Visible Light Mediated, Redox Neutral Remote 1,6 ... - ACS Publications

Research Article Cite This: ACS Catal. 2018, 8, 6401−6406

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Visible Light Mediated, Redox Neutral Remote 1,6Difunctionalizations of Alkenes Wei Shu,† Estíbaliz Merino,† and Cristina Nevado*,† †

Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland S Supporting Information *

ABSTRACT: A photoinduced cascade strategy is presented here for the remote functionalization of alkenes under redox neutral conditions. A broad portfolio of alkyl groups has been added to double bonds to produce, upon 1,5-HAT, remote Ccentered radicals which can be harvested in the presence of Oor C-nucleophiles to efficiently form Csp3−O and Csp3−Csp2 bonds at room temperature. KEYWORDS: photocatalysis, redox neutral, remote functionalization, alkene, radical, oxy-alkylation, carbo-alkylation

1. INTRODUCTION Alkene difunctionalizations play a prominent role in the efficient assembly of molecular complexity.1 A large degree of diversity in terms of the functional groups added across double bonds has been achieved by means of oxidative conditions, including, but not limited to oxy-arylation,2 carbo-alkylation,3 amino-alkylation,4 and oxy-alkylation5,6 reactions (Scheme 1A).

this context resulted in successful 1,6-oxy- and 1,6-azidotrifluoromethylations of alkenes.11 These protocols utilize stoichiometric amounts of hypervalent iodine reagents12 at elevated temperature to trigger the addition of the trifluoromethyl group onto the alkene. The remote functionalization of the Csp3−H bonds requires a vicinal heteroatom-containing functionality (such as O, N, CO) in combination with MeOH and TMSN3 as nucleophiles (Scheme 1B, left).11a,c,d Photoredox catalysis has emerged as a powerful tool to enable single electron transfer (SET) reactions under mild conditions by taking advantage of photoexcited catalysts.6,7e−j,13 Thus, as part of our ongoing interest in the remote functionalization of Csp3−H bonds,14 we set out to develop a visible-light mediated, redox neutral 1,6-difunctionalization of unactivated alkenes. The mild reaction conditions enabled us to expand the portfolio of C-based functionalities that can be added across the π-system. Further, the functionalization of the remote Csp3−H bonds could be performed with both O- as well as, for the first time, C-based nucleophiles, thus demonstrating the complementarity and extended functional group compatibility of this light-mediated protocol.

Scheme 1. Strategies for the Difunctionalization of Alkenes

2. RESULTS AND DISCUSSION The reaction of diethyl 2-allyl-2-(4-methoxyphenethyl)malonate in the presence of ethyl 2-bromo-2,2-difluoroacetate was selected to find the optimal conditions. After initial screening of different photocatalysts to reduce the C−Br bond,15 we found that the desired 1,6-acetoxy alkylation product 1 could be obtained in 59% yield using 2 mol % of Ir(ppy)3 upon irradiation with blue LED (34 W) in the presence of AgOAc in acetonitrile at room temperature (Table 1, entries 1−3). Different solvents were tested next: while toluene or DMF decreased the reaction efficiency (Table 1,

1,n-Hydrogen atom transfer (HAT) processes provide an exceptional opportunity for the remote functionalization of inert Csp3−H bonds.7 However, examples of 1,n-difunctionalizations of alkenes as a result of the combination of olefin functionalization and 1,n-HAT are still scarce (Scheme 1B).8 Multiple challenges hamper the successful development of these transformations including the promiscuous reactivity of different intermediates (M1/M1′, M2/M2′) as well as their propensity to undergo competitive side reactions. Thus, intermediates M1 and M2 might undergo radical atom-transfer processes to deliver hydroalkylation or haloalkylation products,9 whereas carbocationic intermediates M1′ and M2′ tend to undergo elimination reactions.10 Elegant work by Liu et al. in © XXXX American Chemical Society

Received: February 20, 2018 Revised: May 31, 2018

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DOI: 10.1021/acscatal.8b00707 ACS Catal. 2018, 8, 6401−6406

Research Article

ACS Catalysis Table 1. Optimization of the Reaction Conditionsa

entry

catalyst

additive, solvent

1 (yield, %)

1 2 3 4 5 6 7 8 9 10b 11

Ir(ppy)3 [Ir{dF(CF3)ppy}2(dtbpy)]PF6 Ru(bpy)3Cl·6H2O Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 No [Ir] or no light

AgOAc, CH3CN AgOAc, CH3CN AgOAc, CH3CN AgOAc, toluene AgOAc, DMF AgOAc, 1,2-DCE AgOAc, CH2Cl2 K/LiOAc, CH2Cl2 TBAOAc, CH2Cl2 AgOAc, CH2Cl2 AgOAc, CH2Cl2

36 0 0 31 33 66 71 0 31 71 (67) 0

a Alkene (0.1 mmol), alkyl bromide (2 equiv), MOAc (2 equiv) in solvent (0.1 M), 34 W blue LED. The yield was determined by crude 1H NMR using mesitylene as internal standard. In brackets: isolated yield after column chromatography. bAgOAc (1.5 equiv).

entries 4 and 5), chlorinated solvents had a positive effect on the reaction outcome (Table 1, entries 6 and 7). Different additives were also investigated (Table 1, entries 8−9). The best yield in 1 was obtained when 1.5 equiv of AgOAc were used (Table 1, entry 10). In contrast, in the absence of either Ircatalyst or light, 1 was not observed (Table 1, entry 11) thus confirming the important role of both parameters (metal and light) for a successful outcome in these transformations. Using diethyl 2-allyl-2-(4-methoxyphenethyl)malonate and ethyl 2-bromo-2,2-difluoroacetate, different oxygen-based nucleophiles were explored (Scheme 2). AgOBz delivered the corresponding 1,6-oxocarbofunctionalization product 2 in 65% yield. Interestingly, the reaction could be carried out in the presence of Ag2CO3 and 2 equiv of propanoic or p-toluic acid, to deliver the corresponding esters in comparable yields (compounds 3 and 4). The nature of the alkyl halide was explored next under the optimized conditions with AgOAc as

O-donor. 2-Bromo-2,2-difluoro-1-(piperidin-1-yl)ethan-1-one delivered 5 in 84% yield. Less activated bromides also proved to be compatible with the reaction protocol. Thus, 2-bromo-1(piperidin-1-yl)ethan-1-one delivered 6 in 56% yield, whereas ethyl 2-bromo-2-fluoroacetate furnished 7 in 72% as a 1:1 mixture of diastereoisomers. Simple alkyl and aryl 2bromoacetates efficiently furnished the desired remote difunctionalization products 8-11 in good yields, albeit in some cases, longer reaction times were required to obtain complete conversion of the starting material. Interestingly, the reaction could be scaled up to 1 mmol without erosion of the isolated yield. The structure of the remote 1,6-difunctionalization products was confirmed by X-ray diffraction analysis of 9’ stemming from the basic hydrolysis of compound 9.16 α-Bromo butyrolactone furnished the corresponding lactone derivative 12 in 58% as a 1:1 mixture of diastereoisomers. α-Bromoaromatic as well as -alkyl ketones could be efficiently employed in these transformations, delivering the remote functionalized ketones 13−16 in excellent yields with complete regioselectivity. Finally, we also demonstrated that perfluoroalkyl-containing alkyl bromides and iodides could be efficiently engaged in the reaction as shown by the efficient formation of compounds 17− 19 under the standard reaction conditions. These examples showcase the high functional group compatibility of this redox neutral remote difunctionalization as esters, amides, lactones, ketones, C−Cl bonds were well tolerated under the optimized protocols. For a summary of substrates that did not work, see section S3.3 in the Supporting Information, SI. Next, we decided to interrogate the flexibility of the reaction in terms of the olefinic partner (Scheme 3). Alkenes bearing electronically diverse groups on the remote aromatic ring delivered the desired oxocarbofunctionalization products 20− 28 in excellent yields. In the presence of methyl 2bromoacetate, 1,6-oxyalkylation products 29 and 30 could be obtained in good yields. Interestingly, halogen substituents in the aromatic ring both in ortho, meta, and para position proved to be well tolerated as demonstrated by the efficient reaction to produce the corresponding remote oxocarbofunctionalization products in synthetically useful yields (26−28, 31−33). Substrates with different substituents on the aliphatic chain were also accommodated in the reaction as demonstrated by the isolation of 34 and 35 in 58% and 54% yield, respectively.

Scheme 2. Reaction Scope on Alkyl Halide and O-Based Reagent for 1,6-Oxy-alkylation

a

See Table 1, entry 10 for detailed conditions. bAg2CO3 (0.75 equiv) was used. c36 h. dOne mmol scale. e48 h. fPerfluorohexyl iodide was used. 6402

DOI: 10.1021/acscatal.8b00707 ACS Catal. 2018, 8, 6401−6406

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ACS Catalysis

ring of the 6-aryl-1-hexene partner could be tolerated (36−38). Both 2-bromo-2,2-difluoroketones and cyclohexyl amides could also be successfully employed as alkyl partners in the dicarbofunctionalization reaction (39−40). This 1,6-carboalkylation process is also compatible with less activated alkyl radical precursors (41−42) as well as with different substitution patterns on the alkyl chain of the olefinic partner (43). Different indoles were also tested yielding the desired reaction products (44−47) in synthetically useful yields under the standard reaction conditions with EtCN as solvent. Mechanistic studies were also performed (Scheme 5). Reactions in the presence of well-established radical traps

Scheme 3. Reaction Scope on Alkene

Scheme 5. Deuterium Labelling Experiments, DFT Calculations and Proposed Reaction Mechanisma

a

See Table 1, entry 10 for detailed conditions.

Fully linear or heteroatom bridged alkyl chains did not furnish the desired products, thus signalizing the importance of Thorpe-Ingold effects in the reaction (see section S3.3 in the SI).15,17 As discussed earlier, one of the major drawbacks of existing alkene remote difunctionalizations stems from the use of oxidative conditions, incompatible with C-based nucleophiles.11 Given the mild, redox neutral conditions of our protocol, we set out to explore the incorporation of C-based nucleophiles in the reaction (Scheme 4). In the presence of 2-bromo-2,2-difluoroacetate and trimethoxybenzene, different substitution patterns on the aromatic Scheme 4. Extension to 1,6-Carbo-alkylation of Alkene

a

Intermediates and transition states computed at B3LYP/6-311+ +G(d,p) (iefpcm, solvent = dichloromethane) level. Energies are given in kcal/mol (relative to the sum of the starting materials, GI + Galkene = 0 kcal/mol).

showed no desired 1,6-difunctionalization products whereas the alkene could be completely recovered, which is indicative of radical intermediates along the reaction pathway (see SI).15 Deuterium labeling studies involving 48 and d2-48 yielded KIE values of 1.2 and 1.0 for parallel (two-flask) and competitive (one-pot) intermolecular experiments, respectively (Scheme 5a.1). In contrast, a KIE = 3.3 could be determined for the intramolecular competition experiment with substrate d1-48 (Scheme 5a.2).18 DFT calculations15 revealed a slightly higher energy barrier for the addition of the C-centered radical I to the alkene (TSI−II, ΔG‡ = 16.1 kcal/mol) compared to that of the 1,5-HAT taking place on intermediate II (TSII−III, ΔG‡ = 11.8 kcal/mol). Interestingly, the latter process is exergonic (ΔG =

a

Alkene (0.1 mmol), alkyl bromide (0.3 mmol), arene (0.3 mmol), in the presence of 3 mol % of Ir(ppy)3 and Ag2CO3 (0.075 mmol) in DCM (0.1 M) at 25 °C. bEtCN was used as solvent. 6403

DOI: 10.1021/acscatal.8b00707 ACS Catal. 2018, 8, 6401−6406

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ACS Catalysis −11.7 kcal/mol) as a result of the stabilized benzylic radical produced in III.19 In line with these results, our mechanistic proposal involves the activation of the Ir(III)-photocatalyst upon irradiation which in turn, reduces the C−Br bond delivering an alkyl radical I under redox neutral conditions. Subsequent addition of I onto the double bond produces C-centered radical II. A 1,5-Hydrogen atom transfer, presumably aided by the preorganization of the starting material,17 takes place to produce a more stable C-centered benzylic radical III in a remote and site-selective manner. Oxidation of the radical to the corresponding carbocation takes place in the presence of an Ir(IV) complex intermediate to produce IV, which is thus subsequently quenched in the presence of either an O- or a Cbased nucleophile to produce the remote dicarbo- or oxocarbofunctionalization products observed in these transformations. The results of the deuterium labeling experiments, consistent with this proposal, point toward the Csp3−H bond cleavage via 1,5-HAT being irreversible (with a primary KIE observed in the intramolecular experiment, Scheme 5a.2), but taking place after the RDS, which involves the irreversible functionalization of the substrate bearing the C−H/D bond (i.e., no primary KIE observed in the two intermolecular deuterium labeling experiments summarized in Scheme 5a.1).20

9′. The authors would like to acknowledge the support by the COST Action CHAOS (CA15106).

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3. CONCLUSIONS In summary, a visible light mediated, redox neutral protocol is presented here toward the efficient remote functionalization of alkenes. The mild reaction conditions enable the addition of a wide variety of C-centered radicals to the double bond producing a vicinal radical intermediate that is not quenched under the reaction conditions. A subsequent 1,5-HAT results in the site selective generation of a remote benzylic radical which can be trapped with O- or C-nucleophiles to produce, in a highly efficient manner, new Csp3−O and Csp3−Csp2 bonds at room temperature.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.8b00707. General information, experimental procedures, DFT calculations, detailed descriptions for products, and copies of NMR spectra (PDF) Crystallographic data (CIF)

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REFERENCES

(1) For reviews on alkene difunctionalizations, see: (a) Romero, R. M.; Woeste, T. H.; Muñiz, K. Vicinal Difunctionalization of Alkenes with Iodine(III) Reagents and Catalysts. Chem.−Asian J. 2014, 9, 972−983. (b) Courant, T.; Masson, G. Recent Progress in VisibleLight Photoredox-Catalyzed Intermolecular 1,2-Difunctionalization of Double Bonds via an ATRA-Type Mechanism. J. Org. Chem. 2016, 81, 6945−6952. (c) Koike, T.; Akita, M. A Versatile Strategy for Difunctionalization of Carbon−Carbon Multiple Bonds by Photoredox Catalysis. Org. Chem. Front. 2016, 3, 1345−1349. (d) Yin, G.; Mu, X.; Liu, G. Palladium(II)-Catalyzed Oxidative Difunctionalization of Alkenes: Bond Forming at a High-Valent Palladium Center. Acc. Chem. Res. 2016, 49, 2413−2423. (e) Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. Radicals: Reactive Intermediates with Translational Potential. J. Am. Chem. Soc. 2016, 138, 12692−12714. (2) For selected examples, see: (a) Hartmann, M.; Li, Y.; Studer, A. Transition-Metal-Free Oxyarylation of Alkenes with Aryl Diazonium Salts and TEMPONa. J. Am. Chem. Soc. 2012, 134, 16516−16519. (b) Fumagalli, G.; Boyd, S.; Greaney, M. F. Oxyarylation and Aminoarylation of Styrenes Using Photoredox Catalysis. Org. Lett. 2013, 15, 4398−4401. (c) Kindt, S.; Wicht, K.; Heinrich, M. R. Thermally Induced Carbohydroxylation of Styrenes with Aryldiazonium Salts. Angew. Chem., Int. Ed. 2016, 55, 8744−8747. (3) For selected examples, see: (a) Ouyang, X.-H.; Song, R.-J.; Hu, M.; Yang, Y.; Li, J.-H. Silver-Mediated Intermolecular 1,2-Alkylarylation of Styrenes with α-Carbonyl Alkyl Bromides and Indoles. Angew. Chem., Int. Ed. 2016, 55, 3187−3191. (b) Yatham, V. R.; Shen, Y.; Martin, R. Catalytic Intermolecular Dicarbofunctionalization of Styrenes with CO2 and Radical Precursors. Angew. Chem., Int. Ed. 2017, 56, 10915−10919. (4) For selected examples, see: (a) Panchaud, P.; Chabaud, L.; Landais, Y.; Ollivier, C.; Renaud, P.; Zigmantas, S. Radical Amination with Sulfonyl Azides: A Powerful Method for the Formation of C-N Bonds. Chem.−Eur. J. 2004, 10, 3606−3614. (b) Weidner, K.; Giroult, A.; Panchaud, P.; Renaud, P. Efficient Carboazidation of Alkenes Using a Radical Desulfonylative Azide Transfer Process. J. Am. Chem. Soc. 2010, 132, 17511−17515. (c) Wang, F.; Qi, X.; Liang, Z.; Chen, P.; Liu, G. Copper-Catalyzed Intermolecular Trifluoromethylazidation of Alkenes: Convenient Access to CF3-Containing Alkyl Azides. Angew. Chem., Int. Ed. 2014, 53, 1881−1886. (d) Dagousset, G.; Carboni, A.; Magnier, E.; Masson, G. Photoredox-Induced ThreeComponent Azido- and Aminotrifluoromethylation of Alkenes. Org. Lett. 2014, 16, 4340−4343. (e) Liu, Y.-Y.; Yang, X.-H.; Song, R.-J.; Luo, S.; Li, J.-H. Oxidative 1,2-Carboamination of Alkenes with Alkyl Nitriles and Amines toward γ-Amino Alkyl Nitriles. Nat. Commun. 2017, 8, 14720−14726. (f) Bunescu, A.; Ha, T. M.; Wang, Q.; Zhu, J. Copper-Catalyzed Three-Component Carboazidation of Alkenes with Acetonitrile and Sodium Azide. Angew. Chem., Int. Ed. 2017, 56, 10555−10558. (5) For selected examples, see: (a) Hara, T.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. Catalytic Oxyalkylation of Alkenes with Alkanes and Molecular Oxygen via a Radical Process Using N-Hydroxyphthalimide. J. Org. Chem. 2001, 66, 6425−6431. (b) Wetter, C.; Jantos, K.; Woithe, K.; Studer, A. Intermolecular Radical Addition and Addition/ Cyclization Reactions of Alkoxyamines onto Nonactivated Alkenes. Org. Lett. 2003, 5, 2899−2902. (c) Feng, C.; Loh, T.-P. CopperCatalyzed Olefinic Trifluoromethylation of Enamides at Room Temperature. Chem. Sci. 2012, 3, 3458−3462. (d) Yi, H.; Zhang, X.; Qin, C.; Liao, Z.; Liu, J.; Lei, A. Visible Light-Induced γ-Alkoxynitrile Synthesis via Three-Component Alkoxycyanomethylation of Alkenes. Adv. Synth. Catal. 2014, 356, 2873−2877. (e) Liao, Z.; Yi, H.; Li, Z.; Fan, C.; Zhang, X.; Liu, J.; Deng, Z.; Lei, A. Copper-Catalyzed Radical Carbooxygenation: Alkylation and Alkoxylation of Styrenes. Chem. Asian J. 2015, 10, 96−99. (f) Chatalova-Sazepin, C.; Wang, Q.; Sammis, G. M.; Zhu, J. Copper-Catalyzed Intermolecular Carboetherification of Unactivated Alkenes by Alkyl Nitriles and Alcohols. Angew.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (C.N.). ORCID

Estíbaliz Merino: 0000-0002-2960-5404 Cristina Nevado: 0000-0002-3297-581X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the European Research Council (ERC Starting grant agreement no. 307948) and the Swiss National Science Foundation (SNF 200020_146853) for financial support. We thank Prof. Anthony Linden for the X-ray diffraction analysis of 6404

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ACS Catalysis

Visible-Light Photocatalytic Radical Alkenylation of α-Carbonyl Alkyl Bromides and Benzyl Bromides. Chem. - Eur. J. 2013, 19, 5120−5126. (c) Egami, H.; Usui, Y.; Kawamura, S.; Nagashima, S.; Sodeoka, M. Product Control in Alkene Trifluoromethylation: Hydrotrifluoromethylation, Vinylic Trifluoromethylation, and Iodotrifluoromethylation Using Togni Reagent. Chem. - Asian J. 2015, 10, 2190−2199. (11) (a) Yu, P.; Lin, J.-S.; Li, L.; Zheng, S.-C.; Xiong, Y.-P.; Zhao, L.J.; Tan, B.; Liu, X.-Y. Enantioselective C-H Bond Functionalization Triggered by Radical Trifluoromethylation of Unactivated Alkene. Angew. Chem., Int. Ed. 2014, 53, 11890−11894. (b) Yu, P.; Zheng, S.C.; Yang, N.-Y.; Tan, B.; Liu, X.-Y. Phosphine-Catalyzed Remote βC−H Functionalization of Amines Triggered by Trifluoromethylation of Alkenes: One-Pot Synthesis of Bistrifluoromethylated Enamides and Oxazoles. Angew. Chem., Int. Ed. 2015, 54, 4041−4045. (c) Huang, L.; Zheng, S.-C.; Tan, B.; Liu, X.-Y. Metal-Free Direct 1,6- and 1,2Difunctionalization Triggered by Radical Trifluoromethylation of Alkenes. Org. Lett. 2015, 17, 1589−1592. (d) Huang, L.; Lin, J.-S.; Tan, B.; Liu, X.-Y. Alkene Trifluoromethylation-Initiated Remote αAzidation of Carbonyl Compounds toward Trifluoromethyl γ-Lactam and Spirobenzofuranone-Lactam. ACS Catal. 2015, 5, 2826−2831. (e) Li, L.; Ye, L.; Ni, S.-F.; Li, Z.-L.; Chen, S.; Du, Y.-M.; Li, X.-H.; Dang, L.; Liu, X.-Y. Phosphine-Catalyzed Remote α-C−H Bond Activation of Alcohols or Amines Triggered by the Radical Trifluoromethylation of Alkenes: Reaction Development and Mechanistic Insights. Org. Chem. Front. 2017, 4, 2139−2146. (12) (a) Eisenberger, P.; Gischig, S.; Togni, A. Novel 10-I-3 Hypervalent Iodine-Based Compounds for Electrophilic Trifluoromethylation. Chem. - Eur. J. 2006, 12, 2579−2586. (b) Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.; Togni, A. Zinc-Mediated Formation of Trifluoromethyl Ethers from Alcohols and Hypervalent Iodine Trifluoromethylation Reagents. Angew. Chem., Int. Ed. 2009, 48, 4332−4336. (c) Kieltsch, I.; Eisenberger, P.; Togni, A. Mild Electrophilic Trifluoromethylation of Carbon- and Sulfur-Centered Nucleophiles by a Hypervalent Iodine(III)−CF3 Reagent. Angew. Chem., Int. Ed. 2007, 46, 754−757. (13) For selected reviews, see: (a) Narayanam, J. M. R.; Stephenson, C. R. J. Visible Light Photoredox Catalysis: Applications in Organic Synthesis. Chem. Soc. Rev. 2011, 40, 102−113. (b) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. Photoredox Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81, 6898−6926. (c) Yoon, T. P.; Stephenson, C. R. J. Opportunities in Photocatalytic Synthesis. Adv. Synth. Catal. 2014, 356, 2739. (d) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Visible Light Photoredox-Controlled Reactions of NRadicals and Radical Ions. Chem. Soc. Rev. 2016, 45, 2044−2056. (14) For previous efforts in our group towards remote functionalizations, see: (a) Shu, W.; Lorente, A.; Gómez-Bengoa, E.; Nevado, C. Expeditious Diastereoselective Synthesis of Elaborated Ketones via Remote C(sp3)−H Functionalization. Nat. Commun. 2017, 8, 13832− 13839. (b) Shu, W.; Nevado, C. Visible-Light-Mediated Remote Aliphatic C−H Functionalizations through a 1,5-Hydrogen Transfer Cascade. Angew. Chem., Int. Ed. 2017, 56, 1881−1884. (c) Shu, W.; Genoux, A.; Li, Z.; Nevado, C. γ-Functionalizations of Amines through Visible-Light-Mediated, Redox-Neutral C−C Bond Cleavage. Angew. Chem., Int. Ed. 2017, 56, 10521−10524. (15) For additional experiments, see SI. (16) CCDC-1581108 (9′) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/structures. (17) Jung, M. E.; Piizzi, G. gem-Disubstituent Effect: Theoretical Basis and Synthetic Applications. Chem. Rev. 2005, 105, 1735−1766. (18) Note that for d1-48, four diastereotopic TS can be obtained for the 1,5-HAT step. Only in two of them the C−D bond is properly oriented for abstraction by the remote C-centered radical. These two TS will be, to a different extent, responsible for the KIE value determined experimentally. See ref 15. (19) (a) Szabo, Z. G. Stabilization of Free Radicals: Its Importance in Reaction Kinetics. Nature 1952, 170, 246−247. (b) Henry, D. J.; Parkinson, C. J.; Mayer, P. M.; Radom, L. Bond Dissociation Energies

Chem., Int. Ed. 2015, 54, 5443−5446. (g) Wang, Y.; Zhang, L.; Yang, Y.; Zhang, P.; Du, Z.; Wang, C. Alkene Oxyalkylation Enabled by Merging Rhenium Catalysis with Hypervalent Iodine(III) Reagents via Decarboxylation. J. Am. Chem. Soc. 2013, 135, 18048−18051. (h) Ha, T. M.; Chatalova-Sazepin, C.; Wang, Q.; Zhu, J. Copper-Catalyzed Formal [2+2+1] Heteroannulation of Alkenes, Alkylnitriles, and Water: Method Development and Application to a Total Synthesis of (±)-Sacidumlignan D. Angew. Chem., Int. Ed. 2016, 55, 9249−9252. (i) Jian, W.; Ge, L.; Jiao, Y.; Qian, B.; Bao, H. Iron-Catalyzed Decarboxylative Alkyl Etherification of Vinylarenes with Aliphatic Acids as the Alkyl Source. Angew. Chem., Int. Ed. 2017, 56, 3650−3654. (6) For a redox-neutral protocol yielding broader scope at ambient temperature, see: Tlahuext-Aca, A.; Garza-Sanchez, R. A.; Glorius, F. Multicomponent Oxyalkylation of Styrenes Enabled by HydrogenBond-Assisted Photoinduced Electron Transfer. Angew. Chem., Int. Ed. 2017, 56, 3708−3711. (7) For reviews on 1,n-HAT, see: (a) Wolff, M. E. Cyclization of NHalogenated Amines (The Hofmann-Löffler Reaction). Chem. Rev. 1963, 63, 55−64. (b) Breslow, R. Biomimetic Control of Chemical Selectivity. Acc. Chem. Res. 1980, 13, 170−177. (c) Chiba, S.; Chen, H. sp3 C−H Oxidation by Remote H-Radical Shift with Oxygen- and Nitrogen-Radicals: A Recent Update. Org. Biomol. Chem. 2014, 12, 4051−4060. (d) Hu, X.-Q.; Chen, J.-R.; Xiao, W.-J. Controllable Remote C−H Bond Functionalization by Visible-Light Photocatalysis. Angew. Chem., Int. Ed. 2017, 56, 1960−1962. For recent selected examples, see: (e) Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu, C. J.; Knowles, R. R. Catalytic Alkylation of Remote C−H Bonds Enabled by Proton-Coupled Electron Transfer. Nature 2016, 539, 268−271. (f) Chu, J. C.; Rovis, T. Amide-Directed Photoredox-Catalysed C−C Bond Formation at Unactivated sp3 C−H Bonds. Nature 2016, 539, 272−275. (g) Mukherjee, S.; Maji, B.; Tlahuext-Aca, A.; Glorius, F. Visible-Light-Promoted Activation of Unactivated C(sp3)−H Bonds and Their Selective Trifluoromethylthiolation. J. Am. Chem. Soc. 2016, 138, 16200−16203. (h) Jiang, H.; Studer, A. α-Aminoxy-AcidAuxiliary-Enabled Intermolecular Radical γ-C(sp3)-H Functionalization of Ketones. Angew. Chem., Int. Ed. 2018, 57, 1692−1696. (i) Dauncey, E. M.; Morcillo, S. P.; Douglas, J. J.; Sheikh, N. S.; Leonori, D. Photoinduced Remote Functionalisations by Iminyl Radical Promoted C−C and C−H Bond Cleavage Cascades. Angew. Chem., Int. Ed. 2018, 57, 744−748. (j) Becker, P.; Duhamel, T.; Stein, C. J.; Reiher, M.; Muñiz, K. Cooperative Light-Activated Iodine and Photoredox Catalysis for the Amination of C(sp3)-H Bonds. Angew. Chem., Int. Ed. 2017, 56, 8004−8008. (8) (a) Qiu, J.-K.; Jiang, B.; Zhu, Y.-L.; Hao, W.-J.; Wang, D.-C.; Sun, J.; Wei, P.; Tu, S.-J.; Li, G. Catalytic Dual 1,1-H-Abstraction/Insertion for Domino Spirocyclizations. J. Am. Chem. Soc. 2015, 137, 8928− 8931. (b) Hu, M.; Fan, J.-H.; Liu, Y.; Ouyang, X.-H.; Song, R.-J.; Li, J.H. Metal-Free Radical [2+2+1] Carbocyclization of Benzene-Linked 1,n-Enynes: Dual C(sp3)−H Functionalization Adjacent to a Heteroatom. Angew. Chem., Int. Ed. 2015, 54, 9577−9580. (9) For selected examples on haloalkylation and hydroalkylation of alkenes, see: (a) Choi, S.; Kim, Y. J.; Kim, S. M.; Yang, J. W.; Kim, S. W.; Cho, E. J. Hydrotrifluoromethylation and Iodotrifluoromethylation of Alkenes and Alkynes Using an Inorganic Electride as a Radical Generator. Nat. Commun. 2014, 5, 4881−4887. (b) Wilger, D. J.; Gesmundo, N. J.; Nicewicz, D. A. Catalytic Hydrotrifluoromethylation of Styrenes and Unactivated Aliphatic Alkenes via an Organic Photoredox System. Chem. Sci. 2013, 4, 3160−3165. (c) Wu, X.; Chu, L.; Qing, F.-L. Silver-Catalyzed Hydrotrifluoromethylation of Unactivated Alkenes with CF3SiMe3. Angew. Chem., Int. Ed. 2013, 52, 2198−2202. (d) Mizuta, S.; Verhoog, S.; Engle, K. M.; Khotavivattana, T.; O’Duill, M.; Wheelhouse, K.; Rassias, G.; Médebielle, M.; Gouverneur, V. Catalytic Hydrotrifluoromethylation of Unactivated Alkenes. J. Am. Chem. Soc. 2013, 135, 2505−2508. (10) For selected examples, see: (a) Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. An Efficient Generation of a Functionalized Tertiary-Alkyl Radical for Copper-catalyzed Tertiary-Alkylative Mizoroki-Heck Type Reaction. J. Am. Chem. Soc. 2013, 135, 16372− 16375. (b) Liu, Q.; Yi, H.; Liu, J.; Yang, Y.; Zhang, X.; Zeng, Z.; Lei, A. 6405

DOI: 10.1021/acscatal.8b00707 ACS Catal. 2018, 8, 6401−6406

Research Article

ACS Catalysis and Radical Stabilization Energies Associated with Substituted Methyl Radicals. J. Phys. Chem. A 2001, 105, 6750−6756. (c) Zipse, H.; Hioe, J. Radical stability and its role in synthesis and catalysis. Org. Biomol. Chem. 2010, 8, 3609−3617. (20) (a) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry; University Science Books: Sausalito, 2006. (b) Simmons, E. M.; Hartwig, J. F. On the Interpretation of Deuterium Kinetic Isotope Effects in C−H Bond Functionalizations by Transition-Metal Complexes. Angew. Chem., Int. Ed. 2012, 51, 3066−3072.

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DOI: 10.1021/acscatal.8b00707 ACS Catal. 2018, 8, 6401−6406