Visible Light Photoredox Catalyst Intermediates Newsletter

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Visible light photoredox catalyst Intermediates Newsletter

Written by Professor Emeritus Takeo Taguchi, Faculty of Pharmaceutical Science, Tokyo Pharmaceutical University

1. Preface In 2008, Science carried a research paper titled “Merging Photoredox Catalysis with Organocatalysis: The Direct Asymmetric Alkylation of Aldehydes” by MacMillan and Nicewics (Scheme 1) [1]. Using 2+ Ru(bpy)3 complex 5a as a photoredox catalyst, a 15W fluorescent light bulb as a photon source, and imidazolidinone derivative 4 developed by the authors’ group as a chiral amine catalyst, the process is enantioselective alpha-alkylation of aldehyde by alkyl bromide 2 with its beta-position replaced by an electron withdrawing group such as carbonyl group. In the same year, Yoon, et al. reported [2 + 2] 2+ cycloaddition reaction between α,β-unsaturated carbonyl compounds using Ru(bpy)3 complex as a photoredox catalyst [2]. These papers attracted attention as reports of catalytic organic synthesis reactions involving radical species using the characteristics of the one-electron transfer cycle of a visible light photoredox metal catalyst, and research developments have accelerated in the 10-plus years since [3]. In the field of synthesis of fluorine compounds, many new developments using photoredox catalysts have been reported. This article will present an overview of such synthesis centering on action principles of visible light photoredox catalysts. In the next article, I will discuss the latest developments concerning synthesis of fluorine compounds using visible light photoredox catalysts.

Scheme 1 Merging Amine Catalysis and Photoredox Catalysis for Enatioselective Alkylation of Aldehydes

2. Action principles of visible light photoredox catalysts 2.1. Summary of characteristics of visible light photoredox catalysts

A visible light photoredox catalyst can have reaction activity of both one-electron oxidation and one- electron reduction of substrates in the quenching cycle, a process in which the catalyst absorbs visible light and its electron configuration changes from the ground state to a triplet excited state and then from the excited state to the ground state. Therefore, in a system using a photoredox catalyst, various characteristic reactions can be achieved, including those that are difficult otherwise. For example, if an oxidizing agent and a reducing agent coexist in a thermal reaction system, usually the reaction between the oxidizing and reducing agents occurs first. It is difficult to design a reaction system in which each reagent acts selectively on the substrate and the intermediates generated in the system. Furthermore, compared to conventional photochemical reactions using high-energy UV irradiation, such redox catalyzed reactions occur under low-energy (long-wavelength) visible light irradiation and therefore enable selective generation of radical species from substrates while inhibition of side reactions such as decomposition of substrates, intermediates, and products in the system can be expected. In other words, these reactions proceed under relaxed conditions and it is easy to apply late-stage functionalization, which can also be a characteristic. It is also noteworthy that the inexhaustible supply of sunlight is used as an energy source for reactions.

A visible light photoredox catalyst is a photosensitizer which absorbs visible light. It is photoexcited and shows oxidation and reduction reactivity to organic substances that cannot absorb visible light directly (the redox cycle will be described in the next section). Fig. 1 shows the structural formulas of typical visible light photoredox catalysts, the maximum absorption wavelength ( max), and the reduction potential (E0red vs SCE) of the one-electron reduction of the substrate from the triplet photoexcited state (the one- electron oxidation step of the catalyst) and the oxidation potential (E0ox vs SCE) of one-electron oxidation of the substrate [4]. Historically, ruthenium complexes with polypyridine ligands (such as Ru(bpy)3Cl2 5a) and iridium complexes (such as fac-Ir(ppy)3 6a) were the first focus of research, followed by copper complexes and various other metal complexes. Some of these metal complexes are commercially available but are relatively expensive. Recently, reports on the use of organocatalysts such as organic dyes have been on the increase. Eosin (Eosin Y 7a), a typical organic dye, and rhodamine are much cheaper than metal complex reagents. The absorption wavelength ( max) and redox potential (E0ox / E0red) of visible light photoredox catalysts can be varied by the type of metal, chemical modification of the ligand, changing the combination of ligand structures, etc. in the case of a metal complex, and by compounds with different basic structures in the case of an organocatalyst. Therefore, it is important to design the catalyst and select the photon source to match the redox potentials of substrates and intermediates used in the reaction [3, 4, 5].

Fig. 1 Typical Photoredox Catalysts with their max and Redox Properties (E0 vs SCE).

2.2. Oxidative quenching and reductive quenching

This section takes up ruthenium complex Ru(II)(bpy)3Cl2 5a, a typical visible light photoredox catalyst, to outline the principle of catalytic action (Fig. 2). A bivalent ruthenium complex Ru(bpy)3(II) 5a ( max 452 nm) in the ground state changes its electron configuration to the triplet excited state 5a* formed with electron transition from ruthenium metal to the * orbit of the bipyridine ligand (MLCT: metal-to-ligand charge transfer) caused by visible light irradiation. That is, one electron each is located in the two single occupied molecular orbitals HOSO and LUSO in Ru(bpy)3(II)* 5a*. In general, the triplet photoexcited state of metal complexes used as visible light photoredox catalysts is long lasting. The life of Ru(bpy)3(II)* 5a* is reported to be 1100 ns (nanoseconds).

Fig. 2 Oxidative and Reductive Quenching Cycles in Photoredox Catalysis

A direct electron transition from the triplet excited state Ru(bpy)3(II)* 5a* to the original ground state

Ru(bpy)3(II) 5a is a prohibited process. These two single occupied molecular orbitals individually take one- electron oxidation or one-electron reduction action and generate radical intermediates (ED•+, EA•-) by electron transfer from/to electron donors (ED) or electron acceptors (EA) in the system. The univalent

Ru(bpy)3(I) 5a-red or trivalent Ru(bpy)3(III) 5a-ox which is generated at the same time as above returns to the original ground state Ru(bpy)3(II) 5a in the next stage through the process of one-electron reduction or one-electron oxidation, the reverse of the earlier process, of another substrate in the system (it may be the starting material or a radical species of a reaction intermediate generated in the system). As shown in

Fig. 2, the cycle starting from the change to the photoexcited state Ru(bpy)3(II)* 5a* and returning to the original ground state Ru(bpy)3(II) 5a with the catalyst at the center has two directions – the clockwise (right side) reduction-oxidation cycle (reductive quenching cycle) and the counterclockwise (left side) oxidation-reduction cycle (oxidative quenching cycle). Either way, the cycle consists of a two-stage one- electron transfer system. Therefore, an atomically efficient reaction can be designed by making the radical species generated in the first step react and then incorporating a reverse electron transfer process in the second step. As an aside regarding the terms of redox catalytic reaction, the clockwise (right side) cycle starting from the reduction of excited state catalyst in Fig. 2 is referred to as a reductive quenching cycle. In this case, the external substrate is involved in a reaction in the order of oxidation-reduction.

2.3 Example of reaction of visible light photoredox metal catalyst: Asymmetric alkylation of aldehydes As an example of reaction of the above catalytic cycle, I will take up the asymmetric alkylation of aldehydes (Scheme 1) reported by MacMillan, as mentioned at the beginning of this article, and outline the working hypothesis of the authors and results (Fig. 3, Scheme 2) [1].

Fig. 3 Catalytic Cycles in Enantioselective -Alkylation of Aldehydes

As shown in the redox cycle part of Fig. 3, the reducing power (E0 = -1.33 V vs SCE) of univalent ruthenium complex Ru(bpy)3(I) 5a-red makes it easy to perform one-electron reduction of -bromo carbonyl compound 2 (for example, PhCOCH2Br: E = -0.98 V vs SCE). From their reaction, corresponding radical species 8 is generated. It is thought that at the same time, bivalent ruthenium complex

Ru(bpy)3(II) 5a, the starting material, is regenerated quickly. The radical species 8 generated here has a lower electron density due to adjacent carbonyl substitution and is expected to have electrophilic reactivity. Meanwhile, as shown in the organocatalytic cycle involving chiral amines, the reaction of aldehyde 1 with imidazolidinone 4 generates enamine 9. The olefin part of enamine 9 has a high electron density due to nitrogen substitution and is expected to react smoothly with electrophilic electron-

deficient radical species 8. Furthermore, a conformational analysis using DFT calculation suggested a high degree of asymmetric induction (face selectivity) at the reaction point. The -amino radical 10 (typically E = -0.92 ~ -1.12 V vs SCE) generated by the addition of radical species 8 to enamine 9 is readily one-electron oxidized by the photoexcited state ruthenium complex Ru(bpy)3(II)* 5a* and converted into the iminium intermediate 11. Then by hydrolysis accompanied by the regeneration of imidazolidinone 4, the desired alkylation product 3 is obtained. The initiation step in the catalytic cycle of this reaction is the generation of radical 8 by the reaction of the univalent ruthenium complex Ru(bpy)3(I) 5a-red with -bromocarbonyl compound 2. As experimentally confirmed, the Ru(bpy)3(I) 5a-red required for initiation of the reaction is generated by reduction of photoexcited ruthenium complex Ru(bpy)3(II)* 5a* by amine (imidazolidinone 4) and enamine 9 that coexist as organocatalysts. In other words, in this reaction, an amount of organocatalyst imidazolidinone 4 corresponding to the ruthenium catalyst (0.5 mol%) is sacrificed to initiate the reaction. In some reactions, amines and other substances added as a reducing agent in a redox metal catalyst cycle system are used to act only as an electron source so that their structure does not affect the product. Such amines are called sacrificial reductant or sacrificial electron-donor.

Scheme 2 Examples of Enantioselective -Alkylation of Aldehydes

Scheme 2 shows part of the results. By reaction with bromides of ketones, malonic esters, -keto esters and acetic trifluoroethyl esters using 0.5 mol% ruthenium catalyst, the desired alkylation products 3 are obtained with a good yield (70-93%) and high enantioselectivity (90-99% ee). It is noteworthy that the reaction of sterically bulky tertiary halogenides also generates the corresponding product 1d with a good yield.

2.4 Example of reaction of visible light photoredox organocatalyst: Anti-Markovnikov addition reaction of carboxylic acids and hydrogen chlorides Addition reaction of alcohols, carboxylic acids, sulfonic acid amides and hydrogen halogenides to alkenes by acid catalysts is an important industrial process. As a mechanism, the term Markovnikov addition is well

known in connection with electrophilic addition and regioselectivity of products. It is explained on the basis of the stability of carbocation 13 or 14, intermediates generated by the protonation of alkenes (Scheme 3).

Scheme 3 Markovnikov Addition of Nucleophiles to Alkenes under Acidic Conditions

On the other hand, as an example of reaction of anti-Markovnikov addition showing regioselectivity the reverse of the above, radical addition reaction of HBr to alkenes using peroxides or the catalytic action of peroxides coexisting as impurities is described in organic chemistry textbooks (Scheme 4). This reaction is specific to HBr and the reaction of the homologous hydrogen halogenides HF, HCl and HI with alkenes always proceeds by electrophilic addition (Markovnikov type products).

Scheme 4 Anti-Markovnikov Addition of HBr to Alkenes under Radical Conditions

Concerning types of alkenes and nucleophilic agents to be used, generally usable anti-Markovnikov selective addition reaction has been an issue not solved yet. As an approach to this issue, a method of activating alkenes by one-electron oxidation has been studied. It is suggested that regioselectivity of reaction of polar nucleophiles (NuH) such as alcohols and hydrogen halogenides to cationic radical species 18 generated by one-electron oxidation of alkenes is determined by the stability of the cation radicals with electric charge detached 19A, 19B (distonic cation radicals) which are generated by bonding of nucleophiles. Because polysubstituted radicals 19A are dominant in percentage terms, anti- Markovnikov type adduct 20 is obtained (Scheme 5) [6, 7].

Scheme 5 Regioselectivity in Addition of Polar Nucleophile to Alkene Cation-radical Defined by Distonic Cation-Radical Stability

The key to the success of this reaction is efficient one-electron oxidation of alkenes, and Nicewicz et al. report anti-Markovnikov type addition reactions (Alkene Hydrofunctionalization) of various polar nucleophiles (NuH) to styrene derivatives and alkyl group trisubstituted alkenes as alkenes using acridinium salt (7b Mes-Acr-Me+, Scheme 6) found by the pioneering work of Fukuzumi et al. and its analogues as visible light photoredox organocatalysts. The reactions are outlined below.

Scheme 6 Mes-Acr-Me+ 7b, Exited State 7b* and Reductive Quenching via Radical 7b•

Concerning one-electron oxidation of alkenes, the structures of typical alkenes and the redox potentials of oxidants are shown below (Fig 4) [4]. In the case of a metal complex such as ruthenium complex 2+ 3+ [Ru(bpy)3] , a typical visible light photoredox catalyst, for example ([Ru(bpy)3] : Ered = +1.29 V) can oxidize alkenes with an oxidation potential of +1.3 V or less, but as Fig. 6 shows clearly, it cannot oxidize very common alkenes such as styrene derivatives (A, D) and alkyl-substituted alkenes (B, C, E). 1- cyanonaphthalene (1-CN-Np) is a powerful photo-oxidizer, but it is not easy to use because it can cause side reactions involving cyano groups. In 2004, Fukuzumi et al. reported that 9-mesityl-10- methylacridinium perchlorate 7b (Mes-Acr-Me+) in the triplet excited state 7b* has strong oxidizing power with reduction potential (E*red 7b*/7b•) of +2.06 V vs SCE and it is also long lasting [8].

Fig. 4 Some Oxidants and Alkene Redox Potentials

Nicewicz proposed to use Mes-Acr-Me+ 7b in triplet excited state 7b* for one-electron oxidation of alkenes (step 1: from 12 to 18), and considered interconnection of the catalytic cycle of Mes-Acr-Me+ 7b and the hydrogen atom donation cycle from the cation radical 19A combined with a nucleophilic agent via radical 19A’ to the final product 46 (Scheme 7). Scheme 7 is a conclusive cycle diagram. Nicewicz reported that the use of thiophenol 21 as a hydrogen atom donor results in efficient hydrogen atom donation in step 4 and efficient regeneration of catalyst 7b by one-electron oxidation of catalytic radical species 7b• in step 5 [7], [9, 10].

Scheme 7 Proposed Mechanism of Photoredox-Catalyzed Anti-Markovnikov Alkene Hydrofunctionalization Reactions

Typical examples of anti-Markovnikov addition reaction of carboxylic acids, sulfonic acid amides (TfNH2), and hydrogen chlorides (2,6-lutidine•HCl) to alkenes using Mes-Acr-Me+ 7b as a visible light photoredox catalyst are shown below (Scheme 8) [7], [9, 10]. To alkenes, 1-5 mol% Mes-Acr-Me+ 7b was used as a

redox catalyst and 2,6-lutidine was added as base to form a salt with the nucleophilic agent.

Scheme 8 Catalytic Anti-Markovnikov Addition of RCOOH, TfNH2, HCl to Alkenes

Conclusion In this article, I have mainly discussed the principle of one-electron transfer cycle of visible light photoredox catalysis, an area in which research developments have accelerated significantly in the last 10-plus years. For specific examples of reaction, please refer to the review of references cited and the original papers. The use of visible light photoredox catalysts enables reactions at lower temperatures than in conventional reactions due to efficient transfer of light energy. This means simple and inexpensive compounds such as oxygen and amines can be used as oxidizing and reducing agents. In cross-coupling and other reactions, it is possible to avoid the use of conventional highly toxic reagents and expensive reagents, and strict water- and oxygen-free conditions are not required. As a result, a large number of more controlled radical reactions have been achieved. Reagent manufacturers have also quickly established systems to sell metal complexes and other related reagents and photo-reaction apparatus, which has brought about deepening of research and acceleration of competition among researchers. In the next article, I will review visible light photoredox catalyst reactions in fluorine compound synthesis.

References cited [1] D. A. Nicewics, D. W. C. MacMillan, Science 2008, 322, 77-80. [2] (a) M. Ischay, M. Anzovino, J. Du, T. P. Yoon, J. Am. Chem. Soc. 2008, 130, 12886−12887. See also (b) T. P. Yoon, Acc. Chem. Res. 2016, 49, 2307−2315. [3] Selected reviews on photoredoxcatalysis: (a) D. Ravelli, S. Protti, M. Fagnoni, Chem. Rev. 2016, 116, 9850. (b) K. L. Skubi, T. R. Blum, T. P. Yoon, Chem. Rev. 2016, 116, 10035. (c) M. H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org. Chem. 2016, 81, 6898. (d) T. Gensch, M. Teders, F. Glorius, J. Org. Chem. 2017, 82, 9154. (e) L. Marzo, S. K. Pagire, O. Reiser, B. König, Angew. Chem. Int. Ed. 2018, 57, 10034-10072. [4] (a) J. Tucker, C. Stephenson, J. Org. Chem. 2012, 77, 1617−1622. (b) H. Roth, N. Romero, D. A. Nicewicz, Synlett 2016, 27, 714−723. [5] M. Akita, T. Koike, Farumashia, 2017, 53, 865-869. [6] D. Mangion, D.R. Arnold, Acc. Chem. Res. 2002, 35, 297−304. [7] K. A. Margrey, D. A. Nicewicz, Acc. Chem. Res. 2016, 49, 2295−2306. [8] (a) S. Fukuzumi, H. Kotani, K. Ohkubo, S. Ogo, N. V. Tkachenko, H. Lemmetyinen, J. Am. Chem. Soc. 2004, 126, 1600−1601. (b) K. Ohkubo, K. Mizushima, R. Iwata, K. Souma, N. Suzuki, S. Fukuzumi, Chem. Commun. 2010, 46, 601. [9] T. M. Nguyen, D. A. Nicewicz, J. Am. Chem. Soc. 2013, 135, 9588−9591. [10] D. J. Wilger, J.-M. M. Grandjean, T. R. Lammert, D. A. Nicewicz, Nat. Chem. 2014, 6, 720−726.

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