Visible light-mediated photoredox catalysis has emerged as one of the fastest growing fields in organic synthesis. Typically, a photoactive catalyst absorbs light
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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 1 This work is licensed under a Creative Commons Attribution – NonCommercial – ShareAlike 4.0 International License . Photoredox catalysis Visible light – mediated photoredox catalysis has emerged as one of the fastest growing fields in organic synthesis . Typically, a photoactive catalyst absorbs light in the visible region and participates in single electron transfer processes with organic substrates. This is a mild, economical and environmentally friendly approach to promote radical – based organic transfo rmations and potentially unlock unique reaction pathways. The most well studied photoredox catalysts are complexes of ruthenium and iridium . Typical examples include tris(2,2 – bipyridine)ruthenium(II) and tris[2 – phenylpyridinato – C 2 , N ]iridium(III) . These complexes are unique in that the ligand – – centered e g orbital. Upon irradiation with visible light, an electron is transferred from the t 2g (ligand) which (afte r rapid intersystem crossing) results in an excited triplet state. The long lifetime of the triplet state (1100 ns) allows the photocatalyst to engage in single electron transfer (SET) reactions with organic molecules. Excited photocatalysts will initiall y act as either oxidants (reductive quenching cycle) or reducing agents (oxidative quenching cycle) depending on the substrate of the reaction. The resulting metal species will then undergo a second single electron oxidation/reduction, returning the cataly st to its original oxidation state. Substrates of photocatalyzed reactions may participate in either redox step in the catalytic cycle and will often participate in both. Redox potentials can be readily tuned for a given reaction by altering the metal used or changing the ligands (see above for examples). Kalyanasundaram. Coord. Chem. Rev. 1982, 46, 159; MacMillan, Chem. Rev . 2013 , 113 , 5322
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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 2 This work is licensed under a Creative Commons Attribution – NonCommercial – ShareAlike 4.0 International License . Early examples Chemical reactions that are promoted by light absorption (photochemistry) have been studied since the early 20 th century. The application of photocatalysts as a means of harvesting light energy in fields such as artificial photosynthesis and the production of chemical fuels has also been extensively studied. In contrast, up until recently, the application of photocatalysis for organic synthesis using visible light was relatively rare. Some key early examples, which paved the way for the recent explosion in this field, are outlined below. One of the earliest examples of visible light photoredox catalysis w as the reduction of electron – poor alkenes using Ru(bpy) 3 Cl 2 as the catalyst and BNAH as a stoichiometric reducing agent. Pac, JACS , 1981 , 103 , 6495 Fukuzumi and co – workers provided an – bromocarbonyl compounds using Ru(bpy) 3 Cl 2 as a photocatalysis. Fukuzumi, J. Phys. Chem ., 1990 , 94 , 722 One of the first examples of photocatalytic oxidation was reported by Cano – Yelo and Deronzier in 1984. A ruthenium photocatalyst along with a stoichiometric aryldiazonium salt could be employed for the oxidation of benzylic alcohols to aldehydes. Cano – Yelo and Deronzier, Tet. Lett ., 1984 , 25 , 5517 Fukuzumi also reported the use of the 9 – mesityl – 10 – methylacridinium ion as an effective photoredox catalyst. The first reaction reported using this catalyst was the cycloaddition of dioxygen with anthracene derivatives. This catalyst has since been applied to a range of other transformations (see section 3). Fukuzumi, JACS , 2004 , 126 , 15999
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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 3 This work is licensed under a Creative Commons Attribution – NonCommercial – ShareAlike 4.0 International License . Seminal reports While the examples of published during the 1980s and 1990s provided some early precedent for the concept of visible light – mediated photoredox catalysis, the dramatic increase of interest in this field is often attributed to 3 key papers from 2008 – 2009. In 2008, MacMillan et al . demonstrated that it is possible to merge SOMO organocatalysis and photoredox catalysis. This dual – catalysis system expanded the scope of enamine catalysis to include alky l halides as electrophiles. MacMillan, Science , 2008 , 322 , 77 Concurrently, Yoon and co – workers demonstrated that the intramolecular [2+2] cycloaddition of dienones can be promoted by photoredox catalysis. This report demonstrated how photoredox catalysis allows known, redox – mediated processes to proceed under relati vely mild conditions. Yoon, JACS , 2008 , 130 , 12886 In 2009, Stephenson employed photoredox catalysis for the reductive cleavage of aliphatic halides. A broad range of functional groups were tolerated and this transformation provided an alternative to the use of toxic tin reagents (commonly employed for red uctive dehalogenation). Stephenson, JACS , 2009 , 131 , 8756
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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 4 This work is licensed under a Creative Commons Attribution – NonCommercial – ShareAlike 4.0 International License . 1. Photoredox reactions catalyzed by ruthenium or iridium complexes Photoredox – catalyzed reactions can be classified according to whether the substrates undergo a net oxidative, reductive or redox neutral transformation. For net oxidative or net reductive reactions a stoichiometric oxidant or reducing agent is required, whilst in redox neutral processes substrates will undergo bot h single electron reduction and oxidation as part of the reaction mechanism. 1.1 Net oxidative reactions 1.1.1 Formation of i min ium ions via photoredox catalysis Iminium i ons can be generated by two – electron oxidation of tertiary amine substrates . Tertiary a mines are good e lectron donors, which can readily form aminium radical cation s by single – electron oxidation. The C – H bond dissociation energy of the – protons of an a minium radical cation is low, allowing a reducing agent to abstract a hydrogen atom to form an iminium ion. Alternatively, the aminium radical c – – amino radical, which then undergoes a second single electron oxidation to give the iminium ion. I minium ion s generated by photoredox catalysis can react with nucleophiles to form new carbon – carbon bond s . An early example is the photoredox – catalysed aza – Henry r eaction via an iminium ion intermediate . Oxygen acts as the terminal oxidant for this net oxidative process. Stephenson, JACS 2010 , 132, 1464; Wang, ACIE. 2012 , 51 , 8050 Subsequent studies have shown that the iminium ions generated from tetrahydroisoquinoline scaffolds can be trapped with a broad range of nucleophiles.
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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 5 This work is licensed under a Creative Commons Attribution – NonCommercial – ShareAlike 4.0 International License . Lei. Org. Biomol. Chem , 2013 , 11 , 2387 1.1.2 Oxidative cycliz ations Photocatalysis has also been used for the synthesis of benzothiazoles and indoles by oxidativie cyclization, with oxygen as a terminal oxidant. Li, Org. Lett. , 2012, 14 , 98 ; Zheng, ACIE , 2012 , 51 , 9562 1.2 Net Reductive reactions Net reductive reactions are those in which the substrate is reduced using photoredox catalysis in the presence of a stoichiometric reducing agent. 1.2.1 Alkene reduction Photoredox catalysis has be used for the reduction of electron – poor alkenes, with 1 – benzyl – 1,4 – dihydronicotinamide (BNAH) used as the stoichiometric reductant. BNAH reduces the excited ruthenium catalyst and the resultant Ru(I) complex then reduces the electron deficient alkene.
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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 6 This work is licensed under a Creative Commons Attribution – NonCommercial – ShareAlike 4.0 International License . Pac, JACS , 1981 , 103 , 6495 1.2.2 Ring opening/allylation An iridium photocatalyst in combination with stoichiometric Hantzsch ester has been used for the tandem epoxide – opening/allylation of ketoepoxides. Guindon, Synlett , 1998 , 213 1 .2.3 Reductive dehalogenation Reductive dehalogenation can be effected under mild conditions using photoredox catalysis. The reaction proceeds via a reductive quenching cycle, with DIPEA acting as the terminal reducing agent. Labeling studies showed that the DIPEA is the predominant hydrogen source for the radical intermediate. Stephenson, JACS , 2009 , 131 , 8756
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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 8 This work is licensed under a Creative Commons Attribution – NonCommercial – ShareAlike 4.0 International License . 1.3 Redox neutral reactions In redox neutral reactions the substrates participate in both the reductive and oxidative steps of the photocatalytic cycle, with no change to the overall oxidation state from starting materials to product. The ability to have both oxidation and reduction processes occurring simultaneously for one overall reaction can enable reaction pathways that would otherwise not be possible. 1.3.1 [2+2] Cycloadd i tions Thermally – forbidden [2+2] cycloaddition s can be promoted using photoredox catalysis. An example of this is the intramolecular [2+2] cycloaddition of dienones to form cyclobutane derivatives. Intermolecular [2+2] cycloadditions are also possible and proceed with good diastereoselectivity. To favour formation of non – dimeric products, it is important that one of the starting materials is an aryl enone. This reaction has been carried out enantioselectively by using Eu(OTf) 3 as a Lewis acid with an amino acid – derived chiral ligand. Yoon, JACS, 2009, 131 , 14604 ; Org. Lett. 2012, 14 , 1110; Science , 2014 , 34 4 , 392
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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 9 This work is licensed under a Creative Commons Attribution – NonCommercial – ShareAlike 4.0 International License . 1.3.2 [4+2] Cycloadditions Diels – Alder Reaction While m any Diels – Alder reactions proceed readily either under ambien t conditions or when heated, [4+2] cycloaddition of an electron – rich diene with an electron – rich dieneophile is generally not possible, even at high temperatiure. Photoredox catalysis can be used to promote the [4+2] cycloaddition of two electron – rich starting materials. Yoon, JACS , 2011 , 133 , 19350 1.3.3 C H arylation of amines The direct C H arylation of amines with cyano – bearing aromatics can be catalyzed by an Ir – photocatalyst. of catalysts and random organic substrates are rapidly screen ed to find novel and unexpected chemical reactions. MacMillan, Science , 2011 , 334 , 1114
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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 10 This work is licensed under a Creative Commons Attribution – NonCommercial – ShareAlike 4.0 International License . 1.3.4 Late – stage methylation and cyclopropanation of bioactive heterocycles Merck have applied photoredox catalysis for late – stage C H methylation and cyclopropanation of drugs and drug – like compounds. The mild reaction conditions provide an excellent means to alter complex molecules in the presence of a range of functional groups. DiRocco, ACIE , 2014 , 53 , 1 – 6 1.3.5 Trifluoromethylation Direct C H trifluoromethylation of aromatic and heteroaromatic compounds can be carried out using photoredox catalysis, with triflic chloride acting as the CF 3 source. This reaction can be used for late – stage functionalization of complex molecules. MacMillan, Nature , 2 011 , 480 , 224 A more m ild and scalable photocatalytic triflu o romethylation method has also been developed , with trifluoroacetic anhydride as a readily available CF 3 source that is easier to handle than triflic chloride . For this reaction pyridine N – oxide acts as a redox auxiliary, which forms a TFA – ester adduct with a significantly lower oxidation potential than TFAA.
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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 11 This work is licensed under a Creative Commons Attribution – NonCommercial – ShareAlike 4.0 International License . Stephenson , Nature C ommun . 2015 , 6 , 7919 1.3.6 Decarboxylative couplings Radical decarboxylation is an attractive method for organic synthesis. The major advantages are that carboxylic acids are abundant and inexpensive, the radical intermediates produced can be converted into many chemical products and that CO 2 is produced as a traceless byproduct. While there are many known methods for radical decarboxylation, these tend to require harsh conditions, prefunctionalization of the acid or high energy UV light. Photo redox catalysis offers a mild alternative for generating radical intermediates from carboxylic acids. – – oxo acids. The radical intermediates generated can be coupled to cyano – substituted aromatic compounds. Z. Zuo, D. MacMillan, J .Am. Chem. Soc. 2014, 136, 5257
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