Synthesis of Selectively Substituted or Deuterated Indenes via

Mar 23, 2017 - Application of Pd and Ru catalysis allows one to access variously substituted indenes from phenols as cheap and widely available starti...
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Synthesis of Selectively Substituted or Deuterated Indenes via Sequential Pd and Ru Catalysis Anupam Jana,†,§ Kasjan Misztal,‡,§ Anna Ż ak,‡ and Karol Grela*,‡ Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Ż wirki i Wigury 101, 02-089 Warsaw, Poland Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224, Warsaw, Poland

† ‡

S Supporting Information *

ABSTRACT: A strategy for the synthesis of functionalized indenes is presented. The readily available substituted phenols are used as starting materials in the reaction sequence composed of Pd-catalyzed Suzuki coupling and Ru-catalyzed ring-closing metathesis, thus representing a practical method for the controlled construction of functionalized indene derivatives. The methodology has been successfully applied to a broad range of substrates, producing substituted indenes in excellent yields. This approach is also utilized for the synthesis of substituted indenes selectively deuterated in position 3, which are rare in literature.

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nitration or acylation)14,15 or alkylation of the indene carboanion,16 seems to be rather problematic in the case of polysubstituted indenes.17 Thus, development of novel, more efficient, selective, low-cost, scalable, and atom economy synthetic methodologies for the accessing of multisubstituted indenes would be warmly welcomed. Recently, special interest was shown in the case of 3-indenepropionic acid esters which can be coupled with fullerenes in a one-step Diels−Alder type of reaction.18 Products of this reaction were shown to exhibit better properties than commonly exploited in photovoltaics, but expensive, phenyl-C61-butyric acid methyl ester (PCBM).19

INTRODUCTION The indene moiety, an important building block in organic1 and organometallic chemistry,2 is present in a large number of drug candidates possessing interesting biological activities including antitumor, anti-hypercholesterolemic, anticonvulsant, antiallergic, herbicidal, fungicidal, and antimicrobial activities (Figure 1).3 Access to indene systems has gained growing

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RESULTS AND DISCUSSION Herein, we describe an efficient and selective synthesis of indene derivatives from substituted phenols as widely available starting materials, through Suzuki coupling20 and ring-closing metathesis21 (Scheme 1). Our initial goal was to develop a very efficient route for the construction of the diene E (Scheme 1). Synthesis of indenes22−26 and related compounds23 via RCM reaction from corresponding dienes was already reported a number of times. Unfortunately, often starting materials are not easily accessible and need to be synthesized in conditions not compatible with a number of functional groups, e.g., with the use of Grignard22 or organolithium23b reagents, often multistep.24,25 The majority of the reports present synthesis of 1substitued indenes, whereas there are scarce examples of products with substituents attached selectively to position 3.23b In addition, relatively high loading of ruthenium catalysts (min. 5 mol %) was used in the RCM step. Two possible ways for the synthesis of diene E were envisioned by us (Scheme 1). We deduced that the Suzuki coupling of either boronate A with

Figure 1. Selected examples of natural and synthetic products bearing indene skeletons.

interest among the synthetic community owing to the continuing identification of the indene-ring-containing natural products with the appealing pharmacological activities.4 Therefore, a number of considerable efforts for the controlled construction of indene ring systems including the reduction or dehydration of indanone,5 the cyclization of substituted 1,3butadienes in the presence of Lewis acids,6 or the ring expansion of suitably substituted cyclopropenes7 have been developed. A variety of transition-metal complexes, e.g., Pd,8 Ni,9 Pt,10 Co,11 Au,12 and Fe,13 have been used to synthesize indenes. However, the introduction of a wide range of different substituents into the indene ring system often encountered difficulties, when multisubstituted indene derivatives were concerned. For example, functionalization of a preformed indene ring via electrophilic aromatic substitution (e.g., © 2017 American Chemical Society

Received: January 25, 2017 Published: March 23, 2017 4226

DOI: 10.1021/acs.joc.7b00200 J. Org. Chem. 2017, 82, 4226−4234

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during the reaction, the mixture will self-clean. The RCM reaction was conducted under typical conditions,28 in the presence of commercial Grubbs II-generation catalyst [Ru-1]. Inspection by TLC showed a new spot, and we separated this new compound by column chromatography. As a result, nitroindene-derivative 6a was isolated in pure form in 62% yield. Despite the fact that the self-cleaning RCM approach29 apparently worked well, taking into account the low yield of the borylation step and related technical problems, we considered this route being not sufficiently optimal. Therefore, instead of spending efforts in further optimization of Route I, we focused on Route II, in the hope that it will be more selective and will give indene derivatives in better overall yield. To this end, triflate 2a was subjected to Suzuki coupling with pinacol boronic ester 7a at 100 °C, leading to desired diene 5a in 75% yield without any isomerization (Scheme 3).

Scheme 1. Routes Examined for the Controlled Synthesis of Substituted Indenes

appropriate bromide B or the reaction of phenol triflate C with boronate D would be the feasible route to our desired ringclosing metathesis precursor. Compounds A and C can, in principle, be derived from substituted phenols. Compound D could easily be obtained from the corresponding bromide B. The resulting functionalized diene E in the presence of a Ru metathesis catalyst shall yield in the RCM reaction functionalized indene TM. First, we decided to experimentally test the feasibility of both planed routes for accessing the diene E. To do so, we chose para-nitrophenol 1 as a prototypical starting material. Allylation of phenol 1, followed by Claisen rearrangement, provided 2allyl-4-nitrophenol,27 which was converted with triflic anhydride and pyridine into triflate 2a (Scheme 2). Then, Route I was

Scheme 3. Synthesis of Substituted Nitro-Indene 6b Utilizing Route II

Ring-closing metathesis reaction of diene 5a with 1 mol % of commercial nitro-Hoveyda−Grubbs catalyst [Ru-2] produced the substituted indene 6a in almost quantitative yield. Therefore, comparing the both routes, we ended with a conclusion that Route II is apparently more efficient and userfriendly. After successfully demonstrating the effectiveness of Route II for the construction of one arbitrary chosen disubstituted indene (6a), we focused on the synthesis of a small library of indenes having various substituents at different positions. To do so, we prepared a set of RCM precursors using Suzuki coupling under previously elaborated conditions. All the reactions were carried out in a deoxygenated dioxane−water (4:1) mixture at 120 °C in a sealed Schlenk tube in the presence of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate used as base. A variety of triflates were subjected to the reaction, and the corresponding products were obtained in high yields with excellent functional group (FG) tolerance (shown in Scheme 4). To introduce different substituents in the five-membered ring of the indene, we synthesized appropriate dienes by using differently substituted (Me, Ph, CH2CH2CO2Et, para-trifluorophenyl) vinyl boronic pinacol esters 7a−e in Suzuki reaction. The investigation was started with the triflate 2b (FG = orthoMe) that gave a very good yield of diene 5b when treated with vinyl boronic pinacol ester (7b, R1 = H) in the presence of Pd catalyst. Then, the scope of the reaction was studied by using bulkier boronate, i.e., isopropenyl boronic acid pinacol ester (7c, R1 = Me). To our delight, the coupling reaction in the presence of Pd catalyst afforded diene 5c in 82% yield. Encouraged by these results, we then focused on even larger FGs in the ortho-position (CHO, Ph) to check the influence of the steric effect. In all cases, the triflates reacted smoothly to form the corresponding dienes in 63−87% yield (5d, 5e). It is also worth to note that also phenyl and para-trifluorophenyl substituted vinyl boronic pinacol esters (7d and 7e; FG = Ph

Scheme 2. Synthesis of Substituted Nitro-Indene 6a Utilizing Route I and Self-Cleaning RCM

tested. To this end, triflate 2a was converted into a pinacol boronic ester derivative 3. This reagent was subjected to Suzuki cross-coupling reaction with bromide 4. During the C−C coupling reaction, we observed formation of minor impurity 5a′ along with the desired product 5a (ratio 5a/5a′ = 75:25). We assumed that formation of 5a′ is due to the isomerization of the allylic double bond in the presence of Pd catalyst. Unfortunately, despite all optimization attempts, we were not able to stop formation of this impurity. These two products, 5a and 5a′, formed in overall 68% yield, were inseparable by chromatographic methods. Fortunately, we speculated that only the major alkene 5a can undergo ring-closing metathesis reaction, while the impurity 5a′ cannot form the cyclized product (four-membered rings are not formed easily by RCM) but rather undergo oligomerization or other transformations. Therefore, we pursued the indene synthesis using the inseparable mixture of products 5a and 5a′, in the hope that, 4227

DOI: 10.1021/acs.joc.7b00200 J. Org. Chem. 2017, 82, 4226−4234

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The Journal of Organic Chemistry Scheme 4. Suzuki Coupling Leading to Dienes 5a−pa,b

Scheme 5. Synthesis of Substituted Indenes via RCM Reactiona,b

a Conditions: CH2Cl2 (non-degassed), 40 °C, [Ru-2] (1.0 mol %: 6a, 6e, 6h−i, 6l, 6n; 1.7 mol %: 6b−d, 6f−g, 6j−k, 6m, 6o−p). bIsolated yields after flash chromatography.

Conditions: degassed dioxane−water (4:1), 120 °C, Pd(PPh3)4 (12 mol %), K2CO3 (3 equiv). bIsolated yields after flash chromatography.

a

and para-CF3C6H4) can be used, resulting in the corresponding dienes (5f, 5g, 5k, 5l, 5p) in very good yield. Furthermore, electron-donating groups present in the triflate 2 ring are well tolerated, as the corresponding dienes (5h, 5l) were obtained in good yield. Naturally, also triflates substituted with electronwithdrawing groups can be used in the studied Suzuki coupling with excellent results (5a, 5g, 5i−k, 5m−n). On the basis of the results compiled in Scheme 4, one can state that practically all combinations of FG and R1 substituents at the cross-coupling partners lead to good results. Finally, in order to extend our methodology to benzannulated systems, we scheduled to carry out the reaction with 2-allyl-1-naphthol triflate. Coupling of this partner with two vinyl boronic acid pinacol esters underwent efficiently to form the expected products (5o, 5p) in 81% and 92% yield, respectively (Scheme 4). With the dienes ready in hand, we performed ring-closing metathesis to afford the substituted indenes as shown in Scheme 5, using 1.0 or 1.7 mol % (as indicated) nitroHoveyda−Grubbs catalyst [Ru-2] in refluxing dichloromethane (Scheme 5). At first, we attempted cyclization of orthosubstituted diene 5b and observed that 4-methylindene 6b was formed in 90% yield after just 1 h of the reaction as a single product. Similarly, 5c gave the expected indene 6c in 89% yield. Likewise other monosubstituted indenes like 6d, 6e, 6i, 6o were synthesized through RCM reaction in 61−96% yield. Disubstituted indenes were also formed from the corresponding dienes smoothly. When disubstituted dienes like 5a, 5f, 5g, 5n, 5p were subjected to ring-closing metathesis in the presence of 1.7 mol % or less of nitro-Hoveyda catalyst, disubstituted indenes were formed in excellent yield. Relatively lower yields (70−73%) gave dienes like 5h, 5i, 5l. Finally, the

highly conjugated indene 6p was synthesized in a similar way in 96% isolated yield. Selectively deuterated compounds have found a number of important applications in mechanism elucidation and other physico-chemical studies, neutron protein crystallography, pharmacokinetic and toxicological studies, biochemistry, etc.30 Therefore, selective isotope labeling with deuterium of whole molecules or building blocks is of growing importance.30 Regrettably, to the best of our knowledge, methods for the synthesis of functionalized and selectively deuterated indenes are limited in number and scope.31 In particular, the development of practical and general methods for selective deuteration at the 3 position of the indene skeleton is unknown in the literature and shall be considered as a challenging undertaking. Direct deuteration31a,d (Scheme 6) of indene is not a good idea for accessing substituted indenes, as this process is not selective. Therefore, we decided to try our approach in the synthesis of substituted 3-[2H]-indenes (Scheme 6). We anticipated that a properly constructed Scheme 6. Synthesis of Deuterated Indenes

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standard methods.38 Analytical thin-layer chromatography (TLC) was performed on silica gel 60 TLC plates. The spots were visualized with a UV light or by staining with KMnO4 or anisaldehyde solution. Flash column chromatography was performed using silica gel 60 (particle size 0.040−0.063 mm), typically using an n-hexane/ethyl acetate eluent system. FT-IR spectra were recorded with a Thermo Scientific Nicolet iSTM50 FT-IR spectrometer. NMR spectra were measured at room temperature on an Agilent Mercury 400 MHz spectrometer or Varian Mercury 400 MHz. NMR spectra were calibrated to the solvent residual signals of CDCl3. 1H NMR spectra were recorded at 400 MHz. Data are reported as follows: chemical shift, multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, qui: quintuplet, m: multiplet), coupling constant (J in Hz), and integration. 13C NMR spectra were recorded at 100 MHz using broadband proton decoupling, and chemicals shifts are reported in ppm using residual solvent peaks as reference. Carbon multiplicities were assigned by DEPT techniques. High resolution mass spectra were recorded on an MS (ESI) spectra LCMS-IT TOF Shimadzu or SYNAPT G2-S HDMS (Waters). A usual workup of the reaction mixture consists of extraction with ether or ethyl acetate, washing with water, brine, drying over Na2SO4, and then concentration under reduced pressure on a rotary evaporator unless specified. Reported yields are based upon isolation following purification by silica gel column chromatography; isolated materials were judged to be homogeneous based upon TLC and NMR. The compounds 2j,33 6b,34 6c,35 6m,36 and 6o37 are known in the literature. General Procedure for Triflation Reaction. Reactions were carried on an 8.76 mmol scale unless otherwise noted. The substituted phenol (8.76 mmol, 1 equiv) was solubilized in a mixture of 5 mL of pyridine and 5 mL of dry dichloromethane at 0 °C under an argon atmosphere. To the resulting mixture was dropwise added neat trifluoromethanesulfonyl anhydride (9.64 mmol, 1.1 equiv). The reaction mixture was stirred and allowed to reach room temperature overnight. After this time, the solvents were removed by rotary evaporation and the remaining residue was taken up in ethyl acetate (100 mL) and extracted with 5% HCl (3 × 50 mL), followed by sodium bicarbonate (2 × 50 mL), brine (100 mL), and drying over MgSO4. Residue was concentrated in vacuum and purified with column chromatography to obtain the corresponding triflate. 2-Allyl-4-nitrophenyl Trifluoromethanesulfonate (2a). Yellow oil, 2.17 g, 86% yield, eluent: c-hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 2.8 Hz, 1H), 8.19 (dd, J = 2.8, 9.0 Hz, 2H), 7.46 (d, J = 9.0 Hz, 1H), 5.91 (ddt, J = 6.7, 10.1, 17.2 Hz, 1H), 5.31−5.18 (m, 2H), 3.55 (d, J = 6.6 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 151.5, 147.1, 135.3, 132.9, 126.8, 123.7, 122.5, 119.5, 118.6 (q, J = 318 Hz), 34.1; IR νmax 3088, 1536, 1428, 1353, 1219, 1139, 872, 810, 742, 615 cm−1; HRMS (EI) m/z: [M]+ Calcd for C10H8F3NO5S 311.0075; Found: 311.0089. Anal. Calcd for C10H8F3NO5S: C, 38.59; H, 2.59; N, 4.50. Found: C, 38.82; H, 2.67; N, 4.43. 2-Allyl-6-methylphenyl Trifluoromethanesulfonate (2b). Yellow oil, 10.0 mmol scale, 2.51 g, 90% yield; eluent: hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 7.24−7.14 (m, 3H), 5.95−5.88 (m, 1H), 5.17−5.08 (m, 2H), 3.52 (d, J = 6.4 Hz, 2H), 2.42 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 146.1, 135.2, 133.7, 131.9, 130.6, 129.2, 128.3, 118.7 (q, J = 329 Hz), 117.3, 34.6, 17.3; HRMS (EI) m/ z: [M]+ Calcd for C11H11F3O3S 280.0381; Found: 280.0378. 2-Allyl-6-formylphenyl Trifluoromethanesulfonate (2c). Yellow oil, 5 mmol scale, 0.91 g, 62% yield; eluent: hexane/ethyl acetate 95:5; 1 H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 7.86 (dd, J = 1.6, 7.6 Hz, 1H), 7.64−7.61 (m, 1H), 7.51−7.49 (m, 1H), 7.89 (ddt, J = 6.4, 10.0, 17.2 Hz, 1H), 5.22−5.14 (m, 2H), 3.57 (d, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 186.9, 146.95, 137.4, 135.0, 134.2, 129.9. 129.0, 128.7, 118.7 (q, J = 318 Hz), 118.4, 33.7; HRMS (EI) m/z: [M]+ Calcd for C11H9F3O4S 294.0174; Found: 294.0175. 3-Allyl-[1,1′-biphenyl]-2-yl Trifluoromethanesulfonate (2d). Orange crystals, 18.4 mmol scale, 5.42 g, 86% yield; eluent: hexane/ethyl acetate 95:5; 1H NMR (600 MHz, CDCl3) δ 7.47−7.30 (m, 8H), 6.03−5.96 (m, 1H), 5.24−5.21 (m, 2H), 3.62 (d, J = 6.6 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 144.9, 136.6, 135.0, 134.4, 130.6, 130.4,

diene E′ would, upon RCM, provide a selectively deuterated indene (3-[2H]-TM). The boron reagent D′ required in the synthesis of E′ can be prepared in different ways. Grotjahn and co-workers32 demonstrated that an allyl fragment in a number of substrates when treated with bifunctional catalyst [Ru-3] in the presence of D2O can undergo isomerization to a vinylic double bond with simultaneous incorporation of deuterium with excellent regioselectivity.32 We decided to use this methodology to convert commercial allyl boronic pinacol ester 2f to deuterated vinyl boronate derivative 7f′ (Scheme 7). Scheme 7. Synthesis of Substituted Deuterated Indenes

A CD3 group present in the product would be later dropped off in the RCM step. To reduce this idea to reality, 7f was treated in a closed tube for 12 h with 2 mol % of Grotjahn catalyst [Ru3] and deuterium oxide in acetone-d6. Then, without isolation, triflate 2b together with 12 mol % of Pd(PPh3)4, K2CO3, dioxane, and water were added to the same reaction vessel, and the resulting reaction mixture was heated at 120 °C for 18 h. The resulting diene 8, isolated by column chromatography in 74% yield was subjected to ring-closing reaction in the presence of 2 mol % of nitro-Hoveyda−Grubbs catalyst [Ru-2] to afford selectively labeled 4-methyl-1H-indene-3-d 9 in 85% yield (Scheme 7). Interestingly, 6-methoxy-1H-indene-3-d 11 is also synthesized in good yield from triflate 2j.

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CONCLUSION We have developed an efficient approach to form the indene skeleton that is based on Suzuki coupling, followed by olefin metathesis. Application of Pd and Ru catalysis allows one to access variously substituted indenes from phenols as cheap and widely available starting materials. Utilization of Ru isomerization−deuteration catalyst [Ru-3] made it possible to obtain substituted indenes selectively monodeuterated in position 3. Due to the potential utility of functionalized indenes and the mild conditions employed, we expect this method to be of broad utility in organic synthesis. We expect that the developed method would be attractive particularly in photovoltaics where 3-indenepropionic acids functionalized fullerenes constitute a promising alternative to common, but expensive, PCBM. Further studies on application of this methodology in target oriented synthesis are ongoing in our laboratory.

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EXPERIMENTAL SECTION

General Information. All reactions were carried out under an argon atmosphere in oven-dried glassware with magnetic stirring. Commercially available chemicals were used without further purification. Grubbs II catalyst and nitro-Hoveyda−Grubbs catalyst were purchased from commercial suppliers. The boronic acid pinacol esters were bought from a chemical supplier or synthesized from the corresponding bromide (Scheme 1). Solvents were distilled prior to use by a Solvent Purification System, Mbraun MB-SPS-800, or by 4229

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Article

The Journal of Organic Chemistry 129.6, 128.5, 128.4, 128.3,118.2 (q, J = 319 Hz), 117.8, 34.8; HRMS (EI) m/z: [M]+ Calcd for C16H13F3O3S 342.0538; Found: 342.0544. 4-Acetamido-2-allylphenyl Trifluoromethanesulfonate (2e). Orange crystals, 10.5 mmol scale, 2.56 g, 75% yield; eluent: c-hexane/ ethyl acetate 7:3; 1H NMR (400 MHz, CDCl3) δ 7.58−7.44 (m, 2H), 7.35 (s, 1H), 7.20 (d, J = 8.9 Hz, 1H), 5.89 (ddt, J = 16.8, 10.2, 6.6 Hz, 1H), 5.21−5.07 (m, 2H), 3.44 (d, J = 6.6 Hz, 2H), 2.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 143.7, 138.1, 134.3, 133.8, 122.2, 122.0, 119.3, 118.7 (q, J = 319 Hz), 117.9, 34.2, 24.6; HRMS (ESI) m/ z: [M + Na]+ Calcd for C12H12F3NO4SNa 346.0337; Found: 346.0337. Anal. Calcd for C12H12F3NO4S: C, 44.58; H, 3.74; N, 4.33; found: C, 44.74; H, 3.78; N, 4.33. 4-Acetyl-2-allylphenyl Trifluoromethanesulfonate (2f). Orange oil, 8.51 mmol scale, 2.41 g, 91% yield; eluent: c-hexane/ethyl acetate 9:1; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 2.2 Hz, 1H), 7.89 (d, J = 2.2, 8.6 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 5.93 (ddt, J = 6.6, 10.1, 16.8 Hz, 1H), 5.18 (m, 2H), 3.53 (d, J = 6.6 Hz, 2H), 2.61 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 196.4, 150.8, 136.9, 133.9, 133.5, 131.6, 128.5, 121.6, 118.6 (q, J = 319 Hz), 118.3, 34.15, 26.79; IR νmax 3366, 3085, 2985, 1693, 1423, 1217, 1140, 894, 857 cm−1; HRMS (EI) m/z: [M]+ Calcd for C12H11F3O4S 308.0330; Found: 308.0333. Anal. Calcd for C12H11F3O4S: C, 46.75; H, 3.60; found: C, 46.82; H, 3.58. 2-Allyl-4,5-dimethoxyphenyl Trifluoromethanesulfonate (2g). Brown solid, 8.34 mmol scale, 2.66 g, 98% yield; eluent: c-hexane/ ethyl acetate 9:1; 1H NMR (400 MHz, CDCl3) δ 6.74 (d, J = 6.8 Hz, 2H), 5.90 (ddt, J = 6.6, 10.2, 16.8 Hz, 1H), 5.13 (m, 2H), 3.87 (d, J = 4.2 Hz, 6H), 3.40 (d, J = 6.6 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 148.9, 148.3, 140.5, 135.2, 124.7, 118.8 (q, J = 319 Hz), 117.4, 117.2, 112.8, 105.4, 56.4, 56.3, 33.8; IR νmax 3048, 2940s, 1641, 1590, 1516, 1419, 1213, 1142, 1066, 996, 879 cm−1; HRMS (EI) m/z: [M]+ Calcd for C12H13F3O5S 326.0436; Found: 326.0438. Anal. Calcd for C12H13F3O5S: C, 44.17; H, 4.02; S, 9.83; F, 17.74; found: C, 44.31; H, 4.27; S, 10.03; F, 17.64. 2-Allylnaphthalen-1-yl Trifluoromethanesulfonate (2h). Yellow oil, 3.37 mmol scale, 8.65 g, 81% yield; eluent: hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 8.13−8.10 (m, 1H), 7.91−7.88 (m, 1H), 7.82 (d, J = 8.8 Hz, 1H); 7.66−7.57 (m, 2H), 7.48 (d, J = 9.2 Hz, 1H), 6.10 (ddt, J = 6.0, 10.4, 17.2 Hz, 1H), 5.22−5.12 (m, 2H), 4.01 (td, J = 1.6, 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 145.3, 134.5, 132.8, 129.3, 128.8, 128.1, 127.5, 126.8, 125.0, 119.4 (q, J = 1 Hz), 118.8 (q, J = 318 Hz), 117.0, 33.3; HRMS (EI)) m/z: [M]+ Calcd for C14H11F3O4S 316.0379; Found: 316.0381. 2-Allyl-4-fluorophenyl Trifluoromethanesulfonate (2i). Transparent oil, 9.36 mmol scale, 2.20 g, 79% yield; eluent: c-hexane/ ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 7.28−7.19 (m, 1H), 7.07−6.92 (m, 2H), 5.88 (ddt, J = 6.7, 10.1, 16.8 Hz, 1H), 5.18 (m, 2H), 3.46 (d, J = 6.7 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 161.7 (d, J = 247 Hz), 143.6, 135.7 (d, J = 8 Hz), 133.9, 123.1 (d, J = 9 Hz), 118.7 (q, J = 318 Hz), 118.5, 118.0 (d, J = 24 Hz), 115.0 (d, J = 23 Hz), 34.1; 19F NMR (376 MHz, CDCl3) δ −112.4, −73.7; HRMS (EI) m/z: [M]+ Calcd for C10H8F4O3S 284.0130; Found: 284.0141. Anal. Calcd for C10H8F4O3S: C, 42.26; H, 2.84; found: C, 42.19; H, 2.97. 2-Allyl-4-methoxyphenyl Trifluoromethanesulfonate (2j). Colorless oil, 17.7 mmol scale, 4.26 g, 81% yield; eluent: hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 9.0 Hz, 1H) 6.83−6.82 (m, 1H), 6.78 (dd, J = 9.0, 3.0 Hz, 1H), 5.92 (ddt, J = 6.6, 10.2, 16.8 Hz, 1H) 5.18−5.14 (m, 2H) 3.80 (s, 3H) 3.44 (d, J = 6.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 159.1, 141.5, 134.6, 134.3, 122.4,118.8 (q, J = 320 Hz). 117.8, 116.3, 113.0, 55.8, 34.4. General Procedure for Suzuki Coupling. Reactions were carried on a 1 mmol scale unless otherwise noted. A Schlenk flask was charged with triflate 2 (1 mmol), vinyl boronic ester 7 (1.3 mmol), and K2CO3 (3 mmol). Then, 10 mL of a 4:1 1,4-dioxane:water mixture was added and the flask was deoxygenated by freeze−pump−thaw cycle three times. [Pd(PPh3)4] (0.10−0.12 mmol) was added, and the sealed flask was stirred at 100−120 °C for 18 h, resulting in an orange, transparent suspension. After that time, the flask was cooled to RT and all volatiles were removed under reduced pressure. The oily residue was solubilized in AcOEt and filtered through a Celite pad. Volatiles

were concentrated and separated with column chromatography to obtain diene 5. Ethyl 4-(2-Allyl-4-nitrophenyl)pent-4-enoate (5a). Yellow oil, 216 mg, 75% yield; eluent: c-hexane/ethyl acetate 9:1; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 2.4 Hz, 1H), 8.02 (dd, J = 2.4, 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 1H), 5.93 (ddt, J = 6.5, 10.1, 16.6 Hz, 1H), 5.30 (dd, J = 1.5, 2.7 Hz, 1H), 5.17 (dq, J = 1.4, 10.1 Hz, 1H), 5.07 (dq, J = 1.6, 17.0 Hz, 1H), 4.98−4.96 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.46 (dt, J = 1.4, 6.4 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 2.43 (t, J = 7.5 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ172.7, 149.1, 146.2, 139.2, 136.2, 129.8, 124.7, 121.2, 117.6, 116.1, 60.7, 37.0, 32.7, 32.5, 14.4. IR νmax 3083, 2981, 1734, 1521, 1347, 1160, 917 cm−1; HRMS (ESI) m/z: [M + Na]+ Calcd for C16H19NO4Na 312.1212; Found: 312.1205. Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84; found: C, 66.50; H, 6.61; N, 4.86. 1-Allyl-3-methyl-2-vinylbenzene (5b). Yellow oil, 1.0 mmol scale, 136 mg, 88% yield; eluent: 100% hexane, 88% yield; 1H NMR (400 MHz, CDCl3) δ 7.13−7.08 (m, 3H), 6.73 (dd, J = 11.2, 18.0 Hz, 1H), 5.97 (ddt, J = 6.4, 10.0, 17.2 Hz, 1H), 5.54 (dd, J = 1.6, 11.2 Hz, 1H), 5.28 (dd, J = 2.0, 18.0 Hz, 1H), 5.07−4.97 (m, 2H), 3.45−3.43 (m, 2H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.0, 137.7, 137.6, 136.1, 135.0, 128.2, 127.2, 126.9, 119.7, 115.6, 38.1, 21.1; IR νmax 1507, 1401, 1246, 1137, 1117 cm−1; HRMS (EI) m/z: [M]+ Calcd for C12H14 158.1096; Found: 158.1092. 1-Allyl-3-methyl-2-(prop-1-en-2-yl)benzene (5c). Yellow oil, 1 mmol scale, 141 mg, 82% yield; eluent: 100% hexane; 1H NMR (400 MHz, CDCl3) δ 7.20−7.12 (m, 3H), 6.02 (ddt, J = 6.4, 9.6, 17.2 Hz, 1H), 5.36−5.35 (m, 1H), 5.12−5.08 (m, 2H), 4.87−4.86 (m, 1H), 3.45−3.43 (m, 2H), 2.35 (s, 3H), 2.33 (dd, J = 0.8, 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 143.0, 138.5, 136.7, 135.0, 127.8, 126.7, 115.5, 115.3, 37.5, 24.4, 19.9; IR νmax 2970, 2916, 1607, 1495, 1435, 1212, 1227, 967 cm−1; HRMS (EI) m/z: [M]+ Calcd for C13H16 172.1252; Found: 172.1258. 3-Allyl-2-vinylbenzaldehyde (5d). Yellow oil, 0.5 mmol scale, 70 mg, 81% yield; eluent: 100% hexane; 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 7.2 (dd, J = 1.6, 8.0 Hz, 1H), 7.43−7.36 (m, 2H), 6.98 (dd, J = 11.0, 17.6 Hz, 1H), 5.94 (ddt, J = 6.4, 10.4, 17.0 Hz, 1H), 5.78 (dd, J = 1.6, 11.2 Hz, 1H), 5.25 (dd, J = 1.2, 17.6 Hz, 1H), 5.10 (dd, J = 1.6, 10.0 Hz, 1H), 5.00 (dd, J = 2.0, 17.2 Hz, 1H), 3.45 (td, J = 1.6, 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 193.0, 142.1, 138.9, 136.2, 134.9, 134.6, 131.6, 127.7, 126.5, 124.5, 116.6, 37.2; HRMS (ESI) m/z: [M + H]+ Calcd for C12H13O 173.0961; Found: 173.0958. 3-Allyl-2-vinyl-1,1′-biphenyl (5e). Yellow oil, 131 mg, 60% yield; eluent: c-hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 7.31 (m, 8H), 6.63 (dd, J = 11.5, 17.9 Hz, 1H), 6.04 (dd, J = 10.2, 17.0 Hz, 1H), 5.32 (dd, J = 1.8, 11.5 Hz, 1H), 5.17−5.01 (m, 3H), 3.55 (dt, J = 6.2, 1.4 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 142.4, 141.7, 138.0, 137.7, 136.7, 135.0, 130.1, 129.0, 128.5, 127.9, 127.0, 126.7, 120.6, 116.0, 38.27. HRMS (EI) m/z: [M]+ Calcd for C17H16 220.1252; Found: 220.1251. 3-Allyl-2-(1-(4-(trifluoromethyl)phenyl)vinyl)benzaldehyde (5f). Yellow oil, 0.5 mmol scale, 138 mg, 87% yield; eluent: hexane/ethyl acetate 97:3; 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.92 (dd, J = 1.6, 8.0 Hz, 1H), 7.59−7.32 (m, 6H), 6.26 (s, 1H), 5.78 (ddt, J = 6.4, 10.0, 16.8 Hz, 1H), 5.37 (s, 1H), 5.00 (qd, J = 1.6, 10 Hz, 1H), 4.92 (qd, J = 1.6, 17.2 Hz, 1H), 3.24 (td, J = 6.4, 16.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 192.6, 143.1, 143.0 (d, J = 2 Hz), 142.2, 139.4, 136.5, 135.6, 134.8, 130.3 (q, J = 33 Hz), 128.5, 126.5, 126.1, 125.8 (q, J = 4 Hz), 124.1 (q, J = 271 Hz), 120.1, 116.7, 36.9; 19F NMR (376 MHz, CDCl3) δ −62.70; IR νmax 1690, 1616, 1588, 1322, 1114, 1065, 1014, 915 cm−1; HRMS (ESI) m/z: [M + H]+ Calcd for C19H16F3O 317.1148; Found: 317.1136. 2-Allyl-4-nitro-1-(1-(4-(trifluoromethyl)phenyl)vinyl)benzene (5g). Yellow oil, 0.5 mmol scale, 145 mg, 87% yield; eluent: hexane/ ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 8.14−8.11 (m, 2H), 7.59−7.56 (m, 2H), 7.41−7.33 (m, 3H), 5.98 (d, J = 0.4 Hz, 1H), 5.77 (ddt, J = 6.4, 10.0, 16.8 Hz, 1H), 5.40 (s, 1H), 5.06 (dq, J = 1.6, 10.0 Hz, 1H), 4.95 (dq, J = 1.6, 17.2 Hz, 1H), 3.22 (dt, J = 1.6, 6.4 Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 147.9, 147.2, 146.2, 142.8 (d, J = 1 Hz), 140.3, 135.2, 131.4, 130.3 (q, J = 33 Hz), 126.8, 125.7 (q, J = 4 4230

DOI: 10.1021/acs.joc.7b00200 J. Org. Chem. 2017, 82, 4226−4234

Article

The Journal of Organic Chemistry

νmax 2927, 1487, 1435, 1243, 1086 cm−1; HRMS (EI) m/z: [M]+ Calcd for C12H13F 176.1001; Found: 176.0988. Ethyl 4-(2-Allyl-4-fluorophenyl)pent-4-enoate (5n). Yellow oil, 0.5 mmol scale, 78 mg, 60% yield; eluent: c-hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, J = 6.0, 8.4 Hz, 1H), 6.98−6.80 (m, 2H), 5.90 (ddt, J = 6.5, 10.1, 16.7 Hz, 1H), 5.22 (q, J = 1.5 Hz, 1H), 5.12−4.98 (m, 2H), 4.93−4.87 (m, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.36 (d, J = 6.5 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H), 2.40 (t, J = 7.6 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.0, 162.1 (d, J = 244 Hz), 147.1, 139.5 (d, J = 7 Hz), 138.0 (d, J = 3 Hz), 137.2, 130.2 (d, J = 8 Hz), 116.6, 116.2 (d, J = 22 Hz), 115.4, 112.9 (d, J = 21 Hz), 60.6, 37.2, 33.4, 32.7, 14.4. 19F NMR (376 MHz, CDCl3) δ −115.76. HRMS (EI) m/z: [M]+ Calcd for C16H19FO2 262.1369; Found: 262.1369. 2-Allyl-1-vinylnaphthalene (5o). Yellow oil, 0.5 mmol scale, 79 mg, 81% yield; eluent: 100% hexane; 1H NMR (400 MHz, CDCl3) δ 8.08−8.05 (m, 1H), 7.85−7.83 (m, 1H), 7.78−7.69 (m, 2H), 7.56− 7.45 (m, 2H), 7.26−7.18 (m, 1H), 6.10 (ddt, J = 5.6, 10.0, 17.2 Hz, 1H), 5.80 (dd, J = 1.6, 17.2 Hz, 1H), 5.45 (t, J = 1.6, 10.8 Hz, 1H), 5.08 (dq, J = 1.6, 10.0 Hz, 1H), 4.95 (dq, J = 1.6. 17.0 Hz, 1H), 3.95 (td, J = 2.0, 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 135.2, 134.0, 133.5, 132.5, 132.4, 128.6, 127.2, 127.1, 125.6, 124.6, 124.1, 116.5, 116.1, 32.3; IR νmax 3042, 2925, 2853, 1584, 1509, 1454, 1395, 1375, 1337, 1162, 906, 859, 815, 746 cm−1; HRMS (EI) m/z: [M]+ Calcd for C15H14 194.1096; Found: 194.1090. 2-Allyl-1-(1-(4-(trifluoromethyl)phenyl)vinyl)naphthalene (5p). Yellow oil, 0.5 mmol scale, 155 mg, 92% yield; eluent: 100% hexane; 1 H NMR (400 MHz, CDCl3) δ 8.12−8.10 (m, 1H), 7.93−0 7.90 (m, 1H), 7.82−7.79 (m, 1H), 7.60−7.31 (m, 7H), 6.03 (d, J = 1.2 Hz, 1H), 5.93 (ddt, J = 6.0, 10.4, 17.2 Hz, 1H), 5.44 (d, J = 0.8 Hz, 1H), 5.00 (qd, J = 1.6, 10 Hz, 1H), 4.87 (qd, J = 1.6, 17.2 Hz, 1H), 3.24 (td, J = 2.0, 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 147.8, 144.2 (d, J = 2 Hz), 138.3, 137.0, 133.5, 133.3, 132.6, 129.8 (q, J = 32 Hz), 128.7, 128.2, 127.9, 127.1, 126.4, 125.8, 125.4 (q, J = 4 Hz), 125.2, 124.3 (q, J = 271 Hz), 117.6, 116.0, 34.1; 19F NMR (376 MHz, CDCl3) δ −62.47; IR νmax 1615, 1322, 1264, 1163, 1114, 1064, 1014, 848 cm−1; HRMS (EI) m/z: [M]+ Calcd for C22H17F3 338.1282; Found: 338.1286. General Procedure for Ring-Closing Metathesis. The diene (1 mmol unless otherwise noted) was dissolved in 5 mL of dry CH2Cl2, and nitro-Hoveyda−Grubbs catalyst [Ru-2] (1−1.7 mol %) was added and refluxed for 1 h. Then, the reaction mixture was concentrated and purified by column chromatography. Ethyl 3-(6-Nitro-1H-inden-3-yl)propanoate (6a). Beige solid, 0.43 mmol scale, 113 mg, quantitative yield; eluent: c-hexane/ethyl acetate 9:1; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.21 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.43 (s, 2H), 2.90 (t, J = 7.1 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.8, 151.4, 145.9, 145.0, 142.8, 134.4, 122.8, 119.0, 118.9, 77.5, 77.2, 76.8, 60.7, 38.2, 32.7, 22.9, 14.3; IR νmax 3068, 2981, 2934, 1731, 1514, 1339, 1172, 1065, 884, 816, 763 cm−1; HRMS (ESI) m/z: [M + Na]+ Calcd for C14H15NO4Na 284.0899; Found: 284.0896. 4-Methyl-1H-indene (6b). Yellow oil, 0.872 mmol scale, 102 mg, 90% yield; eluent: 100% hexane; 1H NMR (400 MHz, CDCl3) δ 7.35−7.32 (m, 1H), 7.15−7.01 (m, 3H), 6.58 (td, J = 2.0, 5.6 Hz, 1H), 3.44−3.43 (m, 2H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.8, 143.7, 133.6, 130.3, 130.3, 127.4, 124.7, 121.3, 39.5, 18.7. 3,4-Dimethyl-1H-indene (6c). Yellow oil, 0.872 mmol scale, 112 mg, 89% yield; eluent: 100% hexane; 1H NMR (400 MHz, CDCl3) δ 7.32−7.30 (m, 1H), 7.12−7.04 (m, 2H), 6.18 (dd, J = 1.6, 3.6 Hz, 1H), 3.29−3.28 (m, 2H), 2.36 (s, 3H), 2.39 (dd, J = 2.0, 4.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 145.6, 143.5, 141.6, 131.1, 129.9, 128.8, 124.7, 121.8, 37.4, 20.0, 17.8. 1H-Indene-4-carbaldehyde (6d). Yellow oil, 0.348 mmol scale, 46 mg, 92% yield; eluent: hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 10.2 (s, 1H), 7.74−7.66 (m, 3H), 7.34 (t, J = 3.6 Hz, 1H), 6.86−6.83 (m, 1H), 3.42−3.41 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 192.5, 145.4, 145.3, 138.9, 130.4, 129.9, 128.9, 128.8, 124.8, 38.6; IR νmax 2727, 1690, 1587, 1387, 1270, 1219, 987, 770 cm−1;

Hz), 124.7, 124.1 (q, J = 271 Hz), 121.7, 118.8, 117.7, 37.4; 19F NMR (376 MHz, CDCl3) δ −62.66; IR νmax 1520, 1348, 1324, 1166, 1117, 1067, 850 cm−1; HRMS (EI) m/z: [M]+ Calcd for C18H14F3NO2 333.0977; Found: 333.0975. Ethyl 4-(4-Acetamido-2-allylphenyl)pent-4-enoate (5h). Beige solid, 0.6 mmol scale, 102 mg, 68% yield; eluent: c-hexane/ethyl acetate 7:3; 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 1.8, 8.1 Hz, 1H), 7.25 (m, 2H), 7.05 (d, J = 8.2 Hz, 1H), 5.91 (ddt, J = 16.7, 10.2, 6.5 Hz, 1H), 5.26−4.83 (m, 4H), 4.11 (q, J = 7.1 Hz, 2H), 3.35 (d, J = 6.4 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H), 2.39 (dd, J = 8.5, 6.8 Hz, 2H), 2.16 (s, 3H), 1.24 (dt, J = 9.2, 6.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 173.1, 168.4, 147.3, 138.3, 138.0, 137.7, 137.0, 129.4, 120.9, 117.9, 116.2, 115.1, 60.5, 37.2, 33.4, 32.8, 24.7, 14.4. HRMS (ESI) m/ z: [M + Na]+ Calcd for C18H23NO3Na 324.1576; Found: 324.1568. Anal. Calcd for C18H23NO3: C, 71.73; H, 7.69; N, 4.65; found: C, 71.50; H, 7.60; N, 4.66. 1-(3-Allyl-4-vinylphenyl)ethan-1-one (5i). Transparent oil, 147 mg, 79% yield; eluent: c-hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 1.8, 8.1 Hz, 1H), 7.76 (d, J = 1.7, 1H), 7.58 (d, J = 8.1 Hz, 1H), 6.98 (dd, J = 11.0, 17.4 Hz, 1H), 5.97 (ddt, J = 6.1, 10.1, 16.3 Hz, 1H), 5.76 (dd, J = 1.2, 17.4 Hz, 1H), 5.42 (dd, J = 1.2, 11.0 Hz, 1H), 5.10 (dq, J = 1.5, 10.1 Hz, 1H), 4.98 (dq, J = 1.7, 17.1 Hz, 1H), 3.50 (dt, J = 1.5, 6.1 Hz, 2H), 2.59 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 217.2, 197.9, 141.7, 137.6, 136.6, 136.2, 134.0, 130.0, 126.9, 126.1, 118.1, 116.6, 37.5, 26.7; IR νmax 3347, 3082, 3005, 1682, 1603, 1410, 1264, 918 cm−1; HRMS (ESI) m/z: [M + H]+ Calcd for C13H15O 187.1123; Found: 187.1115. Anal. Calcd for C13H14O: C, 83.83; H, 7.58; found: C, 83.79; H, 7.65. 1-(3-Allyl-4-(prop-1-en-2-yl)phenyl)ethan-1-one (5j). Yellow oil, 0.75 mmol scale, 137 mg, 91% yield; eluent: hexane/ethyl acetate 97:3; 1 H NMR (400 MHz, CDCl3) δ 7.81−7.74 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 5.95 (ddt, J = 6.4, 10.0, 17.2 Hz, 1H), 5.24−5.22 (m, 1H), 5.08 (dq, J = 1.6, 10.0 Hz, 1H), 5.03 (dq, J = 1.6, 17.0 Hz, 1H), 4.88− 4.87 (m, 1H), 3.45 (td, J = 1.6, 6.4 Hz, 2H), 2.58 (s, 3H), 2.04−2.03 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 198.0, 148.9, 144.5, 137.3, 137.1, 135.9, 129.7, 128.5, 126.2, 116.4, 115.7, 37.2, 26.7, 24.8; IR νmax 2922, 1679, 1414, 1356, 1262, 1202 cm−1; HRMS (ESI) m/z: [M + H]+ Calcd for C14H17O 201.1274; Found: 201.1284. 1-(3-Allyl-4-(1-(4-(trifluoromethyl)phenyl)vinyl)phenyl)ethan-1one (5k). Yellow oil, 0.5 mmol scale, 144 mg, 87% yield; eluent: hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 7.87−7.84 (m, 2H), 7.56−7.54 (m, 2H), 7.36−7.31 (m, 3H), 5.92 (d, J = 1.2 Hz, 1H), 5.78 (ddt, J = 6.4, 10.0, 17.0 Hz, 1H), 5.36 (d, J = 1.2 Hz, 1H), 5.00−4.88 (m, 2H), 3.20−2.18 (m, 2H), 2.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.0, 147.1, 145.5, 143.5, 138.7, 137.0, 136.3, 130.8, 130.0 (q, J = 30 Hz), 129.7, 126.8, 126.5, 125.5 (q, J = 268 Hz), 125.6 (q, J = 4 Hz), 118.1, 116.7, 37.6, 26.8; 19F NMR (376 MHz, CDCl3) δ −62.59; IR νmax 1683, 1356, 1322, 114, 1084, 848 cm−1; HRMS (ESI) m/z: [M + H]+ Calcd for C20H18OF3 331.1304; Found: 331.1306. 1-Allyl-4,5-dimethoxy-2-(1-phenylvinyl)benzene (5l). Yellow oil, 0.6 mmol scale, 102 mg, 61% yield; eluent: c-hexane/ethyl acetate 9:1; 1 H NMR (400 MHz, CDCl3) δ 7.29 (m, 5H), 6.73 (d, J = 6.2 Hz, 2H), 5.86−5.70 (m, 2H), 5.20 (d, J = 1.4 Hz, 1H), 4.98−4.86 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.12 (d, J = 6.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 148.7, 148.5, 147.2, 141.1, 137.9, 133.7, 130.4, 128. 5, 127.8, 126.8, 124.7, 115.5, 115.3, 113.7, 112.6, 56.2, 56.0, 37.4; IR νmax 3078, 2999, 2933, 2843, 1511, 1252, 1221, 907, 782 cm−1; HRMS (ESI) m/z: [M + Na]+ Calcd for C19H20O2Na 303.1361; Found: 303.1354. Anal. Calcd for C19H20O2: C, 81.40; H, 7.19; found: C, 81.17; H, 7.05. 2-Allyl-4-fluoro-1-(prop-1-en-2-yl)benzene (5m). Yellow oil, 1 mmol scale, 145 mg, 82% yield; eluent: 100% hexane; 1H NMR (400 MHz, CDCl3) δ 7.09 (dd, J = 6.0, 8.4 Hz, 1H), 6.94−6.85 (m, 2H), 5.93 (ddt, J = 6.4, 11.2, 16.8 Hz, 1H), 5.22−5.21 (m, 1H), 5.12− 5.03 (m, 2H), 4.85−4.84 (m, 1H), 3.40 (dd, J = 1.6, 6.4 Hz, 2H), 2.33 (dd, J = 0.8, 1.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.9 (d, J = 244 Hz), 144.6, 139.6 (d, J = 3 Hz), 139.0 (d, J = 7 Hz), 137.3, 130.0 (d, J = 8 Hz), 116.4, 116.03 (d, J = 21 Hz) 115.7, 112.9 (d, J = 21 Hz), 37.3 (d, J = 2 Hz), 25.3; 19F NMR (376 MHz, CDCl3) δ −116.27; IR 4231

DOI: 10.1021/acs.joc.7b00200 J. Org. Chem. 2017, 82, 4226−4234

Article

The Journal of Organic Chemistry HRMS (EI) m/z: [M]+ Calcd for C10H8O 144.0575; Found: 144.0572. 4-Phenyl-1H-indene (6e). Transparent oil, 0.3 mmol scale, 35 mg, 61% yield; eluent: c-hexane 100%; 1H NMR (400 MHz, CDCl3) δ 7.57−7.27 (m, 8H), 7.10−7.04 (m, 1H), 6.60 (dt, J = 5.6, 2.0 Hz, 1H), 3.49 (t, J = 1.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ144.5, 142.7, 141.1, 135.4, 134.6, 131.3, 129.1, 128.6, 127.1, 126.8, 125.0, 122.9, 39.6; HRMS (EI) m/z: [M]+ Calcd for C15H12 192.0939; Found: 192.0938. Anal. Calcd for C15H12: C, 93.71; H, 6.29; found: C, 93.49; H, 6.46. 3-(4-(Trifluoromethyl)phenyl)-1H-indene-4-carbaldehyde (6f). Yellow oil, 0.417 mmol scale, 116 mg, 96% yield; eluent: hexane/ ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 9.91 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 1.2, 8.0 Hz, 1H), 7.76−7.69 (m, 3H), 7.57−7.55 (m, 2H), 7.41- 7.37 (m, 1H), 6.70 (t, J = 2.0 Hz, 1H), 3.61 (d, J = 2.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 190.4, 145.9, 144.3, 142.4 (d, J = 2 Hz), 138.1, 130.6, 130.2 (q, J = 32 Hz), 129.4, 128.4, 126.0 (q, J = 4 Hz), 125.9, 125.8, 124.1 (q, J = 271 Hz), 38.6; 19F NMR (376 MHz, CDCl3) δ −62.57; IR νmax 2933, 1324, 1230, 1158, 1124, 1104, 1066, 847 cm−1; HRMS (EI) m/z: [M]+ Calcd for C17H11F3O 288.0762; Found: 288.0757. 6-Nitro-3-(4-(trifluoromethyl)phenyl)-1H-indene (6g). Yellow oil, 0.35 mmol scale, 101 mg, 95% yield; eluent: hexane/ethyl acetate 95:5; 1 H NMR (400 MHz, CDCl3) δ 8.39 (t, J = 0.8, 2.0 Hz, 1H), 8.24 (ddd, J = 0.8, 2.0, 8.4 Hz, 1H), 7.77−7.67 (m, 4H), 7.61 (dd, J = 0.8, 8.8 Hz, 1H), 6.98 (t, J = 2.4 Hz, 1H), 3.68 (d, J = 2.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 149.6, 146.1, 145.4, 143.9, 138.4 (d, J = 2 Hz), 138.2, 130.4 (q, J = 32 Hz), 128.1, 125.8 (d, J = 4 Hz), 124.2 (q, J = 271 Hz), 122.9 (d, J = 1 Hz), 120.2, 120.0, 38.8; 19F NMR (376 MHz, CDCl3) δ −62.60; IR νmax 1507, 1335, 1319, 1275, 1174, 1130,1062 cm−1; HRMS (ESI) m/z: [M − H]− Calcd for C16H10F3NO2 304.0591; Found: 304.0598. Ethyl 3-(6-Acetamido-1H-inden-3-yl)propanoate (6h). Beige solid, 0.17 mmol scale, 32 mg, 71% yield; eluent: c-hexane/ethyl acetate 7:3; 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.59 (s, 1H), 7.33−7.15 (m, 2H), 6.15 (s, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.28 (s, 2H), 2.84 (t, J = 7.0 Hz, 2H), 2.66 (dd, J = 18.0, 11.0 Hz, 2H), 2.16 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.4, 168.6, 145.5, 142.6, 141.6, 135.4, 127.7, 118.9, 118.3, 116.6, 60.6, 38.0, 32.9, 24.6, 23.1, 14.3; HRMS (ESI) m/z: [M + Na]+ Calcd for C16H19NO3Na 296.1263; Found: 296.1253. 1-(1H-Inden-6-yl)ethan-1-one (6i). Yellow solid, 0.54 mmol scale, 82 mg, 70% yield; eluent: c-hexane/ethyl acetate 9:1; 1H NMR (400 MHz, CDCl3) δ 8.14−8.03 (m, 1H), 7.97−7.86 (m, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.01−6.87 (m, 1H), 6.78 (dt, J = 5.5, 2.0 Hz, 1H), 3.47 (t, J = 1.7 Hz, 2H), 2.63 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 198.4, 149.8, 143.9, 138.6, 134.1, 132.0, 127.7, 123.6, 120.9, 39.4, 26.9; IR νmax 3438, 2919, 1677, 1607, 1426, 1260, 833 cm−1; HRMS (ESI) m/z: [M + Na]+ Calcd for C11H10ONa 181.0629; Found: 181.0621. 1-(3-Methyl-1H-inden-6-yl)ethan-1-one (6j). Colorless oil, 0.649 mmol scale, 101 mg, 90% yield; eluent: hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 8.03−7.93 (m, 2H), 7.36 (d, J = 8.0, 1H), 6.41−6.40 (m, 1H), 3.37−3.35 (m, 2H), 2.62 (s, 3H), 2.19−2.17 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 198.4, 151.0, 144.4, 139.9, 133.8, 133.2, 127.4, 123.4, 118.7, 37.9, 26.9, 13.1; IR νmax 1681, 1610, 1424, 1357, 1260, 1176, 1093 cm−1; HRMS (ESI) m/z: [M + H]+ Calcd for C12H13O 173.0961; Found: 173.0963. 1-(3-(4-(Trifluoromethyl)phenyl)-1H-inden-6-yl)ethan-1-one (6k). Yellow solid, 0.40 mmol scale, 111 mg, 92% yield; eluent: hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 0.8, 1.6 Hz, 1H), 7.98−7.96 (m, 1H), 7.74−7.67 (m, 4H), 8.14 (dd, J = 0.8, 8.0 Hz, 1H), 6.86 (t, J = 2.4 Hz, 1H), 3.61 (d, J = 2.4 Hz, 2H), 2.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.2, 148.0, 144.8, 144.0, 139.1 (d, J = 2 Hz), 136.5 (d, J = 2 Hz), 134.4, 130.0 (q, J = 32 Hz), 128.1, 127.6, 125.8 (d, J = 4 Hz), 124.1 (d, J = 2 Hz), 124.3 (q, J = 271 Hz), 120.0 (q, J = 2 Hz), 38.7, 26.9 (d, J = 3 Hz); 19F NMR (376 MHz, CDCl3) δ −62.53; IR νmax 1685, 1359, 1326, 1267, 1167, 1125, 1067 cm−1; HRMS (ESI) m/z: [M + H]+ Calcd for C18H14F3O 303.0991; Found: 303.0994.

5,6-Dimethoxy-3-phenyl-1H-indene (6l). Beige solid, 0.36 mmol scale, 66 mg, 73% yield; after workup product was purified by triple recrystallization from methanol; 1H NMR (400 MHz, CDCl3) δ 7.63− 7.56 (m, 2H), 7.47 (t, J = 7.4 Hz, 2H), 7.38 (ddd, J = 6.4, 4.5, 1.2 Hz, 1H), 7.13 (d, J = 7.0 Hz, 2H), 6.48 (t, J = 2.1 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.45 (d, J = 1.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ148.4, 147.7, 145.2, 137.4, 136.9, 136.6, 129.7, 128.8, 127.7, 127.7, 108.5, 104.4, 56.5, 38.2; IR νmax 2936, 2830, 1493, 1345, 1274, 1204, 1081, 854, 821, 749, 700 cm−1; HRMS (ESI) m/z: [M + Na]+ Calcd for C17H16O2Na 275.1048; Found: 275.1042. Anal. Calcd for C17H16O2: C, 80.93; H, 6.39; found: C, 80.87; H, 6.29. 6-Fluoro-3-methyl-1H-indene (6m). Yellow oil, 0.248 mmol scale, 35 mg, 83% yield; eluent: 100% hexane; 1H NMR (400 MHz, CDCl3) δ 7.26−7.14 (m, 2H), 7.04−6.99 (m, 1H), 6.17 (t, J = 2.0 Hz, 1H), 3.30 (d, J = 2.0 Hz, 2H), 2.17−2.15 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6 (d, J = 241 Hz), 146.5 (d, J = 8 Hz), 142.2 (d, J = 2 Hz), 139.4, 128.4 (d, J = 4 Hz), 119.3 (d, J = 8 Hz), 112.9 (d, J = 23 Hz), 111.4 (d, J = 23 Hz), 37.8 (d, J = 2 Hz), 13.2; 19F NMR (376 MHz, CDCl3) δ −119.54. Ethyl 3-(6-Fluoro-1H-inden-3-yl)propanoate (6n). Transparent oil, 0.19 mmol scale, 44 mg, 99% yield; eluent: c-hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ 7.33−7.22 (m, 1H), 7.16 (dd, J = 8.8, 2.2 Hz, 1H), 7.07−6.93 (m, 1H), 6.28−6.11 (m, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.31 (d, J = 2.0 Hz, 2H), 2.86 (ddd, J = 8.1, 5.0, 1.4 Hz, 2H), 2.76−2.63 (m, 2H), 1.26 (dd, J = 9.3, 4.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.2, 161.7 (d, J = 241 Hz), 146.5 (d, J = 8 Hz), 142.5, 141.1 (d, J = 2 Hz), 127.6 (d, J = 3 Hz), 119.4 (d, J = 8 Hz), 113.1 (d, J = 23 Hz), 111.6 (d, J = 23 Hz), 60.6, 37.9 (d, J = 3 Hz), 32.9, 23.2, 14.4; 19F NMR (376 MHz, CDCl3) δ −118.96; HRMS (EI) m/z: [M]+ Calcd for C14H15FO2 234.1056; Found: 234.1060. Anal, Calcd for C14H15FO2: C 71.78; H 6.45; found: C 71.67; H 6.52. 3H-Cyclopenta[a]naphthalene (6o). Yellow solid, 0.386 mmol scale, 62 mg, 96% yield; eluent: hexane/ethyl acetate 98:2; 1H NMR (400 MHz, CDCl3) δ 8.01−7.99 (m, 1H), 7.91−7.80 (m, 2H) 7.64− 7.42 (m, 3H), 7.06 (td, J = 2.0 Hz, 1H), 6.68 (td, J = 2.0 Hz, 1H), 3.75 (d, J = 2.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 142.4, 140.3, 133.8, 132.8, 131.6, 130.2, 128.0, 127.2, 126.3, 124.6, 123.6, 120.6, 38.2. 1-(4-(Trifluoromethyl)phenyl)-3H-cyclopenta[a]naphthalene (6p). Yellow solid, 0.429 mmol scale, 128 mg, 96% yield; eluent: hexane/ethyl acetate 98:2; 1H NMR (400 MHz, CDCl3) δ 8.04 (dq, J = 0.8, 8.0 Hz, 1H), 7.93−7.90 (m, 1H), 7.85−7.83 (m, 1H), 7.78−7.69 (m, 5H), 7.56−7.52 (m, 1H), 7.48- 7.43 (m, 1H), 6.75 (t, J = 2.0 Hz, 1H), 3.87 (d, J = 2.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 145.0, 141.6, 140.7, 139.9 (q, J = 1 Hz), 131.9, 131.8, 130.4, 129.8 (q, J = 32 Hz), 129.0, 128.1, 127.4, 126.6, 125.7 (q, J = 4.0 Hz), 125.2, 124.4 (q, J = 271 Hz), 123.7, 119.3, 38.6; 19F NMR (376 MHz, CDCl3) δ −62.44; IR νmax 3054, 1613, 1513, 1408, 1324, 1164, 1066 cm−1; HRMS (EI) m/z: [M]+ Calcd for C20H13F3 310.0969; Found: 310.0963. General Method for Isomerization−Deuteration of Allylboronic Acid Pinacol Ester. In a Schlenk tube, acetone-D6 (2 mL), allylboronic acid pinacol ester 7f (1 mmol) and D2O (40 mmol) were taken and deoxygenated, and then catalyst [Ru-3] (2 mol %) dissolved in acetone-D6 (0.5 mL) was added. The mixture was kept for 12−16 h in the glovebox. Isomerization and disappearance of protons was checked by NMR. Then, the whole reaction mixture was used in the next reaction without purification. Triflate 2 (0.5 mmol), Pd(PPh3)4 (12 mol %), and 10 mL of dioxane−water (4:1) were added to the same Schlenk tube and, after deoxygenation of the whole solution, heated for 18 h at 120 °C. After that time, the flask was cooled to room temperature and all volatiles were removed under reduced pressure. The oily residue was solubilized in ethyl acetate and filtrated through a Celite pad. Volatiles were concentrated in vacuo and purified by column chromatography ethyl acetate/hexane 2:98 to afford pure product. 1-Allyl-3-methyl-2-(prop-1-en-1-yl-1,3,3,3-d4)benzene (8). Yellow oil, 0.5 mmol scale, 65 mg, 74% yield; 1H NMR (400 MHz, CDCl3) δ 7.10−7.03 (m, 3H), 6.05−5.91 (m, 1H), 5.68−5.66 (m, 1H), 5.06− 4.96 (m, 2H), 3.42 (td, J = 1.6, 6.4 Hz, 2H) 2.29 (s, 3H); 13C NMR 4232

DOI: 10.1021/acs.joc.7b00200 J. Org. Chem. 2017, 82, 4226−4234

Article

The Journal of Organic Chemistry (100 MHz, CDCl3) δ 137.9, 137.7, 136.4, 130.4, 128.1, 127.0, 126.5, 115.5, 38.3, 21.2; IR νmax 2924, 2854, 1682, 1465, 1378, 1261, 1044, 994, 764 cm−1; HRMS (EI) m/z: [M]+ Calcd for C13H12D4 176.1503; Found: 176.1503. 2-Allyl-4-methoxy-1-(prop-1-en-1-yl-1,3,3,3-d4)benzene (10). Yellow oil, 0.5 mmol scale, 62% yield; 1H NMR (400 MHz, CDCl3) δ 7.38−7.54 (m, 2H), 6.76−6.52 (m, 3H), 6.01−5.93 (m, 2H), 5.09− 4.99 (m, 2H), 3.79 (s, 3H), 3.41 (d, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 158.7, 136.9, 127.1, 127.0, 116.0, 114.9, 112.1, 55.3, 37.8. RCM: The diene (0.34 mmol) was dissolved in 5 mL of CH2Cl2, and nitro-Hoveyda−Grubbs [Ru-2] (2 mol %) was added and refluxed for 1 h. Then, the reaction mixture was concentrated and purified by column chromatography ethyl acetate/hexane 2:98. 4-Methyl-1H-indene-3-d (9). Yellow oil, 0.34 mmol scale, 38 mg, 85% yield; 1H NMR (400 MHz, CDCl3) δ 7.35−7.32 (m, 1H), 7.15− 7.09 (m, 2H), 6.59−6.57 (m, 1H), 3.44−3.43 (m, 2H), 2.48 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 143.8, 143.7, 133.6, 130.3 (t, J = 3 Hz), 128.5 (t, J = 24 Hz), 127.3, 124.8, 121.3 (t, J = 2 Hz), 39.5, 18.7; IR νmax 2924, 2854, 1720, 1601, 1465, 1379, 1268, 1201, 1041, 971, 772 cm−1; HRMS (EI) m/z: [M]+ Calcd for C10H9D 131.0845; Found: 131.0845. 6-Methoxy-1H-indene-3-d (11). Yellow oil, 0.208 mmol scale, 27 mg, 88% yield; 1H NMR (400 MHz, CDCl3) δ 7.31−7.28 (m, 1H), 7.09−7.08 (m, 1H), 6.86−6.81 (m, 1H), 6.43−6.41 (m, 1H), 3.84 (s, 3H), 3.38−3.37 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 157.9, 145.7, 138.1, 131.9, 131.6, 130.5 (t, J = 23 Hz), 121.2, 112.0, 110.4, 95.7, 39.3; IR νmax 2935, 2833, 1608, 1478, 1290, 1255, 1201, 1032, 809 cm−1; HRMS (EI) m/z: [M]+ Calcd for C10H9DO 147.0794; Found: 147.0789.

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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/acs.joc.7b00200. NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel: +48-22-8220211, ext. 420. Fax: +48-22-8220211. E-mail: [email protected]. ORCID

Karol Grela: 0000-0001-9193-3305 Author Contributions §

These authors contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank the Polish-Singapore Grant (3/3/ENG-SIN/2012) “Green and Sustainable Catalysts for Chemical, Agrochemical and Pharmaceutical Industry” 20122015 NCBR.

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REFERENCES

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DOI: 10.1021/acs.joc.7b00200 J. Org. Chem. 2017, 82, 4226−4234

Article

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DOI: 10.1021/acs.joc.7b00200 J. Org. Chem. 2017, 82, 4226−4234