photoredox catalysis by [ru(bpy) to trigger

PHOTOREDOX CATALYSIS BY [Ru(bpy)3]2+ TO TRIGGERTRANSFORMATIONS OF ORGANIC MOLECULES. ORGANICSYNTHESIS USING VISIBLE-LIGHT PHOTOCATALYSIS AND ITS20th CENTURY ROOTS

Filip TEPLÝ

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i.,Flemingovo nám. 2, 166 10 Prague 6, Czech Republic; e-mail: [email protected]

Received April 17, 2011Accepted June 10, 2011

Published online June 29, 2011

Dedicated to Professor Pavel Kočovský on the occasion of his 60th birthday.

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8602. Photoredox Manifold of [Ru(bpy)3]2+ . . . . . . . . . . . . . . . . . . . . . 8603. Early Examples from the 1970s to 1990s . . . . . . . . . . . . . . . . . . . . 8624. Photoredox Catalysis in the First Decade of the 21st Century . . . . . . . . . . . 8805. Photoredox Chemistry as a Tool for Making and Breaking Bonds in

Chemical Biology and Materials Chemistry. . . . . . . . . . . . . . . . . . . 9055.1. Chemical Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9055.2. Materials Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . 907

6. Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . 9117. Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9128. References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913

Reactions triggered by light constitute a treasure trove of unique synthetic methods that areavailable to chemists. Photoinduced redox processes using visible light in conjunction withsensitizing dyes offer a great variety of catalytic transformations useful in the realm of or-ganic synthesis. The recent literature amply shows that this preparative toolbox is expand-ing substantially. This review discusses historical and contemporary work in the area ofphotoredox catalysis with [Ru(bpy)3]2+. Elegant examples from the most recent literaturedocument the importance of this fast developing area of research. The photoredox chemis-try has also emerged as a promising bond-making and bond-breaking tool for chemicalbiology and materials chemistry. A review with 96 references.Keywords: Ruthenium complexes; Catalysis with dyes; Photocatalysis; Photoredox catalysis;[Ru(bpy)3]2+; Visible light; Organic synthesis; Chemical biology; Materials chemistry; Syn-thetic methods.

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 7, pp. 859–917

Photoredox Catalysis 859

© 2011 Institute of Organic Chemistry and Biochemistrydoi:10.1135/cccc2011078

1. INTRODUCTION

Transformations induced by light have been attracting attention of chem-ists since the early 20th century1–3. Among various photochemical reac-tions, photoredox catalysis using combination of [Ru(bpy)3]2+ catalyst andvisible light has been considered as a tool for preparative organic chemistrysince the 1970s. However, only a few research groups dealt with this topicuntil the beginning of the 21st century. Remarkably, since 2008, the impor-tance of this bond-forming strategy for organic synthesis has been dramati-cally highlighted due to the seminal studies by MacMillan, Yoon, andStephenson groups4–7. With this rejuvenated interest in organic transforma-tions triggered by metal-based dyes, and very recently also purely organicdyes8, as photoredox catalysts, it is interesting to look for the 20th centuryroots of this branch of research. In this review we will focus on the pioneer-ing examples from the 20th century as well as elegant examples from themost recent literature to document the significance of this fast developingarea of research. Throughout the review the emphasis will be placed mainlyon [Ru(bpy)3]2+ (Fig. 1) and the transformations where this complex hasbeen used as a photoredox catalyst.

2. PHOTOREDOX MANIFOLD OF [Ru(bpy)3]2+

Salts of [Ru(bpy)3]2+ (1, bpy = 2,2′-bipyridine) were first reported by Burstallin 1936 (Fig. 1)9. Notably, Burstall also achieved resolution of the two enan-tiomers of 1 via diastereomeric tartrate salts9. At that time, it was shownthat [Ru(bpy)3]2+ was not only chemically robust, but also remarkably con-figurationally stable species10. Whereas chirality of this C3-symmetric com-plex cation has been recognized at the time of its first synthesis, its uniquephotochemical and electrochemical properties have attracted attentionwith a more than 30-year delay11,12. However, then the reseach focused onphotoredox manifold of [Ru(bpy)3]2+ and its applications has experienced amassive expansion and especially the conversion of solar radiation intoother forms of energy has been studied vigorously. In particular, conversionof solar energy into electrical current13 and into chemical energy of fuels byphotoreduction of small molecules, such as water and CO2, have receivedfocused attention due to the practical implications of harnessing solar en-ergy to meet the global energy needs14. Besides this, even in the beginningof the 21st century, [Ru(bpy)3]2+ and its rich spectrum of useful propertiescontinues to inspire important conceptual advances in other areas, as re-cently discussed by Balzani et al. in the context of a novel molecular en-coder–decoder for sensing, labeling, or molecular computing15.


860 Teplý:

Visible light matches well a broad absorption band of [Ru(bpy)3]2+ com-plex (λmax = 452 nm) leading to efficient excitation that gives the lowestsinglet excited state (1Ru2+* in Scheme 1). This initially generated singletstate (1MLCT state, MLCT = metal-to-ligand charge transfer) then undergoesintersystem crossing yielding a long-lived luminescent triplet excited state[Ru(bpy)3]2+* (3MLCT, 3Ru2+* in Scheme 1). The triplet excited state is gen-



N

N

N

NN

NRu

2+

N

N

N

NN

NRu

2+

enantiomer enantiomer

mirror

∆ Λ

FIG. 1Structure of [Ru(bpy)3]2+ (1) and its chirality

Oxidative and reductive quenching photoredox cycles of [Ru(bpy)3]2+

-0.83 V

+1.29 VRu2+

2.12 eV

3Ru2+*

hν

1Ru2+*

ηisc = 1

φ = 0.04hν

+0.84 V

-1.33 V

452 nmλmax

oxidative quenching reductive quenching

oxidative quenchers:Ar-N2

+

Ar-NO2viologens[Co(acac)3][Co(C2O4)3]3-

Fe3+

[Cr(bpy)3]3+

-O3S-O-O-SO3-

Ar2I+

ArSO2-SeArCBr4CHI3

reductive quenchers:Et3NPh3NEDTAiPr2NEtEu2+

-O2C-CO2-

xanthateascorbateRu+

strongreductant

Ru3+

strongoxidant

SCHEME 1Photoredox manifold of [Ru(bpy)3]2+ and representative oxidative and reductive quenchers

erated with highest quantum efficiency and is long-lived (~600 ns). Thishigh energy species can serve either as a single-electron oxidant orreductant depending on other chemical species present. If reductivequenching of the [Ru(bpy)3]2+* takes place, strongly reducing species[Ru(bpy)3]+ is produced (–1.33 V vs SCE in CH3CN), whereas oxidativequenching pathway generates [Ru(bpy)3]3+ that is a strong oxidant (+1.29 Vvs SCE in CH3CN). Depending on the choice of suitable reductive or oxida-tive quencher, the [Ru(bpy)3]2+ catalyst can be used to trigger photo-reduction and photooxidation, respectively (Scheme 1). As the recentliterature shows, this photoredox manifold offers unique opportunities howvisible light can be channeled to trigger formation of chemical bonds thatare of interest for preparative organic chemistry4.

3. EARLY EXAMPLES FROM THE 1970s TO 1990s

In 1978, Kellogg’s group reported reduction of phenacylsulphonium salts(e.g. 2) by 1,4-dihydropyridine 3 (2 + 3 → 4, Scheme 2). The reaction wasfound to be induced by irradiation with visible light and greatly acceleratedin the presence of [Ru(bpy)3]2+ and other dyes, such as TPP (meso-tetraphenylporphine), or eosin disodium salt16. Importantly, the roles oflight and dyes were carefully tested. Thus, a control reaction performed inthe dark in an absence of sensitizing dye did not lead to any conversion atroom temperature even after 72 h. However, the reaction reached completeconversion upon exposure of the same reaction mixture to incident roomlight for 48 h (neon fluorescent lamps at ca. 2 m distance). Addition of


862 Teplý:

2

O

S+Ph

O

N+

O

BF4

O

N

CO2EtEtO2C

25°C, room light

[Ru(bpy)3]Cl2 1 mol%S

PhN

CO2EtEtO2C

BF4

PPh3

D6-acetone or CD3CN

0.3 h

ClO4

BF4

quant.

5 60% 16%

X

O2N O2N

O

Me3N PPh3

O

6

7a X=Cl

3

7b Br

KELLOGG, 1978 & 1979

4

SCHEME 2Dye-accelerated photoreduction of phenacyl sulfonium salt 2 and related substrates (refs16,17)

1 mole % of [Ru(bpy)3]Cl2, TPP, or eosin disodium salt led to acceleration ofthe irradiated reactions resulting in complete conversions within signifi-cantly shorter reaction times of 0.3, 1 and 3 h, for the three dyes, respec-tively. The authors suggested that light-induced single-electron transfersteps are responsible for the observed sulfonium salt reduction and pro-posed that the large acceleration effect of [Ru(bpy)3]Cl2 might be due to theinvolvement of this photoredox catalyst in the single-electron transfers(SET)16. Later on, results of a more detailed mechanistic study were dis-closed17. Although the authors did not arrive at a definitive conclusionabout the exact role of [Ru(bpy)3]2+ in this process, an impressively insight-ful discussion of the gathered body of evidence was presented17.

Reductions of other substrates such as ammonium, phosphonium salts,and 4-nitrobenzyl halides have been also achieved (5, 6, 7a and 7b, respec-tively, Scheme 2)16,17. In 1985, the same group described reductions ofphenacylbromide, bromomalonates, and related substrates (Scheme 3) us-ing 3-methyl-2,3-dihydrobenzothiazoles using [Ru(bpy)3]Cl2 or rose bengalas photocatalysts18. All these examples provided important early evidencethat various dyes can function as remarkable accelerators of some light-induced reductions.



Br CN

O

Br

Br CN

CN

Br CO2Et Br CO2Et

CO2Et

O

Cl

O

S+PhBF4

O

20°C, 1.3 h

[Ru(bpy)3]Cl2 5 mol% Br

>95%

S N

H

S N+

fluorescent lampsCD3CN

SBrO O

40 h, >95% 0.7 h, >95% 70 h, 75-85% 1 h, quant.

60 h, 50% 90 h, >95%40 h, 90%

KELLOGG, 1985

SCHEME 3Dye-enhanced photoreductions at saturated carbon atoms using 3-methyl-2,3-dihydro-benzothiazole reductant (ref.18)

Another type of transformations photosensitized by [Ru(bpy)3]2+ havebeen independently discovered by the group of Pac (Scheme 4)19,20. In theirwork, Pac et al. studied reactions of various olefins with 1-benzyl-1,4-di-hydronicotinamide (BNAH) as an NADH model. The outcome of these pro-cesses were shown to be substrate specific. For example, dimethyl maleate 8afforded mainly dimethyl succinate (9), whereas olefin 11 led to a product12 containing dihydropyridine moiety.

To account for the observed results, the authors provided a mechanisticrationale depicted in Scheme 5. Ruthenium catalyst was proposed to partic-ipate in this transformation via reductive quenching cycle. To this end, thephotocatalyst excited state [Ru(bpy)3]2+* is reductively quenched by BNAHto form in situ [Ru(bpy)3]+ and BNAH•+. The latter species can subsequentlylose proton leading to BNA• that will result in production of the dimer 10.Strongly reducing [Ru(bpy)3]+ was proposed to transfer its electron onto theolefin substrate to generate the radical anion 13 that is then protonated togive radical intermediate 14. The resultant radical 14 can be either reducedto the product 15 or can alternatively lead to the structure 16 containingdihydropyridine moiety. Whether radical 14 undergoes electron transfer re-sulting in structure 15 or leads to radical-coupling giving dihydropyridineproduct 16, depends on steric and electronic properties of 14 that shouldbe affected by the substituents at the radical center.

In a related work, Pac and coworkers disclosed reactivity of aromatic car-bonyl compounds with BNAH under similar conditions (Scheme 6)21,22.The reaction course was found to be governed by the structural parameters


864 Teplý:

8 2 h

[Ru(bpy)3]Cl2 2 mol%

96%

pyridine-CH3OHN

Ph

CO2NH2

BNAH

N

NPhCO2NH2

H2NO2CPh

35% yield (based on BNAH)

910

10:1

MeO2C CO2Me

2 eqMeO2C

CO2Me

11


38%

CH3OHN

Ph

CO2NH2

BNAH

N

NPhCO2NH2

H2NO2CPh

9% yield (based on BNAH)

1210

2 eqON

Ph

CO2NH2

PhCOCH3

3-5 h

hν

hνPAC, 1981 & 1984

SCHEME 4[Ru(bpy)3]2+-catalyzed photoreduction of olefins with l-benzyl-1,4-dihydronicotinamide(refs19,20)

of the used carbonyl compound. Thus, di-2-pyridylketone (17) led to thealcohol 18 together with a dimeric dihydronicotinamide structure 10,whereas benzaldehyde was converted to a secondary alcohol 19 in high



N

Ph

CO2NH2

BNAH

hν

[Ru(bpy)3]2+*

[Ru(bpy)3]2+

[Ru(bpy)3]+

BNAHBNA

H+

BNA

N

Ph

CO2NH2

R1

R1

H+

R1

+H+

R2

R2

R2

BNA

H

14

13

PAC, 1981 & 1984

reductive quenching

N NPh

H2NO2C

CO2NH2

Ph10

N

Ph

CO2NH2

R1R2

16

R1

R2

HH

15

SCHEME 5Mechanistic picture proposed for the transformations of olefins in Scheme 4 (refs19,20)

17

OH

N

2 h

[Ru(bpy)3]Cl2 0.5 mol%

95% yield

CH3OHN

Ph

CO2NH2

BNAH

N

(at 79% conversion)

N

NPhCO2NH2

H2NO2CPh

10% yield

H

O

15 h


85% yield

CH3OHN

Ph

CO2NH2

BNAH(at 85% conversion)

N

Ph

CO2NH2

OHPh

O

N N

1810

19

hν

hν

PAC, 1983 & 1987

SCHEME 6[Ru(bpy)3]2+-photosensitized reactions of carbonyl compounds with an NADH model (refs21,22)

yield. It was reasoned that the exclusive formation of alcohol 18 fromdi-2-pyridylketone (17) is governed by the two pyridyl groups that have adual role. Because of electron-withdrawing nature of these groups, the oneelectron reduction of the radical HO–C•(2-py)2 is favored (see single-electron transfer to 20 leading to 21 in Scheme 7). In addition to that, radi-cal coupling of the species 20 (leading to possible product 22) is inhibitedbecause of steric hindrance around the radical center in HO–C•(2-py)2.

Photoinduced electron transfer has been extensively studied because ofsolar energy conversion and storage12–14. In this context, the photoinducedproduction of 4,4′-bipyridinium radical cations from the correspondingdications (viologens) with visible light is very well-known. Usually,[Ru(bpy)3]2+ or zinc porphyrins are used as sensitizers and triethanolamine,ethylenediaminetetraacetic acid (EDTA), or cysteine are introduced as elec-tron donors. Inspired by this, Willner group studied several photochemicaltransformations involving photogenerated reductant [Ru(bpy)3]2+* 23–25.Based on their research of viologen/Na2S2O4 reduction system in ethylacetate–water, they described a photocatalytic version of their debromina-


866 Teplý:

N

Ph

CO2NH2

BNAH

hν

[Ru(bpy)3]2+*

[Ru(bpy)3]2+

[Ru(bpy)3]+

BNAHBNA

H+

BNA

N

Ph

CO2NH2

OAr

R

OAr

R

H+

OHAr

R

BNA

+H+20

PAC, 1983 & 1987

reductive quenching

N NPh

H2NO2C

CO2NH2

Ph

N

Ph

CO2NH2

Ar OHR

22

OHAr

R

H

21

SCHEME 7Mechanistic picture proposed for transformations of carbonyl compounds in Scheme 6(refs21,22)

tion of meso-1,2-dibromostilbene (23) triggered by light/[Ru(bpy)3]2+ anddi(n-octyl) viologen (C8V2+, Scheme 8)23,24. Disproportionation of viologenradical cation C8V•+ in ethyl acetate/water biphasic system generatesneutral species C8V0 that is believed to be the key reducing agent in the re-ported debrominations. Interesting enzyme-catalyzed variant of this bi-phasic photodebromination reaction involves ethanol/alcohol dehydrogenase/NADH reduction system26. In this process, enzymatically generated NADH

serves instead of EDTA or other amines to reduce [Ru(bpy)3]3+ to[Ru(bpy)3]2+ 27. Importantly, these reports from Willner group providedearly examples showing that oxidative quenching cycle of [Ru(bpy)3]2+* byusing strong oxidants (e.g. viologens) can be taken advantage of in trans-formations interesting to organic synthesis. Later on, photocatalysis inthe debromination reactions has been also described to proceed with[Ru(bpy)3]Cl2/Et3N in acetonitrile solvent in absence of viologen catalyst(e.g. 24 → 25, Scheme 9)28. Under similar conditions, successful reduction



meso

23

3 h


70%

(NH4)3EDTA

EtOAc-H2O

hν

BrH

Br

H

viologen (C8V)Br2 7 mol%

N+ N+n-C8H17 n-C8H17

hν

[Ru(bpy)3]3+

[Ru(bpy)3]2+* [Ru(bpy)3]2+

H2O

CH3CO2Et

(NH4)3EDTA

oxidationproducts

C8V2+

C8V2+ =

C8V C8V C8V2+ C8V0

WILLNER, 1983 & 1984

oxidative quenching

SCHEME 8Photosensitized debromination of meso-1,2-dibromostilbene in a two-phase system (refs23,24)

of activated ketones has been demonstrated (Scheme 10). In this way, ethylbenzoylformate (26) is reduced to ethyl mandelate (27) and benzil (28) tobenzoin (29).

In 1986, Tomioka group reported examples of reduction of nitroalkenesto oximes using photoredox catalysis with [Ru(bpy)3]2+/viologen/Na2EDTAsystem in biphasic medium (Scheme 11)29. The corresponding ketones werealso isolated in small quantities. Viologen species serves as an electron-phase transfer catalyst shuttling electrons between the aqueous and organicphase and, in this respect, the roles of the ruthenium photocatalyst,Na2EDTA and viologen are similar to those in the debromination reactionmechanism depicted in Scheme 8. In this case, the authors stated that thereducing species that directly transfers its electrons to the nitroalkene sub-


868 Teplý:

24 25


Et3NCH3CN

hν

5 min

>80%

CO2Et

Br

Br

CO2Et

WILLNER, 1990

SCHEME 9Photocatalyzed debromination of ethyl dibromocinnamate (ref.28)

262 h


>80%

Et3N

O

O

CH3CN

hνO

27

OH

O

O

28

O

O

29

OH

O


Et3NCH3CN

hν

3 h

>80%

WILLNER, 1990

SCHEME 10Photocatalyzed reduction of activated ketones triggered by [Ru(bpy)3]2+/Et3N system (ref.28)

strate is either the viologen radical cation C8V•+, or the neutral species C8V0

generated by the disproportionation mechanism.

In 1984, Cano-Yelo and Deronzier described photocatalytic Pschorr reac-tion converting aryldiazonium salts 33 to phenanthrene derivatives 34 inpresence of [Ru(bpy)3]2+ photoredox catalyst (Scheme 12)30. The authors



30

3 h


78%

Na2EDTA

EtOAc-H2O

hν

viologen (C8V)Br2 10 mol%

N+ N+n-C8H17 n-C8H17

NO2 NOH

5%

O

31 32

> 400 nmλTOMIOKA, 1986

C8V2+ =

SCHEME 11Photochemical reduction of nitroalkenes using viologen as an electron-phase transfer catalyst(ref.29)

[Ru(bpy)3](BF4)2 5 mol%

MeCN

hν

quantitative

> 410 nmλ

R

CO2H

33R

CO2H

N2+

R=H, Br, or OMeBF4-

R

CO2H

+ N2

R

CO2H

hν

H

[Ru(bpy)3]3+

[Ru(bpy)3]2+* [Ru(bpy)3]2+H+

34

35

36

DERONZIER, 1984

oxidative quenching

SCHEME 12Pschorr reaction via visible-light photoredox catalysis with [Ru(bpy)3]2+ (ref.30)

proposed mechanism involving oxidative quenching of photoexcited[Ru(bpy)3]2+* with aryldiazonium salt leading to aryl radical species 35 and[Ru(bpy)3]3+ which is a strong oxidant31. Radical cyclization of 35 gives in-termediate 36. In the next step, the radical intermediate 36 is oxidized by[Ru(bpy)3]3+ and subsequently restores aromaticity upon loss of proton af-fording phenanthrene skeletons 34.

Importantly, when the aryldiazonium salts 33 are subjected to directphotolysis in absence of a photoredox catalyst, the phenanthrene prod-ucts 34 become minor component of the reaction mixture (10–20%,Scheme 13). The major products are acetanilides 37 isolated in 80% yields.They result from interaction of a photogenerated aryl cation 38 with aceto-nitrile and subsequent hydrolysis of the intermediate 39 (Scheme 13).

The oxidative quenching cycle of Ru-photocatalyst was also used fortransformation of carbinols (e.g. 40, Scheme 14) to aldehydes with aryl-diazonium salts as oxidants32,33. Besides the aldehyde 41, this process re-sults in benzophenone 42 and fluorenone 43, which is a product of the


870 Teplý:

MeCN

hν

10-20%

> 360 nmλ

R

CO2H

33

R

CO2H

R=H, Br, or OMe

BF4-

R

CO2HNH

O

80%

R

CO2H

+ N2

N2+

MeCN

R

CO2HN+

H2O

hν

37

0°C

direct photolysis

34

38

39

DERONZIER, 1984

SCHEME 13Direct photolysis of aryldiazonium salts 33 in absence of a photoredox catalyst and the path-way leading to major acetanilide products 37 via aryl cations 38 (ref.30)

Pschorr cyclization pathway similar to that outlined in Scheme 12. Oxida-tion of other primary32 and secondary33 alcohol substrates was investigatedin the presence of various bases and the results were compared with electro-chemical variant of this reaction (electrochemical redox catalysis)33.

In 1984, Tanaka group reported a reaction of benzyl bromide (44) with1-benzyl-1,4-dihydronicotinamide (BNAH) photosensitized by [Ru(bpy)3]2+

resulting in 1,2-diphenylethane (45) as the main product (Scheme 15).However, in absence of [Ru(bpy)3]2+ sensitizer, irradiation of the absorptionband of BNAH triggers a different photoinduced electron-transfer processleading to reduction of benzyl bromide (44) to yield toluene as the majorproduct (Scheme 15 bottom and Scheme 16 right)34. Reaction in absence of[Ru(bpy)3]2+ proceeds by a radical chain mechanism involving benzyl radi-cal, as the chain carrier, formed by a single-electron transfer from the ex-cited state of BNAH to benzyl bromide (Scheme 16 right). By contrast, inthe presence of [Ru(bpy)3]2+, benzyl bromide is subject to two-electron re-duction by [Ru(bpy)3]+ generated by reductive quenching of [Ru(bpy)3]2+*



[Ru(bpy´)3](PF6)2 4-8 mol%

MeCN

hν

quantitative

> 410 nmλ

43

MeO

OH

40

MeO

O

41

H

O

ON2

BF4-

O

+ N2

hν

[Ru(bpy)3]3+

[Ru(bpy)3]2+* [Ru(bpy)3]2+

O

O

H

MeO

O

MeO

OH

O

H

H H

H

H

42

collidine

N+H

collidine

O

- e-

H+

3 eq

DERONZIER, 1984 &1987

oxidative quenching

N N

CO2iPriPrO2C

bpy´ =

SCHEME 14Photooxidation of carbinols to aldehydes via visible-light photoredox catalysis witharyldiazonium salt as a sacrificial oxidant (refs32,33)

with BNAH (Scheme 16 left). The authors noted there is some similarity be-tween [Ru(bpy)3]+ reductant and sodium naphthalenide that can also, as astrong reductant, trigger reduction of benzyl halides to generate anionic


872 Teplý:

2.6 h

80%

CH3CNN

Ph

CO2NH2

BNAH

2%

45

1 eq

TANAKA, 1984

Br

177 eq

pyridine 16 eq

hν > 360 nmλ

yields based on BNAH


CH3CN

N

Ph

CO2NH2

0.8 h

hν > 400 nmλ

Br

trace

H

yields based on BNAH

pyridine 26 eq

44 BNAH

1 eq177 eq

44

50%

45

H

SCHEME 15[Ru(bpy)3]2+-photosensitized reaction of l-benzyl-1,4-dihydronicotinamide with benzyl bro-mide and non-photosensitized process (ref.34)

TANAKA, 1984

BNA

Ph Br BNAH

BNAHPh Br

Ph

PhPh

BNAH

Ph Br

BNA

hν> 360 nmλ

[Ru(bpy)3]2+*

[Ru(bpy)3]2+

[Ru(bpy)3]+

reductivequenching

BNAH

BNAH

Ph BrPh

Ph

[Ru(bpy)3]2+

[Ru(bpy)3]+

Ph Br

hν> 400 nmλ

46

PhPh

45

PhCH3

SCHEME 16Comparison of photoinduced electron-transfer pathways in reaction of benzyl bromide andBNAH in presence (left) and absence (right) of [Ru(bpy)3]2+ photocatalyst (ref.34)

species PhCH2– (46) via two-electron transfer35a,35b. In 1987, related photo-

assisted C–C coupling of benzyl halide substrates with Cu(dap)2+ photo-

catalyst (dap = 2,9-bis(p-anisyl)-1,10-phenathroline) has been described byKern and Sauvage35c. The authors suggested that oxidative quenching path-way of photoexcited Cu(dap)2

+* with benzyl halide is operative. Radicalcoupling of the resulting benzyl radical, or alternatively, two-electron trans-fer pathway have been proposed as possible mechanistic scenarios.

In 1990, Fukuzumi et al.36 reported reduction of phenacyl halides bydihydroacridine derivative 48 photocatalyzed by [Ru(bpy)3]2+ (Scheme 17).

Remarkable influence of perchloric acid on the mechanistic pathway wasinvestigated37. In absence of acid, the reaction was found to proceed viareductive quenching of [Ru(bpy)3]2+* by 48 generating [Ru(bpy)3]+ reduc-tant. Conversely, in the presence of perchloric acid, oxidative quenching of[Ru(bpy)3]2+* by phenacyl halides is operative producing [Ru(bpy)3]3+ oxi-dant in situ. The two proposed mechanistic pathways are depicted inScheme 18.

In 1991, Okada and Oda published a photocatalytic decarboxylativeMichael addition of N-(acyloxy)phthalimides (Scheme 19)38. Reductivequenching of the photoexcited [Ru(bpy)3]2+* with electron rich BNAH leadsto strongly reducing [Ru(bpy)3]+ that transfers its electron to phthalimidemoiety to generate species 52. This leads to decarboxylation and generationof the key alkyl radical intermediate 54 and subsequent incorporation of



FUKUZUMI, 1990


CH3CN

N

8 h, 25°C

hν > 452 nmλ

no HClO4

47 AcrH2

1 eq3 eq

O

BrN

AcrH+

75%

74%

O

H


CH3CN

N

hν > 452 nmλ

HClO4 2 eq

47 AcrH2

1 eq3 eq

O

BrN

AcrH+

98%

98%

O

H

H H

H H

8 h, 25°C

48

48

via reductive quenching pathway

via oxidative quenching pathway

SCHEME 17[Ru(bpy)3]2+-photosensitized reduction of phenacyl bromide by a NADH analogue in absenceand presence of acid additive (ref.36)


874 Teplý:

FUKUZUMI, 1990

[Ru(bpy)3]2+*

[Ru(bpy)3]2+

[Ru(bpy)3]+

reductivequenching

AcrH2

AcrH2

Ph

hν

oxidative quenching

-H+

AcrH

O

Br

Ph

OH

Br

AcrH

Ph

O

H

Br

no added HClO4 with HClO4

[Ru(bpy)3]2+*

[Ru(bpy)3]2+

[Ru(bpy)3]3+

AcrH2

AcrH2

hν

-H+AcrH

Ph

OH

Br

AcrH

Ph

O

H

Br

Ph

O

Br

H

AcrH3

H+

H+

SCHEME 18Electron-transfer pathways in reduction of phenacyl halides by dihydroacridine derivative 48photocatalyzed by [Ru(bpy)3]2+ with and without perchloric acid (ref.36)

4950

THF-H2O, 2 h

68%


hν > 460 nmλ

O N

O

O

N

Ph

CO2NH2

BNAH1 eq

O

O O

O

51

10%

1.9 eq

hν

[Ru(bpy)3]2+*

[Ru(bpy)3]2+

52

[Ru(bpy)3]+

BNAHBNA

H+

O N

O

OR

O

53

O N

HO

OR

O

H2O

HN

O

OCO2

O

R

OBNA

BNA

BNAH

BNA

O

OKADA, ODA, 1991

reductive quenching

R

54

SCHEME 19Decarboxylative Michael addition of N-(acyloxy)phthalimide 49 to electron-deficient olefin(ref.38)

Michael acceptors such as methyl vinyl ketone to give products 50 and 51.In a related work, the key alkyl radical intermediates 54 generated as de-picted in Scheme 19 can give rise to reduced species R-H when t-BuSHreagent is used as a source of the hydrogen atom39. Alternatively the al-kyl radicals 54 can be trapped with PhSeSePh to give phenyl selenidesR-SePh 40.

In 1994 Barton et al. reported additions of Se-phenyl p-tolueneseleno-sulfonate 55 to olefins promoted by [Ru(bpy)3]2+ and light (Scheme 20)41.Oxidative quenching pathway of excited [Ru(bpy)3]2+* with p-TolSO2SePh(55) as the oxidant was proposed to initiate the radical chain reaction(Scheme 20). Electron rich olefins give products such as sulfone 57 in high



55

hν

56

57

SeS

O O



CO2CH3

hν

CO2CH3S

SeO O

84%CH3CN

O

CH3CN, 0°C, 10 min

OS

SeO O

95%10 eq

10 eq

hν

[Ru(bpy)3]3+

[Ru(bpy)3]2+* [Ru(bpy)3]2+

58

59

Se

O2S

OR

ORS

O O

SeS

OO

PhSe (PhSe)2

BARTON, 1994

oxidative quenching

SCHEME 20[Ru(bpy)3]2+-photocatalyzed addition of Se-phenyl p-tolueneselenosulfonate to electron richolefins (ref.41)

yield. Interestingly, transformation 55 → 57 also worked with Ru(CO)3Cl2(86% yield of 57) and [Ru(bpy)3]Cl2 catalysts. In this report, the authorspredicted that [Ru(bpy)3]2+ in combination with light could be used as aninitiator for various other radical reactions.

In 1993, Ohkubo et al. devised photoredox catalytic process for oxidativehomocoupling of 2-naphthol leading to non-racemic (R)-(+)-1,1′-bi-2-naphthol (BINOL)42,43. Visible-light irradiation of the substrate in pres-ence of enantiopure ∆-[Ru(menbpy)3]2+ 60 afforded non-racemic BINOLwith 16% ee (Scheme 21). In this transformation, that features oxidative


876 Teplý:

N

N

N

NN

NRu

2+-[Ru(menbpy)3]2+

CO2R

RO2C

RO2C

CO2R

CO2R

CO2R

R = O

MeCN

hν

-[Ru(menbpy)3]X2 0.5 mol%

[Co(acac)3]

-[Ru(menbpy)3]3+

-[Ru(menbpy)3]2+

hν

-[Ru(menbpy)3]2+*

[Co(acac)3]

[Co(acac)2] acac

25°C

OH

R OH

R

OH

R

R = H 16% ee

= OMe 4% ee

OH

O

+H+

OOH

HH

H

-[Ru(menbpy)3]3+

-[Ru(menbpy)3]2+

61

OHKUBO, 1993 & 1994

oxidativequenching

60

∆

∆∆

∆

∆

∆

∆

SCHEME 21Enantioselective oxidative homocoupling of 2-naphthol by photoredox catalysis with∆-[Ru(menbpy)3]2+ (refs42,43)

quenching pathway of the excited ruthenium photocatalyst, [Co(acac)3]was used as a sacrificial oxidant. As the authors proposed, the enantio-selectivity is presumably governed by the counterclockwise molecularhelicity along the C3 axis of the ruthenium complex during the oxidationof the radical intermediate 61. Remarkably, the ruthenium photocatalyticsystem based on [Ru(menbpy)3]2+ is able to trigger a very efficient enantio-selective photocatalytic reduction of [Co(acac)3] (Scheme 22)44. ∆ enantio-mer of the octahedral complex [Co(acac)3] reacts considerably faster ascompared to the Λ enantiomer.

This transformation proceeds via oxidative quenching of the enantio-pure ruthenium photocatalyst with racemic [Co(acac)3], that occurs with asignificantly different rate for the ∆ and Λ enantiomer in the mixture ofethanol–water 9:1 (k∆/kΛ = 14.7). With the rate being larger for consump-tion of ∆-[Co(acac)3], the reaction mixture can be enriched in Λ-[Co(acac)3]enantiomer (up to 94% ee at 30% conversion). Notably strong dependenceon the composition of the solvent system has been observed. When thecontent of ethanol in the solvent system has been decreased to 8:1 relative



EtOH-H2O 9:1

hν > 300 nmλ

-[Ru(menbpy)3]X2 1 mol%-[Co(acac)3]

-[Co(acac)3]racemate [Co(acac)2] acac

EtOH

CH3CHO

-[Ru(menbpy)3]3+

-[Ru(menbpy)3]2+

hν

-[Ru(menbpy)3]2+*

-[Co(acac)3]

-[Co(acac)3]

[Co(acac)2] acac

-[Co(acac)3]

> 90% ee at 30% conversion

OHKUBO, 1993

oxidative quenching

∆

∆

∆

∆

∆

∆

Λ

ΛΛ

SCHEME 22Enantioselective decomposition of [Co(acac)3] by photocatalysis with ∆-[Ru(menbpy)3]2+

(ref.44)

to water, the ratio of the individual enantiomer consumption rates de-creased considerably to k∆/kΛ = 8.7.

In a related work Ohkubo group described enantioselective photoredoxsynthesis of [Co(acac)3] from racemic [Co(acac)2(H2O)2] and acetylacetoneusing various non-racemic ruthenium photocatalysts in ethanol/watersolvent system in the presence of molecular oxygen45. The best catalyst was∆-[Ru(menbpy)3]2+ with which they achieved 37% ee in favor of Λ-[Co(acac)3]enantiomer. The authors proposed a reaction pathway, where the excitedstate of the ruthenium catalyst is oxidatively quenched by the molecularoxygen to generate strongly oxidizing ∆-[Ru(menbpy)3]3+. This in turn trig-gers the enantioselective key step that involves non-equal rates of forma-tion of the individual enantiomers of [Co(acac)3] favoring Λ-[Co(acac)3]enantiomer. Although the previous examples by Ohkubo are more from therealm of inorganic chemistry, they might be inspiring to organic chemistsinterested in enantioselective electron transfer reactions46.

In 2000, group of Katsuki published work on enantioselective oxidativehomocoupling of phenolic substrates using a different ruthenium catalyticsystem based on [(NO)Ru(II)-salen] motif (Scheme 23)47,48. The reaction


878 Teplý:

hν

air, toluene

25°C

OH

OHOH

R = H 72% yield 65% ee

OMe 73% 33% ee

N NRuCl

NO

O OPhPh

[(NO)Ru(II)-salen] complex 62

[(NO)Ru(II)-salen] 2 mol%

R

R

R

Br 30% 71% ee

Ra Ra

visible lightKATSUKI, 2000

hν

Ruox

XRured

X

SET

O2Rured

X

X'

X,X' = Cl, or NO

-2H+

Ra

SCHEME 23Enantioselective oxidative dimerization of 2-naphthol by catalysis with [(NO)Ru(II)salen] com-plex 62 in the presence of molecular oxygen (ref.47)

mixture was irradiated with 150 W halogen lamp in presence of molecularoxygen and the enantioselectivities achieved for various BINOLs rangedfrom 30 to 71%. The authors provided a mechanistic outline depicted inScheme 23. Light was proposed to induce release of the nitrosyl ligand fromthe ruthenium center of the precatalyst. However, it was not disclosed atthis point if the light can play an active role also during the key single-electron transfer steps in the catalytic cycle. Importantly, investigation ofanother oxidation reaction catalyzed by Ru(II)-salen system by Katsuki49a

showed that light can participate in certain single-electron transfer stepsinvolving this catalyst. In this report, enantioselective desymmetrization ofmeso-diols leading to non-racemic lactols under visible-light photo-irradiation49a was disclosed (e.g. 63 → 64, Scheme 24). The mechanism ofthis transformation has been studied in great detail and spectroscopic anal-ysis revealed that irradiation with visible light was indispensable not onlyto trigger dissociation of the nitrosyl ligand but also to promote single-electron transfer from the alcohol-bound ruthenium ion to molecular oxy-gen. Fine ligand tuning of the ruthenium(salen) complexes was required toachieve high enantioselectivities (up to 93% ee).

Very recently, Katsuki group reported a detailed study49b on photo-promoted Ru-catalyzed asymmetric aerobic sulfide oxidation and epoxida-tion. Oxidation of various sulfides using again ruthenium(salen) complexes



hν

CHCl3 , air, rt

N NRuL

NO

O O

Ar Ar


visible light

KATSUKI, 2005 & 2010

R

R

OHOH

meso-diols

O

OHR

R

*

*R = alkyl, aryl, or -(CH2)n-

up to 93% ee

hν

O2 (1 atm)


visible light

SR2R1

up to 98% ee

S+R2R1

*

O-

EtOAc, 25°C

H2O (1.0 eq)

hν

O2 (1 atm)


visible light

up to 92% eeC6H5Cl, 25°C

Ar

R5

R3

R4Ar

R5

R3

R4

O

R'R'

R' = Me, or HL = Cl, or OH

a)

b)

N NRuCl

NO

O O

PhPhRa Ra

R'R'

R' = Me, or H

63 64

SCHEME 24a) Aerobic oxidative desymmetrization of meso-diols promoted by [(NO)Ru(II)-salen] photo-catalysts (ref.49a). b) Asymmetric aerobic sulfide oxidation and epoxidation (ref.49b)

as the catalysts proceeded with enantioselectivities of up to 98% ee. Theepoxidation of conjugated olefins showed also moderate to high enantio-selectivities (76–92% ee, Scheme 24). The role of water as a proton-transfermediator has been investigated.

4. PHOTOREDOX CATALYSIS IN THE FIRST DECADE OF THE 21st CENTURY

In 2003, Zen group reported a clean and selective photocatalytic oxidationof sulfides to sulfoxides. A heterogeneous nafion membrane doped with alead ruthenate pyrochlore catalyst (Pyc) and [Ru(bpy)3]2+ photosensitizer(designated as NPycx–Ru(bpy)) was used to achieve selective sulfoxide for-mation with no overoxidation to the sulfone (Scheme 25)50. The success ofthis system lies in the combination of catalyst, photosensitizer, solvent

composition, pH value, molecular oxygen, and light illumination. In a pro-posed mechanistic scheme, Pyc plays a dual catalytic role in the dioxygenreduction to generate H2O2 and as an oxidant in the oxidative quenchingof the photoexcited ruthenium species (Ru2+*). Hydrogen peroxide thenserves as an oxidant for sulfide to sulfoxide oxidation. Purging of the sys-


880 Teplý:

ZEN, 2003

oxidative quenching

NPycx-Ru(bpy) cat

O2 , pH 1

visible light

3 h

R

SMe

R

S

MeCN-H2O 3:4

O500W halogen lamp

R = H >97%

COMe 96%

OMe 90%

hν

Ru3+

Ru2+*

Ru2+

Pycox

Pycred

O2

H2O2

SS

O + H2O2

NPycx-Ru(bpy)

SCHEME 25Photocatalytic oxidation of sulfides to sulfoxides catalyzed by doped nafion membraneNPycx–Ru(bpy) (ref.50)

tem with O2 proved to be essential for the formation of H2O2 during the re-action. The control experiment with 30% H2O2 solution gave only about47% conversion with poor selectivity.

In 2004, Hirao group published photoinduced reduction of nitrobenzeneswith hydrazine hydrate in presence of [Ru(bpy)3]Cl2 or related catalysts51.Among them, [Ru(bpy)2(MeCN)2](PF6)2 was the most efficient and gave thebest yields of anilines with both electron-withdrawing and -donating sub-stituents (Scheme 26). The authors proposed oxidative quenching pathwayduring which photoexcited ruthenium catalyst gets oxidized by the nitro-compound (Scheme 27). Corresponding anilines were isolated in good



[Ru(bpy)2(MeCN)2](PF6)2 6 mol%

MeOH, argon

hν

5 h 70%

> 300 nmλ

CN

NO2

CN

NH2

NH2NH2.H2O 10 eq

HIRAO, 2004

Further examples

92%a

NH2

82%

Cl

NH2

88%

OMe

NH2

a) isolated as acetanilide

SCHEME 26Reduction of nitrobenzenes to anilines using hydrazine hydrate reductant and rutheniumphotocatalyst (ref.51)

HIRAO, 2004 NO2

NO2 NH2NH2.H2O

oxidized species

hνRu2+*

oxidative quenching

NH2

Ru2+

Ru3+

SCHEME 27Oxidative quenching pathway proposed for photoexcited ruthenium catalyst in reduction ofnitrobenzenes with hydrazine hydrate (ref.51)

yields and cyano group was reported to stay intact in this process. The ini-tial study with parent nitrobenzene showed that methanol is a suitable sol-vent while reduced efficiency was observed with CH2Cl2 (GC yields 99 and52%, respectively). Use of THF and acetonitrile led to drastically diminishedyields (GC: 18 and 12%).

In 2006, Hasegawa group reported a study on photoinduced electron-transfer (PET) reactions of several ketones in presence of organic photo-sensitizers such as substituted pyrenes and anthracenes 68–71 cooperatingwith 2-aryl-1,3-imidazolines as reductants (e.g. 66, Scheme 28)52. In areductive epoxide opening 65 → 67 also [Ru(bpy)3]Cl2 has been investi-gated besides purely organic photosensitizers 68–71.

In 2006, intriguing photocatalytic Meerwein–Ponndorf–Verley-type(MPV) reduction using a [Ru(bpy)3]2+/viologen couple has been disclosed byGarcia group (Scheme 29)53. Oxidative quenching catalytic cycle has beenproposed involving oxidation of photoexcited [Ru(bpy)3]2+* by viologenspecies. The reduced viologen MVH+ (Scheme 29) was suggested to transferhydride to carbonyl substrate resulting in alcohol product. The proposedmechanism invites to investigate enantioselective variants of this photo-catalytic MPV process with chiral non-racemic viologen catalysts. Interest-ingly, there is some relation of this work to studies by Willner23,24,28

(Schemes 8–10), where alternative conditions and mechanistic pathwaysare discussed.


882 Teplý:

6567

O OH[Ru(bpy)3]Cl2 1 mol%

DMF

hν

3 h

70% by NMR (at 45% conversion)

OO

N N

HOH

66 1.2 eq

NMe2

Me2N

OMe

MeO

NMe2

NMe2

OMe

OMe

other sensitizers

hν

> 340 nmλ

> 390 nmλ

68 69 70 71

HASEGAWA, 2006

SCHEME 28Photoinduced electron-transfer reduction of epoxide triggered by [Ru(bpy)3]2+/2-aryl-1,3-imidazolines (ref.52)

In 2007, Osawa group published visible-light promoted copper-freeSonogashira coupling reaction of aryl bromides at room temperature using[Ru(bpy)3]2+ photocatalyst (Scheme 30)54. When irradiated, 4-bromoanisoleand phenylacetylene gave Sonogashira coupling product in 84% isolatedyield, whereas the same reaction run in the dark led to only 18% yield (GC



GARCIA, 2006

[Ru(bpy)3]2+

hν

[Ru(bpy)3]2+*

Proposed mechanism

[Ru(bpy)3]3+

oxidative quenching

MV

MV2

TEOA

TEOAox

MVHOH

O

R R'

O

R R'

OH

72

[Ru(bpy)3](PF6)2 cat.

TEOA,

O

O

CH3CN

hν

O

73

OH

O

O

OH

viologen MV(PF6)2 cat.

N+ N+MV2 =

N+ NMVH =H

Other viologens used

N

N

N

N

TEOA = N(CH2CH2OH)3

SCHEME 29Photocatalytic Meerwein–Ponndorf–Verley-type reduction of ketones using a [Ru(bpy)3]2+/viologen couple (ref.53)

OSAWA, 2007

[Ru(bpy)3](PF6)2 8 mol%

rt, 8 h

Br

DMF-Et3N 4:1 84%

MeOMeO

1.2 eq

hν > 420 nmλ

[PdCl2(MeCN)2] 6 mol%

P(tBu)3 6 mol%

no light: 18% GC yield

SCHEME 30Light-promoted copper-free Sonogashira coupling reaction (ref.54)

yield, Scheme 30). The [Ru(bpy)3]2+ photocatalyst has been suggested totake part in the formation of Pd(0) species from the Pd(II) precursor andalso during oxidative addition of arylbromide. Notably, when the light isturned off, the coupling reaction slows down significantly and acceleratesagain after irradiation is resumed. Osawa work represents a unique exampleof metal-catalyzed coupling reaction promoted by visible light.

Since 2008, the development of methods exploring visible-light photo-redox catalysis for organic synthesis experienced remarkable acceleration.This latest work from groups of MacMillan5,55,56, Yoon6,57–59, Stephen-son7,60–65, Koike and Akita66, Gagné67, Zeitler8 and Rueping68 is turning thisstrategy into a powerful synthetic tool.

In 2008, MacMillan group demontrated that photoredox catalysis using[Ru(bpy)3]Cl2 can be merged with amine organocatalysis4,5, specifically sin-gly occupied molecular orbital (SOMO) catalysis69. This seminal work intro-duced a powerful concept that offers many opportunities for asymmetrictransformations. Intermolecular α-alkylation of aldehydes (Scheme 31) was


884 Teplý:

74 2 eq

76

O CO2Et

CO2Et


DMF, 23°C, 5h

93% yield, 90% ee

H

75

2,6-lutidine 2 eq

15 W fluorescent light bulb

5

O CO2Et

CO2EtH 5 Br

NH

NO Me

. TfOH

20 mol%

MacMILLAN, 2008

O

H CO2Et

CO2Et

86% 90% ee

O

H

5

84% 96% ee

O

O

H CO2Et

CO2Et

66% 91% ee

Representative examples

Et

80% 92% ee

O

H

5

CO2Me

80% 88% ee 70%, 5:1 dr, 99% ee

NBoc

O

H

5

OCH2CF3

O

Me CO2Me

O

5O

tBuO2C

SCHEME 31Direct α-alkylation of aldehydes by merging amine organocatalysis with [Ru(bpy)3]2+

photoredox catalysis to achieve asymmetric C–C bond formation (ref.5)

proposed to proceed via enamine activation mode for the aldehyde sub-strate cooperating with photoredox manifold of [Ru(bpy)3]2+ (Scheme 32)5.In this work, SOMO concept earlier introduced by MacMillan took a newdirection. To initiate the reaction, sacrificial quantity of enamine has beenproposed to serve as a reductive quencher of the photoexcited [Ru(bpy)3]2+*to generate strongly reducing [Ru(bpy)3]+ (–1.33 V vs SCE in CH3CN). Thisspecies will be able in turn to transfer electron onto α-bromocarbonylsubstrate 77 to produce electron deficient radical 78 and regenerate[Ru(bpy)3]2+ (E1/2 for phenacyl bromide = –0.49 V vs SCE in CH3CN). Elec-tron deficient radical 78 has been proposed to attack electron-richSOMOphilic enamine to give radical intermediate 79 with a substantial ten-dency to lose electron (–0.92 to –1.12 V vs SCE in CH3CN). Subsequent oxi-dation of this species leading to iminium 80 via single-electron transferonto [Ru(bpy)3]2+* to generate [Ru(bpy)3]+ (ox → red, Scheme 32) has beenproposed. Alternatively, radical intermediate 79 can transfer its electron toanother molecule of α-bromocarbonyl 77 4b. Although the plausible mecha-



[Ru(bpy)3]2+

hν

HR

O

NH

N

tBu

OMe

N

N

tBu

OMe

[Ru(bpy)3]2+*

[Ru(bpy)3]+

R'

O

R'

OBr

N

N

tBu

OMe

R

R'

O

+ Br-

R

SET

N

N

tBu

OMe

R

R'

O

O

R

R'

O

[Ru(bpy)3]2+

N

NtBu

OMe

R

N

NtBu

OMe

RSET

SET

initial SET only

79

80

or

77

78

red ox

[Ru(bpy)3]2+*[Ru(bpy)3]+

R'

O + Br-

78

R'

OBr

77

SCHEME 32Merging amine catalysis and organometallic photoredox catalysis to achieve asymmetric C–Cbond formation

nistic picture of the transformation has been outlined, the details of this in-tricate photoredox process that combines two modes of activation are notfully established at the moment and will therefore require more extensivemechanistic study.

Photoredox organocatalysis is also a powerful way to accomplish chal-lenging enantioselective α-trifluoromethylation and α-perfluoroalkylationof aldehydes (e.g. 80 → 82, Scheme 33)55 using a readily available iridiumphotocatalyst and a commercial imidazolidinone catalyst. The presence of2,6-lutidine is necessary to remove hydroiodic acid that is formed duringthe reaction. Although [Ir(ppy)2(dtb-bpy)]PF6 was found to be the optimalphotocatalyst, commercially available [Ru(bpy)3]Cl2 could also be used toafford the desired products in slightly diminished yields and enantio-selectivities (ppy = 2-phenylpyridinato-C2,N, dtb-bpy = 4,4′-di-tert-butyl-2,2′-bipyridine). The resulting α-trifluoromethyl aldehydes were subse-quently shown as versatile precursors for the construction of a variety ofenantioenriched trifluoromethylated building blocks.

In 2010, enantioselective aldehyde α-benzylation using electron-deficientaryl and heteroaryl substrates has been accomplished (e.g. 83 → 85,Scheme 34)56. Majority of example transformations proceed best withfac-[Ir(ppy)3] photocatalyst (ppy = 2-phenylpyridinato-C2,N). Nevertheless,


886 Teplý:

80

82

CF3

O[Ru(bpy)3]Cl2 0.5 mol%

DMF, -20°C

67% yield, 87% ee

H

81 8 eq

2,6-lutidine 1.1 eq

26 W household light

5

CF3

O

H 5 I

NH

NO Me

. CF3CO2H

20 mol%

8 h

optimal catalyst gives product 24 in N

NN

NIr

PF6-

tBu

tBu

79% yield, 99% ee

MacMILLAN, 2009

SCHEME 33Enantioselective α-trifluoromethylation of aldehydes by merging amine organocatalysis withphotoredox catalysis (ref.55)

[Ru(bpy)3]Cl2 works also as a competent photoredox catalyst in this processalbeit usually with lower conversions. This strategy directly allows thestereocontrolled formation of compounds with homobenzylic stereogeniccenters in good to excellent yield under mild conditions.

Important extension of the enantioselective photoredox α-perfluoro-alkylation and α-alkylation concept has been published in 2011 by Zeitleret al.8. The authors demonstrated that the merger of amine organocatalysiswith photoredox catalysis can be achieved in presence of purely organicphotosensitizers such as eosin Y (Scheme 35). Photoredox catalysis usingeosin Y 70 thus represents fully organocatalytic variant of the MacMillanintermolecular α-alkylation of aldehydes. Notably, eosin Y (EY) undergoesphotoredox steps that are comparable to [Ru(bpy)3]2+ (Scheme 35 bottom)suggesting similar catalytic pathways in the two cases (cf. Schemes 32 and35). Interestingly, it has been noticed in this study that α-alkylation contin-ues to proceed even after the initial irradiation is stopped (“dark reac-tion”)8. Electron transfer from 79 onto α-bromocarbonyl substrate 77 to re-generate reactive radical 78 might account for this observed “dark” propa-gation of the reaction (Scheme 32). Such regeneration of the SOMOphilicspecies 78 during the production of iminium 80 will imply that the overallreaction is a radical chain process and light would only be needed to initi-



83 2 eq

85

O[Ru(bpy)3]Cl2 0.5 mol%

DMF, 17°C

74% yield, 90% ee

H

84 2,6-lutidine 2 eq

26 W household light

5

O

H 5

NH

N

Bn

O Me

32 mol%

8 h

fac-[Ir(ppy)3]

N

N

NIr

N

NO2

BrN

NO22,6-lutidinium triflate 20 mol%

MacMILLAN, 2010

SCHEME 34Enantioselective α-benzylation of aldehydes via photoredox organocatalysis (ref.56)

ate the reaction in such a pathway (Scheme 32). The data by Zeitler et al.therefore raised interesting questions about what is the role of light andphotocatalyst during the various stages of such mechanistically complexphotoredox processes.


888 Teplý:

80

87

(CF2)3CF3

O

eosin Y 0.5 mol%

DMF, -15 °C, 18 h

56% 96% ee

H

86 8 eq2,6-lutidine 1.4 eq

5

(CF2)3CF3

O

H 5I

NH

NO Me

. HCl

20 mol%

hν = 530 nm, LEDλ

eosin Y O OBr

Br

Br

BrCOOH

HO

ZEITLER, 2011

Further examples

O

H

5

CO2Et

CO2Et

85% 88% ee

O

H

5

82% 95% ee

O

NO2 O

H

Ph

CO2Et

CO2Et

76% 86% ee

Comparison of reductive quenching photoredox cycles of eosin Y and [Ru(bpy)3]2+

EY

1.89 eV

3EY*

EY

hν

1EY*539 nmλmax

ηisc

hν

+0.83 V

-1.06 VRu2+

2.12 eV

3Ru2+*

Ru+

hν

1Ru2+*

ηisc = 1

φ = 0.04hν

+0.84 V

-1.33 V

oxidant

reductantreductant

452 nmλmax

oxidant

SCHEME 35Purely organocatalytic enantioselective α-perfluoroalkylation and α-alkylation of aliphatic al-dehydes using eosin Y as photoredox catalyst (ref.8)

In 2009, Koike and Akita described α-oxyamination of aldehydes withTEMPO using photoredox catalysis with [Ru(bpy)3]2+ (e.g. 88 → 90,Scheme 36)66. In this transformation, activation mode of the aldehyde

with morpholine is beneficially combined with the photoredox pathway ofRu photocatalyst. The authors suggested a mechanistic scenario depicted inScheme 37. The enamine 92 formed in situ was proposed to reductivelyquench the [Ru(bpy)3]2+* species to generate radical cation 93 that furtherreacts with TEMPO to give oxyaminated aldehyde product. The [Ru(bpy)3]+

generated during the reductive quench should be reoxidized to [Ru(bpy)3]2+

with an electron acceptor that has not been specified. Interestingly, cyclo-hexanone gave no α-oxyamination product 91 under the conditions de-scribed in Scheme 36. However, enamine substrate preformed from cyclo-hexanone and morpholine underwent the reaction smoothly giving 81%yield of the expected product 91.

In 2008, Yoon group introduced intramolecular enone [2+2] cyclo-additions triggered by visible-light photocatalysis (Scheme 38)6. A variety ofaryl enones have been shown to undergo readily this transformation, andthe diastereoselectivity in the formation of the cyclobutane products wasexcellent. The authors proposed a mechanism in which a photogenerated[Ru(bpy)3]+ complex promotes one-electron reduction of the enone sub-strate, which undergoes subsequent radical anion cycloaddition. The reac-



88

90

O

O[Ru(bpy)3](PF6)2 2 mol%

MeCN, rt, 24 h

68%

H

89 1 eq6

O

H 6

20 mol%

hν > 420 nmλKOIKE & AKITA, 2009

Further examples

O

O

H

Ph

56%

O

O

H

54%

N

ONH

O

N

1)

2) H2O

N N

Et

O

O

0%, 81%a)

N

a) from preformed enamine substrate

91

SCHEME 36Photocatalytic oxyamination of aldehydes with TEMPO (ref.66)

tion can be conducted using incident sunlight as the only source ofirradiation. No reaction was observed in the absence of i-Pr2NEt, even uponextended irradiation with higher catalyst loadings (5 h, 20 mole %[Ru(bpy)3]Cl2). This suggests that cycloaddition is not directly initiated bythe photoexcited [Ru(bpy)3]2+* state but rather that the catalytically rele-vant reductant is a [Ru(bpy)3]+ species formed upon reductive quenching bythe amine. The lithium salt was suggested to function as a Lewis acid in thisreaction activating the enone toward one-electron reduction. It is of note,that this work was inspired by the radical anion cyclization step withbis(enone) substrates that has been previously pioneered by Krische andBauld in a different context of one-electron reductions with cobalt71a,71b,and copper catalysts71c, and also upon cathodic71d and homogeneous71e


890 Teplý:

[Ru(bpy)3]2+hν

[Ru(bpy)3]2+*

[Ru(bpy)3]+

- e

R

N

O

R

N

O

R

N

O

N

O

ON

NH

O H

R

O

R

OO

N

reductive quenching

93

92

SCHEME 37Proposed mechanistic pathway of photocatalytic α-oxyamination of aldehydes with TEMPO



94 95MeCN, 1 h

94%, 10:1 dr

i-Pr2NEt 2 eq

O

MeOPh

O

Ph-4-OMe4- HH

O

MeOPh

O

Ph-4-OMe4-[Ru(bpy)3]Cl2 5 mol%

sunlight

992 mg

LiBF4 2 eq

YOON, 2008

O

R

O

R

R3NR3N

hν

[Ru(bpy)3]2+*

[Ru(bpy)3]2+

[Ru(bpy)3]+

HH

O

R

O

R

R

O

HR

O

H

SET SETreductive quenching - e

SCHEME 38Visible-light photocatalysis of bis(enone) [2+2] cycloadditions via reductive quenching ofphotoexcited [Ru(bpy)3]2+* state (ref.6)

89%, >10:1 dr 89%, >10:1 dr 90%, 5:1 dr

68%, 4:1 dr 54%, 6:1 dr 85%, 10:1 dr

96

YOON, 2008

HH

O

Ph

O

Ph

HH

OOOO

O

HH

O

Ph

O

Ph

HH

O

Ph

O

Ph

HH

O

Ph

O

Ph

HH

O

Ph

O

Me

74%, >10:1 dr 84%, 10:1 dr 82%, >10:1 dr

HH

O

Ph

O

NEt2

HH

O

Ph

O

OEt

O

Ph

O

PhMe

Me Me

SCHEME 39Selected products prepared by [2+2] cycloaddition via photoredox catalysis (ref.6)

one-electron reductions. Finally, in this work Yoon and coworkers alsostudied intermolecular [2+2] homodimerizations that were found to pro-ceed smoothly (Scheme 39)6. Here, C2 symmetric products such as 96 wereproduced, which was in contrast to the tethered intramolecular reactions.

In a related work, challenging crossed intermolecular [2+2] cycloadditionof two different enones was accomplished (Scheme 40)57. With thismethod, a diverse range of non-symmetric tri- and tetrasubstituted cyclo-butane structures was produced in good yields and diastereoselectivities(Scheme 41). Importantly, similar cycloadditions under standard UV irradi-ation in absence of photoredox catalyst are inefficient and unselective.


892 Teplý:

97 98MeCN, 4 h

84%, >10:1 dr

i-Pr2NEt 2 eqMe

O

Ph

O

Me

O

Ph

O

Me[Ru(bpy)3]Cl2 5 mol%

sunlight

1.04 g

LiBF4 4 eq Me

2.5 eq

YOON, 2009

SCHEME 40[2+2] Heterodimerizations of enones via visible-light photocatalysis (ref.57)

53%, >10:1 dr 74%, >10:1 dr 64%, >10:1 dr

61%, >10:1 dr 88%, >10:1 dr 57%, 5:1 dr

YOON, 2009OO

Me

OO

MeO

O

Ph

O

Me

Me

MeO

Me

BnO

O

Ph

O

Me

O

Ph

O

SEt

Me

O

Ph

O

SEt

Me

Me

SCHEME 41Selected products prepared by crossed intermolecular [2+2] cycloaddition via photoredox ca-talysis (ref.57)

In 2010, Yoon reported [2+2] cycloadditions of electron-rich olefins(Schemes 42 and 43)58 taking advantage of oxidative quenching cycle ofphotoexcited [Ru(bpy)3]2+* state with methyl viologen (MV2+) as an elec-tron acceptor. This process generates [Ru(bpy)3]3+, a strong oxidant which iscapable of oxidation of 4-methoxystyrene moiety and thus triggers a radical

cation cyclization pathway72 leading to cyclobutane structures. The elec-tron rich diene substrates used in this work cannot be cyclized under condi-tions depicted in Schemes 38 and 40. Thus the reductive quenching cycleusing Ru/amine (Scheme 38) and oxidative quenching cycle employingRu/methylviologen couple (Scheme 42) are complementary strategies for[2+2] cyclization of electron poor and electron rich diene subtrates, respec-tively.



99100

MeNO2

69%, >10:1 dr

MV(PF6)2 15 mol%

O

O

HH


sunlightMeO OMe

MeO OMe

N+ N+

2PF6

MV(PF6)2 =

2.5 h

YOON, 2010

O

R R

hν

[Ru(bpy)3]2+*

[Ru(bpy)3]2+

[Ru(bpy)3]3+

O

RR

HH

O

RH

RH

SET

SET

MV2+MV

MgSO4

oxidative quenching

SCHEME 42Photocatalytic intramolecular [2+2] cycloaddition of an electron rich diene via oxidativequenching of photoexcited [Ru(bpy)3]2+* state with methylviologen electron acceptor (ref.58)

Very recently, a new method for the formal [3+2] reaction of aryl cyclo-propyl ketones with olefins to afford highly substituted cyclopentane ringsystems was disclosed by Yoon (Scheme 44)59. The key initiation step in


894 Teplý:

89% 73% 64%

78% 54% 67%

YOON, 2010

O

HH

O

HH

O

HH

O

HH HH

NTs

HH

MeO

OMe

OMe

OH

F

O

MeO

Me

MeO

SCHEME 43Representative examples of photoredox [2+2] cycloadducts obtained via oxidative quenchingpathway (ref.58)

101 102MeCN, 23 °C, 6.5 h

83%, 6:1 dr

TMEDA 5 eq

O

Ph

O

OEt[Ru(bpy)3]Cl2 2.5 mol%23 W fluorescent bulb

La(OTf)3 1 eq

Me

MgSO4

H

H

CO2EtMeO

Ph

O[LA]

Ph

O

OEtMe

O[LA]

Ph CO2Et

Me

H

H

CO2EtMe[LA]O

Ph

MeCO2Et

O[LA]

Ph

H

H

+ e-

- e-

YOON, 2011

SCHEME 44Formal [3+2] cycloaddition of aryl cyclopropyl ketone with alkene by visible-lightphotocatalysis (ref.59)

this transformation is the one-electron reduction of the ketone to the corre-sponding radical anion, which is accomplished using a photocatalytic sys-tem comprising [Ru(bpy)3]2+, La(OTf)3, and TMEDA. Notably, this methodallows rapid diastereoselective construction of quaternary carbon stereo-centers within a cyclopentane-containing framework. Also one inter-molecular example has been established (Scheme 45, 103).

In 2009, Stephenson reported reductive dehalogenation via photoredoxcatalysis using [Ru(bpy)3]Cl2 in combination with i-Pr2NEt and HCO2H orHantzsch ester (106) as the hydrogen atom donors (Scheme 46)7. Impor-tantly, only activated C–X bonds are reduced with excellent functional-group tolerance and chemoselectivity over aryl and vinyl C–X bonds.Reductions can be accomplished on a preparative scale with as little as0.05 mole % of the Ru catalyst. The authors proposed a mechanism involv-ing reductive quenching pathway of the photoexcited catalyst [Ru(bpy)3]2+*in which the amine serves as electron donor to generate strongly reducing[Ru(bpy)3]+. A subsequent single-electron transfer onto the substrate gener-ates alkyl radical, which leads to the reduced product via hydrogen atomabstraction. Based on labeling study, two concurrent plausible pathways



79%, >10:1 dr

H

H

MeO

Ph

O SEt

55%, >10:1 dr

H

H

MeOO SEt

MeO76%, 1:1 dr

H

H

MeO

Ph

O SEt

63%, >10:1 dr

H

H

PhMeO

Ph

57%, 3:1 dr

Me

H

PhMeO

Ph

69%, 2:1 dr

OH

O

Ph

83%, 9:1 dr

H

O

Ph

79%, >10:1 dr

H

H

MeO

Ph

O OMePh

YOON, 2011

50%, 2:1 dr

MeNCO

Ph

103

SCHEME 45Selected products synthesized by formal [3+2] cycloaddition depicted in Scheme 44 (ref.59)

have been proposed (Scheme 46). Minor pathway A proceeds via hydrogenabstraction Ha from formic acid whereas majority of reduced product isgenerated after hydrogen abstraction Hb from the methine position of theHünig base.

Later on, a related photoredox manifold has been explored byStephenson for the synthesis of valuable indoles and pyrroles (Scheme 47)60.Cyclizations of structurally diverse substrates via electron transfer photo-


896 Teplý:

104 105DMF, rt, 4 h

92%

iPr2NEt 10 eq

[Ru(bpy)3]Cl2.6H2O 2.5 mol%14 W fluorescent bulb

HCO2H 10 eq

STEPHENSON, 2009

NN

Br

H

CO2Me

Boc CO2Me

Br

NN

H

H

CO2Me

Boc CO2Me

Br

[Ru(bpy)3]2+

hν

[Ru(bpy)3]2+*

[Ru(bpy)3]+

N

Hb

HaCO2HN

Hb

HaCO2H

Proposed mechanism

R1 R2

X

R1 R2

R1 R2

Ha

R1 R2

Hb

major

minor

Path B

Path A

Other substrates

NN

Br

H

CO2Me

Boc CO2Me

O N

O

Bn

O OTBS

BrO N

O

Bn

O OH

Ph

Cl

I

O

O

Cl

PhO

O

Cl

PhO

O

Cl

PhI

95% 79% 80%

88%H 81%H 89%H

H ... Hantzsch ester 106 used instead of HCO2H

106NH

EtO2C CO2Et

reductivequenching

SCHEME 46Photocatalytic reductive dehalogenation via photoredox catalysis (ref.7)

redox catalysis were triggered by [Ru(bpy)3]2+/amine system. Similarly tothe previous transformation depicted in Scheme 46, this process also relieson generation of radical intermediate from a C–X bond via single-electrontransfer by taking advantage of the strong reductant [Ru(bpy)3]+ formed byreductive quenching pathway from [Ru(bpy)3]2+* and amine (Scheme 47).Malonyl radical generated this way is then intramolecularly trapped byelectron rich heterocyclic system to form a new C–C bond. In this process,



107

109

DMF, rt

40%

[Ru(bpy)3]Cl2 2.5 mol%15 W fluorescent bulb

STEPHENSON, 2010

Other examples

N CO2Me

CO2Me

Br

N CO2Me

CO2Me

H

NCO2Me

CO2Me

108 52%

107DMF, rt, 12 h

[Ru(bpy)3]Cl2 1 mol%15 W fluorescent bulb

N CO2Me

CO2Me

Br NCO2Me

CO2Me

10860%

Initial result

Optimized conditions

NCO2Me

CO2Me

73%

NCO2Me

CO2Me

60%O

NCO2Me

CO2Me

55%

Br

NCO2Me

CO2Me

60%

CN

NCO2Me

CO2Me

95%

N

89%

O

N O

O

N

62%

CO2MeCO2Me

N

CO2Me

CO2Me

55%

NCO2Me

CO2Me

79%MeO2C

Et3N 2 eq

iPr2NEt 2 eq

SCHEME 47Electron-transfer photoredox catalysis for intramolecular radical addition to indoles andpyrroles (ref.60)

reduced by-product 109 is formed when i-Pr2NEt is used. However, by re-placing i-Pr2NEt with Et3N it is possible to suppress the simple reductionpathway and enhance the desired cyclization. Apart from a broad applica-bility, the cascade radical cyclization has been demonstrated by the synthe-sis of tetracyclic compound 111 that is formed as a single diastereoisomer(Scheme 48).

By judicious choice of the amine used, this reaction has been optimizedto allow for challenging intermolecular malonation of electron-rich hetero-cycles with diethyl bromomalonate reagent (Schemes 49 and 50)61. Use oftriethylamine instead of 4-methoxy-N,N-diphenylaniline (CH3OC6H4NPh2,113) led to the malonylindole product 114 in only 25% yield. Light-emitting diode proved to be an advantageous source of visible light for thediscussed photoredox processes. Use of 14 W fluorescent light bulb resultedin slow reactions. Thus, for example complete conversion in the transfor-mation 112 → 114 was reached in 5 days.

A radical cyclization onto unactivated π-systems, which counts as a clas-sic free radical mediated reaction, has been initiated by photoredox cataly-sis under mild conditions using Ru- as well as Ir-based photocatalysts andEt3N as a reductive quencher of the catalyst excited state (Schemes 51 and52)62.

Gagné group disclosed recently a way to synthesize C-glycosides by addi-tion of glycosyl halides into alkenes using visible light, an amine reductant,and [Ru(bpy)3](BF4)2 photocatalyst (Scheme 53)67. Notably, this transforma-tion features exclusive α selectivity. The work builds on the classical freeradical addition methodology pioneered by Giese73 that relied on use ofBu3SnH.

In 2010, Stephenson disclosed a protocol to effect an oxidative aza-Henryreaction. Valuable substituted amines are produced by the formation ofnovel C–C bond between tertiary N-arylamine and nitroalkane. The reac-


898 Teplý:

110 DMF, rt, 16 h

Et3N 2 eq

[Ru(bpy)3]Cl2 1 mol%15 W fluorescent bulb

STEPHENSON, 2010

NCO2Me

CO2Me

BrN

111

79%

H

H CO2Me

CO2Me

SCHEME 48Cascade radical cyclization initiated by visible-light photoredox catalysis (ref.60)



112 114

DMF, rt, 12 h


STEPHENSON, 2010

Further examples

N

CO2Et

CO2Et

Br

N CO2Et

CO2Et

MeO

NPh2

113

82%

75 2 eq

2 eq

= 435 nmλmax

blue LEDs

N CO2Et

CO2Et

91%

Br

NH

CO2Et

CO2Et

84%

NH

CO2Et

CO2Et

76%

Br

N

92%

CO2Me

CO2EtEtO2C

N CO2Et

CO2Et

67% 49%

NH

68%

O CO2Et

CO2Et

N CO2Et

CO2Et

O

72% 68%

NH

CO2Et

CO2Et

NHBoc

O

HN

Ph

MeO2C

N

Br

CO2Et

CO2Et

SCHEME 49Intermolecular C–H functionalization of electron-rich heterocycles with malonate byphotoredox catalysis (ref.61)

[Ru(bpy)3]2+hν

[Ru(bpy)3]2+*

[Ru(bpy)3]+EtO2C CO2Et

Br

EtO2C CO2Et

R3N

R3N

N CO2Et

CO2EtN

[O]

N CO2Et

CO2Et

N CO2Et

CO2Et

-H+

H

H

blue LED

SET

+ Br

reductive quenching

SCHEME 50Mechanistic scheme proposed for the intermolecular radical C–H functionalization

tion is believed to proceed with intermediacy of an iminium ion generatedvia photoredox process (Scheme 54)63. However, at present, the identity ofthe oxidant leading to the key iminium intermediate is not clear. Based onthe experimental evidence, adventitious atmospheric molecular oxygen hasbeen proposed to participate in the process resulting in net acceleration ofthe reaction. Although [Ru(bpy)3]Cl2 has been shown to catalyze the reac-


900 Teplý:

115 116

DMF, rt, 12 h


STEPHENSON, 2010

Further examples

85%

= 435 nmλmax

blue LEDs

77% 100% 69%

O N

OO

O N

OO

BrEt3N 2eq

MeO2C CO2Me MeO2C CO2Me

TMS

CO2MeMeO2C

Examples with Ir-photocatalyst

N

NN

NIr

PF6-

tBu

tBu

85%

NTs

CO2Et

74%

MeO2C

MeO2C

TMS

CO2Et Br

OH

85%

SCHEME 51Tin-free radical cyclization with unactivated π-systems initiated by visible-light photoredox ca-talysis (ref.62)

117 DMF

Et3N 2 eq

[Ru(bpy)3]Cl2 1 mol%blue LEDs

STEPHENSON, 2010

118 69%

BrMeO2C CO2Me MeO2C CO2Me

SCHEME 52Cascade radical cyclization with unactivated π-systems (ref.62)

tion, Ir-based catalyst [Ir(ppy)2(dtb-bpy)]PF6 is a significantly faster catalystand therefore substrate scope of this reactions has been explored with it(Scheme 55). Mechanistic studies suggest that reductive quenching ofthe Ir3+ excited state by the tertiary amine leads to the ammonium radicalcation, with subsequent catalyst turnover (Ir2+ → Ir3+) likely effected byatmospheric oxygen.

Interesting example of dual catalysis has been recently reported byRueping group (Scheme 56)68. The Mannich reaction has been triggered bycombining oxidative in situ generation of iminium ion with formation ofa reactive enamine nucleophile from proline and ketone. The nucleophile



119 120

CH2Cl2 , rt

92%

iPr2NEt 3 eq

[Ru(bpy)3](BF4)2 5 mol%14 W fluorescent bulb

GAGNÉ, 2010

Further examples

95%

85%

51%

NH

EtO2C CO2Et

OBzOBzO

BrBzO

BzOH2COBzO

BzOBzO

BzOH2C

CO2Me

CO2Me

2 eq

63%

OAcOAcO

AcO

AcOH2C

R

R = CO2Me

2 eq

86% COMe

85% CHO

CN

OBzOBzO

BzO

BzOH2C

P OEt

O

OEt

OAcOAcO

AcO

AcOH2C

CO2Me

81%

OBzOBzO

BzOBzOH2C

CO2Me

O

AcO

AcOAcO

CH2OAc

CO2Me80%

OAcOAcO

AcO

AcOH2C

OO

H

98%, 1.8:1 dr

106

SCHEME 53Photoredox catalysis of intermolecular addition of glycosyl halides to alkenes leading toC-glycosides with exclusive α selectivity (ref.67)


902 Teplý:

121122

MeNO2

81%


visible light

20 h

STEPHENSON, 2010

hν[Ru(bpy)3]2+

[Ru(bpy)3]+

[Ru(bpy)3]2+*

SET

NPh

NPh

NO2

NPh

[O]

H

NPh-H

N+O

Oreductive quenching

SCHEME 54Oxidative aza-Henry reaction via visible-light photoredox catalysis with plausible mechanism(ref.63)

93% 96%90%

95% 27% at 40% conversion

STEPHENSON, 2010

Examples with Ir-photocatalyst

N

NN

NIr

PF6-

tBu

tBu

N

NO2

N

OMeNO2

N

NO2

OMe

NPh

NO2

Cl

92%

NPh

NO2

N

NO2

92%

NPh

NO2

MeO

MeO

96%, 2:1 dr

NPh

NO2

Br

SCHEME 55Products of visible-light photoredox catalysis of aza-Henry reaction with Ir-photocatalyst(ref.63)

formed intercepts the iminium to afford the Mannich product. By carefulchoice of light source and catalyst, the reaction conditions can be tuned tomatch the rates of the two individual processes. In this way various tetra-hydroisoquinolines (Scheme 56) can be made in a very straigthforwardfashion under mild reaction conditions.

In a recent publication, Stephenson group described a useful photo-catalytic variant of the venerable Appel reaction (Scheme 57)64. In thisphotocatalytic halogenation, alcohols are converted to bromides or iodides(R-OH → R-X) using DMF, [Ru(bpy)3]Cl2 catalyst, and CBr4 or CHI3. Addi-tion of 2 equivalents of NaBr substantially improved the yield in the modelreaction. Notably, this transformation involves DMF playing a crucial rolein the alcohol activation (R-OH) as has been revealed by isolation of thecorresponding formate esters R-OCHO after early quenching of the reactingmixture. The authors proposed oxidative quenching of [Ru(bpy)3]2+* byCBr4, leading to CBr3

• and subsequently to the iminium species 126 that



121 123

MeCN, 24 h95%


5W fluorescent lampRUEPING, 2010

NPh

NPh

O

10 eq

O

NH

CO2H 10 mol%

47% 62%

N N

Further examples

O

O

OMeMeO 63%

N

O

78%

N

O

OMe

72%

N

O72%

N

O

F

SCHEME 56Dual catalysis combining photoredox and Lewis base catalysis for direct Mannich reactions(ref.68)

leads to the alcohol activation (Scheme 57). As compared to the original Appelreaction74, this photocatalytic version is substantially more atom-economicobviating the use of stoichiometric triphenylphosphine reductant andavoiding disposal of its unpleasant oxidation product triphenylphospineoxide. Functional group tolerance (Scheme 58) and mild conditions makethis new photocatalytic alkylhalide synthesis an attractive alternative to theother established protocols used to convert alcohols to halides.

Most recently, Stephenson group disclosed a related oxidative quenchingpathway to effect atom transfer radical addition (ATRA) of haloalkanes toolefins65a. The reaction is efficiently performed with the [Ir(dF(CF3)ppy)2-(dtb-bpy)]PF6 photocatalyst. Furthermore, oxidation of electron rich arenesresulting in the selective deprotection of para-methoxybenzyl (PMB) ethershas been reported65b. Similarly to the ATRA, in this reaction too, oxidativequenching cycle of the Ir photocatalyst is effected by using haloalkanessuch as BrCCl3.


904 Teplý:

124 DMF

70%


blue LEDs

25°C, 5 h

STEPHENSON, 2011

hν[Ru(bpy)3]2+

[Ru(bpy)3]3+

[Ru(bpy)3]2+*

SET

CBr4 2 eq

OH

125

Br

with added NaBr 2 eq 90%

CBr4

CBr3

Br

DMF

H

N

O

Br

Br

Br

H

N

O

Br

Br

Br

CBr4 CBr3 Br

O

N

HR

Br

OHR

oxidative quenching

126

SCHEME 57Halogenation of alcohols via visible-light photoredox catalysis (ref.64)

5. PHOTOREDOX CHEMISTRY AS A TOOL FOR MAKING AND BREAKING BONDS INCHEMICAL BIOLOGY AND MATERIALS CHEMISTRY

5.1 Chemical Biology

In a seminal paper from 1999, Kodadek group introduced [Ru(bpy)3]2+

photocatalyst as new tool for chemical biology. Specifically, oxidativequenching pathway of [Ru(bpy)3]2+* has been taken advantage of to effecta very rapid and efficient protein cross-linking (Scheme 59)75a. Ammoniumpersulfate was used as an oxidative quencher to generate [Ru(bpy)3]3+ asa potent one-electron oxidant. It has been proposed that this strongly oxi-dizing species, generated in situ using visible-light excitation, can oxidizetyrosine moieties in proteins. The resultant radical was suggested to cross-link two associated proteins by at least two mechanisms depicted inScheme 59. In case another tyrosine residue is in proximity, aryl–aryl bondformation can take place. Alternatively, a nucleophilic lysine or cysteinegroup can attack the phenol radical to afford a new heteroatom–arenebond. In both pathways, a hydrogen atom is lost to form stable products,



95%

STEPHENSON, 2011

92%

78% 77%

Br

MeO

BnO BrN

Ts

Br

90%

83%

Br

NHCbz

81%

MeO Br

NHCbz

O

86%

N

Ts

Br

Br

HO

84%

OMe

86%

O

Br

Br

75%

I

ICbzHN I

75%

SCHEME 58Examples of products of photocatalytic phosphine-free halogenation of alcohols (ref.64)

and the sulfate radical produced during Ru(III) formation was proposed toplay a key role in this step. Very high yields of cross-linked products werereported with irradiation times of less than 1 s. Later study on this photo-induced cross-linking of proteins revealed more details about the scope,limitations, and mechanistic aspects75b. This method was shown to be use-ful for quantitative characterization of protein–protein and protein–peptidecomplexes76.

Notably, chemical principle of Kodadek method of making dityrosinelinkages is similar to that of Ohkubo method for synthesis of BINOL from2-naphthol (cf. Schemes 59 and 21). Both methods utilize oxidativequenching cycle of Ru2+* complex leading to generation of reactive phenolradical from phenolic substrate.


906 Teplý:

KODADEK, 1999

hν[Ru(bpy)3]2+

[Ru(bpy)3]3+

[Ru(bpy)3]2+*

oxidative quenching

O O SO3--O3S

SO42- SO4

OH

O

-H+

nearby Tyr

O

Protein1

OH

Protein2

H

OSOO

O

OSOO

OH

nearbynucleophilic side chainX=S, NH or OH

Protein2

O

X

XH

Protein2

H

OSOO

O

OSOO

OH

Protein1

Protein1

Protein1

OH

Protein1

OH

Protein2

OH

X

Protein2

Protein1

SCHEME 59Phototriggered protein cross-linking using photoredox manifold of [Ru(bpy)3]2+ in conjunc-tion with persulfate oxidative quencher (ref.75)

Kodadek group also used [Ru(bpy)3]2+ warheads in chromophore-assistedlight inactivation (CALI) of proteins77. [Ru(bpy)3]2+ moiety was shown towork as a competent chromophore for singlet oxygen generation, which isable to inactivate target proteins. A specific and unusually efficient inacti-vation of a biological target with [Ru(bpy)3]2+ constructs is due to a local re-lease of very reactive singlet oxygen that takes place on the rutheniumwarhead in the direct proximity of the target protein. In this context, theperformance of [Ru(bpy)3]2+ was found superior to the most common or-ganic sensitizers such as fluorescein that has been employed as a warheadin the initial CALI experiments. In 2010, this attractive strategy was used totransform modest protein binders into much more potent inhibitors with-out lengthy compound optimization78. The only step required is to attachthe [Ru(bpy)3]2+ warhead to the protein binder of interest. To this end, syn-thetic peptoid-[Ru(bpy)3]2+ conjugates were designed to bind to proteins,resulting in highly potent and specific inactivation of the target proteintriggered by singlet oxygen production upon irradiation with visible light.

In general, biological applications of photoredox complexes related to[Ru(bpy)3]2+ are in focus of trully fascinating research endeavors with prom-ising future. As the more extensive coverage of this territory is beyond thescope of this review, the interested readers are referred to excellent reviewssummarizing the status and challenges in the area79.

5.2 Materials Chemistry

In 2005, light-activated [Ru(bpy)3]2+/persulfate combination discussed inconjunction with Scheme 59 has been used by Elvin group to form di-tyrosine cross-links in natural rec1-resilin. This procedure led to rapid,quantitative and controllable formation of very high molecular weightrubber-like polymeric biomaterial80. Other interesting photoredox cross-linked materials generated from tyrosine-rich protein precursors, such asfibrinogen, have been disclosed recently by Elvin81 and Tranquillo82

groups. Because of their superior mechanical properties, Elvin proposed useof these biomaterials in various surgical applications.

Visible light-triggered chemical cross-linking has been recently reportedfor facile preparation of microgels83 with interesting stability. Phenolgroups grafted on sodium alginate give rise to novel bonds that are similarto the dityrosine linkages discussed above. Applications of this biocompati-ble and biodegradable microgel in biology have been proposed. Cui grouphas also utilized related cross-linking strategy as a method to fabricate ro-bust multilayer films by forming bonds between primary amine groups and



phenol moieties84. Visible-light irradiation of hydrogen-bonded layers ofpoly(allylamine) and poly(4-vinylphenol) led to formation of highly stablecovalent –Ar–NH– interlayer bonds (e.g. 127 + 128 → 129, Scheme 60).Solid-state 13C NMR, FT-IR, and N 1s XPS spectra were used to confirm theformation of new C–N bonds on the aromatic rings. Thus, layer-by-layerself-assembled polymer composed of 15-bilayers was made significantlymore corrosion-resistant by photoredox cross-linking as compared to thenative non-cross-linked polymer film. All the discussed bond formations re-lying on oxidizable phenol moiety are based on oxidative quenching path-way of [Ru(bpy)3]2+* generating strongly oxidizing [Ru(bpy)3]3+ speciesgiving rise to the reactive phenol radical as outlined in Scheme 59.

In 2008, Zou group described solid-state polymerization of diacetylenemonomers initiated by [Ru(dpphen)3]2+ and visible light. Embedding of thephotocatalyst into the hybrid films of the diacetylene monomer led aftervisible-light irradiation to polydiacetylene conjugated polymer 131(Scheme 61)85. The mechanism of the photoinitiation is discussed, and anexplanation based on photoinduced electron transfer from excited state of[Ru(dpphen)3]2+ to diacetylene moiety of the 10,12-pentacosadiynoic acid(130) monomer has been suggested (Scheme 61). Recently, polymerizationof epoxides involving [Ru(bpy)3]2+ photocatalyst has been disclosed byLalevée group86. This fast transformation relies on photoinitiation systemcomposed of [Ru(bpy)3]2+, Ph2I+, and (TMS)3SiH additive.

Recently, photoredox manifold of [Ru(bpy)3]2+ complexes has been usedto effect release of carboxylic acids from their N-methyl-4-picolinium esters(Schemes 62 and 64)87,88. In their report, Boncella, Rasmussen, and cowork-ers showed that decanoic acid 133 can be released from its N-methyl-


908 Teplý:

127 [Ru(bpy)3]Cl2 cat

visible light

CUI, 2011

m

O

n

H2N

HO

H

NH

ammonium persulfate

250W tungsten-halide lamp

128129

SCHEME 60Hydrogen-bonding directed chemical cross-linking using visible-light photoredox manifold of[Ru(bpy)3]2+ and reativity of phenol moieties in the presence amine nucleophiles (ref.84)

4-picolinium ester 132 by irradiation in presence of [8-oxo-G-Ru(bpy)3]2+

photocatalyts (Schemes 62)87. After the photoinitiated bond scission andrelease of the free fatty acid, spontaneous formation of bilayer assemblies



130

[Ru(dpphen)3]Cl2 0.5 - 4.6 mol%

visible light

ZOU, 2008

Cl2

[Ru(dpphen)3]Cl2

N

N

N

NN

NRu

10,12-pentacosadiynoic acid

CO2H

7

11

HO2C

7

11

n

[Ru(dpphen)3]2+hν

oxidative quenching

[Ru(dpphen)3]2+*

[Ru(dpphen)3]3+

diynoic acid

diynoic acidpolymerization

polydiacetylene 131

+ e-

131

solid state

SCHEME 61Ruthenium(II) complex-sensitized solid-state polymerization of diacetylene monomer (ref.85)

132

133Ru photocatalyst

visible light

BONCELLA & RASMUSSEN, 2009

N

O

O

CF3SO3

7N

CF3SO3

HO

O

7

NH3

CO2

N

N

N

NN

NRu

N NH

HN

N

O

H2NO Cl2

Ru photocatalyst

NH3

CO2

self-assembly

bilayer vesicles

SCHEME 62Nucleobase mediated photocatalytic vesicle formation by release of decanoic acid from itspicolinium ester (ref.87)

such as vesicles was observed. This is a conceptually interesting example oftriggering self-assembly of compartmentalized bilayer system from a homo-geneous precursor mixture. Because it is very easily oxidized, 8-oxoguaninemoiety has been selected for attachment to the photoredox active[Ru(bpy)3]2+ center. It can be oxidized even more readily than the most eas-ily oxidized conventional nucleobase guanine. In this context, 8-oxo-Gmoiety has been proposed to serve as a sufficiently strong electron donor toprovide an electron to reductively quench the excited state of the Ru2+ coreof the photocatalyst resulting in strongly reducing Ru+ species. The Ru+

reductant then transfers its electron onto the N-methyl-4-picolinium moi-ety of the ester which in turn leads to the release of the free acid 133(Scheme 63). Notably, when 8-oxoguanine moiety was replaced by simpleguanine, the catalytic system led only to mediocre production of the freedecanoic acid as indicated by the NMR study.

Recently, Falvey group studied photodeprotection of 2-cyano-4-picolin-ium esters to release free carboxylic acids (e.g. 134 → 135, Scheme 64)88. Bytaking advantage of ascorbic acid as the water soluble reductant, they trig-gered reductive quenching pathway of excited state [Ru(bpy)3]2+* photo-catalyst in an aqueous system.


910 Teplý:

HN

N N

HN

O

H2N

O

HN

N N

HN

O

H2N

O

Eox = -0.6 VHN

N N

N

O

H2N

O

NH3

CO2

NH3

CO2N

N

O

O

R

Eox = -0.82 V

N

Ru+

Ru2+

-H+

O

O

R

SCHEME 63Proposed mechanistic pathway of nucleobase mediated photocatalytic release of carboxylicacid from its ester precursor

In a related publication, by using visible-light photodeprotection 136 →137 in the environment of aqueous solution of cationic surfactantcetyltrimethylammonium bromide (CTAB), viscosity of the solution hasbeen shown to increase significantly by a factor of ca. 105 (Scheme 64)89.This dramatic change of the liquid physical properties has been ascribed toa formation of long entangled wormlike micelles resulting from a combina-tion of photoreleased trans-cinnamate anions 137 with cationic surfactantCTAB. Remarkably, the follow-up UV irradiation can be used to attenuatethe viscosity by cis-trans isomerization of the cinnamate double bond. Withthis bi-modal photocontrol, the authors introduced a new concept to influ-ence the aqueous solution viscosity by orthogonal use of visible light andUV light. The potential use of this phenomenon in biological and materialsapplications has been proposed90.

6. CONCLUSIONS AND OUTLOOK

Since 2008, the field of visible-light photoredox catalysis for organic syn-thesis has emerged as a very prolific area of research. It is anticipated thatit will have profound impact on preparative organic chemistry in the fu-ture. The current wave of interest is due to the major seminal studies byMacMillan, Yoon, and Stephenson groups. Before the fast accelleration in



134

[Ru(bpy)3]Cl2 0.5 eq

FALVEY, 2009 & 2010

N

O

OCF3SO3

CN

ascorbic acid 100 eq

Br

acetate buffer 135

HO

OBr

10 min89%

hν > 330 nmλ

136


N

OO

ascorbic acid 1 eqCTAB 1.7 eq

15-60 min

Br OOhν1

visible light

UV lighthν2

O

O

NCTAB: Br

relative viscosity: 105 relative viscosity: 102.5

relative viscosity: 1

2 h137

SCHEME 64Photocatalytic cleavage of picolinium esters (refs88,89)

this branch during the last three years, the limited number of scatteredexamples relevant to organic synthesis remained dormant in the literature.However, now, the early attempts published in the 20th century mightserve as an inspiration for the field, which is on the rise. Therefore, aware-ness of the pioneering efforts by groups of Kellogg, Pac, Willner, Deronzier,Tanaka, Tomioka, Fukuzumi, Okada and Oda, Ohkubo, Barton, andKodadek may help to nurture the current formative era and conceptual ex-pansion of this branch of photocatalysis.

In 2010, the essence and promise of research into photoredox catalysiswith visible light has been nicely summarized by Yoon: “The versatility of[Ru(bpy)3]2+ arises from the ability to access either photooxidative or photo-reductive reactivity by choosing the appropriate oxidative and reductive quencher,respectively (see Scheme 2 in this review). In both regimes, the photophysical prop-erties of [Ru(bpy)3]2+ enable a variety of inexpensive, readily available sources ofvisible light to be utilized, including sunlight. In addition, there exists a vastwealth of electrochemical literature that describes synthetically useful organictransformations initiated by one-electron redox processes. It is expected thatphotocatalytic systems exploiting the reactivity of [Ru(bpy)3]2+ should also be ableto efficiently promote similar reactivity“58. Likewise, it can be anticipated thatphotoredox reactivity of complexes based on metals other than Ru (e.g.Ir 91, Re 92,93, and bimetallic photocatalysts94) will also be intensively ex-plored, as indicated by the current shift of interest to Ir photocatalysts inthe recent work of MacMillan55,56 and Stephenson62,63,65. Additionally,transformations triggered by purely organic photoredox catalysts start to at-tract attention as highlighted in the report by Zeitler group8,95. In general,it is eminent that many interesting and useful tools for molecule makerswill arise from this exciting area of research during the 21st century96.

7. ABBREVIATIONS

acac acetylacetonatoATRA atom transfer radical additionBINOL 1,1′-bi-2-naphtholBNAH 1-benzyl-1,4-dihydronicotinamidebpy 2,2′-bipyridineCTAB cetyltrimethylammonium bromidedF(CF3)ppy 2-(2,4-difluorophenyl)-5-trifluoromethylpyridinato-C6,Ndpphen 4,7-diphenyl-1,10-phenanthrolinedtb-bpy 4,4′-di-tert-butyl-2,2′-bipyridineEDTA ethylenediaminetetraacetic acidmenbpy 4,4′-di(1R,2S,5R)-(–)-menthoxycarbonyl-2,2′-bipyridineMLCT metal-to-ligand charge transfer


912 Teplý:

NADH nicotinamide adenine dinucleotidePMB para-methoxybenzylppy 2-phenylpyridinato-C2,NSET single-electron transferTEOA triethanolamine, tris(2-hydroxyethyl)amine

The author would like to thank Dr. U. Jahn of the Institute for stimulating and helpful discussions.This work was supported by the Czech Science Foundation (Grant No. P207/10/2391) and by theInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i.(Z4 055 0506).

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photoredox catalysis by [ru(bpy) to trigger

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