Photoredox Catalysis for Building CâC Bonds from C(sp2

Review Cite This: Chem. Rev. 2018, 118, 7532−7585

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Photoredox Catalysis for Building C−C Bonds from C(sp2)−H Bonds Chang-Sheng Wang, Pierre H. Dixneuf, and Jean-François Soulé*

Chem. Rev. 2018.118:7532-7585. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 10/04/18. For personal use only.

Univ Rennes, CNRS, ISCR UMR 6226, F-35000 Rennes, France ABSTRACT: Transition metal-catalyzed C−H bond functionalizations have been the focus of intensive research over the last decades for the formation of C−C bonds from unfunctionalized arenes, heteroarenes, alkenes. These direct transformations provide new approaches in synthesis with high atom- and step-economy compared to the traditional catalytic cross-coupling reactions. However, such methods still suffer from several limitations including functional group tolerance and the lack of regioselectivity. In addition, they often require harsh reaction conditions and some of them need the use of strong oxidant, in a stoichiometric amount, avoiding these processes to be truly eco-friendly. The use of photoredox catalysis has contributed to a significant expansion of the scope of C(sp2)−H bond functionalizations which include the direct arylations, (perfluoro)alkylations, acylations, and even cyanations. Most of these transformations involve the photochemical induced generation of a radical followed by its regioselective addition to arenes, heteroarenes, or alkenes, leading to the building of a new C(sp2)−C bond. The use of photoredox catalysis plays crucial roles in these reactions promoting electron transfer, enabling the generation of radical species and single electron either oxidation or reduction. Such reactions operating at room temperature allow the building of C−C bonds with high chemo-, regio-, or stereoselectivity. This review surveys the formation of C(sp2)−C bonds initiated by photoredox catalysis which involves a C(sp2)−H bond functionalization step, describes the advantages compared to traditional C(sp2)−H bond functionalizations, and presents mechanistic insights into the role played by the photoredox catalysts.

CONTENTS 1. Introduction 2. Photocatalyzed Arylation of C(sp2)−H Bonds 2.1. Aryl Diazonium Salts as Aryl Radical Precursors 2.1.1. For Arylation of Arene Derivatives 2.1.2. For Arylation of Heterocycles 2.1.3. For Arylation of Alkenes 2.2. Diaryliodonium Salts As Aryl Radical Precursors for Arylation of (Hetero)arenes 2.3. Aryl Halides as Aryl Radical Precursors 2.3.1. For Arylation of Arenes 2.3.2. For Arylation of Heteroarenes 2.4. Aryl Carboxylic Acids as Aryl Radical Precursors for Arylation of Heteroarenes and Arenes 2.5. Benzenesulfonyl Chlorides as Aryl Radical Precursors for Arylation of Heteroarenes 3. Photocatalyzed Perfluoroalkylation of C(sp2)−H Bonds 3.1. Trifluorosulfonyl Chloride and Sodium Trifluoromethanesulfinate as Fluorinated Radical Sources for Trifluoromethylation of Arenes and Heteroarenes 3.2. Fluorinated Alkyl Halides As Radical Sources 3.2.1. For Perfluoroalkylation of Heteroarenes 3.2.2. For the Perfluoroalkylation of Arenes 3.2.3. For the Perfluoromethylation of Alkenes

© 2018 American Chemical Society

3.2.4. For the Perfluoroalkylation of Hydrazones 3.3. Togni and Umemoto’s Reagents As Trifluoromethyl Radical Precussors 3.3.1. For the Trifluoromethylation of Arenes 3.3.2. For the Trifluoromethylation of Heteroarenes 3.3.3. For the Trifluoromethylation of Alkenes 3.4. Trifluoroacetic Anhydride As Radical Source for Trifluoromethylation of Arenes and Heteroarenes 4. Photocatalyzed Alkylation of C(sp2)−H Bonds 4.1. Alkyl Bromides As Alkyl Radical Precursors 4.1.1. For Intramolecular Alkylation of Heteroarenes 4.1.2. For Intramolecular Alkylation of Arenes 4.1.3. For Intermolecular Alkylation of Heteroarenes 4.1.4. For Intermolecular Alkylation of Arenes 4.2. Alkylation of Pyridine Derivatives Using Alkylperoxides As Alkyl Radical Precursors 4.3. Alkylation of Pyridine Derivatives and Other Heterocycles Using Alkylboronic Acids As Alkyl Radical Precursors

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Received: February 5, 2018 Published: July 16, 2018 7532

DOI: 10.1021/acs.chemrev.8b00077 Chem. Rev. 2018, 118, 7532−7585

Chemical Reviews 4.4. Alkylation of Pyridine N-Oxides and Pyridine Derivatives Using Alkyltrifluoroborates as Alkyl Radical Precursors 4.5. Alkylation of Pyridine Derivatives Using Methanol and Alcohols as Methyl and Alkyl Radical Precursors 4.6. Alkylation of Pyridine Derivatives and FiveMembered Heterocycles Using Alkylcarboxylic Acid Derivatives as Alkyl Radical Precursors 4.7. Alkylation of Pyridine Derivatives and FiveMembered Heterocycles Using Primary Amines and Amino Acids as Alkyl Radical Precursors 4.8. Alkylation of Electron-Rich Arenes and FiveMembered Heterocycles through the Generation of N-Acyliminium Radical from Photoredox Catalysis of α-Amidosulfides 4.9. Alkylation of Pyridine and Pyrimidine Derivatives through the Generation of α-Oxyalkyl Radicals from Photoredox Catalysis of Dialkyl Ethers 5. Photoredox-Catalyzed Acylation of Heteroarenes C(sp2)−H Bonds 5.1. α-Oxo Acids as Acyl Radical Precursors 5.2. Aldehydes as Acyl Radical Precursors 6. Photoredox-Catalyzed Cyanation of Arenes C(sp2)−H Bonds 7. C(sp2)−H Bond Functionalization via Intramolecular Radical Relay Induced by Photoredox Catalysis 7.1. Alkyne Functions as SOMO-philic Relays 7.2. Alkene Functions as SOMO-philic Relays 7.2.1. Photoredox-Catalyzed 1,2-Difunctionalization of N-Arylacrylamide Derivatives 7.2.2. Photoredox-Catalyzed 1,2-Difunctionalization of N-Aryl Cinnamamide Derivatives 7.3. Isocyanide Functions as SOMO-philic Relays 8. C(sp2)−H Bond Functionalization via PhotoredoxCatalyzed Atom-Transfer Radical Addition to Alkenes 9. Photoredox Catalyst as Green Oxidant in C(sp2)− H Bond Functionalization 9.1. Combination of Rhodium(III)-Catalyzed C−H Bonds Activation with Photoredox Catalysts 9.2. Combination of Palladium(II)-Catalyzed C−H Bond Activation with Photoredox Catalysts 9.3. Combination of Ruthenium(II)-Catalyzed C− H Bonds with Photoredox Catalysts 9.4. Combination of Cobalt(II) and Organic Photoredox Catalysts for the C−H Bond Alkenylation of Arenes and Heteroarenes 10. Conclusions and Outlook Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

Review

1. INTRODUCTION Since the two last decades, metal-catalyzed C−H bond functionalizations for the cross-coupling of C−C bonds are moving into mainstream synthesis for the preparation of complex medicinal drugs, (poly)functional ligands, and even molecular materials, including industrial applications.1−21 These methods constitute a useful alternative to classical catalytic cross-coupling reactions. Beside atom economy and cost efficiency, C−H bond functionalizations allow straightforward building of complex molecules from simple and affordable raw starting materials. However, C−C cross-couplings from C−H bonds still suffer from difficulty to regioselectively activate only one C(sp2)−H bond among many other usually present, except by the use of directing group.22−24 One of the main drawback is that whereas C−H bond cleavage by metal catalyst is easy, the functionalization of the formed C−M bond often requires high energy. In addition, the use of stoichiometric amounts of oxidant is often required to regenerate the active metal catalysts after each C−H bond transformation process. Another useful revolution in synthesis has been brought by photoredox-initiated reactions, catalyzed either by transition metal complexes25 or by organic dyes (organic photoredox catalysts)26,27 (Figure 1a). Among the transition metal-based photoredox-catalyzed reactions, they typically employed metal polypyridyl complexes, offering metal−ligand charge transfer (MLCT) properties,28 such as Ru(II) polypyridine complexes or cyclometalated Ir(III) complexes. Alternatively, metal free conditions have been employed using organic dyes or large organic molecules such as eosin, rhodamine, 9-fluorenone, xanthone, methylene blue, rose Bengal, acridiniums, etc., capable of absorbing the light in the visible or near-visible light regions (Figure 1b). Both types of photoredox catalysts (PC), i.e., transition metal complexes or organic dyes, are able to valorize sunlight as an inexpensive, nonpolluting, and abundant renewable source of clean energy. When the PC is irradiated by visible light, it gives long lifetime photoexcited states (PC*). In contrast to the ground state (PC), the photoexcited state (PC*) can be easily engaged in a bimolecular electron-transfer event to release or capture one electron to or from molecule.28 In the reductive quenching cycles, PC* accepted an electron from a substrate [Sub] or a reductant [Red] generating the radical anion [PC]•− followed by its oxidation (Figure 2a, blue pathway). In most of the cases, oxidative quenching cycles are involved for the C−H bond functionalization through photoredox reactions. In such a scenario, PC* gives an electron either to substrate [Sub] or an oxidant [Ox] present in the reaction mixture, generating radical cation of the photocatalyst [PC]•+, which is later reduced (Figure 2b, red pathway). Such single electron transfer (SET) events have led to improve radical generation and give a new life to radical transformation in synthesis. Since the seminal report in 1972 by Gafney and Adamson of the electron-transfer quenching of the triplet charge-transfer excited state of [Ru(bpy)3]2+,29 the application of the visible light photochemistry of ruthenium polypyridine complexes has raised.30 However, their use in organic synthesis to promote radical reactions is more recent.31 As early as 1984, Deronzier employed [Ru(bpy)32+] for the photocatalyzed intramolecular C−H arylation of stilbenediazonium salts, a reaction reported before the conceptualization and the emergence of C−H bond functionalizations.32 Since these major breakthroughs, the use of photoredox catalysis in the construction/modification of

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Figure 1. (a) Representative metal-based photoredox catalysts. (b) Representative organic photoredox catalysts.

point for practitioners looking to enter this area and (ii) to inspire researchers looking for new C−C bond formations. Specifically, recent advances in photochemical C−C bond formation from C(sp2)−H bond functionalization of arenes, heteroarenes, and alkenes have been highlighted, with an emphasis on their scope, limitations, regioselectivity, and mechanisms discussion. This overview is organized by C(sp2)−H bond type of functionalizations: arylations, perfluoroalkylations, alkylations, acylations, cyanations, radical cascade cyclizations, and the use of photoredox catalysts as green oxidants in metal-catalyzed C−H bond functionalizations.

organic molecules has become a hot topic and it even has become one of the most powerful method to functionalize C(sp3)−H at the alpha-position of heteroatoms (via radical oxidation), and this topic is already covered by reviews.25,33,34 The research on C(sp2)−H bond functionalizations using photoredox catalysts started only from 2011 with the trifluoromethylation of (hetero)arenes developed by MacMillan.35 Since this discovery, there is a fast-growing number of publications on this topic. Photoredox systems have now been shown to largely contribute to improve the formation of C(sp2)−C(sp3) or C(sp2)−C(sp2) bonds from C(sp2)−H bonds and very often under mild reaction conditions at room temperature. These reactions generally operate via single electron transfer (SET) and provide alternatives to classical transition metal-catalyzed C(sp2)−H bond activation operating by concerted-metalation deprotonation, such as different regioselectivity, or functional group tolerance. Polypyridyl metal photoredox catalysts are often employed. However, some organic molecules display efficient photoredox catalyst properties (i.e., organic dyes), enabling achievement of similar C(sp2)−H bond functionalization as with Ru(bpy)32+. Alternatively, photosensitizer-free conditions through the formation of electron donor−acceptor (EDA) complex36 are also able to achieve C−H bond functionalizations of (hetero)arenes, albeit this method is very substrate dependent. Both approaches are often complementary to polypyridyl metal photoredox catalysis allowing to develop metal-free reaction conditions and are also discussed in this review. However, the C(sp2)−H bond functionalizations carried out with heterogeneous semiconductors37 such as mesoporous carbon nitride,38,39 and various metal oxides,40 are not discussed in this review. Photocatalyzed C(sp2)−H bond functionalization has been covered in the last years by several relevant reviews25,41−48 or personal accounts.49−52 However, these reviews were mostly devoted to a specific subject such as the trifluoromethylation reactions,42 applications of dual catalysis,45,53 behavior of benzenesulfonyl chlorides,47 atom transfer radical reactions,43 or synthesis of heterocycles.46,48 This review focus on general modifications of C(sp2)−H bond by photoredox catalysis, describing the advantages and limits brought by photoredox catalysts. This review will hopefully serve as (i) a useful starting

Figure 2. Photoredox catalyst quenching pathway.

2. PHOTOCATALYZED ARYLATION OF C(sp2)−H BONDS 2.1. Aryl Diazonium Salts as Aryl Radical Precursors

2.1.1. For Arylation of Arene Derivatives. One of the best-known aryl radical precursors described in the Pschorr and Meerwein reaction commenced in 1896 with the synthesis of phenanthrene and 1939 with the arylation of olefins by aryl diazonium salts. Both reactions were catalyzed by copper(II) species in which the aryl radical is generated after heterolytic cleavage of aryl diazonium salts.54 However, it is only in 1984 that Deronzier and co-workers reinvestigated the Pschorr reaction in the phenanthrene series with the light of photoredox catalysts (Scheme 1).32 They demonstrated that the irradiation of diazonium stilbenes without photosensitizer gave the 7534


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arylation under mild conditions. This initiative was launched by Sanford and co-workers with the development of dual catalysis for the C−H bond arylation of phenylpyridine derivatives at room temperature (Scheme 3).56 From Deronzier results, they

Scheme 1. Pschorr Reaction in Phenanthrene Series by Deronzier

Scheme 3. Merging Pd-Catalyzed C−H Functionalization and Visible Light Photoredox Catalysis

cyclization in poor yields (20%). However, when they added 5 mol % of Ru(bpy)32+ salt in the presence of light (410 nm), the desired products were isolated in very high yields and the reaction tolerated the carboxylic acid group. This study seems to be the first photoredox catalyzed C(sp2)−H bond functionalization. The authors have proposed an oxidative quenching pathway for the production of phenanthrene (Figure 3). After photo-

envisioned that palladacycle resulting from the C−H bond activation could potentially be intercepted by aryl radicals formed at room temperature via visible light photoredox catalysis. Indeed, in the presence of both Pd(OAc)2 and Ru(bpy)32+, 2-phenylpyridine was arylated at ortho-position at room temperature using aryldiazonium salts as aryl sources. The reaction tolerates some functionalities on the phenylpyridine such as halogen, trifluoromethyl, methoxy, or nitro groups. Other directing groups such as amides, pyrazoles, pyrimidines, and oxime ethers were also successfully employed with a broad range of substituted aryl diazonium salts. The authors proposed two separate catalytic cycles including the photoredox catalytic cycle and the palladium catalytic cycle (Figure 4). The photoreduction of the aryldiazonium salt gives aryl radical species (A), concomitantly affording oxidized-state photosensitizer [Ru(bpy)33+]. Pd(II)-mediated directed C−H activation gives palladacycle, which could be oxidized by addition of an aryl radical to give Pd(III) intermediate (B). Single electron oxidation of this Pd(III) by [Ru(bpy)33+] affords Pd(IV) intermediate (C) and regenerates the [Ru(bpy)32+]. Finally, reductive elimination of Pd(IV) intermediate (C) produces the desired C−H bond arylated product and regenerates the Pd(II) catalyst. Inspired by this work, Guo and co-workers reported the arylation of purine nucleosides under mild reaction conditions (Scheme 4).57 The arylation is regioselective and tolerates a wide range of substituents at the N9 position of purine such as alkyl-, cycloalkyl-substituents but also some more reactive groups such as bromine, ester, or sugar. In 2017, Xu and co-workers reported the merge of palladium catalysis with organic photoredox catalysis for the ortho-directed arylation of acetanilides and benzamides (Scheme 5).58 The

Figure 3. Proposed mechanism for photocatalyzed Pschorr−Deronzier reaction.

sensibilization of Ru(bpy)32+, SET occurs from the exited state catalyst to the diazonium salt, generating the free aryl radical (B) after dinitrogen extrusion. Then they suggest that the cyclization occurs by a radical pathway followed by oxidation by Ru(bpy)33+ of the cyclized radical (C) which leads to the cation (D). Finally, the rearomatization by loss of a proton gives the desired phenanthrene.32 A few years later, the same group has studied the synthesis of fluorenone, fluorene, and dibenzofuran through a similar photoredox-catalyzed Pschorr reaction (Scheme 2).55 The Scheme 2. Photocatalized Intramolecular Arylation via Pschorr Reaction

reaction is more sluggish and requires additives such as 4methoxybenzyl alcohol, which is easily photo-oxidized in basic media (collidine) to the corresponding aldehyde, allowing a faster regeneration of Ru(bpy)32+. Recent years have seen renewed significance for diazonium salts under photoredox conditions, especially for the C−H bond 7535


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Scheme 5. Dual Catalysis Pd(OAc)2/9,10-Dihydroacridine for Arylation of Acetanilides and Benzamides Using Aryldiazonium Salts

Figure 4. Proposed catalytic cycle of C−H bond arylation via dual catalysis.

Scheme 6. Arylation of Benzene Derivatives with Aryldiazonium Salts

Scheme 4. Dual Catalysis Pd(OAc)2/Ru(bpy)32+ for Arylation of Purine Nucleosides Using Aryldiazonium Salts

Scheme 7. Arylation of N-Heteroarenes with Aryldiazonium Saltsa

concept is similar to the one described by Sanford,56 although Ru(bpy)2+ is replaced by 9,10-dihydroacridine. These photoredox couplings with aryldiazonium salts are not limited to substrates bearing a directing group. In 2015, Malacria and co-workers reported the intermolecular C−H bond arylation of phenyl rings using [Ru(bpy)3]Cl2·6H2O as a photoredox catalyst (Scheme 6).59 However, a huge amount (40 equiv) of arene is required to promote the C−C bond coupling, and when the arene is substituted, a mixture of the regioisomers are often obtained, which is in line with a radical process. 2.1.2. For Arylation of Heterocycles. In 2014, Xue and coworkers reported visible light-promoted C−H bond arylation of N-heteroarenes with aryldiazonium salts in water (Scheme 7).60 The reaction proceeds at room temperature with only [Ru(bpy)3]Cl2·6H2O as a photosensitizer and a commercial household light bulb as a light source. C4-Substituted pyridines are efficiently arylated at C2 position, whereas unsubstituted, C2- or C3- substituted pyridines give a mixture of regioisomers.

a

Reaction performed in formic acid instead of water.

The authors showed that using aqueous formic acid as solvent, an array of xanthenes, thiazoles, pyrazines, and pyridazines were also compatible with this arylation reaction. The authors suggested a similar mechanism oxidative quenching cycle than that of Deronzier, albeit the last step of 7536


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range of heteroarenes with aryl diazonium salts using green light and the organic dye eosin Y as a photoredox catalyst (Scheme 9).62 The reaction is not sensitive to both electronic and steric

resulting radical oxidation into a carbocation intermediate (Figure 5). They proposed two possible pathways: (i) a

Scheme 9. Metal-Free C−H Bond Arylation of Heteroarenes with Aryldiazonium Salts in the Presence of Eosin Y

Figure 5. Proposed mechanism for arylation of N-heteroarenes with aryldiazonium salts.

common oxidation by the strongly oxidizing [Ru(bpy)3]3+ or (ii) an oxidation by the aryldiazonium salts leading to an autocatalytic reaction. A few months later, Lei and co-workers reported a similar strategy for the arylation of isoquinolines in the presence of [Ru(bpy)3]2+. In addition, they applied this methodology to the total synthesis of menisporphine and daurioxoisoporphine C (Scheme 8).61 In contrast to the previous work, which required

factors on the aryl diazonium salts, and it regioselectively affords C2 arylated furans, thiophenes, and N-Boc pyrroles. However, when the thiophenes bear a substituent at C2, a mixture of C5 and C3 arylated products is obtained in a 5:1 ratio. Similarly, from 3-bromothiophene, the formation of a mixture of C5 and C2 regioisomers is observed. Notably, palladium-catalyzed C− H arylation of bromothiophenes also affords a mixture of regioisomers.63 The authors proposed a mechanism where eosin Y replaces [Ru(bipy)3]2+ as an organic photoredox catalyst. The C−H (hetero)arylation of heteroarenes could be also achieved through visible light photoredox-catalyzed by in situ diazotization of heteroarylamines with tBuONO at room temperature in the presence of eosin Y (Scheme 10).64

Scheme 8. Arylation of Isoquinolines with Aryldiazonium Salts

Scheme 10. C−H Bond Arylation of Heteroarenes with in Situ Generation of Aryldiazonium Salts with tBuONO

In 2013, Zhao et al. introduced iodo-bodipys as visible light absorbing dual-functional photoredox catalysts for preparation of (hetero)biphenyl derivatives through C−H bond arylation with aryldiazonium salts (Scheme 11). 65 The authors mentioned that the major advantage of such organic photoredox catalysts is that they act as either electron acceptors (reductive quenching) or electron donors (oxidative quenching), and the reactions are greatly accelerated with the organic photoredox

the use of pyridinium salts as starting materials, the authors employ trifluoroacetic acid to in situ protonate the heterocycle. Isoquinoline is arylated at C1 position and acridine at the C9. A similar mechanism than that of Xue is proposed (Figure 5). Visible light induced C−H bond arylation of heteroarenes is not limited to the use of cyclometalated photoredox catalysts. In 2012, König and co-workers succeeded to develop metal-free conditions for intermolecular C−H bond arylation of a wide 7537


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thiophenes and pyrroles displayed lower reactivities. Notably, a huge amount of heteroarenes are required (10 equiv), which make this approach not synthetically viable. 2.1.3. For Arylation of Alkenes. König and co-workers demonstrated that aryl diazonium salts could be also employed for the C−H bond arylation of alkenes and alkynes (Scheme 14).68 The arylation of styrene derivatives is performed using 1

Scheme 11. Iodo-bodipys Photoinduced C−H Bond Arylation of Heteroarenes with Aryldiazonium Salts

Scheme 14. Photocatalytic Arylation of Alkenes, Alkynes, and Enones with Diazonium Salts

catalyst compared to the reactions performed with the metal complex photoredox catalysts such as Ru(bpy)3Cl2 or Ir(ppy)3. The reaction time can be reduced from 72 h to 1−2 h. 9,10-Dihydro-10-methylacridine has been also employed as organic photoredox catalyst by Xu and co-workers for the C−H bond arylation of furans, thiophenes, pyrroles, and benzene with aryldiazonium salts (Scheme 12).66 Again, the arylation occurred at the most acidic alpha-position. Scheme 12. 9,10-Dihydro-10-methylacridine Photoinduced C−H Bond Arylation of Heteroarenes with Aryldiazonium Salts mol % [Ru(bpy)3]2+ under blue LEDs or using 7.5 mol % of eosin Y under green LEDs. The stilbene products are obtained in good yields with high functional group compatibilities. Higher yields are often observed using ruthenium photoredox catalyst than with organic dye. The reaction is not completely stereoselective, as in all cases the formation of a mixture of (Z) and (E) isomers is observed. In addition, enones such as benzoquinone and coumarin can also be arylated, although fac[Ir(ppy)3] photoredox catalyst must be employed. Moreover, C(sp)−H bond arylation of phenylacetylene derivatives is also successful using [Ru(bpy)3]2+. Metal-free C−H arylation of coumarins was later achieved by Kanai and co-workers using catalytic amounts of 5,10,15,20tetrakis(4-diethylaminophenyl)porphyrin (Scheme 15).69 This method displays a high functional group tolerance and mild reaction conditions, while providing versatile access to a wide variety of 3-arylcoumarins in moderate to high yields.

In 2017, Gryko and co-workers employed a porphyrin as organic photoredox catalysts for the direct arylation of heteroarenes using aryl diazonium salts (Scheme 13).67 They showed that electron-poor tetra(pentafluorophenyl)porphyrin had the best photoredox catalytic activity. Furan was arylated in high yield using a wide range of diazonium salts, whereas

2.2. Diaryliodonium Salts As Aryl Radical Precursors for Arylation of (Hetero)arenes

Xue, Xiao, and co-workers demonstrated that aryl radicals could be also produced from the irradiation of diaryliodonium salts using [Ru(bpy)3]2+ in concert with blue LEDs. This protocol affords mild conditions for C−H arylation of (hetero)arenes, albeit a huge amount of (hereto)arene is required (Scheme 16).70 Both symmetrical diaryliodonium triflates and unsymmetrical ones were employed; in the later case, the sterically less hindered aromatic moiety is preferentially transferred. The reaction tolerates a wide range of substituents on the diaryliodonium moieties including halogen atom such as bromine. Pyrroles, (benzo)furans, and (benzo)thiophenes are regioselectively arylated at the C2 or C5 position. Pyrazines, as well as electron rich arenes, are also suitable substrates for C(sp2)−H bond arylation. The authors have proposed a mechanism based on oxidative quenching pathway similar to that using aryl diazonium salts (Figure 5).

Scheme 13. Porphyrin-Induced Arylation of Heteroarenes with Diazonium Salts

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Scheme 15. Porphyrin-Induced Arylation of Coumarins with Diazonium Salts

Scheme 17. Phenylation of (Hetero)arenes with Diaryliodonium Salts

electron-poor arenes such as diazonium or iodonium salts due to a more negative reduction potential (e.g., E°ArCl = −2.78 V vs SCE, E°ArBr = −2.44 V vs SCE, E°ArI = −2.24 V vs SCE), higher carbon-halide bond dissociation energy, and a different, stepwise cleavage mechanism.72 In most of the cases, these cleavages leading to a radical cannot be initiated by common photoredox catalysis. In 2012, Stephenson’s group succeeded in dehalogenation of aryl iodides via a radical pathway initiated by fac[Ir(ppy)3] photoredox catalyst and formic acid as proton source.73 Later, Lee et al. developed photoredox conditions for the radical intramolecular cyclization of aryl iodides using [Ir(ppy)2(dtbbpy)]PF6.74 In 2013, Li and co-workers found that C−H bond arylation of arenes with aryl halides could be carried out in the presence of potassium tert-butoxide and dimethyl sulfoxide under visible light irradiation (Scheme 18).75 fac-[Ir(ppy)3] photoredox

Scheme 16. Arylation of (Hetero)arenes with Diaryliodonium Salts

Scheme 18. C−H Bond Arylation of Arenes Using Aryl Halides and Ir-Photoredox Catalyst

catalyst was found to be the most effective to allow the generation of aryl radial from aryl iodides at room temperature, whereas 70 °C was required from aryl bromides. Chlorobenzene was also evaluated; at 90 °C the photoredox coupling with benzene allows the formation of biphenyl in 35% yield. It is important to mention that a huge amount of arenes is required in this procedure, which prevents synthetic applicability’s. Mechanistic pathway involves the generation of aryl halide radical anion by SET from the visible light excited photoredox catalyst, followed by the formation of the aryl radical via the dissociation of C−X bond to give up a halogen anion (Figure 6). The aryl radical then reacts with arene to form a biaryl radical. In the presence of a strong base, the resulting biaryl radical is deprotonated to give biaryl radical anion. The reductive biaryl radical anion then give an electron to the oxidized photoredox

The same year, Tobisu, Chatani and co-workers reported similar reaction conditions for the C−H bond phenylation of (hetero)arenes such as benzene, pyridines, pyrazines, imidazoles, and thiophenes but using [Ir(ppy)2(bpy)]PF6 as photoredox catalyst (Scheme 17).71 In all cases, the arylation takes place mainly at the α-position. In some cases, the reaction is also performed without the use of photoredox catalyst. The authors explained this result by the formation of a colored chargetransfer (CT) complex, which could absorb visible light and promote SET. 2.3. Aryl Halides as Aryl Radical Precursors

2.3.1. For Arylation of Arenes. The generation of aryl radical from aryl halides, by photoinduced electron transfer (PET) from photoredox catalysts, is more challenging than from 7539


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Figure 6. Proposed mechanism for arylation of benzene with aryl halides Ir-based photoredox catalyst. Figure 7. Proposed mechanism for eosin photocatalyzed perfluoroarylation of (hetero)arene.

catalyst to afford the biaryl product and regenerate the Ir photoredox catalyst. However, the exact role of tBuOK is not clear, as without photoredox catalyst the reaction in also operative but in 20% only yield. König and co-workers showed that fluorinated aryl bromides could play the role of aryl radical precursors for the C−H bond arylation of (hetero)arenes using an organic photoredox catalyst (Scheme 19).76 Simple arenes and heteroarenes are arylated

spectroscopy, transient spectroscopy, and quantum yield determination reveals that reductive quenching pathway is the most favorable. An electron transfer event can occur without the need of any photoredox catalyst due the association between an electronrich (a donor, D) and an electron-poor molecule (an acceptor, A), which produces an electron donor−acceptor (EDA) complex that can sometimes absorb light in the visible region and promote electron-transfer event.36 Such an EDA strategy has been employed by König and co-workers for the arylation of anilines (Scheme 20).77 They demonstrated by spectroscopic

Scheme 19. Organic Photoredox Catalyst for the Perfluoroarylation of (Hetero)arene Derivatives

Scheme 20. Arylation of Anilines via EDA Complex

using green light with the organic dye eosin Y as a photoredox catalyst and triethylamine as a sacrificial electron donor. The aryl radical precursors are limited to electron-poor arenes such as pentafluoro-, 1,2,4,5-tetrafluoro-bromobenzenes and 4-bromo2,3,5,6-tetrafluoropyridine. Two plausible mechanisms for the photocatalytic perfluoroarylation of benzene with fluorinated aryl bromides have been proposed (Figure 7). Part a shows that reductive quenching cycle involves a photoinduced electron transfer from Et3N to the excited eosin Y followed by the reoxidation of the generated eosin radical anion by bromopentafluorobenzene. The reduced fluorinated arene cleaves the CAr−Br bond, yielding the pentafluorophenyl radical, which reacts with arenes. Part b shows that the oxidative quenching cycle is based on photoinduced electron transfer from excited eosin Y to bromopentafluorobenzene. Mechanistic investigations based on thermodynamic analysis of the electron transfer, steady state

studies that electron-withdrawing substituted (hetero)aryl halides and anilines forms donor−acceptor complexes, which under blue LED irradiation allows the synthesis of ortho and para (hetero)arylated anilines in moderate to good yields. The reaction has a high functional group tolerance. On the basis of spectroscopy studies, they proposed mechanistic model starting with the formation of the excited (EDA)* by absorption of one photon under blue LED irradiation (Figure 8). SET, followed by C−Br bond scission, affords the radical intermediate A. Next, the radical intermediate A reacts with aniline to generate the radical intermediate C, which affords the desired arylated product after hydrogen atom transfer (HAT) and the aromatization. 2.3.2. For Arylation of Heteroarenes. In 2014, König and co-workers reported a visible light-mediated chemical photo7540


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Scheme 21. C−H Bond Arylation of Pyrroles with Aryl Halides Using N,N-Bis(2,6-diisopropylphenyl)perylene3,4,9,10-bis(dicarboximide) (PDI) as Organic Photoredox Catalyst

Figure 8. Proposed catalytic cycle for arylation of anilines via EDA complexes.

redox catalysis using less reactive aryl halides without the use of strong base by using the energies of two photons in one catalytic cycle with perylene diimides [N,N-bis(2,6-diisopropylphenyl)perylene-3,4,9,10-bis(dicarboximide) (PDI)] as organic photoredox catalysts.78 Upon irradiation with blue light (455 nm) in the presence of triethylamine (Et3N) as electron donor, PDI forms a colored radical anion PDI•− that can again be excited by visible light. In the absence of oxygen, the radical anion is very stable, and a consecutive PET process can generate the strong reducing PDI•−*, which allows the formation of the aryl radical from ArX (Figure 9).

Scheme 22. Photocatalyzed C−H Bond Heteroarylation of Pyrroles with Bromoheteroarenes Using Rhodamine 6G as Organic Photoredox Catalysta

Figure 9. Proposed mechanism for arylation of pyrroles with aryl halides by two photons in one catalytic cycle with perylene diimides as organic photoredox catalyst.

a

Reaction carried out in DMSO.

halide bonds for C−H arylation with different reduction potentials by simply applying different colors (530 and 450 nm) of light for excitation of rhodamine 6G photoredox catalyst.82 Chlorobenzene has been also employed as aryl radical precursor for the C−H bond phenylation of N-methylpyrrole by merging metal-ion (LnI2)-coupled electron transfer (MCET) with consecutive photoinduced electron transfer (conPET). Such combination allows the one-electron reduction of chlorobenzene with blue light in the presence of diisopropylethylamine as an electron donor (Scheme 23).83 The presence of the lanthane ions allows to generate photoredox catalysis displaying extreme reduction potentials (beyond −3 V vs SCE). In 2018, anthraquinones have been employed as organic photoredox catalysts for the generation of aryl radical from aryl halides followed by the in situ trap with a large excess of heteroarenes (Scheme 24). A similar substrate scope to reaction with rhodamine 6G is observed. A similar pathway with PDI (Figure 7) is proposed. Under visible light 1,8-dihydroxyanthraquinone (Aq−OH) forms its colored radical anion and semiquinone anion in the presence of R3N. Then, the radical

During their investigations on the reduction of aryl halides by consecutive visible light-induced electron transfer processes from PDI, they also employed a trapping reagent such as pyrrole to allow the formation of the C2-arylated pyrroles (Scheme 21).78 The reaction is active for aryl iodides, aryl bromides, and aryl chlorides. However, only aryl halides bearing an electronwithdrawing substituent have been employed. It is noteworthy from NH-pyrrole that the authors observed only formation of C−C bond products in contrast to other radical crossdehydrogenative couplings using peroxide which often offered the C−N bond products.79 König’s group applied the energies of two photons in one catalytic cycle with rhodamine 6G for the synthesis of biheteroarenes via the generation of hereteroaryl radical from hereteroaryl bromides (Scheme 22).80 They also extended this catalytic system to the preparation of arylated nucleobases from brominated or chlorinated nucleobases.81 As demonstrated by König’s group, it is also possible to perform iterative C−H bond arylations starting from tribromobenzene derivatives via selective activation of aryl− 7541


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Scheme 23. Phenylation of Pyrrole Using Lanthanide Ions Coupled with Photoinduced Electron Transfer

Scheme 26. Heteroarylation of (Hetero)arenes with 2Bromoazoles Using Ir-Based Photoredox Catalyst

Scheme 24. Anthraquinone as Organic Photoredox Catalyst for C−H Bond Arylation of Heteroarenes

oxidative quenching cycle allows the formation of aryl radical, which could be trapped by electron-rich arenes, pyrroles, indoles, imidazoles, pyridines, and thiophenes to allow the formation of heterobiaryls in good yields. A wide range of 2bromazaoles including the one bearing sensitive halo-bonds have been employed. In 2016, during their investigation of photoinduced coppercatalyzed C−H arylation at room temperature, Ackermann and co-workers disclosed that dual catalysis composed by an photoredox catalyst, fac-[Ir(ppy)3], associated with CuI in the presence of t-BuOK, allowed a more efficient coupling between benzothiazole and aryl iodide (Scheme 27).86 However, no

anion and the semiquinone anion are excited a second time by visible light and transfer a single electron to aryl halides, which react in C−C bond-forming reactions. 10-Phenylphenothiazine in concert with Bu3N was also found to be a very efficient organic photoredox catalyst for the arylation of pyrrole with 4-bromobenzonitrile derivatives. Interestingly, Hawker, Alaniz, and co-workers showed that from a benzonitrile bearing C−I and C−Br bonds, chemoselective cross-couplings could be achieved depending on the organic photoredox catalyst (Scheme 25).84 In 2016, Weaver and co-workers reported the formation of 2azolyl radicals from 2-bromoazoles using fac-[Ir(ppy)3] photoredox catalysis (Scheme 26).85 In the presence N-cyclohexyl-Nisobutyl-N-cyclohexanamine as a sacrificial oxidizing agent, an

Scheme 27. Arylation of Thiazole with Aryl Iodide Using Ir/ Cu Dual Catalytic System

Scheme 25. 10-Phenylphenothiazine as Organic Photoredox Catalyst for C−H Bond Arylation of Pyrroles

investigation is conducted toward the rationalization of the dual effect. We can postulate the formation of benzothiazol-2ylcopper derivative followed by oxidative addition of aryl iodide initiated by a SET.45,87,88 In search of highly reducing species generated upon visible light excitation, König and co-workers reported the use of a visible light absorbing photoredox catalyst, [Ru(bpy)3]2+, to produce radical anions of UV-absorbing polycyclic aromatic hydrocarbons, such as pyrene, which in turn are able to drive the reductive activation of chemical bonds for carbon−carbon and carbon−heteroatom bond formation (Scheme 28).89 This strategy, called sensitization-initiated electron transfer, is employed for the direct arylation of pyrroles and indoles, used in large excess, at the C2 position as well as pyridines and electron-rich arenes using simple aryl halides. This catalytic system is also operative using aryl triflate instead to aryl halides. On the basis of spectroscopic investigations, the authors proposed a catalytic cycle depicted in Figure 10. After visible 7542


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using photoredox catalysis (Scheme 29).94 Benzoyl hypobromite, which is in situ prepared by reaction of carboxylic acid and

Scheme 28. Arylation of (Hetero)arenes Using Aryl Bromides and Chloridesa

Scheme 29. Arylation of (Hetero)arenes with Aryl Carboxylic Acids

a

From Ar−Cl instead of Ar−Br.

diethyl 2-bromo-2-methylmalonate, easily decomposes into aryl radical by the action of [Ir{dF(CF3)ppy}2(dtbbpy)](PF6)2 under blue LEDs irradiation. This protocol leads to the direct arylation of arenes and some pyridines. The reaction conditions tolerate a wide range of substituents including electron donating groups. However, the weakness of this reaction is that a large excess of diethyl 2-bromo-2-methylmalonate and 100 equiv of substrate are required. Nevertheless, there is not requirement of an ortho-substituent on the aryl carboxylic acid, unlike previously decarboxylative protocols.95 Stern−Volmer luminescence quenching experiments revealed a reductive quenching of PC (Ir(III)*/Ir(II)) by the benzoate anion providing aroyloxy radical (Figure 11). The authors Figure 10. Proposed Catalytic Cycle for Pyrene Sensitization-Initiated Electron Transfer Catalytic C−H Arylation Reactions.

light photoexcitation of Ru(bpy)32+, Ru(bpy)32+* transfers its energy to pyrene (Py). The excited Py* is then reductively quenched by N,N-diisopropylethylamine (DIPEA) to generate the radical anion [Py]•− and the radical cation [DIPEA]•+. Then [Py]•− transfers one electron to the (hetero)aryl halide, yielding the (hetero)aryl radical precursor [(Het)ArX]•−, which generates the aryl radical (Ar•) and neutral Py to complete the catalytic cycle. Finally, Ar• reacts with (hetero)arenes to afford C−C coupling products. In a competing pathway, the Ar• abstracts a hydrogen atom either from [DIPEA]•+ or from the solvent (in this case DMSO) to give undesired reduction products and diisopropylamine.

Figure 11. Proposed mechanism for arylation with carboxylic acids.

denied the direct decarboxylation of carboxylic acid due to energetically feasible at room temperature. Therefore, they proposed pathway involving bromination of radical anion of carboxylic acid generated by SET of PC* to carboxylic acid to form the benzoylhypobromite A. The resulting hypobromite can be reduced by the Ir(II) (E1/2III/II = −1.37 V vs SCE), leading to intermediate B and its decarboxylation to afford the key aryl radical (Ar•). Finally, the aryl radical is trapped by (hetero)arene

2.4. Aryl Carboxylic Acids as Aryl Radical Precursors for Arylation of Heteroarenes and Arenes

Carboxylic acids are suitable source of radicals via a visible lightmediated decarboxylation.90−93 However, until 2017, there was no example of formation of aryl radical from aryl carboxylic acids. Glorius and co-workers reported the first example of aryl radical formation via decarboxylation of aryl carboxylic acids 7543


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to generate the cyclohexadienyl radical C, which, following oxidation to the aryl cation and deprotonation, affords the cross biaryl product. 2.5. Benzenesulfonyl Chlorides as Aryl Radical Precursors for Arylation of Heteroarenes

Arenesulfonyl chlorides are known to undergo desulfitative coupling for the C−H bond arylation of heteroarenes at elevated temperature using palladium catalysis.96−100 In 2016, Natarajan et al. reported the arylation of heteroarenes using arenesulfonyl chlorides via desulfitative coupling promoted by photoredox catalyst at room temperature (Scheme 30).101 Using [RuScheme 30. Arylation of Heteroarenes with Arenesulfonyl Chlorides Figure 12. Proposed mechanism for the visible light induced desulfonylative coupling of arylsulfonyl chlorides with five-membered heteroarenes.

moieties included CF3I,106 (CF3)2Te,107,108 and CF3SO2Na (Langlois reagent).109 However, such methodologies require often harsh reaction conditions and provide the desired trifluoromethyl(hetero)arene in poor regioselectivity.109 In contrast, recent advances on photoredox catalyzed radical trifluoromethylation of (hetero)arenes through C−H bonds functionalization were performed under mild reaction conditions, allowing sometimes impressive regioselectivity, which are discussed in this section, which is organized based on different trifluoromethyl radical precursors. Early example of trifluoromethylation of arenes was reported in 1993 by Mallouk and co-worker using TiO2 as heterogeneous photosensitizer and trifluoroacetic acid as trifluoromethyl radical precursors.110 (bpy)3]Cl2 as photoredox catalyst under blue LEDs irradiation, a broad variety of arene sulfonyl chlorides including halogen substituted ones could allow this reaction. With pyrroles and furans, the regioselectivities are similar to those obtained with palladium catalysts, namely the α-position. It is noteworthy that α-arylated thiophenes are obtained using photoredox catalysis reaction, whereas β-arylated thiophenes are synthesized by palladium-catalyzed C−H bond desulfitative arylation.96−100 In contrast to palladium-catalyzed direct arylation of heteroarenes,96−100 photocatalyzed desulfitative couplings occurred though a radical pathway (Figure 12).47 The irradiation of [Ru(bpy)3]Cl2 with a visible light promotes metal-to-ligand charge transfer, generating a photoexcited [Ru(bpy)3]2+*, followed by a SET to the arylsulfonyl chloride, affording the aryl radical (Ar•) by extrusion of SO2 and Cl−. The coupling of Ar• with an electron-rich heterocycle gives a new radical (A) which undergoes oxidation by the [Ru(bpy)3]3+ to deliver the carbocation intermediate (B). Deprotonation of the intermediate (B) gives the desired heterobiaryl.

3.1. Trifluorosulfonyl Chloride and Sodium Trifluoromethanesulfinate as Fluorinated Radical Sources for Trifluoromethylation of Arenes and Heteroarenes

In 2011, MacMillan and co-workers reported the first example of trifluoromethylation of a broad range of (hetero)arenes under visible light photoredox-catalyzed conditions (Scheme 31).35 They showed that the use of CF3• as an electrophilic radical, generated via a photoredox process under mild conditions, allows its incorporation at specific positions of (hetero)arenes. Different photoredox catalysts are used depending on the (hetero)arenes to form a C−CF3 bond from a simple C−H bond. The trifluoromethylation of five-membered ring heteroarenes such as pyrroles, furans, thiophenes, and thiazoles are performed at the C2 or C5 position using 1 mol % [Ru(phen)3]Cl2. In the cases of indoles, the reaction occurs with a low regioselectivity depending on the nitrogen substituent. fac-[Ir(dF·ppy)3] is used for the trifluoromethylation of six-membered ring heteroarenes (e.g., pyridines, pyrazines, pyrimidines, pyranone, ...). The regioselectivity is substrate dependent. The same photoredox system is used in the case of arenes. Notably, the reaction tolerates sensitive functional groups such as bromide, trifluoroborate, and trimethylsilyl on the arenes unit, allowing further functionalizations. The authors also extended this protocol to synthesize trifluoromethyl derivatives of biologically active uracil, aricept, flavones, lidocain, and ibuprofen. An oxidative quenching cycle is proposed (Figure 13): SET reduction promoted by photoexcited PC* allows the formation of [CF3SO2Cl•]− radical anion, which is then rapidly

3. PHOTOCATALYZED PERFLUOROALKYLATION OF C(sp2)−H BONDS The installation of the trifluoromethyl group on heterocycles is an important reaction as many common pharmacophores bear CF3 motifs linked to an aromatic system.102−104 The incorporation of the CF3 group by direct C−H bond functionalization represents a major achievement compared to the multistep process.105 A number of pioneering methods for the direct radical trifluoromethylation of (hetero)arene C−H 7544


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Scheme 31. Trifluoromethylation Using Trifluoromethanesulfonyl Chloride

Scheme 32. Trifluoromethylation of (Hetero)arenes Using Trifluoromethanesulfinate and Anthraquinone-2-carboxylic Acid As Organic Photoredox Catalyst

Scheme 33. Trifluoromethylation of (Hetero)arenes Using Trifluoromethanesulfinate Using 4,4′Dimethoxybenzophenone As Organic Photoredox Catalyst

3.2. Fluorinated Alkyl Halides As Radical Sources

3.2.1. For Perfluoroalkylation of Heteroarenes. Cho and co-workers reported similar visible light photoredoxcatalyzed conditions for the trifluoromethylation of fivemembered ring heteroarenes but using trifluoroiodomethane as a coupling partner (Scheme 34).116 The reaction was Scheme 34. Trifluoromethylation of Heterocycles with Trifluoroiodomethane Using [Ru(bpy3)]Cl2

Figure 13. Proposed mechanism for visible light mediated trifluoromethylation of (hetero)arenes with CF3SO2Cl.

decomposed into the desired CF 3 • radical, SO 2 , and chloride.111,112 Addition of CF3• radical on a electron-rich position of a substrate followed by single-electron oxidation by Ru(phen)33+ affords the intermediate cation (B) and Ru(phen)32+. Subsequently, B undergoes base-induced deprotonation to give the desired trifluoromethylated compounds. The photoredox desulfitative trifluorometlylation of (hetero)arenes could be also performed under metal-free conditions. In 2013, Itoh and co-workers showed that anthraquinone-2carboxylic acid, acting as organic photoredox catalyst, is able to produce CF3• radical under visible light irradiation of sodium trifluoromethanesulfinate (Scheme 32).113 Later, 4,4′-dimethoxybenzophenone have been introduced by Rueping’s group as an organic photoredox catalyst for the trifluoromethylation of heteroarenes using also the Langlois reagent (Scheme 33).114 In 2017, Noël and co-workers developed flow reaction systems for the trifluoromethylation of (heteroarenes using the Langlois reagent and fac-[Ir(ppy)3] as photoredox catalyst.115

performed using 1 mol % [Ru(bpy)3]Cl2 as a photoredox catalyst in the presence of 2 equiv of TMEDA (N,N,N′,N′tetramethylethylenediamine) as a base in acetonitrile under visible light. Indoles are successfully trifluoromethylated at C2 or C3 depending on the indolyl substituent, whereas pyrroles, thiophenes, and furans are regioselectively functionalized at the C2 or C5 position. 7545


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To overcome the limitations of photoredox catalysis associated with these batch protocols, i.e., (i) limited scale-up potential, (ii) inefficient light transmission in the batch reactor according to the Lambert−Beer law, especially when there is a significant scattering of the incident light in a heterogeneous mixture, (iii) prolonged reaction times, and (iv) complicated handling of gaseous reagents and gas diffusion, Noël and coworkers developed a continuous flow version (Scheme 35).117 A

Scheme 36. Cyclometalated Pt(II) Complex in Photoredox Catalytic Trifluoromethylation of Hereroarenesa

Scheme 35. Trifluoromethylation of Heterocycles with Trifluoroiodomethane in Continuous Flow a

Trifluoromethylation at the phenyl moiety of indole occurred at +0.35 V vs SCE) by the reduced form of the photoredox catalyst [MesAcr+Me]• (Ered = +0.49 V vs SC) generates the sulfate dianion and sulfate radical anion, regenerating the photoredox catalyst. Finally, H atom abstraction transfer (HAT) of B by the sulfate radical anion leads to the desired alkylated heteroarene by rearomatization.

a dual photoredox and organocatalysis process. The Ir3+ photoredox catalyst [Ir(ppy)2(dtbbpy)]PF6 after visible light excitation is oxidized into a Ir4+ species, which captures one electron from the thiol organocatalyst, generating a thiyl radical able to extract a hydrogen atom from the methanol by the hydrogen-atom-transfer (HAT) process. The generated HOCH2• radical adds to the C2 position of the heterocycle and is subsequently transformed into a CH3 group. This dual photoredox-organocatalysis method has been applied very successfully to the alkylation of heteroaromatic C−H bonds using a variety of primary alcohols R-CH2OH, which were able to generate the R-CH•−OH radical, leading to alkylated products (heteroarene)Cx-CH2R. This reaction can be applied to the generation of α-radical of ethers such as tetrahydrofuran and to the direct alkylation of functionalized compounds such as fasudil and milrinone. 7561


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formation of hydroxymethylation of heteroaromatics after oxidation.

The proposed mechanism on methylation with methanol is presented on Figure 30. The Ir3+ photoredox catalyst excitation/

4.6. Alkylation of Pyridine Derivatives and Five-Membered Heterocycles Using Alkylcarboxylic Acid Derivatives as Alkyl Radical Precursors

Glorius’ group has recently reported a new method to alkylate N-heteroarenes using the photoredox-catalyzed generation of alkyl radical by decarboxylation of carboxylic acids RCO2H in the presence of ammonium persulfate (NH4)2S2O8 (2 equiv) and of the photoredox catalyst [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 under 5 W of blue LED irradiation (λmax = 455 nm).170 The alkylation of a variety of N-heteroarenes such as isoquinoline, quinoxaline, benzoimidazole, and benzothiazole derivatives and fasudil from carboxylic acids were successful, as illustrated in Scheme 86. This photoredox-catalyzed alkylation can be Scheme 86. Alkylation of N-Heteroarenes with Radical Generated from Carboxylic Acids

Figure 30. Proposed mechanism for the direct methylation of heteroaromatic C−H bond.

SET steps lead to an Ir4+ species able to oxidize the deprotonated thiol organocatalyst to provide a thiyl radical A able to capture H atom of methanol. This HOCH2• (or HOCH•-R) radical (B) adds to the C2 of the protonated heterocycle. The generated hydroxymethyl-heterocycle cation (C) eliminates water via a spin-center shift and generates the heterocycle-CH2• radical (E) that is reduced by the excited [Ir3+]* to give on further protonation the methylated product F and the Ir4+ oxidant. Later, DiRocco, Krska, and co-workers developed conditions to prevent the dehydration in order to get selectively the formation hydroxymethylation of heteroaromatics by using benzoyl peroxide as terminal oxidant in concert with photoredox catalyst (Scheme 85).169 Under these conditions, the thiol organocatalyst is replaced by a phenyl radical, which is obtained by SET from [Ir3+]* to benzoyl peroxide, and no spin center shift with elimination of water is observed, allowing the

performed by a variety of alkyl radicals arising from primary, secondary, and tertiary carboxylic acids but also containing a heterocycle or a fluorinated group. However, a huge amount (10 equiv) of carboxylic acid derivatives are required to get high yields. Most importantly, amino acids and fatty acids also allow the alkylation of lepidine, and the alkylation of isoquinoline with homoveratric acid allows the formation of a papaverine analogue. The proposed mechanism is illustrated in Figure 31. The light excited Ir3+* (E1/2IV/III* = −0.88 V vs SCE) transfers a single electron to the S2O82− dianion to give the Ir4+ with SO42− and SO4−•. The later radical captures the hydrogen atom from RCO2H which then affords CO2 and the radical R• (A). The R• radical adds to the N-heteroarene at C2 position. The resulting radical (B) allows the reduction of the Ir4+ species (E1/2IV/III = +1.70 V vs SCE) to regenerate the Ir3+ and to afford, after deprotonation, the 2-alkylated heteroarene C. N-(Acyloxy)phthalimides have been also successfully employed as alkyl radical precursors for the direct alkylation of pyridines derivatives using [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 as photoredox catalyst.171 However, the reactions with this radical precursor is less atom economy than the reaction performed directly from carboxylic acids. In 2018, Sherwood and coworkers showed that N-(acyloxy)phthalimides can be in situ generated from carboxylic acids and N-hydroxyphthalimide and

Scheme 85. Hydroxymethylation of Heteroaromatic C−H Bonds with Alcohols via the Dual Photoredox Organocatalytic Platform

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Figure 32. Alkylation of N-heteroarenes arising from primary amines via photoredox radical generated from Katritzky salts.

Figure 31. Proposed catalytic cycle for alkylation of N-heteroarenes with carboxylic acid and S2O82−.

Thus, with 1.2 equiv of Katritzky salt and 1 equiv of isoquinoline or quinoline in DMA at room temperature for 48 h, a variety of 2-alkylated isoquinolines and quinolones were thus obtained in good yields (Scheme 88). The alkylated

irradiated in the presence of an organic photoredox catalyst such as 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) to give alkyl radical precursors able to add to pyridine derivatives (Scheme 87).172 The in situ generation of N-

Scheme 88. Examples of Alkylation of N-Heteroarenes with Radical from Primary Amines and Amino Acids via Katritzky Salts

Scheme 87. Alkylation of N-Heteroarenes with in Situ Generated N-(Acyloxy)phthalimides

(acyloxy)phthalimides required the use of DMAP, and N,N′diisopropylcarbodiimide (DIC). Quinolines and set of fivemembered ring heterocycles are alkylated in moderate yields in the presence of 1 mol % of organic photoredox catalyst. 4.7. Alkylation of Pyridine Derivatives and Five-Membered Heterocycles Using Primary Amines and Amino Acids as Alkyl Radical Precursors

Glorius has also reported a synthetic method allowing to alkylate heteroarenes with alkyl groups arising from deamination of primary amines or amino acids.173 The method, illustrated in Figure 32, is based first on the stoichiometric formation of a Katritzky salt on reaction of a primary amine (or amino acid) with a pyrylium salt. Then a single electron is transferred with the help of [Ir(ppy)2(dtbbpy)]PF6 as photoredox catalyst on its irradiation with visible light (λmax = 455 nm, 5 W blue LED). The formed radical releases the pyridine derivative and the deaminated radical adds to the heteroarene at C2 position. The formed heterocyclic radical loses a single electron and a proton to generate the 2-alkylated heteroarene.

imidazopyridazine, phenanthridine, and dialkylated phenanthroline were regioselectively formed. The akylation of heteroarenes was also performed with radicals arising from deamination of α-amino acids via formation of Katritzky salts on reaction with pyrylium salts and SET with the same excited photoredox catalyst [Ir(ppy)2(dtbbpy)+PF6−]*. Thus, these amino acid derived radicals can be used for the regioselective alkylation of indoles and pyrroles (Scheme 88, bottom). 7563


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4.8. Alkylation of Electron-Rich Arenes and Five-Membered Heterocycles through the Generation of N-Acyliminium Radical from Photoredox Catalysis of α-Amidosulfides

α-Amidosulfides can easily generate a N-acyliminium cation and a RS• radical by one electron oxidation. Masson et al. have profited from this property to generate this N-acyliminium ion by easy oxidation of α-amidosulfides with visible light excited photoredox [Ru(bpy)3](PF6)2.174 This cation adds to nucleophiles such as electron rich arenes or heterocycles, leading to electrophilic substitution and formation of α,α-disubstituted amine derivatives via formal C−H bond functionalization (Scheme 89). This reaction is performed in acetonitrile in the Figure 33. Plausible reaction mechanism of photoredox-catalyzed azaFriedel−Crafts reaction of α-amidosulfide derivatives.

Scheme 89. Photoredox-Catalyzed Aza- Friedel−Crafts Reaction of α-Amidosulfide Derivatives with Trimethoxybenzene and Heterocycles

nucleophile (arene or heterocycle), the deprotonation can be favored by the previously produced superoxide radical anion O2−•, leading to the HO2• precursor of O2 and H2O2. 4.9. Alkylation of Pyridine and Pyrimidine Derivatives through the Generation of α-Oxyalkyl Radicals from Photoredox Catalysis of Dialkyl Ethers

One of the most elegant way to prepare C−C bonds is resulting from the functionalization of two C−H bonds. In 2015, MacMillan’s group established the generation of α-oxyalkyl radicals from a variety of widely available ethers through hydrogen atom transfer (HAT), followed by their coupling with a range of heteroarenes in a Minisci-type mechanism (Scheme 90).175 In the presence of [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 as Scheme 90. Photoredox-Catalyzed C−H Bond Arylation of Pyridines Derivatives from Ethers

presence of hexafluoroisopropanol (HFIP) or better with 10 equiv of t-BuOH at room temperature. The oxidation potential of α-aminosulfide decreases in the presence of t-BuOH. Eosin Y was also found suitable as a photoredox catalyst for this transformation. This photoredox-catalyzed aza-Friedel−Crafts reaction can be obtained for a variety of α-amidosulfides and αcarbamoylsulfides and is applicable to imine precursors containing tolerated functional groups as shown in Scheme 89. Chiral precursors led selectively to one diastereoisomer without racemization. This photoredox-catalyzed regioselective aza- Friedel−Crafts reaction can be also applied to the C−H bond functionalization of heterocycles such as thiophenes or indoles. However, the use of indazole or pyrazole as nucleophile leads to their N-alkylation via addition of the photoredoxcatalyzed generated functional imine. An interesting electrochemical study showed that the oxidation potential of the BnCH2CH(NHBoc)SEt is 1.17 V vs SCE in CH3CN, whereas that of the light excited [Ru(bpy)32+]* system is 0.77 V vs SCE in CH3CN. Thus, [Ru(bpy)32+]* cannot oxidize the α-amidosulfide directly. The one electron capture from BnCH2CH(NHBoc)SEt is rather made by Ru(bpy)33+ (1.33 V vs SCE in CH3CN) generated by the reaction of oxygen with [Ru(bpy)32+]* to give as well the superoxide radical anion O2−•. The plausible mechanism is shown in Figure 33. It is worth noting that if the N-acyliminium cation B, generated beside the RS• radical, adds to the

photoredox catalyst associated with (NH4)2S2O8 as the oxidant in the presence of acetic acid in CH3CN under the irradiation of a 26 W household, HAT on dialkyl ethers allows the formation of α-oxyalkyl radicals. These radicals could later react with isoquinoline, quinoxaline, quinoline, pyrimidine, and pyridine derivatives to afford the C2-alylated heteroarenes in good yields. The reaction tolerates sensitive group such as halogen, nitrile, and ester. Cyclic and acyclic ethers could be used, albeit a large excess has to be employed in order to get high yields. The authors proposed that *[Ir{dF(CF3)ppy}2(dtbbpy)]PF6 species, which is a strong reductant (E1/2IV/*III = −0.88 V vs SCE in MeCN/H2O = 2:1), is capable of reducing the persulfate anion to afford [IrIV{dF(CF3)ppy}2(dtbbpy)]PF6, the sulfate dianion, and the sulfate radical anion. Then HAT between the 7564


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Scheme 91. Acylation of Indoles with α-Oxo Acids at C3 Position

dialkyl ether and the sulfate radical anion should allow the formation of the desired α-oxyalkyl radical A, which is sufficiently nucleophilic to add to the protonated electrondeficient heteroarene in a Minisci-type pathway to afford the amine radical cation B. The cation B, upon loss of a proton, gives the α-amino radical C, which undergoes a second SET event with the oxidized photosystem IrIV(E1/2IV/III = +1.70 V vs SCE in MeCN/H2O = 2:1) to regenerate the ground state of photoredox catalyst and deliver the desired α-aryl ether product (Figure 34).

Figure 34. Plausible reaction mechanism of photoredox-catalyzed alkylation of heteroarenes with ethers.

5. PHOTOREDOX-CATALYZED ACYLATION OF HETEROARENES C(sp2)−H BONDS Only a few examples of acylation of (hetero)arenes through C(sp2)−H bond functionalization have been reported, and most of them involve a cross-dehydrogenative coupling using aldehyde in the presence of oxygen101 as oxidant or peroxide at elevated temperature.176−178 Since 2016, alternative strategies have emerged enabling to perform direct acylation under mild reaction conditions using photoredox catalysis.

Figure 35. Plausible mechanism for acylation of indoles at C3 position with α-oxo acids.

5.1. α-Oxo Acids as Acyl Radical Precursors

Gu, Yuan, and co-workers disclosed the acylation of indoles with α-oxoacids under visible light catalysis (Scheme 91).179 They were inspired by MacMillan works focusing on dual catalysis (Ni/Ir) for the radical decarboxylative coupling of simple α-oxo acids with aryl halides.180 The key step is the in situ iodination of indole with iodine. In the presence of photoredox catalyst, [Ir{dF(CF3)ppy}2(dtbbpy)]PF6, NiCl2 catalyst, and I2, direct acylation of indole at C3 position is performed. The reaction tolerates a wide range of substituents on both partners and NHindole could also be used. This reaction is not a real C−H bond functionalization as the C−H bond is transitory modified into C−I bond. However, compared to other palladium procedures for the C−H bond acylation with α-oxo acids, this photoredoxcatalyzed reaction does not require the use of a stoichiometric amount of peroxide.181 The proposed mechanism is shown in Figure 35. After a classical photoexcitation of Ir3+, the long-lived photoexcited Ir3+* rapidly accepts one electron from α-oxo acids to produce the reduced photoredox catalyst Ir2+ and the corresponding carboxyl radical species (A). Then, acyl radical (B) is generated via extrusion of CO2. Within the same time frame, the second

catalytic cycle is initiated by oxidative addition to Ni0 catalyst into 3-iodo-1-methyl-indol (C), generated by the action of I2 on indole. The resulting NiII species (D) is rapidly trapped by the nucleophilic acyl radical (B), producing NiIII acyl complex (E). Then, reductive elimination of this complex gives the desired product while generating the corresponding NiI−dtbbpy complex. Both catalytic cycles are closed by SET from IrII species to the NiI−dtbbpy, regenerating Ni0 and the groundstate IrIII catalyst. 5.2. Aldehydes as Acyl Radical Precursors

In 2017, Noël, van der Eycken, and co-workers reported dual catalysis constituted by Pd catalysis in concert with Irphotosensitizer to promote C2-acylation of indoles using aldehydes as acyl radical sources. The reaction is operative under both batch and flow systems (Scheme 92).182 Notably, this paper is the first example of the use of aldehydes as acyl surrogates under visible light photoredox. N-Pyrimidylindoles are acylated at C2 position (directed C−H bond cleavage) using Pd(OAc)2 (10 mol %), fac-[Ir(ppy)3] (2 mol %), monoprotected amino acids (Boc-Val-OH, 20 mol %) as ligand, and 4 7565


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excited state (Ir3+*), which is oxidatively quenched by tBuOOH to generate the key radical intermediate t-BuO•. Next a hydrogen abstraction occurs between the t-BuO• radical and benzaldehyde to afford the acyl radical (RCO•, A). The acyl radical (A) is then trapped by the palladacycle, which results in the formation of palladium(III) species (C). This intermediate can undergo a single-electron oxidation to palladium(IV) (D), which closes the photoredox catalytic cycle via a back-electron donation to [Ir4+]. Finally, a reductive elimination takes place, releasing the acylated product and regenerating the palladium(II) catalyst. At almost the same time, Jana and co-workers disclosed a similar acylation reaction using same catalytic system, albeit [Ru(bpy)3]Cl2 was used as photosensitizer (Scheme 93).184

Scheme 92. Photoredox Acylation of Indoles with Aldehydes at C2 Position with Pd(OAc)2

Scheme 93. Acylation of Indoles with Aldehydes at C2 Position

equiv of tert-butyl hydroperoxide (TBHP) in acetonitrile under argon and blue light irradiation. The acylation reaction tolerates a broad range of substituents on the benzaldehyde coupling partner (e.g., p,m,o-alkyl, -aryl, -halogen, -CF3, -NO2, -CN, etc.). Heteroaryl aldehydes as well as aliphatic aldehydes nicely react too. However, the reaction is limited to indole bearing directing group (e.g., N-pyrimidyl or N-pyridinyl) for the C−H bond cleavage by Pd(OAc)2, but some substituents on the 3, 5, 6, and 7 positions are tolerated. In addition, and to overcome the scale limitation in photoredox catalysis (light attenuation effect through absorbing media as dictated by the Bouguer− Lambert−Beer law), the authors developed a flow version of this transformation using continuous-flow capillaries. Performed the reaction at room temperature is the major advantage compared to the 120−140 °C employed when photoredox catalysis is not used.178,183 The authors proposed a mechanism depicted in Figure 36. An ortho directed C−H bond activation of N-pyridinylindole affords a five-membered palladacycle (B). Meanwhile, acyl radical (A) is generated via the photoredox catalytic process, i.e., the photoexcitation of the photoredox catalyst produces the

6. PHOTOREDOX-CATALYZED CYANATION OF ARENES C(sp2)−H BONDS Direct C−H bond cyanation of arenes was reported by Nicewicz and co-workers using Fukuzumi’s organic photoredox catalysis (Scheme 94).185,186 In basic media and in the presence of 5 mol Scheme 94. Direct Cyanation of Arenes Using Organic Photoredox Catalyst

Figure 36. Proposed mechanism for photoredox-acylation of indoles at C2 position with aldehydes. 7566


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of a diverse range of 10-a,11-dihydrobenzo[b]fluorene architectures in one pot and one manipulation. The authors show that arylsulfonyl chlorides play two roles (i) aryl radical precursors by the cleavage of the SO2Cl group and (ii) provide an orthoC(aryl)−H bond to participate in the tandem cyclization. The reaction likely starts with the formation of aryl radical (Ar•) by a SET from the excited state [Ru(bpy)3]2+* to arylsulfonyl chlorides (Figure 37). Subsequently, the regiose-

% of 3,6-di-tert-butyl-9-mesityl-10-phenylacridinium tetrafluoroborate, trimethylsilyl cyanide gives nitrile radical precursors under blue LEDs irradiation. Monosubstituted aromatics undergo C−H bond functionalization at the para-position, allowing the formation of arene nitriles in good yields and regioselectivity. Heteroaromatics (e.g., indoles, indazoles, or chromane) were also suitable substrates, albeit the reaction preferentially occurred on the phenyl moiety. The authors also demonstrated the potential of this cyanation reaction by latestage diversification of bioactive substrates such as naproxen methyl ester and gemfibrozil methyl ester.

7. C(sp2)−H BOND FUNCTIONALIZATION VIA INTRAMOLECULAR RADICAL RELAY INDUCED BY PHOTOREDOX CATALYSIS In cascade reactions, multiple chemical steps occur one after another in a well-defined sequence, without the need for external intervention, allowing the formation of multiple bonds in only one manipulation.48 The recent development of new, mild methods for the generation of radical species using photoredox catalysis has strengthened cascade reactions, especially the one involving at least one step of C(sp2)−H bond functionalization. The general scheme for such cascade reaction involves a radical generation followed by the addition to this radical to a SOMOphilic (singly occupied molecular orbital) group, generating a novel radical which could react intramolecularly with (hetero)arenes. SOMO-philic reagents can be defined as molecules which could accept one radical to deliver a more stable radical (e.g., alkenes, alkynes, isocyanide, ...).187

Figure 37. Proposed mechanism for tandem cyclizations of 1,6-enynes with arylsulfonyl chlorides.

lective addition of Ar• to the carbon−carbon triple bond of the substrate occurs to deliver the intermediate A, followed by cyclization reaction (5-exo-trig) with the alkene to yield the radical intermediate B, which undergoes a second intramolecular cyclization at the ortho-position of the arene to give the radical C. Finally, oxidation of C by [Ru(bpy)3]3+ and subsequent deprotonation takes place to furnish 10-a,11-dihydro-10Hbenzo[b]fluorene and regenerate the active [Ru(bpy)3]2+ species. Instead, to access various functionalized coumarins through transition metal-catalyzed radical cyclization of aryl propiolate,189,190 Weijun Fu and co-workers reported in 2015 the radical initiation from ethyl bromodifluoroacetate under visible light irradiation to construct difluoroacetylated coumarins under mild reaction conditions (Scheme 96).191 Optimized conditions indicates that fac-[Ir(ppy)3] under blue LEDs irradiation is the best catalytic cycles to promote the 1,2-difunctionalization of alkynes. The reaction tolerates a broad range of functional groups on aryl propiolate component. However, under these reaction conditions, ethyl bromofluoroacetate and diethyl bromodifluoromethylphosphonates are not suitable radical precursors. The catalytic cycle is depicted in Figure 38.191 First, the • CF2COOEt radical is generated by SET from excited state fac[Ir(ppy)3]*. This radical regioselectively adds to alkynoate to produce the radical intermediate A, which undergoes intramolecular homolytic aromatic substitution to give the radical intermediate B. The intermediate B is then oxidized by fac[IrIV(ppy)3]+ to form the cyclohexadienyl cation C and regenerates fac-[Ir(ppy)3]. The cyclohexadienyl cation C undergoes rearomatization by the action of the base to furnish the desired coumarin. In 2016, Zhou and co-workers reported the metal-free phenanthrene synthesis through eosin Y-catalyzed, visible

7.1. Alkyne Functions as SOMO-philic Relays

In 2013, Jin-Heng Li and co-workers reported tandem cyclization of 1,6-enynes with arylsulfonyl chlorides (Scheme 95).188 This tandem cyclization is triggered by visible light photoredox catalysis and involves the use of 1,6-enynes as radical acceptors (SOMO-philic reagent), thus allowing the formation Scheme 95. Tandem Cyclizations of 1,6-Enynes with Arylsulfonyl Chlorides

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Scheme 96. Synthesis of Difluoroacetylated Coumarins from Ethyl Bromodifluoroacetate and Aryl Propiolate

Scheme 97. Synthesis of Phenanthrenes from Biaryldiazonium Salts with Alkynes

demonstrated that photoredox-catalyzed 1,2-difunctionalization of alkenes could also be conducted through the formation of two C−C bonds. Indeed, intramolecular radical addition to a (heteo)arene leads to a formal C(sp2)−H bond functionalization. 7.2.1. Photoredox-Catalyzed 1,2-Difunctionalization of N-Arylacrylamide Derivatives. Radical cascade reactions from N-arylacrylamides promoted by photoredox catalysis have been widely studied with different radical precursors. In 2013, Zhu et al. described the first example of such cascade reactions for the difunctionalization of alkenes via the formation of two C−C bonds using (diacetoxyiodo)benzene as methyl radical source (Scheme 98).194 The cascade reaction occurs using facScheme 98. Synthesis of 3,3-Disubstituted Oxindoles with (Diacetoxyiodo)benzene

Figure 38. Proposed mechanism for the synthesis of difluoroacetylated coumarins.

light-induced [4 + 2] benzannulation of biaryldiazonium salts with alkynes (Scheme 97).192 In the presence of eosin Y, biaryldiazonium salts decomposed to aryl radical species, then cascade radical addition onto alkyne and cyclization sequence allows the formation of a variety of 9-substituted or 9,10disubstituted phenanthrenes. Several substituted biaryldiazonium salts underwent [4 + 2] benzannulation reaction, whereas only methyl propiolate has been employed. This methodology also allows the straightforward preparation of [4]helicene and a conjugated heteroaromatic system. An oxidative quenching cycle, where the eosin Y plays the role of an exited state reductant, has been proposed by the authors.

[Ir(ppy)3] as photoredox catalyst and tolerates different substituents on the N-arylacrylamides including a C−Br bond and an allylic group. The scope of the reaction is extended to phenyliodine(III) dicarboxylates using a one-pot procedure (Scheme 99).194 Ligand metathesis between (diacetoxyiodo)benzene and aliphatic carboxylic afforded a variety of phenyliodine(III) dicarboxylates, which can be used in the next step without further purification. Interestingly, such protocol is applied to lithocholic acid allowing the formation of desired oxindole without the loss of stereochemistry. The proposed mechanism is shown in Figure 39. First, SET from the excited-state of fac-[Ir(ppy)3]* to PhI(OAc)2 gives the

7.2. Alkene Functions as SOMO-philic Relays

Photoredox catalyst-promoted radical addition to alkenes is a blooming research area, as it allows the intramolecular or intermolecular 1,2-difunctionalization of alkenes in a single operation.43 For a long time, such multicomponent reactions were limited to the 1,2-difunctionalization of alkenes by the formation of one C−C bond together with another C−X (X = OR, N, S, ...) bond.193 However, some recent advances have 7568


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Scheme 99. Synthesis of 3,3-Disubstituted Oxindoles Using Generated Phenyliodine(III) Dicarboxylate from Carboxylic Acids and (Diacetoxyiodo)benzene

Scheme 100. Synthesis of CF3-Containing Oxindoles Using Togni’s Reagent

Scheme 101. Synthesis of CF3-Containing Oxindoles Using Trifluoromethanesulfonyl Chlorides

of CF3 group, as other fluorinated sulfonyl chlorides (e.g., C4F9SO2Cl and MeO2CCF2SO2Cl) are successfully employed. However, the authors found that the reaction is more sluggish when the CF2H• radical is generated. They attributed this lack of reactivity to a more negative reductive potential of HCF2SO2Cl compared to CF3SO2Cl. Therefore, [Ru(phen)3]* (E1/2III/*II = −0.87 V vs SCE in MeCN) or [Ru(bpy)3]* (E1/2III/*II = −0.81 V vs SCE in MeCN) catalysts might not be effective in reducing HCF2SO2Cl to provide the CF2H• radical. In that case, fac[Ir(ppy)3]* (E1/2IV/*III = −1.73 V vs SCE in MeCN) needed to be employed to get higher yields (Scheme 102).196

Figure 39. Proposed mechanism for the synthesis of 3,3-disubstituted oxindoles with phenyliodine(III) dicarboxylate.

radical (A) and a strong oxidant [Ir(ppy)34+]. Subsequently, the carbonyl group-coordinated iodine radical (B) undergoes a decarboxylation/radical C−H functionalization cascade to give the adduct (C) with N-arylacrylamide and extrude CO2 as well as PhI. Then, the resulting cyclohexadienyl radical (C) is converted to the corresponding cation (D) by SET with [Ir(ppy)34+] to complete the photoredox cycle. It is noteworthy that such a cascade reaction did not work using trifluoroacetic acid,194 albeit the importance of CF3containing oxindoles. In continuing efforts, Zhu et al. found that the use of Togni’s reagent, instead of (bis(trifluoroacetoxy)iodo)benzene, associated with Ru(phen)3]Cl2 under blue LED irradiation overcomes this limitation (Scheme 100).195 A similar substrate scope as for the previous examples is reported for the trifluoromethylation. A similar catalytic pathway as that shown in Figure 39 is proposed. Alternatively, trifluoromethanesulfonyl chloride was employed by Dolbier Jr. et al. as a trifluoromethyl precursor in such a cascade reaction with N-arylacrylamides (Scheme 101).196 Various N-arylacrylamides are cyclized using [Ru(phen)3]Cl2 as photoredox catalyst under visible light in the presence of base. The reaction is not limited to the introduction

Scheme 102. Synthesis of CF3-Containing Oxindoles Using Less Reactive Fluorinated Sulfonyl Chlorides

Interestingly, when the reaction is performed from N(phenylsulfonyl)acrylamide derivatives, oxindole products are also obtained through an aryltrifluoromethylation/desulfonylation cascade reaction (Scheme 103).197 Moreover, if the substituent on N atom is changed from alkyl to aryl group, a unique 1,4-aryl shift is observed rather than the radical cyclization. 7569


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Scheme 103. Trifluoromethylation of α,β-Unsaturated Imide Alkenes

Scheme 104. Synthesis of 3,3-Disubstituted Oxindoles with Aryl Diazonium Salts

A plausible mechanism involves classical CF3• radical addition to the alkene followed by a cyclization to afford the radical intermediate B. Then, this intermediate involves fragmentation to generate the amidyl radical C, which cyclizes to deliver the oxindole radical D (Figure 40).

[Ru(bpy)]3+ regenerates the photoredox catalyst and forms the cation from (C), and the desired product after deprotonation (Figure 41).

Figure 41. Proposed mechanism for the synthesis of 3,3-disubstituted oxindoles with aryl diazonium salts.

In 2014, Li and co-workers reported that when this reaction involving aryldiazonium salts is performed in the presence of acetonitrile, the addition of a •CH2CN radical occurs instead of the aryl radical to deliver the corresponding oxindoles via radical cascade difunctionalization of alkenes (Scheme 105).199 In addition to the classical photoredox catalytic system (i.e., [Ru(bpy)3]Cl2 under white irradiation), this reaction is operative only in the presence of both base Na2CO3 and aryl diazonium salts. Notably, the desired product was isolated in 55% yield without photoredox catalyst. These authors suggest that thermal decomposition of aryl diazonium salts is responsible for the radical initiation.200 The reaction is not limited to acetonitrile, but acetone can be also used as a radical precursor. The authors proposed that this cascade reaction involves a photoinduced catalytic cycle (Figure 42). The 4-methoxyphenyldiazonium readily decomposed into an aryl radical (A) by the action either of [Ru(bpy)3]Cl2/visible light or heat. Subsequent selective hydrogen atom abstraction by the 4-methoxyphenyl

Figure 40. Proposed mechanism for aryltrifluoromethylation/ desulfonylation cascade reaction.

Fu, Zhou, and co-workers reported a similar cascade reaction for the difunctionnalization of N-arylacrylamides, albeit they employed aryl diazonium salts as coupling partners (Scheme 104).198 The authors found that [Ru(bpy)3]Cl2 as photoredox catalyst under visible light irradiation in methanol allows the synthesis of 3,3-disubstituted oxindoles with a broad functional group tolerance (e.g., F, Br, Cl, OMe, CN, CF3, and pyridine). It is important to note that the reaction did not require any additive such as a base or a reductant. As previously reported, the aryl radical is likely generated by SET from excited-sate of [Ru(bpy)]2+* generated by the photoexcitation of [Ru(bpy)]2+. Then, the addition of an aryl radical to N-arylacrylamide gives the tertiary alkyl radical (A) followed by a radical cyclization to produce the more stable sp2 radical (B). A single-electron oxidation of this intermediate by 7570


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Scheme 105. Synthesis of 3,3-Disubstituted Oxindoles with Acetonitrilea

Scheme 106. Synthesis of 3,3-Disubstituted Oxindoles with Dichloromethane

a

Reaction performed in acetone instead of CH3CN.

Scheme 107. Synthesis of 3,3-Disubstituted Oxindoles with Alkylhalides

Figure 42. Proposed mechanism for the synthesis of 3,3-disubstituted oxindoles with aryl diazonium salts in the presence of acetonitrile.

groups are necessary for selective abstraction of H atom. The authors showed that from alkyl bromide both C−H bond and C−Br bond cleavages take place using alkyl bromides, giving a mixture of products. In 2014, Fu and co-workers reported the synthesis of difluoroacetylated oxindoles from N-arylacrylamides and BrCF2CO2Et through radical cascade reaction initiated by the formation of the EtO2CCF2• radical arising from the SET promoted by fac-[Ir(ppy)3] under blue LED iradiation (Scheme 108).202 In 2015, Wallentin and co-workers reported a new strategy for the generation of an acyl radical from carboxylic acid by visible light fac-[Ir(ppy)3] photoredox catalysis through the formation of transient anhydride intermediate (Scheme 109).203 The desired acyl radical species, along with CO2 and methanoate, are generated by the irradiation of transient benzoic (methyl carbonic) anhydrides, which are in situ prepared by mixed carboxylic acids in the presence of dimethyl dicarbonate. The scope of the reaction is similar to those previously reported (Scheme 101, Scheme 104, or Scheme 107).

radical (A) from either CH3CN or cation radical CH3CN•+, which is generated in situ from CH3CN through visible light catalysis, yields the •CH2CN radical (B). The addition of the • CH2CN radical (B) to the activated alkene followed by intramolecular cyclization produces the radical oxindole (C). Finally, hydrogen atom abstraction from the CH3CN•+ cation radical takes place to generate the •CH2CN radical and the desired product. However, a more classical oxidative quenching pathway could not be completely denied. The same group also explored this cascade reaction in the presence of dichloromethane as precursor of •CHCl2 radical (Scheme 106).201 The scope of the reaction tolerates different N-substituents on the N-arylacrylamides as well as on the phenyl part. In addition, N-methyl-N-phenylcinnamamide, an internal alkene, also undergoes radical cascade reaction. Later, this cyclization reaction was extended to other alkyl halides (Scheme 107). The coupling reaction, which requires large excess of alkyl halides, occurs at the C(sp3)−H bond adjacent to at least two chloride atoms, suggesting that halo 7571


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strong reductant fac-[IrIII(ppy)3]*. Single-electron reduction of the mixed anhydride A (generated in situ from carboxylic acid in the presence of dimethyl dicarbonate under basic conditions) by fac-[IrIII(ppy)3]* provides fac-[IrIV(ppy)3] and the acyl radical anion C resulting from fragmentation of B. Subsequently, acyl radical undergoes selective radical addition to olefin giving the radical intermediate D, which cyclized. The resulting radical E is oxidized by fac-[IrIV(ppy)3], providing final product after rearomatization along with the ground state of the photoredox catalyst. One year later, the same group reported this cascade reaction using symmetric aromatic carboxylic anhydrides as acyl radical sources instead of mixed anhydride in situ prepared from carboxylic acid and dimethyl dicarbonate (Scheme 110).204 Comparable yields are observed for the formation of oxindoles, and a similar oxidative quenching catalytic cycle is proposed.

Scheme 108. Synthesis of Difluoroacetylated Oxindoles with BrCF2CO2Et

Scheme 109. Cascade Reaction through Acyl Radicals Generated from Aromatic Carboxylic Acids and Dimethylcarbonate

Scheme 110. Cascade Reaction through Acyl Radicals Generated from Aromatic Carboxylic Anhydrides

In 2017, Xu and co-workers demonstrated that aroyl chlorides are also a suitable acyl radical precursor in a cascade reaction with N-arylacrylamides (Scheme 111).205 Similar reaction Scheme 111. Cascade Reaction through Acyl Radicals Generated from Aroyl Chlorides Leading to Radical Cascade Cyclization

A mechanistic study revealed that the reaction likely proceeds via an oxidative quenching cycle (Figure 43). The photoexcitation of fac-[IrIII(ppy)3] under blue LEDs generates the

conditions (i.e., catalysts, light, and base) than the one used by Wallentin is employed and the desired products are obtained in comparable yields. It is important to note that this work is the f irst example of a photo redox generation of acyl radicals f rom aroyl chlorides. On the basis of cyclic voltammetry experiments, the authors proposed that the reduction of benzoyl chloride (Ep = −0.972 V vs Ag/AgCl) takes place by excited photoredox catalyst fac[Ir(ppy)3] (E1/2IV/*III = −1.73 V vs SCE) to generate the acyl radical through a redox neutral catalytic cycle (Figure 44).

Figure 43. Proposed mechanism for acyl radicals generated from carboxylic acids. 7572


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Figure 45. Proposed mechanism for synthesis of 3,4-disubstituted dihydroquinolinones.

Figure 44. Proposed mechanism for acyl radicals generated from aroyl chlorides.

tion (1,4-aryl shift) desulfonylation cascade reactions (Scheme 103), Yiang, Xia, and co-workers discovered that trifluoromethylated isoquinolinediones are obtained when N-methacryloylbenzamides are used as starting materials (Scheme 113).197 Substrates bearing methyl and F groups at the para position of the aryl ring or having different substituents at N atoms are also tolerant of the reaction conditions.

7.2.2. Photoredox-Catalyzed 1,2-Difunctionalization of N-Aryl Cinnamamide Derivatives. In contrast to Narylacrylamides, with which a photoredox process with Togni’s reagent II affords five-membered oxindoles (Scheme 100),195 Xia and co-workers demonstrated that the radical coupling with N-aryl cinnamamide derivatives undergoes cascade reaction to lead to the formation of six-membered ring dihydroquinolinones (Scheme 112).152 The cyclization of diversely substituted N-aryl

Scheme 113. Trifluoromethylation of α,β-Unsaturated Imide Alkenes with Trifluoromethylsulfonyl Chloride as Radical Precursor

Scheme 112. Synthesis of 3,4-Disubstituted Dihydroquinolinones Using Togni’s Reagent II

Tang and co-workers generalized this reaction to the synthesis of perfluorinated isoquinolinediones using perfluorinated alkyl halides as RF• radical precursors (Scheme 114).206 7.3. Isocyanide Functions as SOMO-philic Relays

Yu and co-workers described the synthesis of 6-alkylated phenanthridine derivatives from alkyl bromides and biphenyl isocyanides through a SOMO-philic isocyanide insertion (i.e., isocyanides are the radical acceptors) followed by radical cinnamamides is carried out using a CF3• radical arising from photoexcitation of Togni’s reagent by fac-[Ir(ppy)3] under visible light irradiation. It should be noted that when the paraposition of the aniline ring is replaced by a methoxy, OH, or OTBS groups, a spiro product is obtained instead of the corresponding six-membered ring product. A classical photoredox-catalyzed cascade reaction involving radical addition followed by intramolecular homolytic aromatic substitution (6-endo-dig) is proposed by the authors, albeit the addition of a CF3• radical occurred at the α-position of the enone (A intermediate, Figure 45). In the course of their investigation on trifluoromethylation of α,β-unsaturated imide alkenes with N-(phenylsulfonyl)acrylamide, which undergoes successive trifluoromethylaryla-

Scheme 114. Synthesis of Isoquinoline-1,3-diones with Perfluorinated Alkyl Halides as Radical Precursors

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cyclization (Scheme 115).207 The reaction is photoredoxcatalyzed by fac-[Ir(ppy)3] and tolerates an electron-donating or

derivatives using alkylation (SOMO-philic isocyanide insertion) and decarboxylation sequences (Scheme 116).208

Scheme 115. Synthesis of 6-Alkylated Phenanthridine Derivatives Using Alkyl Bromides as Radical Precursors

Scheme 116. Two-Step Procedure for the Preparation of 6Mono- and Difluoromethylated Phenanthridine Derivatives

An alternative strategy for the one-step room temperature synthesis of difluoromethylated phenanthridine derivatives is proposed by Dolbier Jr. et al. using CF2HSO2Cl instead of ethyl bromo(di)fluoroacetates (Scheme 117).209 A similar reaction Scheme 117. One-Step Procedure for the Preparation of 6Difluoromethylated Phenanthridine Derivatives

withdrawing groups on the biphenyl isocyanide partner. Only alkyl bromides with an ester group at the α-position of perfluorinated alkyl bromides are operative due to a strong stabilization of the radical. Although the mechanism is not entirely clear, it is proposed that first, irradiation of the photoredox catalyst fac-[Ir(ppy)3] gives the excited state fac-[Ir(ppy)3]*, which is oxidatively quenched by R−Br with the generation of a fac-[Ir(ppy)3]+. The addition of radical to the SOMO-philic isocyanide affords the radical intermediate A, which undergoes intramolecular homolytic aromatic substitution to give the radical intermediate B. The intermediate B is then oxidizes by fac-[Ir(ppy)3]+ to form the cationic intermediate C and regenerates the photoredox catalyst. Ultimately deprotonation assisted by base yields 6alkylated phenanthridines (Figure 46).207 Later, the same group reported a two-step procedure for the preparation of 6-mono- and difluoromethylated phenanthridine

pathway is described and the phenanthridine derivatives are isolated in comparable yields with similar functional groups tolerance. Other easy to handle gem-difluoroalkylsulfonyl chlorides, such as difluoro(phenyl)methanesulfonyl chloride and difluoro(methyl)methanesulfonyl chloride, display similar reactivities. In 2016, Ni, Hu, and co-workers profited from this reaction to employ mono-, di-, and trifluoromethyl heteroaryl sulfones as radical precursors.210 They evaluated the formation of CF2H• radical using [Ru(bpy)2]Cl2 as a photosensitizer from several difluoromethyl heteroaryl sulfones, and the chemical yields are in accordance to the first reduction potentials of difluoromethyl

Figure 46. Proposed mechanism for synthesis of phenanthridine derivatives. 7574


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sulfones that they have measured using cyclic voltammetry (Scheme 118).

Scheme 120. One-Step Procedure for the Preparation of 6Substituted Phenanthridines with Hydrazines

Scheme 118. Trifluoromethyl Heteroaryl Sulfones As Radical Precursors

The substrate generality of biphenyl isocyanide is similar to the previous reports (Scheme 119). A range of readily available,

8. C(sp2)−H BOND FUNCTIONALIZATION VIA PHOTOREDOX-CATALYZED ATOM-TRANSFER RADICAL ADDITION TO ALKENES Photoredox catalyst-promoted reactions, in which the aryl radical transfer occurred in an intermolecular fashion, is still more rare and only limited examples are reported in the literature to date.212,213 In 2014, efforts by Masson and co-workers established multicomponent photoredox-catalyzed reaction combining an arene, an alkene, and a CF3• radical source (Umemoto’s reagent) as viable method for the formal alkylation of arenes (Scheme 121).212 In such a reaction, [Ru(bpy)3](PF6)2 is used as photoredox catalyst to generate the CF3• radical, which reacts with a wide range of substituted styrenes before the addition of the resulting reagent to electron rich arenes (e.g., 1,3,5,-trimethoxybenzene, 1,2-dimethoxybenzene, 1,3-dimethoxybenzene, 1-methylanisole, and anisole). In

Scheme 119. One-Step Procedure for the Preparation of 6Difluoromethylated Phenanthridine Derivatives with Trifluoromethyl Heteroaryl Sulfones

Scheme 121. Multicomponent Alkylation of (Hetero)arenes with Alkenes and Umemoto’s Reagent

bench-stable, and reactivity-tunable fluoroalkyl sulfones are used as radical precursors of monofluoromethyl, difluoromethyl, 1,1difluoroethyl, (phen yl)difluoromethyl, (benzoyl)difluoromethyl, and trifluoromethyl radicals. Mao, Zhou, and co-workers showed that organic dye eosin B is an efficient initiator for generation of radical species from hydrazines upon visible light irradiation in the open air and that radicals could be trapped by 2-isocyanobiphenyls to give a series of 6-substituted phenanthridines in good yields (Scheme 120).211 Various types of radicals including alkyl, aryl, acyl, and alkoxycarbonyl are generated from their hydrazine precursors. 7575


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addition, electron-rich heterocycles such as indoles or benzofurans are alkylated at the C3 position, whereas pyrrole is alkylated at its C2 position. The authors mentioned that this multicomponent process occurs with high chemoselectivity as only traces of trifluoromethylated benzofuran, indole, or pyrrole derivatives were observed (

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