Visible Light Mediated Photoredox Catalytic Arylation Reactions

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Visible Light Mediated Photoredox Catalytic Arylation Reactions Published as part of the Accounts of Chemical Research special issue “Photoredox Catalysis in Organic Chemistry”. Indrajit Ghosh, Leyre Marzo, Amrita Das, Rizwan Shaikh, and Burkhard König* Institute of Organic Chemistry, University of Regensburg, D-93040 Regensburg, Germany CONSPECTUS: Introducing aryl- and heteroaryl moieties into molecular scaffolds are often key steps in the syntheses of natural products, drugs, or functional materials. A variety of crosscoupling methods have been well established, mainly using transition metal mediated reactions between prefunctionalized substrates and arenes or C−H arylations with functionalization in only one coupling partner. Although highly developed, one drawback of the established sp2−sp2 arylations is the required transition metal catalyst, often in combination with specific ligands and additives. Therefore, photoredox mediated arylation methods have been developed as alternative over the past decade. We begin our survey with visible light photo-Meerwein arylation reactions, which allow C−H arylation of heteroarenes, enones, alkenes, and alkynes with organic dyes, such as eosin Y, as the photocatalyst. A good number of examples from different groups illustrate the broad application of the reaction in synthetic transformations. While initially only photo-Meerwein arylation− elimination processes were reported, the reaction was later extended to photo-Meerwein arylation−addition reactions giving access to the photoinduced three component synthesis of amides and esters from alkenes, aryl diazonium salts, nitriles or formamides, respectively. Other substrates with redox-active leaving groups have been explored in photocatalyzed arylation reactions, such as diaryliodonium and triarylsulfonium salts, and arylsulfonyl chlorides. We discus some examples with their scope and limitations. The scope of arylation reagents for photoredox reactions was extended to aryl halides. The challenge here is the extremely negative reduction potential of aryl halides in the initial electron transfer step compared to, e.g., aryl diazonium or diaryliodonium salts. In order to reach reduction potentials over −2.0 V vs SCE two consecutive photoinduced electron transfer steps were used. The intermediary formed colored radical anion of the organic dye perylenediimide is excited by a second photon allowing the one electron reduction of acceptor substituted aryl chlorides. The radical anion of the aryl halide fragments under the loss of a halide ion and the aryl radical undergoes C−H arylation with biologically important pyrrole derivatives or adds to a double bond. Rhodamine 6G as an organic photocatalyst allows an even higher degree of control of the reaction. The dye is photoreduced in the presence of an amine donor under irradiation with green light (e.g., 530 nm), yielding its radical anion, which is a mild reducing reagent. The hypsochromic shift of the absorption of the rhodamine 6G radical anion toward blue region of the visible light spectrum allows its selective excitation using blue light (e.g., 455 nm). The excited radical anion is highly reducing and able to activate even bromoanisole for C−H arylation reactions, although only in moderate yield. Photoredox catalytic C−H arylation reactions are valuable alternatives to metal catalyzed reactions. They have an excellent functional group tolerance, could potentially avoid metal containing catalysts, and use visible light as a traceless reagent for the activation of arylating reagents.

1. INTRODUCTION Arylation reactions are widely used in organic synthesis. Transition metal catalyzed cross-coupling and C−H arylation protocols have been established and their scopes and limitations are well described.1 However, there are applications in synthesis where the required metal catalysts, ligands, and elevated temperatures are drawbacks. Visible light mediated photoredox arylations can proceed under very mild conditions and have therefore become an attractive alternative. We discuss in this Account recent contributions to the fast developing field of visible light photoredox catalytic generation of aryl radials as arylating reagents mainly for C−H arylation reactions. We © XXXX American Chemical Society

organize our survey by the redox-active functional groups of the aryl radical precursors (Scheme 1), and start with aryl diazonium salts, which are easily photoreduced giving aryl radicals. Alternative starting materials are diaryliodonium and triarylsulfonium salts and arylsulfonyl chlorides. The most convenient starting materials are stable aryl halides, but they require extremely negative reduction potentials that can be reached utilizing the energies of more than one photon. The typical photocatalysts used in photoredox arylation reactions Received: May 15, 2016

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DOI: 10.1021/acs.accounts.6b00229 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research Scheme 1. Chemical Structures of Photocatalysts and Aryl Radical Precursors Typically Used in Visible-Light Photoredox C−H Arylation Reactionsa

Scheme 2. Ligand Directed C−H Arylation Using Dual Catalysis

Scheme 3. Direct C−H Arylation of Heteroarenes Using Eosin Y

a

Aryl diazonium salts and diaryliodonium salts are typically synthesized in the laboratory and normally stored in the fridge (low temperature). Note that aryl diazonium salts and diaryliodonium salts are also commercially available but relatively expensive. Arylsulfonyl chlorides are commercially available, relatively inexpensive, and stable at ambient temperature. Aryl halides are commercially available, inexpensive, and, more importantly, bench-stable. The reduction potential trend normally follows: aryl diazonium salts < diaryliodonium salts < arylsulfonyl chlorides ≪ aryl halides.

are shown in Scheme 1. Notably, using redox active organic dyes is particularly advantageous, as they do not contain metal ions and are cheaper than ruthenium or iridium complexes. Good product yields were obtained with substituted aryl diazonium salts and different heteroarenes as radical trapping partners. The proposed catalytic cycle (Scheme 4) starts with a SET from the excited state of eosin Y to the aryl diazonium salt 2, forming the aryl radical 6 and the radical cation of eosin Y. The aryl radical 6 is then trapped by the heteroarene 4 giving the radical intermediate 7, which is oxidized by the eosin Y radical cation affording the carbocation intermediate 8 and closing the catalytic cycle, or by the aryl diazonium salt 2 in a radical chain transfer mechanism. Finally, the carbocation intermediate 8 is rearomatized yielding product 5. Notably, Rueping et al. in 2015 reported that C−H arylation of heteroarenes using aryl diazonium salts could also be accomplished using heterogeneous TiO2 catalyst and visible light.7 Xiao et al. developed the [Ru(bpy)3Cl2]·6H2O-photocatalysed arylation of N-heteroarenes.8 A variety of pyridine hydrochlorides 11 were arylated in aqueous media with aryldiazonium salts 2 to yield 12 (Scheme 5a). Caffeine (13) could be arylated to obtain 14 using the photocatalytic conditions, but required the use of 88% aqueous formic acid as solvent (Scheme 5b).

2. ARYLATION REACTIONS USING ARYL DIAZONIUM SALTS 2.1. C−H Arylation of Hetero(arenes)

Aryl diazonium salts have attracted much interest over the years because of their wide applications as reagents in aromatic substitution reactions, or as precursors of aryl radicals.2 After the first example of a photocatalyzed Pschorr reaction using [Ru(bpy)3]2+ as photoredox catalyst reported by Cano-Yelo and Deronzier 30 years ago,3,4 Sanford et al. in 2011 reported ligand-directed C−H arylation reactions using aryl diazonium salts 2 and 1 as substrates to afford 3 by using a combination of palladium catalysis with visible light photoredox catalysis (Scheme 2).5 The dual catalytic system is compatible with a wide range of aryl diazonium salts and different directing groups, e.g., amides, pyrazoles, oxime ethers, and pyrimidines, affording the coupling products in good to excellent yields. A year later, our group developed direct C−H arylations of heteroarenes 4 with aryldiazonium salts 2 using eosin Y as a photoredox catalyst (Scheme 3).6 The main advantage of this method, compared to other C−H arylation methods, is the use of an organic dye as a photoredox catalyst at room temperature. B


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lines 18 in acidic media giving 19 in moderate yields.10 Other heterocycles, e.g., quinoline, acridine, phthalazine, pyridine, and pyrazine, are arylated in good to moderate yields (Scheme 7).

Scheme 4. Proposed Mechanism for the Photocatalytic C−H Arylation of Heteroarenes Using Aryl Diazonium Saltsa

Scheme 7. Photocatalyzed Direct C−H Arylation of NHeteroarenes

a

Note: TEMPO trapped adducts 9 and 10 support the proposed radical pathway of the catalytic cycle.

Scheme 5. Photoarylation of N-Heteroarenes in Aqueous Solution

2.2. Arylation of Olefins

Benzothiophenes 22 could be synthesized through a radical annulation photocatalytic process using eosin Y.11 When aryldiazonium salts 20 and alkynes 21 were irradiated in the presence of eosin Y, single regioisomers 22 were obtained in moderate to good yields (Scheme 8). Interestingly, 6-methoxy2-(4-methoxyphenyl)benzo[b]thiophene, a key intermediate in the synthesis of commercialized drug Raloxifene 23, was synthesized in 70% yield. Scheme 8. Eosin Y Photocatalyzed Radical Annulation Synthesis of Benzothiophenes

Ranu et al. reported the C−H heteroarylation of heteroarenes 16 with aryl diazonium salts, generated in situ from aryl amines 15 and t-BuONO (Scheme 6),9 using eosin Y to yield 17. This method was applied to the heteroarylation of alkynylated arenes to obtain useful synthons for the synthesis of therapeutically important compounds. An additional application of the photo-Meerwein reaction is the [Ru(bpy)3Cl2]·6H2O-photocatalyzed arylation of isoquinoScheme 6. C−H Heteroarylation of Heteroarenes by Photoredoxcatalysis

The proposed mechanism (Scheme 9) demonstrates that the photochemically generated aryl radical 24 adds to alkyne 21 affording a vinyl radical intermediate 25, which then undergoes homolytic substitution at the sulfur atom yielding the sulphuranyl radical intermediate 26 that upon successive oxidation (generates 27) and demethylation yields product 22. Zhou et al. reported eosin Y-catalyzed synthesis of phenanthrenes (32) using diazonium salts 30 and alkynes 31 (Scheme 10).12 The reaction tolerates a broad range of functional groups, but the presence of base decreases the yields due to the direct reaction of the base and the diazonium salt. Our group developed photocatalytic intermolecular photoMeerwein reactions for the arylation of alkenes, alkynes, and C


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using aryl diazonium salts and [Ir(ppy)2(dtbbpy)PF6] (Scheme 11b) to obtain 36.14 The same year, our group developed an efficient photocatalytic α-arylation of enol acetates 37 using aryl diazonium salts (Scheme 12).15 Different aryldiazonium salts and terminal

Scheme 9. Proposed Mechanism for the Photoannulation Reactiona

Scheme 12. α-Arylation of Enol Acetates via Photoredox Catalysis

a


Scheme 10. Visible Light Induced Synthesis of Phenanthrenes enol acetates are suitable substrates. The proposed mechanism (Scheme 13) demonstrates that aryl radical 6 adds to enol Scheme 13. Proposed Mechanism for the α-Arylation of Enol Acetates Using Aryldiazonium Salts

enones using aryl diazonium salts and Ru(bpy)32+ or eosin Y to obtain 34 (Scheme 11a).13 The reaction is limited to activated unsaturated compounds (33) including coumarins, styrenes, quinones, and phenyl acetylenes. Later, Yu et al. extended the photo-Meerwein arylation to enamides and enecarbamates 35 Scheme 11. Photocatalytic Arylation of Alkenes, Alkynes, and Enones Using Diazonium Salts

acetate 37 to generate radical intermediate 39, which upon oxidation generates intermediate 40 that upon successive release of an acyl cation affords product 38. We further extended the reaction to other trapping reagents and nucleophiles.16 The challenge of this reaction is the competing reaction between the trapping reagent and the nucleophile with the diazonium salt (Scheme 14). Here, the Ritter reaction conditions are used to trap the carbocation generated during photoredox Meerwein arylation reactions allowing intermolecular amino-arylation of alkenes 42. Substituted aryl diazonium salts react smoothly to the desired products in good to excellent yields. Primary, secondary, and tertiary alkyl nitriles and cyclopropane carbonitrile undergo the transformation providing excellent yields. The proposed mechanism is described in Scheme 15. Photochemically generated aryl radical 6 reacts with olefins to afford the radical intermediate 44, which can be oxidized either by Ru(bpy)33+ closing the photocatalytic cycle or by the diazonium salt 2 in a chain transfer mechanism. The alkyl nitrile then adds to the D


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Accounts of Chemical Research Scheme 14. Photoredox Meerwein Arylation−Addition

Scheme 16. Intermolecular Formyloxy-Arylation of Alkenes by Photo-Meerwein Reaction

Scheme 15. Proposed Mechanism for the Photo-Meerwein Arylation−Additiona

Scheme 17. Metal-Free Carbonylation via Photoredox Catalysis

a


2.4. Arylation Reactions Using Dual Catalytic Protocols and C−X Bond Formation

carbocation 45 to form intermediate 46, which upon hydrolysis gives the desired product 43. Later we reported the formyloxy-arylation of alkenes 49 in moderate to good yields by photo-Meerwein addition in the presence of dimethylformamide (Scheme 16).17 DMF was employed to generate the Vilsmeier reagent. Jiang et al. reported the synthesis of α-aryl esters utilizing visible-lightinduced Meerwein cascade reaction using aryl diazonium salts, acrylonitrile, O2, Ru(bpy)3Cl2·6H2O as photocatalyst, and alcohols as both reagent and solvent.18

Glorius et al. reported the dual photoredox and gold catalytic oxy- and amino-arylation of alkenes to afford 58, starting from aryldiazonium salts 2 and 4-penten-1-ol or 4-penten-1-amine derivatives 57 (Scheme 18a).22 Using similar dual catalytic systems, other groups also reported the arylative ring expansion of cyclopropanols and cyclobutanols 59 for the synthesis of cyclobutanones or cylopentanones 60 (Scheme 18b),23 and the synthesis of 3-arylated butenolides 62 from tert-butyl allenoates 61 and aryldiazonium salts 2 (Scheme 18c).24 In addition, terminal acetylenes 63 were arylated taking advantage of the ability of Au-complexes to activate triple bonds, affording disubstituted acetylenes 64 in moderate to excellent yields (Scheme 18d).25 The dual catalytic system gave arylphosphonates 66 from aryldiazonium salts 2 and H-phosphonates 65 (Scheme 18e).26 Notably, following this C−heteroatom bond formation concept, although using only eosin Y, Yan et al. reported borylations of arenes to afford 68 in moderate to good yields.27 However, heteroaromatic diazonium salts gave the desired products only with low conversion (Scheme 19).

2.3. Carbonylations of Arenes

Aryl diazonium salts have also been used as starting materials in photoredox catalytic carbonylations of arenes. Liu et al. showed the synthesis of aryl ketones 55 from aryl diazonium salts, CO, and (hetero)arenes (Scheme 17a).19 In the same year, Jacobi von Wangelin and Majek reported the photocatalytic synthesis of aromatic esters 56 in moderate to excellent yields using aryl diazonium salts, CO, eosin Y, and MeOH (and other alcohols) as both reagent and solvent (Scheme 17b).20 Xiao et al. also reported the same synthetic methodology, however, using fluorescein as a photoredox catalyst.21 E


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Accounts of Chemical Research Scheme 18. Dual Photoredox and Gold Catalyzed Arylation Reactions

Scheme 20. Diaryliodonium Salts as Aryl Radical Source and C−C Coupling

Scheme 19. Borylation of Aryldiazonium Salts via Photoredox Catalysis

Ollivier et al. reported the [Cu(dpp)2][PF6]-assisted reductive photocatalytic generation of aryl radical from diaryliodonium salts 71 that subsequently react with allyl sulfones 74 affording the allylation product 75 (Scheme 20c).30 Greaney et al. used diaryliodonium salts 76 in the oxy arylation of styrenes (77, Scheme 20d).31 The three-component reaction allowed the conversion of a reactive styrene moiety affording useful products 78 with no polymerized side products. 3.2. Arylation Reactions Using Dual Catalytic Protocols

Sanford merged visible light photochemistry of diaryliodonium salts with palladium catalysis for the C−H bond activation and arylation (Scheme 21a).32 Combination of Ir(ppy)2(dtbbpy)PF6 as photocatalyst and Pd(NO3)2 as transition metal catalyst delivered C−C coupled products (80) in good yields. This catalytic method does not require additives or halogen prefunctionalization. Glorius reported the reaction of alkenes (85) with diaryliodonium salt and alcohol in the presence of Ir(ppy)2(dtbbpy)PF6 and [Ph3PAu]NTf2 as dual catalytic system giving the arylated ethers 86 in excellent yields (Scheme 21b).33

3. DIARYLIODONIUM SALTS AS ARYL RADICAL PRECURSOR 3.1. Arylation of Hetero(arenes) and Olefins

4. ARYL SULFONYL CHLORIDES AS ARYL RADICAL PRECURSOR Bhasin et al. used the photocatalyzed desulfitative crosscoupling between aryl sulfonyl chloride 88 and N-methylpyrrole, thiophene, and furan derivatives (87) giving heterobiaryls 89 (Scheme 22).34 Li et al. demonstrated the use of aryl sulfonyl chloride 90 as a source of aryl radicals followed by C(sp3)−H functionalization

Xiao et al. described the [Ru(bpy)3][Cl]2·6H2O photocatalyzed reduction of iodonium salts and C−H arylation of arenes and heteroarenes to afford 69 and 70 (Scheme 20a).28 Chatani et al. used [Ir(ppy)2(bpy)]PF6 photocatalyzed reductive conversion of diaryliodonium salts 71 to aryl radicals for the cross-coupling with heteroaryls 72 (Scheme 20b) to afford 73.29 Notably, the C−H arylation reactions with pyrroles proceed also under direct photoirradiation (i.e., in the absence of a photocatalyst). F


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(91) and subsequent carbocyclization with a benzylic C−H results in the desired product 92. The same group also showed tandem cyclization with 1,6enynes (93) yielding fused 10a,11-dihydro-10H-benzo[b]fluorene 94 (Scheme 23b).36 Fan et al. reported the synthesis of substituted phenanthridines 97 using aryl sulfonyl chloride 95 and 2-isocyanobiphenyls 96 (Scheme 23c).37

Scheme 21. Application of Diaryliodonium Salts for C−H Bond Activation

5. TRIARYL SULFONIUM SALTS AS ARYL RADICAL PRECURSOR Sulfonium salts 98 and the chemistry of the corresponding ylides are well developed. Ollivier et al. used sulfonium salts for the generation of aryl radicals under visible light photocatalytic reduction conditions. The aryl radicals undergo addition to activated olefins (99) giving allylation products 100 (Scheme 24).38 Scheme 24. Photocatalytic Aryl Radical Generation from Sulfonium Salts

Scheme 22. Photocatalytic Desulfitative Cross-Coupling of Aryl Sulfonyl Chloride with Heteroarenes

6. C−H ARYLATION REACTIONS USING ARYL HALIDES Aryl halides are ideal stable precursors for aryl radicals, but unlike the previously discussed aryl radical precursors their reduction potentials are extremely negative.39,40 Light induced single electron transfer processes using commonly known catalysts such as Ru(bpy)32+,41 Cu(dap)2+,42 Ir(ppy)3,41 and eosin Y2 do not provide sufficient reduction power. However, aryl radicals can be generated from aryl halides using strong bases,43 such as potassium tert-butoxide or nucleophiles under ultraviolet (UV) (λEx ≤ 350 nm) irradiation (SRN1). The base promoted C−H arylation reactions are believed to proceed via a radical chain mechanism.44,45 The combination of a photoredox catalyst with a strong base has also been reported in the literature.46 Murphy et al. have shown that the electron transfer to aryl halides is possible from highly reactive neutral organic reducing agents, such as N2,N2,N12,N12-tetramethyl-7,8dihydro-6H-dipyrido[1,4]diazepine-2,12-diamine under UV-A (365 nm) irradiation.47 Stephenson et al.48 and Lee and Kim49 have demonstrated that aryl radicals can be generated using redox active Ir-complexes and visible light, but the methods are limited to aryl iodides. As the reduction potentials of polyfluorinated aryl halides, such as pentafluorophenyl bromide, are moderate the corresponding polyfluorinated aryl radical is generated by electron transfer from moderately reducing photocatalysts.50 The radical anion of eosin Y, generated in situ via a PET process, is able to transfer an electron to polyfluorinated aryl bromides, and upon successive C−Br bond cleavage, the polyfluorinated aryl radical is obtained, which reacts with arenes and heteroarenes in moderate to good yields. Weaver and Senaweera have reported that aryl radicals could be generated by activating C−F bonds using Ir-complexes, and substituted arenes and heteroarenes were functionalized in moderate to

and carbocyclization reaction under visible light irradiation affording fused 1H-indenes moieties 92 (Scheme 23a).35 Single electron transfer from the excited photocatalyst to the aryl sulfonyl chloride results in the formation of aryl radicals after the loss of SO2 and Cl−. The aryl radical reacts with acetylene Scheme 23. Photocatalytic Generation of Aryl Radicals from Aryl Sulfonyl Chlorides

G


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Accounts of Chemical Research good yields.51 de Alaniz et al. reported that aryl radicals could be generated using 10-phenylphenothiazine (PTH) as photocatalyst upon 380 nm light excitation.52 The reduction potential of excited PTH is so negative that aryl radicals are obtained from aryl halides with electron donating substituents. Recently, we have shown that aryl radicals are obtained using the excited doublet states of stable radical anions, formed in situ via a photoinduced electron transfer (PET) processes (Scheme 25).40,53 Among others, perylene bisimides (PDIs, for chemical

Scheme 27. C−H Arylations and Photoreduction Yields Using Aryl Halides as Substrates

Scheme 25. Photoinduced (Left) vs Consecutive Photoinduced Electron Transfer (conPET, Right) Catalytic Cycles

structures see Scheme 1), are a class of photostable organic dyes that form stable and colored radical anions under nitrogen.40,54 Upon visible light irradiation, the photoexcited PDI (PDI*) takes an electron from a suitable sacrificial electron donor (e.g., Et3N) giving the radical anion in the ground state (PDI•−). The stable PDI•−, upon successive photoexcitation, is able to transfer an electron to aryl halides producing the aryl radical precursor (ArX•−) and regenerate the neutral PDI. Fragmentation of ArX•− yields the aryl radical, which is trapped by either unsaturated heterocycles or double bonds, giving C− H arylated products, or abstracts a hydrogen atom either from the radical cation of the donor molecule or from the solvent to form the reduction product (Scheme 26).

for the reduction and C−H arylation reactions are similar to the homogeneous system. Reaction times were shorter in the presence of 72 equiv of Et3N in comparison to 8 equiv in homogeneous solution. Jacobi von Wangelin et al. reported that highly energized excited states, generated via a triplet−triplet annihilation process, can activate aryl halides via a single electron transfer processes. 56 Although the laser initiated triplet−triplet annihilation limits synthetic applications, the principle elegantly demonstrates the use of more than one photon in the same photocatalytic cycle for the activation of aryl−halide bonds. The reactivity of aryl halides yielding aryl radicals by one electron reduction is only in part determined by their reduction potentials. In general, aryl iodides are more reactive, due to the lower bond dissociation energy, and a suggested concerted mechanism of electron transfer and C−I bond cleavage.39 Aryl bromides and -chlorides on the other hand undergo bond cleavage by a stepwise mechanism.39 This difference is of importance for photoinduced electron transfer initiated reactions, as the back electron transfer could compete with the bond cleavage. Recent literature examples illustrate this difference:48 While iodobenzoates are photoreduced within a few hours using an Ir-complex, related bromobenzoates with similar reduction potentials give only partially reduced products even after longer reaction time. The importance of the fragmentation kinetics is illustrated by the example p-nitrobromobenzene: The compound is easily reduced to its radical anion, but the slow C−Br bond cleavage kinetics57 inhibit the aryl radical formation most likely due to the favored back electron transfer. Additionally, the yields of C−H arylation reactions under reductive photoredox catalytic conditions, especially in the presence of amine donors (e.g., Et3N, DIPEA), suffer from competition with fast hydrogen atom abstraction of the aryl radicals from the radical cation of the amines and from the solvent molecules (e.g., DMF, DMSO).40,48,49,51,53 When the dehalogenations of aryl halides are performed in D7-DMF, deuterated products are obtained. Additionally, the presence of diethylamine could be confirmed by analyzing the crude reaction mixture with GC−MS. Notably, the abstraction of

Scheme 26. Schematic Representation of the Z-Scheme Using PDI as the conPET Catalyst

The reaction of (hetero)arenes and alkenes with the aryl radical competes with hydrogen atom transfer and therefore determines the yields of C−H arylated products. Pyrrole derivatives were found to react faster at their 2-position with photogenerated aryl radicals, but excess amounts are required. Under these very mild reaction conditions, C−H arylated products were obtained in moderate to good yields (Scheme 27) using aryl-iodides, aryl-bromides, and aryl-chlorides as starting materials. Notably, this is the first example of aryl− chloride bond activation for C−H arylations using visible light. Recently, Zeng et al. demonstrated that the conPET concept can be extended to a heterogeneous system.55 The yields, both H


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Accounts of Chemical Research hydrogen atoms is also observed when the aryl radical is generated from aryl diazonium salts.58

Scheme 28. Selective and Sequential C−H Arylation Reactions

7. SELECTIVE AND SEQUENTIAL C−H ARYLATIONS WITH ARYL HALIDES In a recent report, our group has shown that a higher degree of control on the activation of redox active chemical bonds is achievable by using a xanthene dye, rhodamine 6G (Rh-6G, see Scheme 1 for the chemical structure).53 In the presence of a sacrificial electron donor (DIPEA), when excited with green LEDs (λEx = 530 nm) Rh-6G yields its radical anion (Rh-6G•−) in the ground state via a PET process, whereas, the radical anion is excited again if blue LEDs (λEx = 455 nm) are used as a light source for the photocatalyst excitation.59 As the reduction potential of the excited state of a redox active species differs significantly with respect to its ground state, the reactivity and thus selectivity of this photocatalytic system could be controlled just by using different light sources. Notably, unlike other classes of organic dyes, the special feature of light color regulated reactivity of xanthene dyes stems from the hypsochromic shift of the absorption spectra upon one electron reduction. Using this catalytic method, a series of selective and sequential catalytic bond activations were demonstrated. When 1,3,5-tribromobenzene and 1,4-dibromo-2,5-difluorobenzene, bearing three and two equivalent C−Br bonds, respectively, were irradiated with green light selectively monosubstituted C−H arylated products were obtained. In contrast, when the reaction mixtures were irradiated with blue light two aryl bromine bonds are activated to obtain disubstituted C−H arylated products (Schemes 28 and 29). Biologically important 2,4,6-tribromopyrimidine could be selectively and sequentially functionalized just by changing the light source from green to blue, respectively. The sequential C−H arylation reactions could be performed with the same or with different trapping reagents. As the reduction potential of the arylated products increases, a kinetic control on the sequential C−H arylations is possible using this catalytic method. As exemplified, the conversion of 1,3-dibromobenzene into the corresponding aryl radical requires the reduction power of the excited Rh-6G•−, but as the activation of the second bromide of the resulting compound is kinetically slower owing to the increased reduction potential, a stepwise sequential substitution with N-methylpyrrol and pyrrol is possible. The photoredox catalytic method is also applicable for the selective and sequential activations of chemical bonds possessing different redox potentials.53 For example, the photoredox reaction with ethyl 2-bromo-(4-bromophenyl)acetate, which requires a reduction potential of the ground state Rh-6G•− to form the radical in benzylic position, proceeds smoothly generating ethyl 4-bromophenylacetate under green light. The remaining aryl−bromide bond could subsequently be activated using blue light irradiation and undergoes C−H arylation with pyrrole or unsaturated double bonds. Similarly, selective activation of the diazonium group (in the absence of DIPEA, using the reduction potential of Rh-6G*) is possible, keeping the aryl carbon−bromine bond intact. The same catalyst activates the carbon−bromine bond for C−H arylation reactions after slightly changing the reaction conditions to blue light irradiation in the presence of DIPEA. In addition, the Rh-6G-based catalytic system allows C−H arylations of substituted pyrroles, and unsaturated double

Scheme 29. Proposed Catalytic Cycle Involving Rh-6G

bonds using aryl bromides with electron withdrawing and more importantly electron donating functional groups (yields up to I



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78%, Scheme 30). The C−H arylation reactions proceed under very mild reaction conditions at ambient temperature and

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

Scheme 30. Yields of the C−H Arylated Products Using Rh6G as a Photoredox Catalyst

Notes

The authors declare no competing financial interest. Biographies Indrajit Ghosh received his Ph.D. (2013) from the group of Prof. Werner Nau at the Jacobs University Bremen, Germany, and is now a postdoc at the University of Regensburg. His current research interests include the application of visible light mediated photoredox processes in organic synthesis. Leyre Marzo received her Ph.D. in 2015 from the Universidad Autónoma de Madrid, under the supervision of Prof. José Luis Garciá Ruano and Dr. José Alemán. She is now a postdoc in the group of Prof. König at the University of Regensburg. Her research interests are the development of new synthetic methods using visible light photocatalysis. Amrita Das received her B.Sc. and M.Sc. degrees from Scottish Church College, Kolkata and IIT Madras, India, respectively. She is a Ph.D. student with Prof. König at the University of Regensburg. Her research interests focus on applications of visible light chemical photocatalysis in organic synthesis.

require no metal catalyst or auxiliary ligands, and therefore show a high functional-group tolerance.

8. CONCLUSIONS AND FUTURE PERSPECTIVE Visible light photoredox catalyzed C−H arylation reactions have become a valid alternative to the existing classical transition metal-mediated cross-coupling reactions. Advantages are mild reaction conditions and, in some cases, the use of organic dyes as photocatalysts (i.e., transition metal free conditions). Diazonium salts have been widely applied as aryl radical precursors and many reported examples illustrate their application in synthesis. Although a smaller number of examples are documented, diaryliodonium and triarylsulfonium salts and arylsulfonyl chlorides are useful aryl radical precursors for photoredox arylation reactions. A common feature of all of these starting materials is their low reduction potentials, which is essential due to the limited reduction power of conventional visible light photocatalysts. The conPET photocatalytic concept extends this limit by using the energy of two photon excitations for a single chemical transformation. While a single visible light excitation has an energetic limit (ca. 270 kJ/mol for a blue photon at 440 nm), the consecutive two-photon excitations allows the photocatalytic arylation using stable aryl halides as starting materials. Triplet−triplet annihilation, although less practical in synthetic applications, is an alternative for adding up light excitation energies. The organic dye Rh-6G extends the conPET photocatalysis to a selective activation of carbon−halide bonds by using different light sources for the photocatalyst excitation. The reduction potential of the Rh-6G photocatalytic system allows the activation of OMe- and Ph-substituted aryl bromides for C−H arylations. Despite many achievements of the last years, there are challenges ahead. Aryl chlorides without electron withdrawing substituents are still outside the reduction scope of currently known photocatalysts. The quantum efficiencies of many photoredox arylations are low leading to very long reaction times. Hydrogen atom transfer to the intermediate aryl radicals gives undesired side products and limits the choice of coupling partners. Last, but not the least, the mechanistic details of most photoredox arylations are only little explored, but this knowledge is essential for the rational design of visible light mediated cross coupling reactions.

Rizwan Shaikh received his Ph.D. from the group of Prof. Haufe at the University of Münster, Germany. Presently, he is working as a postdoctoral fellow in the group of Prof. König at the University of Regensburg. His research focuses on visible light photo catalyzed C−C and C−X bond formation. Burkhard König received his Ph.D. in 1991 from the University of Hamburg. He continued his scientific education as a postdoctoral fellow with Prof. M. A. Bennett, Research School of Chemistry, Australian National University, Canberra, and Prof. B. M. Trost, Stanford University. Since 1999 he is a full professor of organic chemistry at the University of Regensburg. His current research interests are the development of synthetic mythologies in photoredox catalysis.

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ACKNOWLEDGMENTS We acknowledge the Deutsche Forschungsgemeinschaft (DFG, GRK 1626) for financial support. REFERENCES

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Visible Light Mediated Photoredox Catalytic Arylation Reactions

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