxylated oxindoles. Detailed mechanistic studies including pulse radiolysis, Stern–Volmer quenching studies, and UV/Vis spectroelectrochemistry reveal a unique single‐electron‐transfer (SET)‐induced concerted mechanistic pathway not reliant upon generation of the nitrate radical.     

Direct Aryl C−H Amination with Primary Amines Using Organic Photoredox Catalysis

The direct catalytic C−H amination of arenes is a powerful synthetic strategy with useful applications in pharmaceuticals, agrochemicals, and materials chemistry. Despite the advances in catalytic C−H functionalization, the use of aliphatic amine coupling partners is limited. Described herein is the construction of C−N bonds, using primary amines, by direct C−H functionalization with an acridinium photoredox catalyst under an aerobic atmosphere. A wide variety of primary amines, including amino acids and more complex amines are competent coupling partners. Various electron‐rich aromatics and heteroaromatics are useful scaffolds in this reaction, as are complex, biologically active arenes. We also describe the ability to functionalize arenes that are not oxidized by an acridinium catalyst, such as benzene and toluene, thus supporting a reactive amine cation radical intermediate.     

Activation of CH Bonds through Oxidant‐Free Photoredox Catalysis: Cross‐Coupling Hydrogen‐Evolution Transformation of Isochromans and β‐Keto Esters

The direct and controlled activation of a C(sp³)?H bond adjacent to an O atom is of particular synthetic value for the conventional derivatization of ethers or alcohols. In general, stoichiometric amounts of an oxidant are required to remove an electron and a hydrogen atom of the ether for subsequent transformations. Herein, we demonstrate that the activation of a C?H bond next to an O atom could be achieved under oxidant‐free conditions through photoredox‐neutral catalysis. By using a commercial dyad photosensitizer (Acr⁺‐Mes ClO₄^?, 9‐mesityl‐10‐methylacridinium perchlorate) and an easily available cobaloxime complex (Co(dmgBF₂)₂?2 MeCN, dmg=dimethylglyoxime), the nucleophilic addition of β‐keto esters to oxonium species, which is rarely observed in photocatalysis, leads to the corresponding coupling products and H₂ in moderate to good yields under visible‐light irradiation. Mechanistic studies suggest that both isochroman and the cobaloxime complex quench the electron‐transfer state of this dyad photosensitizer and that benzylic C?H bond cleavage is probably the rate‐determining step of this cross‐coupling hydrogen‐evolution transformation.     

Heterogeneous Platinum‐Catalyzed CH Perfluoroalkylation of Arenes and Heteroarenes

Fluorinated organic compounds are gaining increasing interest for life science applications. The replacement of hydrogen in arenes or heteroarenes by a perfluoroalkyl group has a profound influence on the physical and biological properties of such building blocks. Here, an operationally simple protocol for the direct C? H perfluoroalkylation of (hetero)arenes with R_fI or R_fBr has been developed, using a robust supported platinum catalyst. The ready availability of the starting materials, the excellent substrate tolerance, and the reusability of the catalyst make this method attractive for the synthesis of a variety of perfluoroalkyl‐substituted aromatic compounds. Preliminary mechanistic studies revealed the formation of radicals to be crucial in the reaction system.     

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.     

Site‐Selective C−H Oxygenation via Aryl Sulfonium Salts

Herein, we report a two‐step process forming arene C?O bonds in excellent site‐selectivity at a late‐stage. The C?O bond formation is achieved by selective introduction of a thianthrenium group, which is then converted into C?O bonds using photoredox chemistry. Electron‐rich, ‐poor and ‐neutral arenes as well as complex drug‐like small molecules are successfully transformed into both phenols and various ethers. The sequence differs conceptually from all previous arene oxygenation reactions in that oxygen functionality can be incorporated into complex small molecules at a late stage site‐selectively, which has not been shown via aryl halides.     

Catalytic C−H Trifluoromethoxylation of Arenes and Heteroarenes

The intermolecular C?H trifluoromethoxylation of arenes remains a long‐standing and unsolved problem in organic synthesis. Herein, we report the first catalytic protocol employing a novel trifluoromethoxylating reagent and redox‐active catalysts for the direct (hetero)aryl C?H trifluoromethoxylation. Our approach is operationally simple, proceeds at room temperature, uses easy‐to‐handle reagents, requires only 0.03 mol % of redox‐active catalysts, does not need specialized reaction apparatus, and tolerates a wide variety of functional groups and complex structures such as sugars and natural product derivatives. Importantly, both ground‐state and photoexcited redox‐active catalysts are effective. Detailed computational and experimental studies suggest a unique reaction pathway where photoexcitation of the trifluoromethoxylating reagent releases the OCF₃ radical that is trapped by (hetero)arenes. The resulting cyclohexadienyl radicals are oxidized by redox‐active catalysts and deprotonated to form the desired products of trifluoromethoxylation.     

Functionalization of Organic Molecules by Transition‐Metal‐Catalyzed C(sp3)?H Activation

Transition‐metal‐catalyzed C? H activation has recently emerged as a powerful tool for the functionalization of organic molecules. While many efforts have focused on the functionalization of arenes and heteroarenes by this strategy in the past two decades, much less research has been devoted to the activation of non‐acidic C? H bonds of alkyl groups. This Minireview highlights recent work in this area, with a particular emphasis on synthetically useful methods.     

Visible‐Light‐Catalyzed Direct Benzylic C(sp3)–H Amination Reaction by Cross‐Dehydrogenative Coupling

A conceptually new and synthetically valuable cross‐dehydrogenative benzylic C(sp³)–H amination reaction is reported by visible‐light photoredox catalysis. This protocol employs DCA (9,10‐dicyanoanthracene) as a visible‐light‐absorbing photoredox catalyst and an amide as the nitrogen source without the need of either a transition metal or an external oxidant.