Synthetic Applications of Eosin Y in Photoredox Catalysis

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Synthetic Applications of Eosin Y in Photoredox Catalysis

Durga Prasad Hari, and Burkhard König*

Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x

Eosin Y, a long known dye molecule, has recently been widely applied as a photoredox catalyst in organic synthesis. Low cost and good availability make eosin Y an attractive alternative to typical inorganic transition metal photocatalysts. We summarize the key photophysical properties of the dye and the recent synthetic applications in photoredox catalysis.

24 μs.31-33 Eosin Y absorbs green light; the UV-Vis spectrum 1. Introduction shows a characteristic peak at 539 nm with a molar extinction coefficient ε = 60803 M-1cm-1. By excitation eosin Y becomes Visible light photoredox processes have recently found many more reducing and more oxidizing compared to its ground state. applications in organic synthesis,1-13 but the general interest in the 14 The redox potentials of the excited state can be estimated from field started much earlier. Unlike thermal reactions, photoredox the standard redox potentials of the ground state, determined by Manuscript processes occur under mild conditions and do not require radical cyclic voltammetry, and the triplet excited state energy. The initiators or stoichiometric chemical oxidants or reductants. measured ground state and the estimated excited state oxidation Typical irradiation sources are LEDs or household lamps, which 34, 35 and reduction potentials are given in Scheme 1. In addition, are cheaper and easier to apply than specialized UV reactors used the photo excited state of eosin Y may also undergo energy in classical photochemistry. Ruthenium and iridium polypyridyl 36 transfer. complexes are commonly employed visible light photocatalysts 1 and their chemistry and application in organic synthesis has 1EY* recently been summarized.14, 15 COOR 3EY* Despite the excellent photophysical properties of ruthenium Br Br - EY Br Br - 1.11 V + 0.83 V Accepted and iridium polypyridyl complexes in visible light photocatalysis, ev hν 1.89 ev RO O O the compounds are expensive and potential toxic, causing - Br Br EY + - 16 Br Br EY EY EY disadvantages on larger scale. Organic dyes have been used as +0.78 V -1.06 V R = H, eosin Y spirit soluble Eosin Y an attractive alternative to transition metal complexes in Eosin Y 17-20 R = Na -eosin Y photoredox catalysis. They are typically less expensive and R = Na, Na2-eosin Y = n less toxic, easy to handle and even outperform organometallic R = (nC4H9)4, TBA-eosin Y 16, 21-24 and inorganic catalysts in some cases. Particularly eosin Y Scheme 1 Different forms of eosin Y and the redox potentials of eosin Y was widely used as organo-photocatalyst in synthetic in CH3CN/H2O (1:1) in ground and corresponding excited states. transformations. The classic dye is known for a long time and found use in cell staining,25 as pH indicator,26 as indicator in the 3. Reduction reactions analytical halide determination by Fajans27, 28 and as dye pigment, 29, 30 The first reaction demonstrating the use of eosin Y e.g. in lip sticks. In this article, we discuss recent applications photocatalysis in organic synthesis was the photoreduction of of eosin Y as visible light photocatalyst in organic synthesis. ChemComm sulfonium salts. 2. Photochemistry of Eosin Y 3.1 Reduction of phenacyl sulfonium salt The photochemistry of eosin Y is well investigated: upon In 1978, Kellogg and coworkers reported the visible light excitation by visible light, eosin Y undergoes rapid intersystem induced reduction of phenacyl sulfonium salts by 1,4 dihydro- 37 crossing to the lowest energy triplet state, which has a life time of pyridines (Scheme 2). Irradiation of a mixture of 1 and 2 in CD3CN or CD3COCD3 without any photosensitizer provided the reduced product 3 in quantitative yield after 48 h using normal Department of Chemistry and Pharmacy room light (neon fluorescent lamp at ca. 2 m distance) at 25°C. Universität Regensburg Addition of 1 mol% of Na2-eosin Y accelerated the reaction Universitätsstr. 31, 93040 Regensburg resulting in complete conversion within 1 h of irradiation. The Fax: (+499419431717) E-mail: [email protected] authors speculated that light induced single electron transfer (SET) steps are responsible for the formation of the reduced

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product and suggested an acceleration effect upon addition of the of eosin Y, which is reduced by TEOA to close the catalytic cycle photocatalyst. However, the exact role of the photocatalyst in the and produce the radical cation of TEOA. The reaction of the reaction mechanism remains undisclosed. radical anion 6 with the TEOA cation radical in the presence of water gives glycolaldehyde, diethanolamine and the further O O EtO C CO Et Na -eosin Y reduced intermediates, which are again reduced in a similar 2 2 2 (1 mol%) S BF4 25°C, rt, 1 h fashion to finally yield aniline. S N Ph CD3COCD3 or CD CN 1 2 3 3 100% visible NO2 Scheme 2 Visible light mediated reduction of phenacyl sulfonium salt. light EY* 3.2. Reduction of nitrobenzene R EY 4 Tung and coworkers utilized eosin Y as photocatalyst and NH triethanolamine (TEOA) as sacrificial reducing agent for the NO2 2 TEOA TEOA efficient photocatalytic reduction of nitrobenzene under green EY R R light irradiation (Scheme 3).38 The reaction is chemoselective and tolerates the presence of other functional groups, such as 6 5 TEOA carbonyls, halogen atoms, and nitriles. The nitro group is the better electron acceptor. Important factors to achieve the optimal Scheme 4 A plausible mechanism for the reduction of nitrobenzene to aniline via visible light photocatalysis. reaction yield are the pH value of the reaction mixture in deoxygenated ethanol-water (3:2, v/v) mixture and the amount of 3.3. Desulfonylation added TEOA. Nitro groups of substrates bearing either electron The use of sulfones as auxiliary groups is an efficient synthetic donating or electron withdrawing substituents are smoothly strategy to generate a wide range of important products. reduced. Commonly the sulfone group is removed using metal containing Manuscript NO NH 2 Eosin Y (1 mol%) 2 reducing agents, such as Bu3SnH, Al (Hg), or Sm/HgCl2. 6 equiv of TEOA Recently an environmental friendly desulfonylation reaction was R R EtOH/H2O reported by Wu and coworkers using eosin Y bis-tetrabutyl- visible light, rt 4 5 11 ammonium salt (TBA-eosin Y) as photocatalyst and diiso- examples 39 98-100% (conversion) propylethylamine (iPr2EtN) as a reducing agent (Scheme 5). NH NH NH2 2 2 O O R2 SO Ar R2 2 TBA-eosin Y (1 mol%) R R R3 R3 R1 iPr CH CN R1 Cl 2NEt, 3 7 3 W 450 nm LED 8

99% (c) 99% (c) 100% (c) Accepted 21 examples 99% (s) 98% (s) 95% (s) 55-99% yield NH NH2 2 NH2 O O O

OMe O O CN O 99% 87% 90% 99% (c) 99% (c) 100% (c)

100% (s) 93% (s) 96% (s) O O c = conversion, s = N selectivity Scheme 3 Photoreduction of substituted nitrobenzenes to anilines. 92% 83% Based on quenching experiments and a flash photolysis study, the authors proposed a tentative mechanism for the photo- Scheme 5 Desulfonylation using TBA-eosin Y as a photocatalyst. catalytic reduction of nitrobenzene as shown in Scheme 4. A SET

ChemComm from eosin Y* to nitrobenzene generates 6 and the radical cation Burkhard König was born in Wiesbaden, Germany. He obtained his PhD in 1991 from the Durga Prasad Hari was born in Jarajapupeta, university of Hamburg under the supervision of Nellimarla, Vizianagaram, A.P, India. He received Prof. de Meijere. He pursued postdoctoral his Bachelor degree from Silver Jubilee Degree studies with Prof. M. A. Bennett, Research College, Sri Krishnadevaraya University, School of Chemistry, Australian National Ananthpur, and then obtained his Master degree University, Canberra, and Prof. B. M. Trost, from IIT Madras. He is currently working under Stanford University. In 1996 he recieved his the supervision of Prof. Burkhard König for his Habilitation at the University of Braunschweig. PhD at the University of Regensburg. His research He became full professor of organic chemistry at interests focus on the applications of visible light the University of Regensburg from 1999. His chemical photocatalysis towards organic synthesis. current research interests include the development of synthetic receptors for the recognition of biological target structures and the application of visible light chemical photocatalysis towards organic synthesis.

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eosin Y (2 mol%) Irradiation of a mixture of 7, TBA-eosin Y and diisopropyl- Nu nm LED N N 530 Ph ethylamine under inert atmosphere using a 3 W blue LED in Ph rt, air Nu CH3CN furnishes the desired product 8 in good yields. 12 13 Sulfonylated aliphatic ketones give no reaction yield due to their 24 examples 55-93% yield very negative reduction potential of -1.94 V vs SCE not accessible by the excited state of TBA-eosin Y. N N N The mechanism for the desulfonylation reaction is proposed in Ph Ph Ph CN MeOOC COOMe Scheme 6. Irradiation of TBA-eosin Y generates its excited state, NO2 which is oxidatively quenched by β-arylketosulfones resulting in 80% 88% 62% the formation of the cation radical of TBA-eosin Y and the N N radical anion of 9. A SET from diisopropylethylamine to the Ph Ph radical cation of TBA-eosin Y regenerates the photocatalyst and P(OEt)2 P(OCH2Ph)2 O closes the cycle. Finally, the radical anion 10 undergoes O 86% 92% desulfonylation to produce a ketone radical which abstracts a Scheme 7 Oxidative C-C and C-P bond formation. hydrogen atom from the cation radical of diisopropylethylamine affording the desired ketone 11. The radical cation of the TBA- The proposed mechanism of the reaction is depicted in Scheme eosin Y was identified in the presence of β-arylketosulfones by 8. A single electron transfer from tetrahydroisoquinoline 12 to the laser-flash photolysis. The observed absorption at 460 nm excited state of eosin Y furnishes the aminyl radical cation 14 and corresponds to the reported value for the eosin Y radical cation. the radical anion of eosin Y, which then transfers an electron to oxygen present in the reaction. The superoxide radical anion may O visible light EY* O abstract a hydrogen atom from 14 to generate the iminium ion 15, 1) -SO2Ar SO2Ar which is finally trapped by a nucleophile resulting in the desired 2) H abstraction O O 17 EY 10 11 product 13. H2O2 has been found as the by product.

O Manuscript visible EY* light EY* iPr2NEt EY SO Ar N 2 Ph O 12 9 EY iPr2NEt EY

EY Scheme 6 Proposed mechanism for the photo-desulfonylation reaction. O2 O2 Nu N N N Ph Ph Ph O2 H2O2 Nu 4. Oxidation reactions 14 15 13 Scheme 8 Proposed mechanism for the photocatalytic oxidative coupling Eosin Y has been used to mediate photooxidation reactions in reaction of tetrahydroisoquinolines. the presence of stochiometric amounts of electron acceptors. The Accepted reported reactions include the oxidation of amines, thioamides, Later, Wu and coworkers reported the photocatalytic oxidative and enol ethers. Mannich reaction under aerobic condition using molecular oxygen (Scheme 9).50 Irradiation of TBA-eosin Y, L-proline, 4.1. Oxidative iminium ion formation tetrahydroisoquinoline 16, and acetone produce the synthetically The construction of C-C and C-P bonds by C-H activation is important product 17 in moderate yields. The catalyst system an emerging research area in organic synthesis.40-48 Our group consists only of organic compounds, which can be an advantage. reported an efficient visible light mediated method for the O TBA-eosin Y (2 mol%) formation of C-C and C-P bonds using eosin Y as photoredox N H L-Proline (20 mol%) N 49 R 450 nm, MeOH, O2 R catalyst in visible light (Scheme 7). Nitroalkanes, dialkyl O

phosphonates, dialkyl malonates, and malononitrile were used as 16 17 nucleophiles to trap the iminium ion leading to new bond 3 examples 51-57% formation at the α-position of tetrahydroisoquinolines. The yield ChemComm reaction does not require the addition of stoichiometric oxidants

and uses molecular oxygen from air as the terminal oxidant. N N N

O O O OCH3 Cl

51% 53% 57% Scheme 9 The photocatalytic oxidative Mannich reaction.

Wu and coworkers combined eosin Y as a photosenestizer with

graphene-supported RuO2 nanocomposites as catalyst for C-C bond formation without external oxidants. Hydrogen is generated in good to excellent yield as the only byproduct (Scheme 10).51 Eosin Y initiates the coupling reaction of the tetrahydroisoquinoline with the nucleophile via visible light

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photoredox catalysis and at the same time RuO2 is used to capture estrone. the excess electron and proton from the C-H bonds of the Na2-eosin Y (1 mol%) CBr , 11 W substrates. Irradiation of eosin Y, grapheme-RuO2, R-H 4 lamp R Br tetrahydroisoquinoline 12, and indole 18 at room temperature morpholine 22 34 24 h 23 affords the desired cross coupling product 19 in good yield. The °C, 16 examples products containing halogen atoms may serve as important 2-76% yield intermediates for further synthetic transformations. The cross O O coupling reaction occurs exclusively at the 3-position of indole 18 irrespective to the substitution on the indole moiety. Br Br Br

N 56% 74% 56% eosin G-RuO R1 R2 Y, 2 Ph H N N 2 2 Ph H2O, visible light R Br R Br R1 N 12 18 19 R

17 examples Br 31% 18-83% yield 38% 57% Scheme 12 Selective bromination of aliphatic and benzylic C-H bonds.

N N N N Ph Ph Ph Ph 4.3. Hydroxylation

NH N NH NH Xiao and coworkers reported a highly efficient method for the Cl hydroxylation of arylboronic acids to aryl alcohols using visible 68% 81% 72% 80% light photoredox catalysis under aerobic oxidative conditions Scheme 10 Oxidative coupling between tetrahydroisoquinoline and (Scheme 13).54 Typical reaction conditions used transition metal indole with dihydrogen as second product. photocatalysts, but in a single example Na2-eosin Y was Manuscript In the reactions described so far, the iminium ion and the successfully adopted. Irradiation of a mixture of 2 mol% Na2- nucleophile react intermolecularly. Recently, Xiao and coworkers eosin Y, arylboronic acid 24 (0.5 mmol), iPr2NEt (2.0 equiv) in reported the synthesis of isoquino[2,1-a]pyrimidine 21 via DMF provided the hydroxylated product 25 in 90% yield after 96 intramolecular trapping of the iminium ion with a pendant N- h. The superoxide radical anion, which is generated in the tosyl moiety using Na2-eosin Y as photoredox catalyst (Scheme photoredox cycle, reacts with arylboronic acid 24. Its Lewis 52 11). Irradiation of Na2-eosin Y, tBuOK, 4-methyl-N-(2-(7- acidity arises from the vacant boron p-orbital. A subsequent methyl-3,4-dihydroisoquinolin-2(1H)-yl)benzyl)benzene series of rearrangements and hydrolysis affords the desired aryl sulfonamide 20 in MeOH/dichloromethane affords 3-methyl-5- alcohol 25. tosyl-4b,5,12,13-tetrahydro-6H-isoquinolino[2,1-a]quinazoline Na2-eosin Y (2 mol%) OH Accepted 21 in 85% yield after 25 h. DIPEA (2 equiv) MeO B MeO OH OH DMF, air, 96 h Na2-eosin Y (0.5 mol%) visible light 36 W fluorescent light 24 25 N N 90% H MeOH/DCM (1:1), 25 h N N Ts tBuOK (2 equiv), air Ts Scheme 13 Hydroxylation of arylboronic acids via visible light catalysis 20 21 using Na2-eosin Y. 85% Scheme 11 Intramolecular trapping of a photogenerated iminium ion with 4.4. Cyclization of thioamides an N-tosyl moiety. 1,2,4-Thiadiazoles have found applications in biology and 4.2. Bromination pharmaceutical sciences. An example is the clinically used antibiotic cefozopram, which contains a 1,2,4-thiadiazole moiety. Selective bromination of C-H bonds under ambient conditions Elegant methods have been reported for synthesis of the is an important synthetic method in organic synthesis. Recently, privileged structure, but most of them require oxidizing agents. ChemComm Tan and coworkers reported a selective method for the Yadav and coworkers reported recently a metal free synthesis of bromination of aliphatic and benzylic C-H bonds with visible 53 1,2,4-thiadiazole avoiding stoichiometric oxidants and using light photoredox catalysis using eosin Y (Scheme 12). The instead visible light and molecular oxygen in the presence of reaction was performed at mild conditions using CBr4 as the eosin Y as a photoredox catalyst.55 This reaction involves the bromine source and morpholine as reducing agent. The amount of oxidative cyclization of thioamides via the sequential formation water is essential for the reaction: a higher ratio of water to of C-N and C-S bonds to afford the 1,2,4-thiadiazole in very good dichloromethane is important for the formation of the brominated yields. Irradiation of benzothioamide 26 under aerobic conditions product 23. The authors conducted experimental and com- in the presence of 2 mol% eosin Y in DMF gave the desired putational studies on the mechanism and suggest that an N- product 27 in good yield (Scheme 14). A wide range of aliphatic, morpholino radical is responsible for the C-H activation step aromatic, and heteroaromatic primary amides underwent in this during the reaction. The reaction tolerates ester, ether, and ketone reaction smoothly. functional groups. Synthetic applications of the method are the selective bromination of (+)-sclareolide and of acetate protected

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R photoreaction tolerates a wide range of functional groups S Eosin Y (2 mol%), DMF N N including nitro, bromo, and methoxy groups. Thioamides bearing R NH R 2 18 W CFL, air S electron donating groups on the aromatic ring reacted faster and rt, 4-6 h 26 27 gave higher yields in comparison to those bearing electron 14 examples withdrawing groups. The reaction was not applicable to primary 72-95% yield thioamides; which form dimers under identical reaction N MeO OMe conditions. N S N S S N Eosin Y O 2 (2 mol%) R air R2 R1 N DMF, rt, 1 87% 95% R N R3 visible light, 6-15 h R3 34 35 N N 17 N N examples 76-96% yield S N S N NO2 O O 76% 91% O N N N H Scheme 14 Photocyclization of thioamides giving 1,2,4-thiadiazoles. H H

The suggested mechanism for the formation of 1,2,4- 93% 95% 79% thiadiazole is depicted in Scheme 15. A single electron transfer from the thiolic form 28 to eosin Y* generates the radical anion O N O of eosin Y and the radical cation 29, which undergoes N N H O H deprotonation to give a sulfur radical intermediate 30. The 85% 88% 84% cyclodesulfurization of intermediate 30 furnishes 31, which gives

another sulfur radical 32 by photooxidation as described before. Scheme 16 Desulfurization of thioamides using eosin Y photocatalysis. Manuscript The intermediate radical 32 is further oxidized by anion radical of The mechanism for the desulfurization of thioamides to amides O2, which is produced in the photocatalytic cycle of eosin Y, to give peroxysulfenate 33. Finally, an intermolecular nucleophilic is shown in Scheme 17. Initial SET from 34 to eosin Y* produces - the radical anion of eosin Y and the radical cation 36. This is attack of the imino nitrogen on the SO2 substituted carbon affords 2- 56 oxidized to intermediate 37 which converts to the desired product the desired product 27 with loss of SO2 . 35 along with the formation of elemental sulfur as byproduct. The R S authors ruled out a singlet oxygen mechanism for this reaction by

NH performing several control experiments. The use of O2 (balloon) N R S SH S instead of open air did not increase the reaction yield and the

SH Accepted -H+ R NH reaction was not affected by singlet oxygen quenchers like 1,4- R 29 NH R NH 30 31 diazabicyclo[2.2.2]octane (DABCO) or 2,3 dimethyl-2-butene. EY SH S visible R2 EY EY* R1 N R NH O2 N R light S R3 34 28 S R NH EY EY* 32 O S 2 S O 1/2 O 2 2 R 2 R1 N R2 -1/8 S R EY R1 N 8 R1 N O 36 3 EY 2 N R R O 3 S S R3 R visible 1/2 O2 light SOO 37 35 R NH 1/2 O2 R NH2 33 26 Scheme 17 Suggested mechanism for the desulfurization of thioamides -SO 2- 2 into the amides. ChemComm S N R 4.6. Aldoximes and primary amides into nitriles R N An efficient method for the transformation of aldoximes and 27 Scheme 15 Proposed mechanism of the cyclization of thioamides. primary amides into nitriles has been reported by Yadav and coworkers (Scheme 18).58 The photoreaction involves the visible 4.5. Desulfurization light initiated in situ generation of the Vilsmeier Haack reagent Aerobic desulfurization of thioamides to amides has been from DMF and CBr4, which is the electrophilic reagent achieved by Yadav and coworkers under visible light photoredox responsible for the conversion of primary amides and aldoximes catalysis using eosin Y as a photocatalyst (Scheme 16).57 Green into the corresponding nitriles. A mixture of aldoxime 38 (1 light irradiation of 2 mol% eosin Y, thioamide 34 in DMF under mmol), 2 mol% eosin Y, 2 equiv of CBr4, and 20 mol% DMF air atmosphere affords the desired product 35 in very good yield. was irradiated in CH3CN for 14-18 h affording the desired Control experiments demonstrated that there was no significant product 40 in good yields. A wide range of aromatic, product formation in the absence of either light or eosin Y. The heteroaromatic, aliphatic aldoximes, and primary amides 39

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reacted smoothly under these conditions. The reaction yield was Scheme 19 Preparation of α, β-unsaturated aldehydes and ketones from higher in the presence of electron donating groups in the aryl silyl enol ethers. moiety of the oxime. The authors proposed a singlet oxygen mechanism for this

Eosin Y (2 mol%), DMF (20 mol%) transformation based on radical clock experiments and literature R CH CN, CBr N 3 4 (2 equiv) R CN reports (Scheme 20). First, singlet oxygen is generated from H OH visible light, rt, 14-18 h sensitization by Na2-eosin Y*. An ene reaction between the silyl 38 40 13 examples enol ether 41 and singlet oxygen produces the intermediate 43, 83-95% yield which is further converted in to a hydroperoxy silyl hemiacetal CN CN 44. The intermediate 44 could undergoes an intramolecular silyl

N Br transfer to afford the desired product 42 along with 85% 85% hydroperoxysilane 45, which further undergoes decomposition to

give O2 and silanol. CN CN H R HO NH2 visible light TBSO OCH3 41 92% 93% EY* R1

1 O2 O Eosin Y (2 mol%), DMF (20 mol%) EY H R CH3CN, CBr4 (2 equiv) O R CN O R NH2 TBSO visible light, rt, 14-18 h 40 39 3 1 O2 R 43 4 examples 85-95% yield CN CN TBSOH R

Me Manuscript TBS O 90% 92% 1 O O 1/2 O2 H TBSOOH 44 CN CN 45 R MeO O N 2 R1 85% 95% O Scheme 18 Conversion of aldoximes and primary amides into nitriles. 42 Scheme 20 Proposed reaction mechanism for the singlet oxygen mediated 4.7. Oxidation of silyl enol ethers oxidation of silyl enol ethers

α, β-Unsaturated carbonyl compounds are essential structural Accepted motifs for the construction of a variety of natural products. 5. Arylation reactions Elegant methods have been reported for their synthesis, but most Aryl radicals can be generated from aryl diazonium salts via of them require either metal catalysts or stoichiometric oxidants. visible light photocatalysis. The method is an efficient alternative Huang and coworkers utilized the photoredox chemistry of Na2- to reported procedures. We have used eosin Y as a photoredox eosin Y in visible light for the synthesis of α, β-unsaturated catalyst for the direct arylation of heteroarenes with aryl aldehydes and ketones from silyl enol ethers under aerobic diazonium salts in green light (Scheme 21).59 The reaction 36 oxidation conditions (Scheme 19). Polar protic solvents like tolerates a wide range of functional groups, such as nitro, ester, MeOH, EtOH as well as the polar aprotic solvent DMSO were cyano, and hydroxyl groups and has a broad scope with respect to identified as suitable for this reaction. The major side product of both aryl diazonium salts and the heteroarenes. In addition to aryl the reaction was the oxidative cleavage of the enol ether double diazonium salt 46, thienyl diazonium salts also reacts providing bond. the corresponding products in good yields. External base

R R decreased the reaction yield due to direct reaction between the ChemComm Na2-eosin Y (0.2 mol%) aryl diazonium salt and the base. This metal free reaction TBSO R1 4 °C, EtOH, O2 represents an efficient alternative to transition metal catalyzed C- R1 AcOK (1.2 equiv) O 41 42 H arylation reactions and avoids the use of copper salts required 17 examples in the classical Meerwein arylation protocol. 25-88% yield

O O O O O 78% 64% 88%

O O 25% 66% 61%

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N2BF4 (Scheme 23).60 Irradiation of a mixture of 5 mol% eosin Y, o- Eosin Y (1 mol%) R R methylthio benzenediazonium salt 54 (0.25 mmol), and alkyne 55 530 nm LED, 20°C X X DMSO (5 equiv) in DMSO afforded the desired product 56 in moderate X = O, S, NBoc 46 47 48 to good yield after 14 h using a 530 nm LED. The scope of the 23 examples reaction is wide and halogen substituted benzothiophenes are 40-86% yield available by this route. We utilized the reaction for the synthesis

O S N of the drug intermediate Raloxifene 57. CN NO NO 2 BOc 2 2 72% 70% 61% R N2BF4 Eosin Y (5 mol%) R1 R2 R3 R1 R3 MeOOC DMSO S LED 530 nm S S 54 55 14 h, 20°C S O 56 27 examples 40-81% yield 65% 60% CO2Me Me TMS Scheme 21 Direct photocatalytic C-H arylation of heteroarenes. CO2 CO2Me S S S The proposed mechanism of the photocatalytic direct C-H 60% 45% 61% arylation reaction is shown in Scheme 22. Initial reduction of the F NO2 aryl diazonium salt 46 by eosin Y* gives aryl radical 49 and the S S S S 81% 62% radical cation of eosin Y. The aryl radical 49 adds to heteroarene 64%

47 yielding radical intermediate 50, which is oxidized by the O O radical cation of eosin Y to carbenium ion 51 while regenerating N OMe OH the neutral form of the photocatalyst eosin Y. Finally, carbenium MeO S HO S 57 Raloxifene ion 51 is deprotonated to the desired product 48. The oxidation of intermediate 50 is also possible by the aryl diazonium salt 46 Scheme 23 Synthesis of substituted benzothiophenes via a photocatalytic directly via a radical chain mechanism. However, monitoring of radical annulation route. Manuscript the reaction progress after shutting off the irradiation indicates The proposed mechanism of the radical annulation is shown in that the radical chains undergo only few turnovers. The radical Scheme 24. Initially, eosin Y* is oxidatively quenched by the intermediates 49 and 50 were trapped with (2,2,6,6-tetramethyl- diazonium salt 54 to generate the reactive aryl radical 57 and the piperidin-1-yl)oxyl (TEMPO) and the corresponding adducts 52 radical cation of eosin Y. Upon addition of the aryl radical 57 to and 53 were confirmed by mass spectrometry. alkyne 55 the radical intermediate 58 is obtained, which 47 undergoes cyclization to give sulphuranyl radical 59. Subsequent X N 2 BF4 R oxidation of 59 by the cation radical of eosin Y followed by 49 transferring of the methyl group to nucleophiles present in the reaction, e.g. the solvent DMSO, yields the product 56. The Accepted

N2BF4 radical intermediate 59 may also be oxidized by the diazonium EY R salt 54 in a radical chain transfer mechanism. TEMPO adducts of R 49 X radical intermediates 57 and 58 were identified, which supports 46 50 EY* the proposed reaction mechanism.

R R2 R3 visible EY X 46 R2 R3 1 1 light 51 R 55 R S S 57 Me 58 Me R X R2 N BF EY 48 2 4 R1 1 3 TEMPO adducts R R 57 trapped ChemComm S S TEMPO 54 Me 59 Me O2N TEMPO EY* R2 O 52 NO2 R1 R3 53 visible EY 54 S light Scheme 22 Proposed mechanism for the direct photocatalytic C-H 60 Me arylation of heteroarenes. O S Substituted benzothiophenes find applications in biology, R2 pharmaceutical and material science. We applied the direct C-H OMe arylation method for the arylation of benzothiophenes, but R1 R3 S S unfortunately a mixture of regioisomers was obtained in low 56 yields. To obtain a single regioisomer, we decided to explore a Scheme 24 Proposed mechanism of the photocatalytic radical annulation radical annulation for the synthesis of the benzothiophene moiety synthesis of benzothiophenes.

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A visible light induced [4+2] benzannulation method for the utilized eosin Y for the borylation of aryl diazonium salts synthesis of phenanthrenes was reported by Zhou et al. using (Scheme 27).62 Acetonitrile was found to be a suitable solvent to eosin Y as photocatalyst under mild conditions (Scheme 25).61 promote the reaction in good yields. Irradiation of a mixture of 5

Eosin Y (1 mol%), biphenyldiazonium salt 61 (0.2 mmol), and an mol% eosin Y, B2Pin2 67 (0.3 mmol), and aryl diazonium salt 46 alkyne (3 equiv) were dissolved in CH3CN and irradiated with a (1.5 equiv) in acetonitrile at room temperature affords the desired 24 W fluorescent bulb at room temperature giving the product 68 in good yields. Aryl diazonium salts bearing electron corresponding product 62 in very good yield. The reaction withdrawing groups showed higher reactivity than those bearing proceeds smoothly in polar solvents. In non-polar solvents the electron donating groups. The photoreaction tolerates a range of solubility of the diazonium salt 61 is poor. Additions of bases, functional groups including acetyl, nitro, alkyl, halo, and alkoxy such as tBuOLi or NEt3 decrease the yield due to the direct groups. Heteroaromatic diazonium salts are not suitable reaction of the diazonium salt 61 and the base. The photoreaction substrates for this reaction. tolerates many functional groups and has a broad scope of Eosin Y (5 mol%) alkynes and biphenyldiazonium salts. N2BF4 B2pin2 Bpin MeCN, rt R 25 W R 1 lamp R 46 67 68 N BF 2 2 4 R 13 examples R Eosin Y (1 mol%) R 60-80% yield 1 2 R R R R F CH3CN, rt 61 530 nm 62 MeO Bpin Cl Bpin Bpin 28 examples 25-81% yield 76% 80% 66% Cl CO2Me CO2Me

O2N Bpin Bpin Bpin

S Cl

80% 60% 80% Manuscript

60% 25% 49% Scheme 27 Borylation of aryl diazonium salts. Scheme 25 Photocatalytic synthesis of phenanthrenes via a [4+2] benzannulation method. The proposed mechanism for the borylation of aryl diazonium salts is depicted in Scheme 28. Initially, a SET from eosin Y* to The proposed reaction mechanism of the [4+2] photo- the aryl diazonium salt 46 gives the aryl radical 49 and the radical benzannulation is similar to the other diazonium salt reactions cation of eosin Y. Addition of the aryl radical 49 to the tetra- (Scheme 26). Initial SET from eosin Y* to biphenyl diazonium coordinated complex 69, which was generated in situ from the salt 61 generates the radical cation of eosin Y and biphenyl - interaction between B2Pin2 and the counter anion BF4 , affords radical 63, which upon addition to alkyne 55 furnishes vinyl the target borylated product 68 and the radical anion intermediate radical 64. Subsequent intramolecular radical cyclization affords Accepted 70. Finally, intermediate 70 was oxidized by the radical cation of the cyclized radical intermediate 65. Oxidation of 65 by the eosin Y to complete the catalytic cycle. eosin Y radical cation closes the catalytic cycle and produces the carbenium intermediate 66. Finally, cation 66 is deprotonated to B2Pin2 represented as B B BF4 afford the desired phenanthrene 62. 67

N BF R 2 4 F3B F B B R SET R 69 R1 R2 R B EY* EY 63 55 61 49 68 R1 R1 reen li ht g g R2 R2 N BF EY R R 2 4 EY F3B F B R 1 R 70 R 2 65 64 ChemComm R 46 EY*

- F3B F B HBF4 visible EY 71 light R1 R2 Scheme 28 A plausible mechanism for the borylation of aryl diazonium R salts.

Arylsulfides are important structural motifs in synthetic and 62 natural molecules and they are usually prepared by treatment of

Scheme 26 Proposed mechanism for the synthesis of phenanthrenes. aryl diazonium salts with thiols under basic or neutral conditions. The intermediate diazosulfide, which is formed during the Photoredox catalysis with eosin Y has been discussed so far, reaction, is a potent explosive. The recently reported method by for the formation of C-C and C-P bonds. Recently, the Yan group Jacobi and coworkers avoids the risk by utilizing eosin Y as a

photoredox catalyst for the synthesis of arylsulfide 73 from aryl with electron deficient alkyl halides to provide the corresponding diazonium salt 46 and disulfide 72 under green light irradiation products in good yields with high enantiomeric excess (Scheme (Scheme 29).63 DMSO was found to be a very good solvent for 31). Eosin Y catalyzed reactions require a little longer reaction this reaction. Without eosin Y and without irradiation no product times compared to the ruthenium-trisbipyridine catalyzed formation is observed, but irradiating the reaction mixture MacMillan reaction,64 but did not give any product racemization. without eosin Y gave very low product yields. The observation is The photoreaction allows the stereospecific incorporation of explained by a charge transfer complex between DMSO and the fluorinated alkyl moieties, which are important structural units in aryl diazonium salt, which absorbs in the visible range. In drug to modulate their properties.

addition, the authors also prepared unsymmetrical diarylselenides O N HOTf from aryl diazonium salts and diphenyldiselenide. 20 mol% tBu N 1 H O N2BF4 SR O 0.5 mol% Eosin Y Eosin Y (2 mol%) R 1 1 X R H R SSR H ( )5 R R 2 equiv of lutidine ( )5 green LED, 18 °C X = Br, I DMF,18 h DMSO, 6 h nm 46 72 73 76 77 530 LED 78 4 18 examples examples 31-89% 56-85% yield yield 86-96% ee SMe SMe SMe O CO2Et O O CO2Et Me F3C O2N (CF2)3CF3 H CO2Et H H CO2Et ( )5 ( )5 Ph 80% 68% 48% 85% 56% 76% 88% ee 96% ee 86% ee

SMe SMe SMe NO O 2

H Cl ( )5 O Br Manuscript 82% 73% 89% 31% 95% ee

Scheme 29 Synthesis of arylsulfides from diazonium salts and disulfides. Scheme 31 Asymmetric α-alkylation of aldehydes.

The suggested mechanism for the photocatalytic thiolation Following mainly the mechanism proposed by Mac Millan and 64 reaction is shown in Scheme 30. A SET reduction of aryl coworkers, the authors suggested a mechanism for the eosin Y diazonium salt 46 by eosin Y* generates aryl radical 49 and the reaction, which is shown in Scheme 32. Initially, a catalytic radical cation of eosin Y. The nucleophilic disulfide 72 attacks amount of enamine is oxidized by eosin Y* to generate the the aryl radical giving a trivalent sulfur radical 74, which is radical anion of eosin Y that reduces the halide 79 to give the electron deficient radical species 80. Addition of radical 80 to the

stabilized by the adjacent aryl and sulfur groups. Oxidation of the Accepted intermediate 74 by the radical cation of eosin Y furnishes an enamine 81 furnishes α-amino radical 82. Subsequent oxidation electrophilic species 75 and completes the photocatalytic cycle. of the amino radical 82 to the iminium ion 83 provides the Finally, the cation intermediate 75 undergoes substitution with electron for the reductive quenching of eosin Y*. Finally, DMSO to give the desired product 73. iminium ion 83 undergoes hydrolysis to afford the desired alkylated product 84. visible N2BF4 EY* light O R R1 46 80 EY N visible light BF4 1 1 1 N SR R S R EY* H S 1 R R R EY H 81 BF4 R O DMSO R O RS SMe2 R 49 photoredox 82 EY catalytic cycle 73 R1S R1 75 S ChemComm O Organo R1SSR1 catalytic cycle N 72 R1 R EY 80 N H 74 O R1 R H 1 R R O 83 Scheme 30 Suggested reaction mechanism for the photocatalytic 79 Br N thiolation reaction. H O OHC R R1 6. Cooperative catalysis H R O A dual catalytic combination of photocatalysis with 84 organocatalysis was reported by Zeitler and coworkers for the Scheme 32 Mechanism for the asymmetric alkylation of aldehydes. enantioselective α-alkylation of aldehydes.35 Eosin Y and Another dual catalytic mode of hydrogen bond promoted imidazolidinone were found to be capable of alkylating aldehydes organophotoredox catalysis was applied for highly diastereo-

65 EtO C CO Et selctive reductive enone cyclization by Zeitler et al. These visible 2 2 S light EY* reactions proceed smoothly at ambient temperature using Na2- Ar Ar N H α,α,α ,α N N eosin Y as a photocatalyst and thiourea or ’ ’-tetraphenyl- H H 90 1,3-di-oxolan-4,5-dimethanol (TADDOL) as organocatalysts EY EtO C CO Et (Scheme 33). The combination of Hantzsch ester and O O 2 2 diisopropylethyl amine (DIPEA) was found to be a very good Ph R EY N H reductive quencher as well as hydrogen donor. Aryl bisenones 91 S 87 bearing electron donating and electron withdrawing substituents S Ar Ar N N Ar Ar undergo reductive enone cyclization to give the desired trans- N N H H cyclopentanes in good yields. However, aliphatic enones are not H H converted in this reaction due to their more negative potential O O O compared to the eosin Y radical anion. In addition, heterocycles Ph and cyclohexanes were also obtained in good yields, while Ph R O cycloheptanes were not accessible. R 88 89 O O O O thiourea (20 mol%) EtO C CO Et 2 2 O R R1 Eosin Y (2.5 mol%) O R R1 X Hantzsch ester (1.1 equiv) n 91 N n X Ph Ph DIPEA (1 equiv) X = CH2, O 86 hv, CH Cl n = 0, 1, 2 2 2 15 examples 86 72-96% 85 yield Scheme 34 Suggested mechanism for the reductive enone cyclization. O O O O O O

Ph Ph Me Me Ph Ph 7. Trifluoromethylation O α-Trifluoromethylation of ketones has been reported by Kappe 92% 93% 95% Manuscript O and coworkers using a continuous flow visible light photoredox O O O O O catalysis with eosin Y (Scheme 35).24 The reaction proceeds in Ph Ph PMP Me Ph Ph two steps: in the first step the ketones are converted into their respective silyl enol ethers by reaction with trimethylsilyl 87% 91% 0% trifluoromethanesulfonat (TMSOTf) and DIPEA. The in situ Scheme 33 Reductive enone cyclization using eosin Y. formed silyl enol ethers are then converted in a visible light mediated trifluoromethylation process. The two step procedure is The proposed mechanism of the reaction starts with the 66 faster compared to reported reactions. Several ketones including reductive quenching of Na -eosin Y* by either the Hantzsch ester 2 acetophenones, heteroaromatic ketones, and aliphatic ketones

90 or DIPEA to generate the radical anion of Na -eosin Y and 91 Accepted 2 were successfully trifluoromethylated. (Scheme 34). Subsequent reduction of 87 by the radical anion of TMSOTf (1.5 equiv) Na2-eosin Y closes the photocatalytic cycle and yields the 1,4- O O DIPEA 1.5 e uiv distonic radical anion 88, which undergoes a 5-exo-trig R1 ( q ) R1 R CF3SO2Cl R Eosin Y (0.5 mol%) cyclization to give α-carbonyl radical 89. The radical abstracts a CF3 visible light hydrogen atom from the radical cation 91 followed by a proton 92 93 94 11 examples transfer to give the final product 92 and a pyridine derivative. An 56-86% yield alternative mechanism is the oxidation of radical 89 followed by O O O CF hydride transfer to give compound 92. CF3 CF3 3

86% 87% 65%

O O O CF CF3 CF 3

3 ChemComm N S

56% 63 72% % Scheme 35 α-Trifluoromethylation of ketones.

8. Conclusions Visible light photoredox catalysis with metal complexes, such 2+ as Ru(bipy)3 or Ir(ppy)3, has already received a lot of attention as tool for organic synthetic transformations. For several applications eosin Y serves as an attractive alternative to redox active metal complexes and even outperform them in some cases.24 Eosin Y photocatalysis has been applied to generate

reactive intermediates including electrophilic α-carbonyl radicals, 28. E. Brennecke, N. H. Furman, H. Stamm, R. Lang, K. Fajans, C. W. aryl radicals, iminium ions, trifluoromethyl radicals, and enone Böttger and R. E. Oesper, Newer Methods of Volumetric Chemical Analysis, D. Van Nostrand Company, Incorporated, 1938. radical anions, which are utilized in arene C-H functionalization, 29. A. Salvador and A. Chisvert, Analysis of Cosmetic Products, Elsevier [2+2] cyclo addition, amine α-functionalization, hydroxylation, Science, 2011. reduction, and oxidation reactions. 30. R. W. Sabnis, Handbook of Biological Dyes and Stains: Synthesis In addition, eosin Y catalysis has been merged with other and Industrial Applications, Wiley, 2010. modes of catalysis, such as enamine catalysis and hydrogen bond 31. A. Penzkofer, A. Beidoun and M. Daiber, J. Lumin., 1992, 51, 297- 314. promoted catalysis to achieve enantioselective reactions. The use 32. A. Penzkofer, A. Beidoun and S. Speiser, Chem. Phys., 1993, 170, of eosin Y photocatalysis in continuous flow technology has been 139-148. described.24, 67 Overall, the good availability, strong absorption in 33. A. Penzkofer and A. Beidoun, Chem. Phys., 1993, 177, 203-216. the visible part of the spectrum and suitable redox potential 34. T. Lazarides, T. McCormick, P. Du, G. Luo, B. Lindley and R. values for a variety of organic transformations make eosin Y an Eisenberg, J. Am. Chem. Soc., 2009, 131, 9192-9194. 35. M. Neumann, S. Füldner, B. König and K. Zeitler, Angew. Chem., appealing and green photocatalyst for organic synthesis. Int. Ed., 2011, 50, 951-954. 36. J. Zhang, L. Wang, Q. Liu, Z. Yang and Y. Huang, Chem. Commun., Acknowledgements 2013, 49, 11662-11664. 37. D. M. Hedstrand, W. H. Kruizinga and R. M. Kellogg, Tetrahedron We thank the GRK 1626 (Chemical Photocatalysis) of the Lett., 1978, 19, 1255-1258. German Science Foundation (DFG) for financial support. 38. X.-J. Yang, B. Chen, L.-Q. Zheng, L.-Z. Wu and C.-H. Tung, Green Chem., 2014, 16, 1082. 39. D.-T. Yang, Q.-Y. Meng, J.-J. Zhong, M. Xiang, Q. Liu and L.-Z. Notes and references Wu, Eur. J. Org. Chem., 2013, 2013, 7528-7532. 40. M. Rueping, C. Vila, R. M. Koenigs, K. Poscharny and D. C. Fabry, 1. M. Reckenthäler and A. G. Griesbeck, Adv. Synth. Catal., 2013, 355, Chem. Commun., 2011, 47, 2360-2362. 2727-2744. 41. M. Rueping, S. Zhu and R. M. Koenigs, Chem. Commun., 2011, 47, 2. D. P. Hari and B. Konig, Angew. Chem., Int. Ed., 2013, 52, 4734- 8679-8681. 4743.

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Manuscript Accepted ChemComm