Light Up the Transition Metal-Catalyzed Single-Electron Allylation

The combination of visible light photocatalysis and transition metal catalysis allows single-electron allylation reactions under mild and green conditions.A variety of feedstocks, including allylic compounds, dienes, alkynes, allenes, and alkenes, can serve as efficient allyl sources for single-electron allylations.The mechanisms of these single-election allylation reactions afford more flexibility than those of traditional two-electron allylations. Transition metal-catalyzed allylations are among the most important tools for the formation of chemical bonds. Unlike soft nucleophiles (pKa < 25), reactions of hard nucleophiles (pKa > 25) usually suffer from requiring organometallic reagents or the use of strong bases. In addition, traditional single-electron allylations always require rigorously controlled reaction conditions as well as the use of a stoichiometric reductant that often reduces functional group tolerance. Single-electron allylation reactions facilitated by synergistic transition-metal catalysis and visible light photocatalysis, however, can provide complementary advantages over traditional allylations. From this perspective, we highlight the recently discovered single-electron allylation reactions exploiting this synergistic catalysis strategy. Transition metal-catalyzed allylations are among the most important tools for the formation of chemical bonds. Unlike soft nucleophiles (pKa < 25), reactions of hard nucleophiles (pKa > 25) usually suffer from requiring organometallic reagents or the use of strong bases. In addition, traditional single-electron allylations always require rigorously controlled reaction conditions as well as the use of a stoichiometric reductant that often reduces functional group tolerance. Single-electron allylation reactions facilitated by synergistic transition-metal catalysis and visible light photocatalysis, however, can provide complementary advantages over traditional allylations. From this perspective, we highlight the recently discovered single-electron allylation reactions exploiting this synergistic catalysis strategy. The coupling of allyl donors (i.e., allyl halides, esters, epoxides, and alcohols) and nucleophilic acceptors (i.e., malonates, enamines, alcohols, and amines) by palladium catalysts, namely, the Tsuji-Trost reaction, has been established as one of the most important tools in modern synthetic chemistry [1.Tsuji J. et al.Organic syntheses by means of noble metal compounds XVII. Reaction of π-allylpalladium chloride with nucleophiles.Tetrahedron Lett. 1965; 6: 4387-4388Crossref Scopus (405) Google Scholar, 2.Tsuji J. Carbon—carbon bond formation via palladium complexes.Acc. Chem. 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Moreover, compared with classic single-electron allylations, metallaphotocatalytic single-electron allylations avoid the use of stoichiometric metal reducing reagents (i.e., Zn, Mn, and [Cp2TiCl]) [39.Zhou W.-J. et al.Merging transition-metal catalysis with photoredox catalysis: an environmentally friendly strategy for C–H functionalization.Synthesis. 2018; 50: 3359-3378Crossref Scopus (32) Google Scholar]. Notably, although the activation of inert C–H and C–C bonds are involved, all the metallaphotocatalytic allylation reactions occur facilely under ambient temperature due to the unique working manner of visible light photocatalysis. In this review, we highlight these recently discovered but rapidly advancing single-electron allylation reactions of unusual nucleophilic allyl acceptors with a variety of allyl donors in the presence of a TM catalyst, a photocatalyst, and low-energy visible light. Moreover, the application of similar dual catalysis strategies to nucleophilic single-electron allylations of aldehydes, aryl bromides, and vinyl bromides will be reviewed here. A general catalytic cycle for traditional two-electron allylations is shown in Figure 2A . Coordination and oxidative addition of the allyl donor to a low-valent TM catalyst is followed by substitution (soft nucleophiles) or transmetalation (hard nucleophiles), and subsequent reductive elimination gives the allylated product. A possible mechanism of the Krische-type nucleophilic allylations is described in Figure 2B. An Ir-catalyzed hydrogen-transfer process is involved with in situ oxidation of the alcohol substrate to generate an aldehyde electrophile and an Ir–H species. When the aldehyde is directly used, additional i-PrOH is required as the hydrogen source to form the Ir–H species. Besides, intramolecular allyl transfer to aldehydes in the electron neutral Ir(III) species is the key to successful nucleophilic allylations. The classic single-electron allylation, as shown in Figure 2C, shares several elementary steps with electrophilic two-electron allylations in Figure 2A. The allylic intermediate is reduced by the metal reductant (e.g., Cp2TiCl), delivering the allylic radical and regenerating Pd(0). The radical is then trapped by homogeneous Cp2TiCl that can be captured by an electrophilic reagent. When combined with visible light photocatalysis, the mechanism of TM-catalyzed allylations is more flexible (Figure 2D–F; some possible reaction pathways were proposed according to different substrates and catalyst systems). The mechanism of reaction has a ready capability to adapt to new, different, or changing requirements. The mechanism for the single-electron allylation (I) is shown in Figure 2D. First, oxidative addition of the allyl donor to the M(n) center gives an M(n+2) intermediate (occasionally this is assisted by a Brønsted acid), which is the same process as in traditional two-electron allylation. Sequential radical addition, reductive elimination, and single-electron reduction (path a), or sequential single-electron reduction, radical addition, and reductive elimination (path b) affords the allylated product with concomitant regeneration of the M(n) catalyst. Otherwise, a reaction sequence involving single-electron reduction, fragmentation of the π-allyl-M(n+1) intermediate, and radical–radical cross-coupling (path c) was also shown to be possible. For the nucleophilic single-electron allylation, nucleophilic addition of η1-allyl-metal species to carbonyl compounds (path d) provides the homoallylic alcohol product. In either case, the photocatalyst facilitates the single-electron allylation processes by providing the electron and thus the intermediate radical. The mechanism for the single-electron allylation (II) is shown in Figure 2E. Oxidative addition of the bromide to the Ni(0) center gives an Ni(II) intermediate that is converted to a Ni(I) intermediate and a bromide radical by the exited photocatalyst via a triplet–triplet energy transfer and subsequent fragmentation. The Ni(I) intermediate captures the allyl radical that was generated from the alkene and a bromide radical via a rapid hydrogen-atom-transfer process to give an allyl-Ni(II) intermediate. Reductive elimination from this species delivers the final allylation product and regenerates the Ni(0) catalyst. The mechanism for the single-electron allylation (III) is shown in Figure 2F. The addition of an allyl radical to a low-valent Cr(II) catalyst gives a Cr(III) intermediate that reacts with an aldehyde to afford a homoallylic alcohol product and a Cr(III) species. Notably, the photocatalytic cycle not only provides the allyl radical from an alkene via a single-electron oxidation/deprotonation process but also reduces the Cr(III) species to regenerate the reactive Cr(II) catalyst. Allylic compounds are used widely in TM-catalyzed allylation [4.Trost B.M. Van Vranken D.L. Asymmetric transition metal-catalyzed allylic alkylations.Chem. Rev. 1996; 96: 395-422Crossref PubMed Scopus (2766) Google Scholar,5.Trost B.M. Crawley M.L. Asymmetric transition-metal-catalyzed allylic alkylations: applications in total synthesis.Chem. Rev. 2003; 103: 2921-2944Crossref PubMed Scopus (2143) Google Scholar,51.Feng J. et al.Enantioselective alcohol C-H functionalization for polyketide construction: unlocking redox-economy and site-selectivity for ideal chemical synthesis.J. Am. Chem. Soc. 2016; 138: 5467-5478Crossref PubMed Scopus (87) Google Scholar]. 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Less stable radicals were more likely to add to the Pd π-allyl complex to generate a Pd(III) intermediate and afford a higher ee (path a in Figure 2D), while a stable radical can directly couple with the free allyl radical generated by reduction of the Pd π-allyl complex to give a racemic product (path c in Figure 2D). Around the same time, Xiao, Lu, and coworkers reported a C–H allylation of amines 13 and 14 by combining Pd and photoredox catalysis (Figure 3C) [55.Xuan J. et al.Redox-neutral α-allylation of amines by combining palladium catalysis and visible-light photoredox catalysis.Angew. Chem. Int. Ed. 2015; 54: 1625-1628Crossref PubMed Scopus (182) Google Scholar]. Both cyclic and linear amines can react smoothly with a series of allylic alcohol derivatives, even free allylic alcohols and allyl bromide 15, under mild reaction conditions. Corresponding C–H allylation products 16 or 17 were afforded in moderate-to-good yields. A plausible reaction pathway (path c in Figure 2D) was proposed based on electron paramagnetic resonance spectroscopy and other experimental results. A breakthrough in the enantioselective allylic alkylation via synergistic photoredox/Pd catalysis was disclosed by the Yu group in 2018 (Figure 3D) [56.Zhang H.-H. et al.Enantioselective allylic alkylation with 4-alkyl-1,4-dihydro-pyridines enabled by photoredox/palladium cocatalysis.J. Am. Chem. Soc. 2018; 140: 16914-16919Crossref PubMed Scopus (88) Google Scholar]. In this work, alkyl radicals were generated from 4-alkyl-1,4-dihydropyridines 19 and coupled with chiral π-allyl-Pd complexes to afford primarily the branched products 20 in good yields and with excellent enantioselectivities. 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Quantum mechanical calculations indicated that the Ni(0)-to-Ni(II) oxidative addition step occurred before the radical addition to Ni (path a in Figure 2D). Compared with (E)-alkenes, (Z)-alkenes are difficult to prepare because of thermodynamic instability (geometrical repulsion). However, alkenes can undergo photoinduced geometric E → Z isomerization [61.Singh K. et al.Facile synthesis of Z-alkenes via uphill catalysis.J. Am. Chem. Soc. 2018; 136: 5275-5278Crossref Scopus (178) Google Scholar, 62.Metternich J.B. Gilmour R. A bio-inspired, catalytic E→Z isomerization of activated olefins.J. Am. Chem. Soc. 2015; 137: 11254-11257Crossref PubMed Scopus (165) Google Scholar, 63.Molloy J.J. et al.Contra-thermodynamic, photocatalytic E→Z isomerization of styrenyl boron species: vectors to facilitate exploration of two-dimensional chemical space.Angew. Chem. Int. 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An Ir-photocatalyst having higher triple-state energy can further convert (E)-1,4-dienes 31 into (Z)-1,4-dienes 30. Stoichiometric amounts of metal reductants are always crucial in the reactions of Ni-catalyzed allylation of carbonyl compounds. In 2019, Gualandi and Cozzi realized a Ni/photoredox cocatalyzed allylation of aliphatic and aromatic aldehydes 32 with allyl acetate 33, using tertiary amine as the terminal reductant (Figure 4C; see the mechanism in Figure 2D, path d) [67.Gualandi A. et al.Allylation of aldehydes by dual photoredox and nickel catalysis.Chem. Commun. 2019; 55: 6838-6841Crossref PubMed Google Scholar]. In the future, more atom-economic acceptors, by activating inert C–H and Si–H bonds for metallaphotoredox-catalyzed single-electron allylations of allylic compounds, should be further investigated. 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In 2019, Kanai and colleagues [99.Mitsunuma H. et al.Catalytic asymmetric allylation of aldehydes with alkenes through allylic C(sp3)–H functionalization mediated by organophotoredox and chiral chromium hybrid catalysis.Chem. Sci. 2019; 10: 3459-3465Crossref PubMed Google Scholar] realized an asymmetric allylation of aldehydes 52 with alkenes 51 by a combination of organophotoredox and chiral Cr complex catalysis, affording chiral homoallylic alcohols 53 with a >20:1 diastereomeric ratio and up to 99% ee (Figure 6C). Chiral indane-BOX ligand and Mg(ClO4)2 were both shown to be responsible for the good yield and enantioselectivity. Photoredox catalytic allylic C–H bond activation has been used to realize the redox-neutral single-electron allylations of bromides and aldehydes with alkenes. In the future, suitable synergistic TM and photocatalytic systems should be developed to address the diversity of substrates and afford a high level of enantiocontrol. The recent exploitation of single-electron allylations through synergistic TM catalysis and visible light photocatalysis has provided a new platform for achieving allylation reactions. However, there are still important issues to be addressed in this nascent research field (see Outstanding Questions). First, although Pd-, Rh-, Ni-, Co-, and Cr-based organometallic catalysts have been demonstrated to be effective, many other TMs, such as Ir, Mo, and even the non-noble metals Cu and Fe, which have unique properties and might be used to address the remaining challenges, are still significantly underexplored. Second, in-depth mechanistic studies to obtain significant insights into the details of single-electron allylation reactions are also missing, even though they might be helpful for the further creative development of new reactions. Third, there are few examples of highly enantioselective single-electron allylations through synergistic TM catalysis and visible light photocatalysis. Thus, the development of general catalytic systems for single-electron allylations with high levels of regio- and enantiocontrol is still highly desirable. Ultimately, we believe that single-electron allylations will continue to grow into a practical synthetic tool that can be applied to a variety of reaction scenarios and will streamline future chemical syntheses.Outstanding QuestionsCan more atom-economic acceptors be developed for metallaphotoredox-catalyzed single-electron allylations of allylic compounds?Can we develop asymmetric variants of atom-economic allyl donors?Are we able to expand the diversity of substrates and afford a high level of enantiocontrol using synergistic transition metal and photocatalytic systems?Can other transition metals (e.g., Ir, Mo, Cu, and Fe) with unique properties be used to address the remaining synthetic challenges and afford new and/or improved reactivity? Can more atom-economic acceptors be developed for metallaphotoredox-catalyzed single-electron allylations of allylic compounds? Can we develop asymmetric variants of atom-economic allyl donors? Are we able to expand the diversity of substrates and afford a high level of enantiocontrol using synergistic transition metal and photocatalytic systems? Can other transition metals (e.g., Ir, Mo, Cu, and Fe) with unique properties be used to address the remaining synthetic challenges and afford new and/or improved reactivity? We are grateful for financial support from the National Science Foundation of China (No. 21772052 , 21772053 , 21822103 , 21820102003 , and 91956201 ), the Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019 ), and the Natural Science Foundation of Hubei Province ( 2017AHB047 ). a reaction of an allyl cation with a nucleophile (e.g., alcohol, amine, or 1,3-dicarbonyl), also called allylic alkylation or substitution. a nucleophile with a >25 pKa value is termed a hard nucleophile; conversely, a nucleophile with a <25 pKa is considered a soft nucleophile. dual catalysis by merging transition-metal catalysis and photocatalysis. a reaction of an allyl anion with an electrophile (e.g., an aldehyde or imine), also called umpolung allylation. the acceleration of a chemical reaction by an added photosensitizer under the lighting condition. a branch of photocatalysis that harnesses the light energy to accelerate a chemical reaction via single-electron transfer events. an allylation reaction involving allyl radical intermediates or single electron transfer events. an allylation reaction involving allyl cation or anion intermediates, wherein allyl radical intermediates or single electron transfer processes are not involved.