Silver-Catalyzed Three-Component Difunctionalization of Alkenes via

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Silver-Catalyzed Three-Component Difunctionalization of Alkenes via Radical Pathways: Access to CF3‑Functionalized AlkylSubstituted 1,4-Naphthoquinone Derivatives Qijun Wang,† Bo Wang,† Hao Deng, Yu Shangguan, Yan Lin, Yaqi Zhang, Zheming Zhang, Yumei Xiao, Hongchao Guo, and Cheng Zhang* Department of Applied Chemistry, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China

J. Org. Chem. 2019.84:1006-1014. Downloaded from pubs.acs.org by TULANE UNIV on 01/18/19. For personal use only.

S Supporting Information *

ABSTRACT: A silver-catalyzed three-component difunctionalization of alkenes by using 2-amino- and 2-hydroxy-1,4naphthoquinone derivatives as the radical-trapping reagents is reported. Various alkenes and 2-amino- or 2-hydroxy-1,4naphthoquinones with diverse structures and electronic properties are applied to the reaction. The methodology provides an alternative method to access CF3-functionalized alkyl-substituted quinone derivatives which are prevalent structures in bioactive molecules. Furthermore, a plausible radical pathway for the reaction is proposed based on results from primary control experiments.

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require excess amounts of strong oxidants,4 albeit with some exceptions.5 Other methods by oxidation of the corresponding dihydroxybenzene derivatives need both the prefunctionalization of substrates and the presence of excessive strong oxidizing reagents,6 which are environmentally unfavorable and labor-intensive. Further, the way to introduce the prevalent CF3 group to such alkyl-substituted 1,4-naphthoquinone derivatives would be much more difficult. Therefore, developing concise and environmentally benign methods to synthesize such 1,4-napthoquinone derivatives is highly desirable. Three-component difunctionalization of alkenes via radical pathways is a highly efficient strategy to construct polyfunctionalized molecules and has gained increasing attention over recent years.7 In this context, developing new radical trapping reagents has been an intensively studied field while oxygen-based,8 nitrogen-based,9 and carbon-based10 as well as other types of radical trapping reagents14 have been developed. Among these, the carbon-based radical trapping reagent has received the most attention. In addition to TMSCN,10−13 other typical carbon-based reagents including N-protected indoles,11 phenyl boronic acids,12 and alkynyl silanes13 have been reported. In these transformations, radical functional

INTRODUCTION Quinone-based organic molecules play important roles in developing therapeutic drugs, agrochemicals, and functional materials and acting as building blocks in total synthesis.1 Notable among these are the 2-hydroxy- and 2-aminoquinone derivatives bearing alkyl substituents, such as lapachol (Figure 1), which usually show important bioactivities including

Figure 1. Important 2-amino- and 2-hydroxy-1,4-naphthoquinone structures.

antibacterial, antiinflammatory, antifungal, and in particular, anticancer activity.2 As a result, the development of synthetic methods to incorporate functional alkyl groups into 2-hydroxyor 2-aminoquinones is of great significance. However, common tactics to access such compounds encounter several drawbacks. The prevalent transition-metal-catalyzed method usually works sluggishly on quinone substrates due to their strong oxidation and metal-binding ability,3 and even feasible examples of these © 2018 American Chemical Society

Received: November 23, 2018 Published: December 28, 2018 1006

DOI: 10.1021/acs.joc.8b02997 J. Org. Chem. 2019, 84, 1006−1014

Article

The Journal of Organic Chemistry

Table 1. Screening for Optimal Reaction Conditionsa

groups generated first from radical precursors add to alkenes, forming radical intermediates, and the radical intermediates are either oxidized to carbon cations followed by trapping with nucleophiles or directly form organocopper intermediates by combination of the catalyst and nucleophile followed by reductive elimination (Scheme 1).7d,15 2-Hydroxy- and 2Scheme 1. Carbon-Based Three-Component Difunctionalization of Alkenes via Radical Pathways

aminoquinones have been reported as nucleophiles in a few examples.16 We therefore envisioned that such quinone derivatives would also be effective as radical-trapping reagents in the three-component difunctionalization of alkenes. Considering the prevalence of the CF3 group and quinone structures in pharmaceuticals and agrochemicals,17 and also as a continuing interest in developing synthetic methods to access quinone-based small molecules in our group,18 we report here a concise and highly efficient silver-catalyzed three-component difunctionalization of alkenes to generate alkyl-substituted 1,4naphthoquinone derivatives along with incorporation of the prevalent CF3 group.

entry

[M]

L

solvent

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13b 14c 15d

CuCl CuBr CuI AgOAc FeCp2 AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc

L1 L1 L1 L1 L1 L2 L3 L4 L4 L4 L4 L4 L4 L4 L4

DCE DCE DCE DCE DCE DCE DCE DCE toluene 1,4-dioxane MeOH DMF DCE DCE DCE

38 13 35 52 41 43 67 80 15 52 55 77 42 21 77

a

Conditions: 1a (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv), 3 (0.22 mmol, 1.1 equiv), [M] (0.02 mmol, 10 mol %), L (0.02 mmol, 10 mol %), in 1.5 mL of solvent, 75 °C, 12 h. bCatalyst loading was 5 mol %. cReaction was performed at room temperature. dReaction was run for 24 h.

effect that results from the diphosphine and FeCp2 motifs because the sole FeCp2 also imparts moderate catalytic activity to the reaction. Using the best ligand and the best metal salt, we further studied the effects of solvents, and the results show that either DCE or DMF is a favorable solvent for the reaction (entry 12). A lower catalyst loading results in a lower chemical yield of the product (entry 13). The reaction performs sluggishly when it is carried out at room temperature, which is probably due to the poor solubility of the starting material (entry 14). A longer reaction time lowers the yield of 4aa slightly (entry 15). After establishing the optimal reaction conditions, we evaluated its feasibility by testing various alkenes that bear diverse electronic properties and substitution patterns in the reaction (Scheme 2). Regarding parasubstituted styrenes, both electron-donating and electronwithdrawing group substitution on the phenyl ring results in high yields of products (4aa−aj). Substitution on the phenyl ring that seems to affect the reaction to some extent is demonstrated by the 2-chloro-substituted styrene, which yields less product than the 3- or 4-chloro-substituted styrene (4ae− ag). The α-vinylnaphthalene affords the corresponding product (4ak) in lower yield than its styrene analogues. Notably, vinylheteroarenes are also suitable substrates, as 4al and 4am were obtained in 61% and 73% yields, respectively. When the alkyl alkene and internal alkene are subjected to the

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RESULTS AND DISCUSSION At the outset of our experiment, we selected 2-phenylamino1,4-naphthoquinone 1a as the radical-trapping reagent, Tongni I reagent 3 as the radical precursor, and 4-methylstyrene 2a to evaluate our hypothesis (Table 1). To our delight, we isolated the desired product 4aa in 38% yield with 10 mol % loading of CuCl and 1,10-phenanthronline as the catalyst (entry 1), and the product was further verified by single crystal diffraction. We are therefore encouraged to optimize the reaction conditions by screening metal salts, ligands, solvents, and temperatures.19 Among several metal salts, including AgOAc, FeCp2 (ferrocene), and different types of copper salts, AgOAc shows the best result when 52% yield of the final product is obtained (entry 4). Ligand screening indicates diphosphine ligands (such as race-BINAP and DPPF) are superior to dinitrogen ligands (such as 1,10-phenanthroline and 2,2′dipyridine), Interestingly, DPPF, which contains the FeCp2 structrual motif, affords the best performance (entry 8). The superiority of the DPPF ligand might come from a cooperative 1007

DOI: 10.1021/acs.joc.8b02997 J. Org. Chem. 2019, 84, 1006−1014

Article

The Journal of Organic Chemistry Scheme 2. Substrate Scope for Alkenesa

a

Conditions: 1a (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv), 3 (0.22 mmol, 1.1 equiv), AgOAc (0.02 mmol, 10 mol %), DPPF (0.02 mmol, 10 mol %), in 1.5 mL of solvent, 75 °C, 12 h.

the yield is lower than that in substrate scope expansions (Scheme 4). Finally, we carried out several control experiments to gain further insights into the mechanism. When 1,4-naphthoquinone 1l or 2-methyl-1,4-naphthoquinone 1m instead of 2amino- or 2-hydroxy-1,4-napthoquinone was subjected to the reaction, none of the corresponding product was detected, and 2-benzamido-1,4-naphthoquinone 1n is not a suitable substrate for the reaction either under the optimal conditions (Scheme 5.1). The results indicated that the free amino or hydroxyl group is indispensable for the success of the reaction, and an enamine or enolate isomerization of the 1,4-naphthoquinone derivative is probably involved. Moreover, the model reaction was completely inhibited with the addition of 2 equiv of TEMPO (Scheme 5.2), which implies that the reaction involves a radical pathway. Combining the results above, we propose here a plausible mechanism. Initially, trifluoromethyl radical was generated via SET (single-electron-transfer) between the silver complex and Togni I reagent. Addition of the CF3 radical to styrene 2a formed radical intermediate A followed by oxidation to carbon cation intermediate B, which was then trapped by 1a′ to afford the desired product 4aa after the deprotonation and rearrangement of intermediate C (path a, Scheme 6). However, a mechanism involving the direct

reaction, the corresponding products 4an, 4ao, and 4ap were also isolated in good yields, along with good diastereoselectivities for 4ao and 4ap. As outlined in Scheme 3, the substrate scope for naphthoquinones was also examined carefully. Initially, 2phenylamino-substituted 1,4-naphthoquinone derivatives were carefully examined under the optimal reaction conditions (4ba−ha). Electronically diverse substituents on the phenyl ring of the phenyl amines show no obvious effects on the yields of the products while all of the corresponding products were obtained with high yields. However, the substrate with a strong electron-rich methoxyl group on the para-position affords the corresponding product in considerably lower yield compared to the ortho- or meta-substituted ones (4ba−da). Multisubstituted phenylamino substrate is also a suitable substrate for the reaction, as 4ha was isolated in 71% yield. Alkylaminoderived 1,4-naphthoquinone is also favorable for the reaction, as 4ia was obtained in high yield. When tertiary amino-derived substrate is subjected to the reaction, the corresponding product 4ja is furnished in good yield as well. Notably, the 2hydroxy-1,4-naphthoquinone also works well under the optimal reaction conditions, producing 4ka in 67% yield. In addition, we also scaled up the synthesis of product 4ga, and 1008

DOI: 10.1021/acs.joc.8b02997 J. Org. Chem. 2019, 84, 1006−1014

Article

The Journal of Organic Chemistry Scheme 3. Substrate Scope for 1,4-Naphthoquinone Derivativesa

a

Conditions: 1a (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv), 3 (0.22 mmol, 1.1 equiv), AgOAc (0.02 mmol, 10 mol %), DPPF (0.02 mmol, 10 mol %), in 1.5 mL of solvent, 75 °C, 12 h. bDMF was used as the solvent.

Scheme 4. Scale-up Synthesis of 4ga

Scheme 6. Proposed Mechanism

Scheme 5. Control Experiments

easily handled, and relatively environmentally benign while no strong oxidant is involved, and the resulting 1,4-naphthoquinone products containing a trifluoromethyl group are of great significance in developing biologically active compounds. We also propose a plausible radical pathway for the reaction based on the results from control experiments.

reaction of intermediate A with 1a cannot be ruled out (path b, Scheme 6). In summary, we have developed a silver-catalyzed threecomponent difunctionalization of alkenes, using the Togni I reagent and 2-amino- or 2-hydroxy-1,4-naphthoquinone derivatives as the functional reagents. The process is concise,

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EXPERIMENTAL SECTION

General Methods. All reactions were carried out under argon atmosphere unless otherwise stated. Solvents were all dried before use according to standard procedures. Commercial reagents were

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DOI: 10.1021/acs.joc.8b02997 J. Org. Chem. 2019, 84, 1006−1014

Article

The Journal of Organic Chemistry

NMR (300 MHz, CDCl3): δ 8.12−8.05 (m, 2H), 7.74 (td, J = 7.5, 1.4 Hz, 1H), 7.64 (td, J = 7.5, 1.4 Hz, 1H), 7.52 (s, 1H), 7.28−7.09 (m, 3H), 7.10−6.97 (m, 6H), 4.15 (t, J = 7.1 Hz, 1H), 3.17−2.98 (m, 2H), 2.29 (s, 3H).; 13C{1H} NMR (75 MHz, CDCl3): δ 183.8, 182.4, 143.6, 139.8, 136.8, 135.8, 134.4, 133.2, 132.1, 129.7, 129.1, 128.6, 127.6, 126.2, 126.3 (q, J = 265.2), 125.9. 125.4, 123.3, 120.0, 37.0 (q, J = 27.0 Hz), 36.7 (q, J = 3.1 Hz), 20.6; 19F{1H} NMR (282 MHz, CDCl3): δ = −64.1. HRMS calcd for C26H21F3NO2 [M + H]+: 436.1519, found: 436.1518. 2-(Phenylamino)-3-(3,3,3-trifluoro-1-(4-methoxyphenyl)propyl)naphthalene-1,4-dione (4ab). Red solid, 66.8 mg, 74% yield. 1H NMR (300 MHz, CDCl3): δ 8.12−8.06 (m, 2H), 7.75 (td, J = 7.5, 1.4 Hz, 1H), 7.65 (td, J = 7.5, 1.4 Hz, 1H), 7.51 (s, 1H), 7.28−7.09 (m, 3H), 7.09−6.94 (m, 3H), 6.79−6.66 (m, 1H), 4.11 (t, J = 7.1 Hz, 1H), 3.75 (s, 3H), 3.19−2.89 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.9, 182.4, 157.9, 143.6, 139.8, 134.4, 133.2, 132.2, 131.8, 129.7, 129.1, 128.8, 126.3 (q, J = 276.4 Hz), 126.2, 125.9, 125.4, 123.3, 120.0, 113.3, 54.9, 37.1 (q, J = 26.9), 36.5 (q, J = 3.0 Hz); 19F{1H} NMR (282 MHz, CDCl3): δ = −64.2. HRMS calcd for C26H21F3NO3 [M + H]+: 452.1468, found: 452.1465. 2-(1-(4-(tert-Butyl)phenyl)-3,3,3-trifluoropropyl)-3(phenylamino)naphthalene-1,4-dione (4ac). Red solid, 74.5 mg, 78% yield. 1H NMR (300 MHz, CDCl3): δ 8.13−8.06 (m, 2H), 7.75 (td, J = 7.5, 1.4 Hz, 1H), 7.65 (td, J = 7.5, 1.4 Hz, 1H), 7.48 (s, 1H), 7.24−7.06 (m, 6H), 7.06−6.94 (m, 4H), 4.15 (t, J = 7.1 Hz, 1H), 3.26−2.85 (m, 2H), 1.28 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.8, 182.4, 149.0, 143.8, 139.8, 136.6, 134.4, 133.2, 132.1, 129.7, 129.0, 127.3, 126.3 (q, J = 265.2), 126.2, 125.9, 125.3, 124.8, 123.4, 120.1, 37.0 (q, J = 26.9), 36.7 (q, J = 2.8 Hz), 34.0, 31.0; 19F{1H} NMR (282 MHz, CDCl3): δ = −64.2. HRMS calcd for C29H27F3NO2 [M + H]+: 478.1988, found: 478.1983. 2-(Phenylamino)-3-(3,3,3-trifluoro-1-phenylpropyl)naphthalene1,4-dione (4ad). Red solid, 67.4 mg, 80% yield. 1H NMR (300 MHz, CDCl3): δ 8.13−8.07 (m, 2H), 7.75 (td, J = 7.6, 1.4 Hz, 1H), 7.66 (td, J = 7.5, 1.4 Hz, 1H), 7.54 (s, 1H), 7.24−6.99 (m, 10H), 4.16 (t, J = 7.1 Hz, 1H), 3.27−2.85 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.8, 182.3, 143.9, 139.8, 139.6, 134.5, 133.2, 132.2, 129.7, 129.1, 127.9, 127.7, 126.2, 126.2, 126.3 (q, J = 276.1 Hz), 125.9, 125.5, 123.5, 119.4, 37.1 (q, J = 27.1 Hz), 37.2 (q, J = 2.9 Hz); 19 1 F{ H} NMR (282 MHz, CDCl3): δ = −64.2. HRMS calcd for C25H19F3NO2 [M + H]+: 422.1362, found: 422.1361. 2-(1-(2-Chlorophenyl)-3,3,3-trifluoropropyl)-3-(phenylamino)naphthalene-1,4-dione (4ae). Red solid, 59.3 mg, 65% yield. 1H NMR (300 MHz, CDCl3): δ 8.17 (dd, J = 7.7, 1.3 Hz, 1H), 8.11 (dd, J = 7.6, 1.4 Hz, 1H), 7.78 (td, J = 7.6, 1.4 Hz, 1H), 7.68 (td, J = 7.5, 1.4 Hz, 1H), 7.63 (br, 1H), 7.49−7.45 (m, 1H), 7.20−6.96 (m, 6H), 6.85−6.77 (m, 2H), 4.33 (dd, J = 9.8, 4.5 Hz, 1H), 3.38−3.26 (m, 1H), 2.89−2.72 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 184.4, 182.1, 144.8, 138.9, 136.3, 134.6, 134.3, 133.3, 132.2, 130.3, 129.7, 129.0, 128.7, 127.8, 126.3, 126.1 (q, J = 276.6 Hz), 126.0, 125.3, 123.1, 122.6, 116.7, 36.4 (q, J = 3.1 Hz), 34.8 (q, J = 26.8); 19F{1H} NMR (282 MHz, CDCl 3 ): δ = −64.4. HRMS calcd for C25H18ClF3NO2 [M + H]+: 456.0973, found: 456.0972. 2-(1-(3-Chlorophenyl)-3,3,3-trifluoropropyl)-3-(phenylamino)naphthalene-1,4-dione (4af). Red solid, 70.2 mg, 77% yield. 1H NMR (300 MHz, CDCl3) δ 8.13−8.08 (m, 2H), 7.77 (td, J = 7.6, 1.4 Hz, 1H), 7.67 (td, J = 7.6, 1.4 Hz, 1H), 7.61 (br, 1H), 7.21−7.11 (m, 5H), 7.07−6.91 (m, 4H), 4.08 (td, J = 6.9 Hz, 1H), 3.25−3.03 (m, 1H), 3.03−2.77 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.7, 182.2, 144.3, 142.0, 139.4, 134.6, 133.6, 133.2, 132.3, 129.5, 129.1, 129.0, 128.0, 126.4, 126.3, 126.1 (q, J = 276.1), 126.0, 125.9, 124.0, 117.9, 37.2 (q, J = 27.4 Hz), 37.1 (q, J = 3.1 Hz); 19F{1H} NMR (282 MHz, CDCl3): δ = −64.3. HRMS calcd for C25H18ClF3NO2 [M + H]+: 456.0973, found: 456.0971. 2-(1-(4-Chlorophenyl)-3,3,3-trifluoropropyl)-3-(phenylamino)naphthalene-1,4-dione (4ag). Red solid, 70.2 mg, 77% yield. 1H NMR (300 MHz, CDCl3) δ 8.11−8.07 (m, 2H), 7.75 (td, J = 7.6, 1.4 Hz, 1H), 7.68−7.62 (m, 2H), 7.25−7.09 (m, 5H), 7.08−6.93 (m, 4H), 4.09 (t, J = 7.0 Hz, 1H), 3.19−2.82 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.7, 182.2, 144.0, 139.5, 138.5, 134.6, 133.2,

obtained from Infinity Scientific, Beijing Ouhe Technology, and Aladdin, and they were used without further purification. Flash chromatography was performed on silica gel 60 (40−63 μm, 60 Å). Thin layer chromatography (TLC) was performed on glass plates coated with silica gel 60 with F254 indicator. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Bruker 300 MHz spectrometer. Chemical shifts for protons are reported in parts per million downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3 = δ 7.26, DMSO = δ 2.52). Carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a Bruker 75 MHz spectrometer. Chemical shifts for carbon are reported in parts per million downfield from tetramethylsilane and are referenced to the carbon resonances of the solvent (CDCl3 = δ 77.07, DMSO = 39.9). Data are represented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants in hertz (Hz), integration. Synthesis of Starting Materials. Substrate for 2-amino-1,4naphthoquinone 1h (known compound) was synthesized by a modified method, and other 2-amino-1,4-naphthoquinones are all known compounds that were synthesized following reported methods.20,21 2-Hydroxy-1,4-naphthoquinone was purchased from Energy Chemical (China). Synthesis of 1h. A mixture of 1,4-naphthoquinone (5 mmol, 790 mg, 1 equiv), 2,4,6-trimethylaniline (6 mmol, 811 mg, 1.2 equiv), and CeCl3·7H2O (0.25 mmol, 93 mg, 0.05 equiv) in 10 mL of EtOH. The reaction mixture was stirred at 75 °C for 24 h. After cooling to room temperature, to the mixture was added 40 mL of cold water, and yellow solids were precipitated. The solids were collected by filtration and washed with the smallest volume of cold ethanol. The final product 1h was obtained as a yellow solid of 466 mg, 32% yield. 1H NMR (300 MHz, CDCl3): δ 8.13 (dd, J = 7.5 Hz, 2.0 Hz, 1H), 8.09 (dd, J = 7.5 Hz, 2.0 Hz, 1H), 7.75 (td, J = 7.5, 1.4 Hz, 1H), 7.66 (td, J = 7.5, 1.4 Hz, 1H), 7.03 (s, 1H), 6.95 (s, 2H), 5.38 (s, 1H), 2.31 (s, 3H), 2.16 (s, 6H). Synthesis of 2-Benzamido-1,4-naphthoquinone (1o).22 To a 25 mL flask were added 1,4-naphthoquinone (5 mmol, 1 equiv), benzhydroxamic acid (5.5 mmol, 1.1 equiv), and iPr2NEt (10 mmol, 2 equiv), followed by addition of 10 mL of acetonitrile. The mixture was stirred at 70 °C for 4 h. Volatiles were then removed under vacuum, and the residue was purified on a silica flash column with AcOEt/petroleum ether to afford the desired product 1o. Alkenes 2k and 2n Were Synthesized by Known Methods.23 A solution of methyltriphenylphosphonium bromide (36 mmol, 12.9 g) in 55 mL of anhydrous THF was cooled to 0 °C, KOtBu (36 mmol, 1.2 equiv, 4.0 g) was added, and the mixture was stirred for 30 min. After that, a solution of corresponding aldehyde (30 mmol, 1 equiv, in 21 mL of THF) was prepared and added dropwise into the mixture above 0 °C. The mixture was allowed to warm to room temperature and was stirred overnight. After the reaction was complete, THF was removed under vacuum and 10 mL of ethyl acetate was added to the residue followed by dilution with 100 mL of petroleum ether. The mixture was filtered, the filtrate was concentrated with a rotavapor, and the residue was purified by column chromatography to get the desired product. Difunctionalization and Characterization of Alkenes. To a dried Schlenk tube were added 2-hydroxy- or 2-aminoquinone (1, 0.22 mmol, 1.1 equiv), Togni reagent (3, 0.22 mmol, 1.1 equiv, 69.5 mg), silver acetate (0.02 mol, 0.1 equiv, 3.3 mg), and DPPF (0.02 mmol, 0.1 equiv, 11.1 mg). The tube was then sealed and backfilled with argon, followed by addition of a solution of alkene (2, 0.2 mmol, 1 equiv, in 1 mL of 1,2-dichloroethane or DMF) with a syringe. The tube was placed in an oil bath and stirred at 75 °C for 12 h. After completion, volatiles were removed under vacuum, and the residues were purified on a silica flash column with AcOEt/hexane eluents (AcOEt/hexane = 1:20 to 1:10) to obtain the final product. Compound 4ka was purified on a silica flash column with AcOEt/ DCM eluents (AcOEt/DCM = 1:2). 2-(Phenylamino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-1,4-dione (4aa). Red solid, 69.7 mg, 80% yield. 1H 1010

DOI: 10.1021/acs.joc.8b02997 J. Org. Chem. 2019, 84, 1006−1014

Article

The Journal of Organic Chemistry 132.3, 132.0, 129.5, 129.2, 129.1, 127.9, 126.2, 126.1 (q, J = 276.3 Hz), 126.0, 125.9, 123.8, 118.3, 37.5 (q, J = 27.1 Hz), 36.7 (q, J = 3.0 Hz); 19F{1H} NMR (282 MHz, CDCl3): δ = −64.3. HRMS calcd for C25H18ClF3NO2 [M + H]+: 456.0973, found: 456.0977. 2-(1-(4-Bromophenyl)-3,3,3-trifluoropropyl)-3-(phenylamino)naphthalene-1,4-dione (4ah). Red solid, 81.0 mg, 81% yield. 1H NMR (300 MHz, CDCl3) δ 8.11−8.07 (m, 2H), 7.76 (td, J = 7.5, 1.5 Hz, 1H), 7.66 (td, J = 7.5, 1.4 Hz, 1H), 7.62 (br, 1H), 7.35−7.27 (m, 2H), 7.25−7.12 (m, 3H), 7.09−7.00 (m, 2H), 6.98−6.90 (m, 2H), 4.06 (t, J = 7.0 Hz, 1H), 3.20−2.80 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.7, 182.2, 144.0, 139.5, 139.0, 134.6, 133.2, 132.3, 130.9, 129.5, 129.5, 129.2, 126.2, 126.1 (q, J = 276.3 Hz), 126.0, 125.9, 123.8, 120.1, 118.2, 37.1 (q, J = 27.1 Hz), 36.8 (q, J = 3.1 Hz); 19F{1H} NMR (282 MHz, CDCl3): δ = −64.3. HRMS calcd for C25H18BrF3NO2 [M + H]+: 500.0468, found: 500.0462. 2-(Phenylamino)-3-(3,3,3-trifluoro-1-(4-fluorophenyl)propyl)naphthalene-1,4-dione (4ai). Red solid, 66.8 mg, 76% yield. 1H NMR (300 MHz, CDCl3) δ 8.12−8.07 (m, 2H), 7.76 (td, J = 7.6, 1.4 Hz, 1H), 7.66 (td, J = 7.5, 1.4 Hz, 1H), 7.59 (br, 1H), 7.25−7.10 (m, 3H), 7.08−6.97 (m, 4H), 6.91−6.80 (m, 2H), 4.10 (t, J = 7.0 Hz, 1H), 3.22−2.81 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.8, 182.2, 161.2 (d, J = 243.7 Hz), 143.9, 139.6, 135.6 (d, J = 3.2 Hz), 134.6, 133.2, 132.3, 129.6, 129.3 (d, J = 7.9 Hz), 129.1, 126.2, 126.1 (q, J = 276.1 Hz), 126.0, 125.8, 123.7, 118.8, 114.6 (d, J = 21.1 Hz), 37.4 (q, J = 27.1 Hz), 36.7 (q, J = 3.1 Hz); 19F{1H} NMR (282 MHz, CDCl3): δ = −64.3, −116.4. HRMS calcd for C25H18F4NO2 [M + H]+: 440.1268, found: 440.1267. 2-(Phenylamino)-3-(3,3,3-trifluoro-1-(4-(trifluoromethyl)phenyl)propyl)naphthalene-1,4-dione (4aj). Red solid, 71.5 mg, 73% yield. 1 H NMR (300 MHz, CDCl3) δ 8.10 (dd, J = 7.6, 1.4 Hz, 2H), 7.77 (td, J = 7.5, 1.4 Hz, 1H), 7.71−7.58 (m, 2H), 7.45−7.42 (m, 2H), 7.24−7.10 (m, 5H), 7.05−7.02 (m, 2H), 4.15 (t, J = 7.0 Hz, 1H), 3.15−2.94 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.7, 182.1, 144.3, 144.1, 139.4, 134.7, 133.2, 132.3, 129.5, 129.2, 128.5 (q, J = 32.3 Hz), 128.0, 126.2, 126.1, 126.1 (q, J = 276.1 Hz), 124.7 (q, J = 3.7 Hz), 123.9, 123.8 (q, J = 270.2 Hz), 117.6, 37.1 (q, J = 3.0 Hz), 37.1 (q, J = 27.5 Hz); 19F{1H} NMR (282 MHz, CDCl3): δ = −64.5, −64.3. HRMS calcd for C26H18F6NO2 [M + H]+: 490.1236, found: 490.1239. 2-(Phenylamino)-3-(3,3,3-trifluoro-1-(naphthalen-1-yl)propyl)naphthalene-1,4-dione (4ak). Red solid, 63.2 mg, 67% yield. 1H NMR (300 MHz, CDCl3) δ 8.22 (dd, J = 7.8, 1.3 Hz, 1H), 8.11 (dd, J = 7.7, 1.4 Hz, 1H), 7.90−7.62 (m, 4H), 7.62−7.47 (m, 2H), 7.47− 7.31 (m, 2H), 7.31−7.16 (m, 2H), 6.81−6.70 (m, 2H), 6.70−6.52 (m, 3H), 4.88 (dd, J = 10.2, 3.9 Hz, 1H), 3.72−3.44 (m, 1H), 2.86− 2.68 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 184.6, 182.2, 144.6, 139.0, 134.8, 134.5, 133.4, 133.4, 132.2, 130.9, 129.7, 128.4, 128.3, 127.5, 126.4 (q, J = 276.5 Hz), 126.3, 126.1, 126.0, 125.7, 124.9, 124.8, 123.1, 122.0, 118.6, 35.9 (q, J = 26.4 Hz), 34.8 (q, J = 2.9 Hz); 19F{1H} NMR (282 MHz, CDCl3): δ = −64.4. HRMS calcd for C29H21F3NO2 [M + H]+: 472.1519, found: 472.1512. 2-(Phenylamino)-3-(3,3,3-trifluoro-1-(pyridin-2-yl)propyl)naphthalene-1,4-dione (4al). Red solid, 51.5 mg, 61% yield. 1H NMR (300 MHz, CDCl3) δ 10.4 (br, 1H), 8.58−8.56 (m, 1H), 8.14− 8.11 (m, 1H), 7.94 (dd, J = 7.6, 1.4 Hz, 1H), 7.73−7.59 (m, 3H), 7.45 (d, J = 7.8 Hz, 1H), 7.36−7.20 (m, 4H), 7.11 (t, J = 7.4 Hz, 1H), 7.01−6.98 (m, 2H), 5.25 (t, J = 7.0 Hz, 1H), 3.32−3.05 (m, 1H), 3.05−2.78 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 182.2, 181.4, 159.8, 148.0, 145.4, 141.6, 137.7, 133.7, 132.4, 132.0, 131.6, 128.8, 126.4 (q, J = 275.5 Hz), 126.1, 126.0, 123.6, 123.4, 122.3, 121.2, 36.5 (q, J = 2.3 Hz), 34.7 (q, J = 27.9 Hz); 19F{1H} NMR (282 MHz, CDCl3): δ = −64.6.HRMS calcd for C24H18F3N2O2 [M + H]+: 423.1315, found: 423.1317. 2-(Phenylamino)-3-(3,3,3-trifluoro-1-(thiophen-2-yl)propyl)naphthalene-1,4-dione (4am). Red solid, 62.4 mg, 73% yield. 1H NMR (300 MHz, CDCl3) δ 8.14−8.08 (m, 2H), 7.76 (td, J = 7.6, 1.5 Hz, 1H), 7.66 (td, J = 7.5, 1.4 Hz, 1H), 7.61 (br, 1H), 7.33−7.16 (m, 3H), 7.16−7.07 (m, 3H), 6.83 (dd, J = 5.2, 3.5 Hz, 1H), 6.52 (dt, J = 3.5, 1.1 Hz, 1H), 4.37 (t, J = 6.9 Hz, 1H), 3.25−3.07 (m, 1H), 2.97− 2.79 (m, 1H). 13C {1H}NMR (75 MHz, CDCl3): δ 183.3, 182.3,

143.5, 142.9, 139.4, 134.6, 133.2, 132.2, 129.6, 129.2, 126.2, 126.1, 126.0, 125.9 (q, J = 276.2 Hz), 125.7, 125.4, 124.3, 124.1, 117.9, 38.7 (q, J = 27.1 Hz), 33.0 (q, J = 3.1 Hz); 19F{1H} NMR (282 MHz, CDCl3): δ = −64.4. HRMS calcd for C23H17F3NO2S [M + H]+: 428.0927, found: 428.0931. 2-(Phenylamino)-3-(1,1,1-trifluoro-5-phenylpentan-3-yl)naphthalene-1,4-dione (4an). Red solid, 68.3 mg, 76% yield. 1H NMR (300 MHz, CDCl3) δ 8.10−8.05 (m, 2H), 7.74 (td, J = 7.5, 1.4 Hz, 1H), 7.65 (td, J = 7.5, 1.4 Hz, 1H), 7.43−7.35 (m, 3H), 7.32− 7.19 (m, 3H), 7.19−7.09 (m, 3H), 7.09−7.01 (m, 2H), 2.84−2.14 (m, 5H), 2.02−1.81 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.8, 182.3, 144.2, 141.2, 140.7, 134.4, 133.3, 132.1, 129.7, 129.3, 128.0, 127.9, 126.6 (q, J = 275.8 Hz), 125.9, 125.7, 125.5, 123.9, 121.0, 35.4 (q, J = 26.9 Hz), 33.9, 33.6, 32.3 (q, J = 2.7 Hz); 19F{1H} NMR (282 MHz, CDCl 3 ): δ = −63.9. HRMS calcd for C27H22F3NO2Na[M + Na]+: 472.1495, found: 472.1491. 2-(Phenylamino)-3-(2-(trifluoromethyl)-2,3-dihydro-1H-inden-1yl)naphthalene-1,4-dione (4ao). Red solid, 64.1 mg, 74% yield. 1H NMR (300 MHz, CDCl3): δ 8.16−8.06 (m, 1H), 8.01−7.92 (m, 1H), 7.73−7.62 (m, 2H), 7.59 (br, 1H), 7.32−7.11 (m, 8H), 7.07−6.95 (m, 1H), 4.47 (d, J = 8.5 Hz, 1H), 3.55−3.43 (m, 1H), 3.36−3.27 (m, 1H), 2.99−2.91 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 182.6, 182.2, 144.9, 142.8, 139.5, 139.4, 134.5, 133.2, 132.1, 129.8, 129.1, 127.6 (q, J = 275.9 Hz), 126.4, 126.4, 126.1, 126.0, 124.3, 124.2, 122.3, 47.8 (q, J = 26.2 Hz), 42.9 (q, J = 2.5 Hz), 32.0 (q, J = 2.8 Hz); 19 1 F{ H} NMR (282 MHz, CDCl3): δ = −70.2. HRMS calcd for C26H19F3NO2 [M + H]: 434.1362, found: 434.1359. 2-(Phenylamino)-3-(2-(trifluoromethyl)cyclohexyl)naphthalene1,4-dione (4ap). Red solid, 55.1 mg, 69% yield. 1H NMR (300 MHz, CDCl3): δ8.08−8.04 (m, 2H), 7.72 (td, J = 7.6, 1.4 Hz, 1H), 7.63 (td, J = 7.5, 1.4 Hz, 1H), 7.51−7.31 (m, 3H), 7.31−7.21 (m, 1H), 7.19− 7.16 (m, 2H), 3.13−2.88 (m, 1H), 2.31−2.23 (m, 1H), 2.06 (qd, J = 13.1, 3.6 Hz, 1H), 1.91−1.82 (m, 1H), 1.65−1.48 (m, 3H), 1.37− 1.17 (m, 1H), 0.77 (qd, J = 13.0, 3.6 Hz, 1H), 0.39 (qt, J = 12.9, 4.0 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 184.1, 182.5, 143.3, 140.7, 134.2, 133.4, 131.9, 129.7, 128.9, 125.7 (q, J = 279.0 Hz), 125.8, 125.8, 125.8, 124.5, 120.7, 42.7 (q, J = 23.5 Hz), 36.9 (q, J = 1.8 Hz), 28.2, 25.7 (q, J = 3.1 Hz), 25.4, 24.1. 19F{1H} NMR (282 MHz, CDCl3): δ = −69.6. HRMS calcd for C23H21F3NO2 [M + H]: 400.1519, found: 400.1517. 2-((2-Methoxyphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-1,4-dione (4ba). Red solid, 68.9 mg, 74% yield. 1 H NMR (300 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.92−7.85 (m, 2H), 7.77 (td, J = 7.5, 1.6 Hz, 1H), 7.70 (td, J = 7.4, 1.5 Hz, 1H), 7.15− 7.07 (m, 4H), 7.06−6.96 (m, 2H), 6.96−6.80 (m, 2H), 4.38 (t, J = 7.2 Hz, 1H), 3.54 (s, 3H), 3.26−3.02 (m, 2H), 2.20 (s, 3H). 13C{1H} NMR (75 MHz, DMSO-d6): δ 182.6, 181.6, 152.1, 146.8, 137.8, 135.3, 134.5, 132.8, 132.8, 130.7, 130.2, 128.7, 127.6, 127.2 (q, J = 276.2 Hz), 125.9, 125.7, 125.6, 124.7, 120.7, 119.4, 112.1, 55.5, 35.6 (q, J = 25.9 Hz), 34.8 (q, J = 2.1 Hz), 20.6; 19F{1H} NMR (282 MHz, DMSO-d6): δ = −62.6. HRMS calcd for C27H23F3NO3 [M + H]: 466.1625, found: 466.1622. 2-((3-Methoxyphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-1,4-dione (4ca). Red solid, 69.8 mg, 75% yield. 1 H NMR (300 MHz, CDCl3): δ 8.12−8.06 (m, 2H), 7.74 (td, J = 7.5, 1.6 Hz, 1H), 7.65 (td, J = 7.4, 1.5 Hz, 1H), 7.48 (br, 1H), 7.14 (t, J = 8.1 Hz, 1H), 7.00 (s, 4H), 6.71−6.65 (m, 2H), 6.49 (t, J = 2.4 Hz, 1H), 4.16 (t, J = 7.2 Hz, 1H), 3.56 (s, 3H), 3.16−2.95 (m, 2H), 2.27 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.8, 182.3, 160.1, 143.7, 140.9, 136.8, 135.8, 134.4, 133.2, 132.1, 129.8, 129.7, 128.6, 127.6, 126.3 (q, J = 276.2 Hz), 126.2, 125.9, 120.0, 115.7, 111.5, 109.0, 54.7, 37.2 (q, J = 27 Hz), 36.8 (q, J = 2.8 Hz), 20.6; 19F{1H} NMR (282 MHz, CDCl3): δ = −64.3. HRMS calcd for C27H23F3NO3 [M + H]: 466.1625, found: 466.1623. 2-((4-Methoxyphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-1,4-dione (4da). Red solid, 57.7 mg, 62% yield. 1 H NMR (300 MHz, DMSO-d6): δ 8.71 (s, 1H), 7.98−7.88 (m, 2H), 7.79 (td, J = 7.5, 1.5 Hz, 1H), 7.71 (td, J = 7.4, 1.5 Hz, 1H), 7.09− 6.97 (m, 7H), 6.80−6.71 (m, 2H), 4.18 (t, J = 7.2 Hz, 1H), 3.67 (s, 3H), 3.29−3.13 (m, 1H), 3.08−2.96 (m, 1H), 2.20 (s, 3H). 13C{1H} 1011

DOI: 10.1021/acs.joc.8b02997 J. Org. Chem. 2019, 84, 1006−1014

Article

The Journal of Organic Chemistry NMR (75 MHz, DMSO-d6): δ 182.9, 182.4, 156.7, 145.9, 137.7, 135.3, 134.8, 134.3, 133.0, 132.8, 130.4, 128.6, 127.7, 127.1 (q, J = 276.4 Hz), 125.9, 125.7, 125.2, 119.5, 114.2, 55.4, 35.6 (q, J = 25.3 Hz), 35.7 (q, J = 2.6 Hz), 20.6; 19F{1H} NMR (282 MHz, DMSOd6): δ = −62.4. HRMS calcd for C27H23F3NO3 [M + H]: 466.1625, found: 466.1621. 2-((4-Methylphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-1,4-dione (4ea). Red solid, 69.2 mg, 77% yield. 1H NMR (300 MHz, DMSO-d6): δ 8.76 (s, 1H), 7.91 (dt, J = 7.7, 1.8 Hz, 2H), 7.79 (td, J = 7.5, 1.5 Hz, 1H), 7.18−7.07 (m, 2H), 7.06−6.92 (m, 6H), 4.24 (t, J = 7.2 Hz, 1H), 3.31−3.18 (m, 1H), 3.11−3.00 (m, 1H), 2.21 (s, 3H), 2.19 (s, 3H). 13C{1H} NMR (75 MHz, DMSOd6): δ 182.9, 182.3, 145.6, 139.3, 137.6, 135.4, 134.7, 133.4, 132.9, 132.9, 130.6, 129.4, 128.7, 127.7, 127.1 (q, J = 276.1 Hz), 125.9, 125.7, 123.0, 121.6, 35.8 (q, J = 2.8 Hz), 35.4 (q, J = 26.2 Hz), 20.6, 20.6; 19F{1H} NMR (282 MHz, DMSO-d6): δ = −62.4. HRMS calcd for C27H23F3NO2 [M + H]+: 450.1675, found: 450.1673. 2-((4-Chlorophenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-1,4-dione (4fa). Red solid, 71.4 mg, 76% yield. 1H NMR (300 MHz, CDCl3): δ 8.13−8.06 (m, 2H), 7.76 (td, J = 7.5, 1.5 Hz, 1H), 7.66 (td, J = 7.5, 1.4 Hz, 1H), 7.34 (s, 1H), 7.19−7.06 (m, 2H), 7.06−6.86 (m, 6H), 4.10 (t, J = 7.0 Hz, 1H), 3.30−3.03 (m, 1H), 3.03−2.76 (m, 1H), 2.29 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.8, 182.1, 143.7, 138.5, 136.4, 136.0, 134.5, 133.1, 132.3, 130.7, 129.7, 129.0, 128.7, 127.4, 126.6 (q, J = 277.2 Hz), 126.3, 126.0, 124.4, 120.8, 37.2 (q, J = 27.1 Hz), 37.0 (q, J = 2.8 Hz), 20.6; 19F{1H} NMR (282 MHz, CDCl3): δ = −64.3. HRMS calcd for C26H19ClF3NO2 [M + H]: 470.1129, found: 470.1135. 2-((4-Trifluoromethylphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-1,4-dione (4ga). Red solid, 77.5 mg, 77% yield. 1 H NMR (300 MHz, DMSO-d6): δ 9.04 (s, 1H), 8.05−7.87 (m, 2H), 7.87−7.68 (m, 2H), 7.57−7.42 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 4.41 (t, J = 7.2 Hz, 1H), 3.48−3.34 (m, 1H), 3.24−3.04 (m, 1H), 2.19 (s, 3H). 13 C{1H} NMR (75 MHz, DMSO-d6): δ 183.5, 181.6, 147.0, 144.7, 136.9, 135.7, 134.6, 133.5, 132.4, 131.0, 130.3, 128.8, 127.7, 127.1 (q, J = 368.5 Hz), 126.1, 126.0 (q, J = 5.4 Hz), 125.9, 124.7 (q, J = 276.4 Hz), 122.0 (q, J = 31.9 Hz), 120.2, 36.3 (q, J = 2.4 Hz), 35.2 (q, J = 26.8 Hz), 20.6; 19F{1H} NMR (282 MHz, DMSO-d6): δ = −60.1; −62.6. HRMS calcd for C27H20F6NO2 [M + H]: 504.1393, found: 504.1392. 2-((2,4,6-Trimethylphenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-1,4-dione (4ha). Red solid, 67.8 mg, 71% yield. 1 H NMR (300 MHz, CDCl3): δ 8.16 (dd, J = 7.7, 1.3 Hz, 1H), 8.09 (dd, J = 7.7, 1.4 Hz, 1H), 7.76 (td, J = 7.6, 1.4 Hz, 1H), 7.65 (td, J = 7.5, 1.4 Hz, 1H), 7.33 (s, 1H), 6.98−6.85 (m, 3H), 6.75−6.65 (m, 2H), 6.59−6.51 (m, 1H), 3.90 (t, J = 7.0 Hz, 1H), 3.32−3.12 (m, 1H), 2.85−2.62 (m, 1H), 2.32−2.19 (m, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.9, 182.2, 144.5, 137.9, 137.0, 135.5, 135.2, 134.9, 134.5, 133.8, 133.6, 131.8, 129.6, 129.1, 128.7, 128.1, 127.9, 126.3 (q, J = 276.3 Hz), 126.1, 125.8, 115.9, 39.0 (q, J = 26.5 Hz), 36.5 (q, J = 3.1 Hz), 20.6, 20.5, 18.0, 17.8; 19F{1H} NMR (282 MHz, CDCl3): δ = −64.3. HRMS calcd for C29H27F3NO2 [M + H]: 478.1988, found: 478.1985. 2-Hexylamino-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene1,4-dione (4ia). Red solid, 67.4 mg, 76% yield. 1H NMR (300 MHz, CDCl3): δ 8.02 (td, J = 7.4, 6.9, 1.4 Hz, 2H), 7.68 (td, J = 7.5, 1.5 Hz, 1H), 7.58 (td, J = 7.5, 1.4 Hz, 1H), 7.33−7.20 (m, 2H), 7.17−7.05 (m, 2H), 5.90 (t, J = 5.3 Hz, 1H), 4.66 (dd, J = 9.0, 4.9 Hz, 1H), 3.61−3.28 (m, 3H), 3.16−2.90 (m, 1H), 2.31 (s, 3H), 1.75−1.56 (m, 2H), 1.41−1.18 (m, 6H), 0.89 (t, J = 6.6 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 182.7, 182.4, 146.2, 138.8, 135.8, 134.3, 133.4, 131.6, 129.8, 128.9, 126.9, 126.9 (q, J = 275.8 Hz), 125.9, 125.7, 114.9, 46.1, 36.6 (q, J = 26.6 Hz), 35.7 (q, J = 2.7 Hz), 30.9, 30.3, 25.9, 22.1, 20.6, 13.6; 19F{1H} NMR (282 MHz, CDCl3): δ = −64.1. HRMS calcd for C26H29F3NO2 [M + H]+: 444.2145, found: 444.2146. 2-(Methyl(phenyl)amino)-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-1,4-dione (4ja). dark blue solid, 65.6 mg, 73% yield. 1H NMR (300 MHz, CDCl3): δ 8.21−8.07 (m, 1H), 8.02−7.89 (m, 1H),

7.72 (pd, J = 7.4, 1.6 Hz, 2H), 7.25−7.18 (m, 4H), 7.06 (d, J = 7.8 Hz, 2H), 6.87 (t, J = 7.5 Hz, 1H), 6.76−6.60 (m, 2H), 4.78 (dd, J = 9.4, 5.6 Hz, 1H), 3.56−3.37 (m, 1H), 3.14 (s, 3H), 3.05−2.79 (m, 1H), 2.29 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 185.6, 181.5, 150.1, 147.9, 146.0, 136.6, 135.7, 133.6, 133.5, 132.2, 131.4, 129.0, 128.8, 128.4, 126.3, 126.3 (q, J = 275.8 Hz), 126.2, 119.3, 114.0, 39.4, 38.1 (q, J = 3.1 Hz), 36.9 (q, J = 27.2 Hz), 20.6; 19F{1H} NMR (282 MHz, CDCl3): δ = −64.4. HRMS calcd for C27H23F3NO2 [M + H]+: 450.1675, found: 450.1675. 2-Hydroxy-3-(3,3,3-trifluoro-1-(p-tolyl)propyl)naphthalene-1,4dione (4ka). Red solid, 48.3 mg, 67% yield. 1H NMR (300 MHz, CDCl3): δ 8.11 (d, J = 7.5 Hz, 1H), 8.03 (d, J = 7.3 Hz, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 4.87 (dd, J = 9.8, 5.2 Hz, 1H), 3.60−3.35 (m, 1H), 3.03−2.80 (m, 1H), 2.30 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 183.5, 181.5, 152.9, 137.3, 136.4, 134.9, 132.7, 132.5, 129.0, 128.8, 127.7, 126.7, 126.5 (q, J = 275.8 Hz), 125.8, 123.1, 35.4 (q, J = 27.5 Hz), 34.0 (q, J = 3.1 Hz), 20.6; 19F{1H} NMR (282 MHz, CDCl3): δ = −64.8. HRMS calcd for C20H16F3O3 [M + H]+: 361.1046, found: 361.1048. Scale-up Synthesis of Compound 4ga. To a dried Schlenk tube were added 2-aminoquinone 1g (1.1 mmol, 1,1 equiv, 348.9 mg), Togni reagent (3, 1.1 mmol, 1.1 equiv, 347.8 mg), silver acetate (0.1 mol, 0.1 equiv, 16.7 mg), and DPPF (0.1 mmol, 0.1 equiv, 55.4 mg). The tube was then sealed and backfilled with argon, followed by addition of a solution of alkene 2a (1.0 mmol, 1 equiv, 129.8 mg in 5 mL of DMF) with a syringe. The tube was placed in an oil bath and stirred at 75 °C for 12 h. After completion, volatiles were removed under vacuum, and the residues were purified on a silica flash column with AcOEt/hexane eluent (AcOEt/hexane = 15:1), affording 312 mg of compound 4ga in 71% yield.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02997. Reaction conditions optimization, copies of single crystallographic data for 4aa, and characterization data (1H, 13C, and 19F NMR) (PDF) Crystallographic data for 4aa (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] or cheunggilbert@gmail. com. ORCID

Hongchao Guo: 0000-0002-7356-4283 Cheng Zhang: 0000-0002-8760-8152 Author Contributions †

These authors contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Key Research and Development Plan of China (2017YFD0200504). This work is also partly supported by the Start-Up Funds from CAU. Support from College of Science (CAU) is also gratefully acknowledged.

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REFERENCES

(1) (a) Sunassee, S. N.; Davies-Coleman, M. T. Cytotoxic and Antioxidant Marine Prenylated Quinones and Hydroquinones. Nat. Prod. Rep. 2012, 29, 513−535. (b) Son, E. J.; Kim, J. H.; Kim, K.; Park, C. B. Quinone and Its Derivatives for Energy Harvesting and 1012

DOI: 10.1021/acs.joc.8b02997 J. Org. Chem. 2019, 84, 1006−1014

Article

The Journal of Organic Chemistry Storage Materials. J. Mater. Chem. A 2016, 4, 11179−11202. (c) Inks, E. S.; Josey, B. J.; Jesinkey, S. R.; Chou, C. J. A Novel Class of Small Molecule Inhibitors of HDAC6. ACS Chem. Biol. 2012, 7, 331−339. (d) Josey, B. J.; Inks, E. S.; Wen, X.; Chou, C. J. Structure-Activity Relationship Study of Vitamin K Derivatives Yields Highly Potent Neuroprotective Agents. J. Med. Chem. 2013, 56, 1007−1022. (e) Mfuh, A. M.; Zhang, Y.; Stephens, D. E.; Vo, A. X. T.; Arman, H. D.; Larionov, O. V. Concise Total Synthesis of Trichodermamides A, B, and C Enabled by an Efficient Construction of the 1,2Oxazadecaline Core. J. Am. Chem. Soc. 2015, 137, 8050−8053. (f) Zhang, Z.; Chen, J.; Yang, Z.; Tang, Y. Rapid Biomimetic Total Synthesis of (±)-Rossinone B. Org. Lett. 2010, 12, 5554−5557. (g) Usui, I.; Lin, D. W.; Masuda, T.; Baran, P. S. Convergent Synthesis and Structural Confirmation of Phellodonin and Sarcodonin ε. Org. Lett. 2013, 15, 2080−2083. (2) (a) Reichstein, A.; Vortherms, S.; Bannwitz, S.; Tentrop, J.; Prinz, H.; Müller, K. Synthesis and Structure−Activity Relationships of Lapacho Analogues. 1. Suppression of Human Keratinocyte Hyperproliferation by 2-Substituted Naphtho[2,3-b]furan-4,9-diones, Activation by Enzymatic One- and Two-Electron Reduction, and Intracellular Generation of Superoxide. J. Med. Chem. 2012, 55, 7273−7284. (b) Dimopoulos, M.-A.; Mitsiades, C. S.; Anderson, K. C.; Richardson, P. G. Tanespimycin as Antitumor Therapy. Clin. Lymphoma Myeloma Leuk. 2011, 11, 17−22. (c) Hadden, M. K.; Lubbers, D. J.; Blagg, B. S. J. Geldanamycin, Radicicol, and Chimeric Inhibitors of the Hsp90 Nterminal ATP Binding Site. Curr. Top. Med. Chem. 2006, 6, 1173−1182. (d) Hadden, M. K.; Hill, S. A.; Davenport, J.; Matts, R. L.; Blagg, B. S. J. Synthesis and Evaluation of Hsp90 Inhibitors that Contain the 1,4-Naphthoquinone Scaffold. Bioorg. Med. Chem. 2009, 17, 634−640. (e) Xu, K.; Wang, P.; Wang, L.; Liu, C.; Xu, S.; Cheng, Y.; Wang, Y.; Li, Q.; Lei, H. Quinone Derivatives from the Genus Rubia and Their Bioactivities. Chem. Biodiversity 2014, 11, 341−363. (3) (a) Jardim, G. A. M.; da Silva Júnior, E. N.; Bower, J. F. Overcoming Naphthoquinone Deactivation: Rhodium-Catalyzed C-5 Selective C-H Iodination as A Gateway to Functionalized Derivatives. Chem. Sci. 2016, 7, 3780−3784. (b) Fujiwara, Y.; Domingo, V.; Seiple, I. B.; Gianatassio, R.; Del Bel, M.; Baran, P. S. Practical C-H Functionalization of Quinones with Boronic Acids. J. Am. Chem. Soc. 2011, 133, 3292−3295. (4) (a) Gutiérrez-Bonet, Á .; Remeur, C.; Matsui, J. K.; Molander, G. A. Late-Stage C-H Alkylation of Heterocycles and 1,4-Quinones via Oxidative Homolysis of 1,4-Dihydropyridines. J. Am. Chem. Soc. 2017, 139, 12251−12258. (b) Galloway, J. D.; Mai, D. N.; Baxter, R. D. Silver-Catalyzed Minisci Reactions Using Selectfluor as a Mild Oxidant. Org. Lett. 2017, 19, 5772−5775. (c) Naturale, G.; Lamblin, M.; Commandeur, C.; Felpin, F.-X.; Dessolin, J. Direct C−H Alkylation of Naphthoquinones with Amino Acids Through a Revisited Kochi-Anderson Radical Decarboxylation: Trends in Reactivity and Applications. Eur. J. Org. Chem. 2012, 2012, 5774− 5788. (d) Ilangovan, A.; Saravanakumar, S.; Malayappasamy, S. γCarbonyl Quinones: Radical Strategy for the Synthesis of Evelynin and Its Analogues by C-H Activation of Quinones Using Cyclopropanols. Org. Lett. 2013, 15, 4968−4971. (e) Baral, E. R.; Kim, S. H.; Lee, Y. R. Copper-Catalyzed C(sp2)-C(sp3) Cross-Dehydrogenative Coupling of Quinones with Cyclic Alkanes: One Step Access to Parvaquone and its Analogs. Asian J. Org. Chem. 2016, 5, 1134−1141. (f) Devari, S.; Shah, B. A. Visible Light-Promoted C-H Functionalization of Ethers and Electron-Deficient Arenes. Chem. Commun. 2016, 52, 1490−1493. (g) Li, G.-X.; Morales-Rivera, C. A.; Wang, Y.; Gao, F.; He, G.; Liu, P.; Chen, G. Photoredox-Mediated Minisci C-H Alkylation of N-Heteroarenes Using Boronic Acids and Hypervalent Iodine. Chem. Sci. 2016, 7, 6407−6412. (5) (a) Xu, X.-L.; Li, Z. Catalytic Electrophilic Alkylation of pQuinones through a Redox Chain Reaction. Angew. Chem., Int. Ed. 2017, 56, 8196−8200. (b) Gu, Y.-R.; Duan, X.-H.; Yang, L.; Guo, L.N. Direct C−H Cyanoalkylation of Heteroaromatic N-Oxides and Quinones via C-C Bond Cleavage of Cyclobutanone Oximes. Org. Lett. 2017, 19, 5908−5911. (c) Han, Q.; Jiang, K.; Wei, Y.; Su, W.

Transition-Metal-Free, TsOH-Mediated Direct C-H Allylation of 1,4Benzoquinone with Allylic Alcohols. Asian J. Org. Chem. 2018, 7, 1385−1389. (6) (a) Veguillas, M.; Rojas-Martin, J.; Ribagorda, M.; Carreño, M. C. Synthesis of Functionalized Alkyl Substituted Benzoquinones by Rh-Catalyzed Additions of Boronic Acids. Org. Biomol. Chem. 2017, 15, 5386−5394. (b) Lang, S.; Groth, U. Total Syntheses of Cytotoxic, Naturally Occurring Kalasinamide, Geovanine, and Marcanine A. Angew. Chem., Int. Ed. 2009, 48, 911−913. (c) Miyamura, H.; Shiramizu, M.; Matsubara, R.; Kobayashi, S. Aerobic Oxidation of Hydroquinone Derivatives Catalyzed by Polymer-Incarcerated Platinum Catalyst. Angew. Chem., Int. Ed. 2008, 47, 8093−8095. (7) For reviews, see: (a) Qiu, G.; Lai, L.; Cheng, J.; Wu, J. Recent Advances in the Sulfonylation of Alkenes with the Insertion of Sulfur Dioxide via Radical Reactions. Chem. Commun. 2018, 54, 10405− 10414. (b) Courant, T.; Masson, G. Recent Progress in Visible-Light 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. New Horizons of Photocatalytic Fluoromethylative Difunctionalization of Alkenes. Chem. 2018, 4, 409−437. (d) Lan, X.-W.; Wang, N.-X.; Xing, Y. Recent Advances in Radical Difunctionalization of Simple Alkenes. Eur. J. Org. Chem. 2017, 2017, 5821−5851. (e) Sauer, G. S.; Lin, S. An Electrocatalytic Approach to the Radical Difunctionalization of Alkenes. ACS Catal. 2018, 8, 5175−5187. (f) Egami, H.; Sodeoka, M. Trifluoromethylation of Alkenes with Concomitant Introduction of Additional Functional Groups. Angew. Chem., Int. Ed. 2014, 53, 8294−8308. (8) (a) Wang, H.; Lu, Q.; Qian, C.; Liu, C.; Liu, W.; Chen, K.; Lei, A. Solvent-Enabled Radical Selectivities: Controlled Syntheses of Sulfoxides and Sulfides. Angew. Chem., Int. Ed. 2016, 55, 1094−1097. (b) Sun, X.; Li, X.; Song, S.; Zhu, Y.; Liang, Y.-F.; Jiao, N. MnCatalyzed Highly Efficient Aerobic Oxidative Hydroxyazidation of Olefins: A Direct Approach to β-Azido Alcohols. J. Am. Chem. Soc. 2015, 137, 6059−6066. (c) Jian, W.; Ge, L.; Jiao, Y.; Qian, B.; Bao, H. Angew. Chem., Int. Ed. 2017, 56, 3650−3654. and references cited therein. (d) Bao, X.; Yokoe, T.; Ha, T. M.; Wang, Q.; Zhu, J. CopperCatalyzed Methylative Difunctionalization of Alkenes. Nat. Commun. 2018, 9, 3725−3732. (9) (a) Wang, F.; Qi, X.; Liang, Z.; Chen, P.; Liu, G. CopperCatalyzed Intermolecular Trifluoromethylazidation of Alkenes: Convenient Access to CF3-Containing Alkyl Azides. Angew. Chem., Int. Ed. 2014, 53, 1881−1886. (b) 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, 14720−14725. (c) Qian, B.; Chen, S.; Wang, T.; Zhang, X.; Bao, H. Iron-Catalyzed Carboamination of Olefins: Synthesis of Amines and Disubstituted β-Amino Acids. J. Am. Chem. Soc. 2017, 139, 13076−13082. (d) Zhang, B.; Studer, A. Copper-Catalyzed Intermolecular Aminoazidation of Alkenes. Org. Lett. 2014, 16, 1790− 1793. (e) Gockel, S. N.; Buchanan, T. L.; Hull, K. L. Cu-Catalyzed Three-Component Carboamination of Alkenes. J. Am. Chem. Soc. 2018, 140, 58−61. (10) (a) Wang, F.; Wang, D.; Mu, X.; Chen, P.; Liu, G. CopperCatalyzed Intermolecular Trifluoromethylarylation of Alkenes: Mutual Activation of Arylboronic Acid and CF3+ Reagent. J. Am. Chem. Soc. 2014, 136, 10202−10205. (b) Wang, D.; Wang, F.; Chen, P.; Lin, Z.; Liu, G. Enantioselective Copper-Catalyzed Intermolecular Amino- and Azidocyanation of Alkenes in a Radical Process. Angew. Chem., Int. Ed. 2017, 56, 2054−2058. (c) Zhang, H.; Pu, W.; Xiong, T.; Li, Y.; Zhou, X.; Sun, K.; Liu, Q.; Zhang, Q. Copper-Catalyzed Intermolecular Aminocyanation and Diamination of Alkenes. Angew. Chem., Int. Ed. 2013, 52, 2529−2533. (11) Ouyang, X.-H.; Song, R.-J.; Hu, M.; Yang, Y.; Li, J.-H. SilverMediated Intermolecular 1,2-Alkylarylation of Styrenes with αCarbonyl Alkyl Bromides and Indoles. Angew. Chem., Int. Ed. 2016, 55, 3187−3191. (12) (a) Wang, F.; Wang, D.; Wan, X.; Wu, L.; Chen, P.; Liu, G. Enantioselective Copper-Catalyzed Intermolecular Cyanotrifluorome1013

DOI: 10.1021/acs.joc.8b02997 J. Org. Chem. 2019, 84, 1006−1014

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The Journal of Organic Chemistry thylation of Alkenes via Radical Process. J. Am. Chem. Soc. 2016, 138, 15547−15550. (b) Wu, L.; Wang, F.; Wan, X.; Wang, D.; Chen, P.; Liu, G. Asymmetric Cu-Catalyzed Intermolecular Trifluoromethylarylation of Styrenes: Enantioselective Arylation of Benzylic Radicals. J. Am. Chem. Soc. 2017, 139, 2904−2907. (c) Wang, D.; Wu, L.; Wang, F.; Wan, X.; Chen, P.; Lin, Z.; Liu, G. Asymmetric Copper-Catalyzed Intermolecular Aminoarylation of Styrenes: Efficient Access to Optical 2,2-Diarylethylamines. J. Am. Chem. Soc. 2017, 139, 6811− 6814. (13) Fu, L.; Zhou, S.; Wan, X.; Chen, P.; Liu, G. Enantioselective Trifluoromethylalkynylation of Alkenes via Copper-Catalyzed Radical Relay. J. Am. Chem. Soc. 2018, 140, 10965−10969. and references cited therein. (14) (a) Liang, Z.; Wang, F.; Chen, P.; Liu, G. Copper-Catalyzed Intermolecular Trifluoromethylthiocyanation of Alkenes: Convenient Access to CF3-Containing Alkyl Thiocyanates. Org. Lett. 2015, 17, 2438−2441. (b) Yuan, Z.; Wang, H.-Y.; Mu, X.; Chen, P.; Guo, Y.-L.; Liu, G. Highly Selective Pd-Catalyzed Intermolecular Fluorosulfonylation of Styrenes. J. Am. Chem. Soc. 2015, 137, 2468−2471. (c) Chen, H.; Zhu, L.; Li, C. Silver-Catalyzed Radical Carbofluorination of Unactivated Alkenes with Acetic Acid in Aqueous Solution. Org. Chem. Front. 2017, 4, 565−568. (15) Zhu, R.; Buchwald, S. L. Copper-Catalyzed Oxytrifluoromethylation of Unactivated Alkenes. J. Am. Chem. Soc. 2012, 134, 12462−12465. (16) (a) Marcos, A.; Pedregal, C.; Avendaño, C. Annulations of 2Aminonaphthoquinone with Aldehydes and Acetals. Tetrahedron 1995, 51, 6565−6572. (b) Zhou, W.-M.; Liu, H.; Du, D.-M. Organocatalytic Highly Enantioselective Michael Addition of 2Hydroxy-1,4-naphthoquinones to Nitroalkenes. Org. Lett. 2008, 10, 2817−2820. (c) Wu, R.; Chang, X.; Lu, A.; Wang, Y.; Wu, G.; Song, H.; Zhou, Z.; Tang, C. Chiral (Thio)phosphorodiamides as Excellent Hydrogen Bond Donor Catalysts in the Asymmetric Michael Addition of 2-Hydroxy-1,4-Naphthoquione to Nitroolefins. Chem. Commun. 2011, 47, 5034−5036. (d) Yang, W.; Du, D.-M. Chiral SquaramideCatalyzed Highly Enantioselective Michael Addition of 2-Hydroxy1,4-naphthoquinones to Nitroalkenes. Adv. Synth. Catal. 2011, 353, 1241−1246. (e) Liu, T.; Wang, Y.; Wu, G.; Song, H.; Zhou, Z.; Tang, C. Organocatalyzed Enantioselective Michael Addition of 2-Hydroxy1,4-naphthoquinone to β,γ-Unsaturated α-Ketophosphonatesθ. J. Org. Chem. 2011, 76, 4119−4124. (17) For direct trifluoromethylation of quinones, see: (a) Wang, X.; Ye, Y.; Ji, G.; Xu, Y.; Zhang, S.; Feng, J.; Zhang, Y.; Wang, J. CopperCatalyzed Direct C-H Trifluoromethylation of Quinones. Org. Lett. 2013, 15, 3730−3733. (b) Li, J.; Zhang, X.; Xiang, H.; Tong, L.; Feng, F.; Xie, H.; Ding, J.; Yang, C. C-H Trifluoromethylation of 2Substituted/Unsubstituted Aminonaphthoquinones at Room Temperature with Bench-Stable (CF3SO2)2Zn: Synthesis and Antiproliferative Evaluation. J. Org. Chem. 2017, 82, 6795−6800. (c) Zhang, Y.; Guo, D.; Ye, S.; Liu, Z.; Zhu, G. Synthesis of Trifluoromethylated Naphthoquinones via Copper-Catalyzed Cascade Trifluoromethylation/Cyclization of 2-(3-Arylpropioloyl)benzaldehydes. Org. Lett. 2017, 19, 1302−1305. (d) Li, C.; Zhang, K.; Xu, X.-H.; Qing, F.-L. Copper-Mediated Oxidative Trifluoromethylthiolation of Quinones. Tetrahedron Lett. 2015, 56, 6273−6275. (18) (a) Zhang, C.; McClure, J.; Chou, C. J. Silver-Catalyzed Direct Thiolation of Quinones by Activation of Aryl Disulfides to Synthesize Quinonyl Aryl Thioethers. J. Org. Chem. 2015, 80, 4919−4927. (b) Zhang, C.; Chou, C. J. Metal-Free Direct Amidation of Naphthoquinones Using Hydroxamic Acids as an Amide Source: Application in the Synthesis of an HDAC6 Inhibitor. Org. Lett. 2016, 18, 5512−5515. (19) For more information, see Supporting Information. (20) Lisboa, C. S.; Santos, V. G.; Vaz, B. G.; de Lucas, N. C.; Eberlin, M. N.; Garden, S. J. C−H Functionalization of 1,4Naphthoquinone by Oxidative Coupling with Anilines in the Presence of a Catalytic Quantity of Copper(II) Acetate. J. Org. Chem. 2011, 76, 5264−5273.

(21) Sieveking, I.; Thomas, P.; Estévez, J. C.; Quiñones, N.; Cuéllar, M. A.; Villena, J.; Espinosa-Bustos, C.; Fierro, A.; Tapia, R. A.; Maya, J. D.; López-Muñoz, R.; Cassels, B. K.; Estévez, R. J.; Salas, C. O. 2Phenylaminonaphthoquinones and Related Compounds: Synthesis, Trypanocidal and Cytotoxic Activities. Bioorg. Med. Chem. 2014, 22, 4609−4620. (22) Zhang, C.; Chou, C. J. Metal-Free Direct Amidation of Naphthoquinones Using Hydroxamic Acids as an Amide Source: Application in the Synthesis of an HDAC6 Inhibitor. Org. Lett. 2016, 18, 5512−5515. (23) (a) Zhang, J.; Tang, Y. Iron Catalyzed Regioselective Oxo- and Hydroxy-Phthalimidation of Styrenes: Access to α-Hydroxyphthalimide Ketones. Adv. Synth. Catal. 2016, 358, 752−764. (b) Pawar, G. G.; Singh, G.; Tiwari, V. K.; Kapur, M. Dehydrogenative Heck Reaction (Fujiwara−Moritani Reaction) of Unactivated Olefins with Simple Dihydropyrans under Aprotic Conditions. Adv. Synth. Catal. 2013, 355, 2185−2190.

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DOI: 10.1021/acs.joc.8b02997 J. Org. Chem. 2019, 84, 1006−1014