Synthesis of Positional Isomeric Phenylphenalenones - The Journal of

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Synthesis of Positional Isomeric Phenylphenalenones Felipe Ospina,† Adrian Ramirez,† Marisol Cano,† William Hidalgo,‡ Bernd Schneider,‡ and Felipe Otálvaro*,† †

Instituto de Química, Síntesis y Biosíntesis de Metabolitos Naturales, Universidad de Antioquia, AA 1226 Medellín, Colombia Max Planck Institute für Chemische Ö kologie, Beutenberg Campus, Hans-Knöll-Strasse 8, 07745 Jena, Germany

‡

S Supporting Information *

ABSTRACT: A series of isomeric phenylphenalenones in which the phenyl ring is located at all possible peripheral positions of the phenalenone nuclei was synthesized. The structural characteristics of the series, in which topological variation is permitted with minimal electronic disturbance, could, in principle, allow for easy pharmacophore recognition when the compounds are aligned in steroidomimetic conformations.

T

he determination of structure−activity relationships (SAR) is crucial during the process of drug development. This process requires a careful selection of structural analogs of the lead compound in order to obtain valuable information regarding binding phenomena.1 Unfortunately, synthetic convenience rather than rational analysis often seems to be the main driving force for analog synthesis.1 Using a convenient chemical approach can be justified if it yields an optimized molecule; however, these campaigns are often limited when relied on exclusively. Addressing important structure−activity relationship questions should be given the preference even at the expense of tackling more challenging syntheses.2 In this regard; positional isomers have proven valuable in examining SAR preferences, especially because they facilitate the interpretation of results.3 In 2013, Guitiérrez and co-workers, using natural 9phenylphenalenones as a scaffold, disclosed 3-(4-methoxyphenyl)-1H-phenalen-1-one (compound 3 in Figure 1 is the parent structure) as an antiplasmodial compound with an invariant IC50 of ∼2 μM against two strains of P. falciparum (F-32 and FCR-3) with different chloroquine susceptibility. 3-(4-Methoxyphenyl)-1H-phenalen-1-one did not show cytotoxicity at concentrations five times greater than its IC50.4 Interestingly, an isomeric compound, namely 9-(4-methoxyphenyl)-1Hphenalen-1-one (compound 9 in Figure 1 is the parent structure), displayed an activity level 15-fold less than its 3(4-methoxyphenyl) isomer in the same assay.4 Previous work has shown similar differential activity between 3-, 4-, and 9-(4methoxyphenyl)phenalenones (analogs of compounds 3, 4, and 9 in Figure 1) in antiprotozoal assays (Leishmania amazonensis and Trypanosoma cruzi).5 Thus, the bioactivity of phenylphenalenones seems to be a function of the spatial positioning of the phenyl group, among other variables, in relation to the carbonyl group.4,5 However, the systematic study of this topological relationship requires the synthesis of isomers of the parent phenylphenalenone for which unambiguous routes have © 2017 American Chemical Society

Figure 1. Phenalen-1-one (1) and isomeric phenylphenalenones (2− 9) synthesized in this work.

been reported only rarely.6,7 Such a series would have the intrinsic advantage of allowing a “fair” comparison of topological factors, which in principle should facilitate the analysis of trends. Received: December 13, 2016 Published: March 27, 2017 3873

DOI: 10.1021/acs.joc.6b02985 J. Org. Chem. 2017, 82, 3873−3879

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The Journal of Organic Chemistry

Compounds 4 and 8 were prepared using our recently described protocols (Scheme 3), and the reader is directed to these publications for further details.7,19

Here we report the synthesis of eight isomeric phenylphenalenones (Figure 1) and discuss their potential as a toolkit for inferring restrictions in the interaction of phenylphenalenones with biological targets. Ideally, compounds 2−9 should be obtained from properly substituted (i.e., halogenated) phenalenones via cross-coupling reactions. However, phenalen-1-one (perinaphthenone, 1) seems to be prone only to electrophilic substitution at position C-2 and nucleophilic addition at C-9.8,9 Therefore, compounds 2 and 9 are, in principle, the only ones that do not require elaborate phenalenone constructions. In fact, compound 9 was prepared via the Michael addition of phenylmagnesium bromide to phenalen-1-one as previously reported (Scheme 1).9,10

Scheme 3. Synthesis of Compounds 47 and 819

Scheme 1. Synthesis of Compounds 2 and 99,10

However, the strategy adopted in the synthesis of 8 proved to be adequate for 5. In this sense, 2-bromo-6-methoxynaphthalene was coupled with phenylboronic acid via the Suzuki− Miyaura reaction to give 2-methoxy-6-phenylnaphthalene (5a) in 79% (Scheme 4). Compound 5a was submitted to a cascade Scheme 4. Synthesis of Compound 5

Interestingly, compound 2 has been prepared via an unexpected intramolecular Friedel−Crafts acylation of 3benzyl-1H,3-H-benzo[de]isochromen-1-one in 68% yield.11 Recently, compound 2 was reported as a natural product from Macropidia f uliginosa and given the trivial name “fuliginone”;12 however, the spectroscopic data of the natural and synthetic compounds did not match. In our case, the direct bromination of phenalenone (1, prepared rapidly via microwave-enhanced synthesis), by means of alumina-supported Nbromosuccinimide (NBS/Al2O3),13 provided 2-bromophenalen-1-one8 (58%, 98% brsm) which was submitted to a Suzuki− Miyaura coupling mediated by [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II)dichloride (PEPPSI-IPr) under microwaves to provide 2-phenyl-1Hphenalen-1-one (2) in 96% yield (Scheme 1). Analytical data for compound 2 closely matches the data for 2-phenyl-1Hphenalen-1-one reported by Asscher and Agranat11 and, therefore, the structure of fuliginone had to be revised.12 The synthesis of compound 3 followed a similar strategy as that for compound 2, starting from 3-hydroxy-1H-phenalen-1one (3a), which was prepared using a small-scale version of the protocol reported by Eistert and co-workers.14 Thus, compound 3a was triflated in the usual way and submitted to Suzuki−Miyaura conditions to afford 3-phenyl-1H-phenalen-1one (3) in a 41% combined yield (Scheme 2). Compound 3, or close analogs, was previously obtained either as a byproduct in a synthesis of 4-phenylphenalenones15 or by following tedious procedures9,16−18 and therefore, our protocol constitutes an unambiguous and straightforward synthesis.

Friedel−Crafts/Michael annulation19 using acryloyl chloride and AlCl3 to afford 9-methoxy-5-phenyl-2,3-dihydro-1Hphenalen-1-one (5b) in 22% (40% brsm). A reductive carbonyl transposition process mediated by silica sulfuric acid (SSA) after reduction of the keto group with NaBH419 afforded 5phenyl-1H-phenalen-1-one (5) in 31% combined yield after preparative thin-layer chromatography (TLC), which seems to accelerate the final dehydrogenation step (Scheme 4). For the synthesis of compounds 6 and 7, a strategy adapted from a previous synthesis of 4-methoxyphenalenone in which the Heck reaction played a pivotal role was implemented.20 Hence, starting from the known symmetrical dibromonaphthalenes 6a and 7a (Scheme 5),21 a statistically controlled Suzuki−Miyaura coupling afforded the corresponding bromophenylnaphthalenes 6b and 7b in 60 and 55% yield, respectively. Installation of the ethyl acrylate fragment by means of a Heck coupling followed to provide 6c and 7c in 46% (85% brsm) and 71% for each compound. Compounds 6c and 7c were hydrogenated, hydrolyzed and submitted to a onepot Friedel−Crafts/DDQ dehydrogenation20 to afford 6phenyl-1H-phenalen-1-one (6) and 7-phenyl-1H-phenalen-1one (7) in 41% and 29% combined yield, respectively (Scheme 5). Compound 7 was previously obtained from a mixture of isomeric phenylaminophenalenones.18 One interesting aspect of this series (compounds 2−9) consists in the way they can be viewed as a phenalen-1-one with a “walking” peripheral phenyl ring (Figure 1). However, fixing the series in a steroidomimetic conformation22 (Figure 2A) offers a unique perspective in which now the carbonyl group

Scheme 2. Synthesis of Compound 3

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The Journal of Organic Chemistry Scheme 5. Synthesis of Compounds 6 and 7

Figure 2. (A) Compounds 2−9 aligned in steroidomimetic conformation (in red) illustrating the “walking carbonyl” perspective. (B) Hypothetical experiment illustrating the combined carbonyl approach for extrapolation.

gives the impression to “walk”. Such scenario, analog to a clock hand with an electron density excess at the tip, can provide, in principle, valuable information about ion−dipole or dipole− dipole interactions in the active site of an enzyme that complexes with these compounds. To illustrate this point, suppose that, out of the series, compounds 3, 4, and 7 are evaluated as the most potent inhibitors of a suitable enzyme (Figure 2B). One can extrapolate this hypothetical result to postulate a compound like 6,9-dihydroxy-3-phenylphenalen-1one (if rapid tautomerism is assumed) as the substrate with improved binding capabilities (Figure 2B). This “combined carbonyl approach” to SAR suggests modifications of the core nuclei that are hard to discover without the series evaluation. In summary, we have prepared a series of positional isomeric phenylphenalenones employing palladium mediated crosscouplings as key steps. The strategies used are applicable to the preparation of different analogues. The biological evaluation of this small-homogeneous phenylphenalenone series in which topological variation is allowed with minimum electronic perturbation can provide useful insights for the further optimization of properties.

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Merck silica gel plates (60-F254) using UV light (254 nm) as a visualizing agent and 98% sulfuric acid/methanol (9:1) solution and heat as developing agents. Melting points were measured on a capillary melting point apparatus and are uncorrected. 1H and 13C NMR spectroscopic analyses were performed on a 500 MHz NMR spectrometer operating at 500.13 MHz (1H) and 125.75 MHz (13C). Chemical shifts are reported relative to residual solvent signals. Signals were assigned with the aid of HMQC, HMBC, and 1H, 1H− COSY spectra measured on 600 or 500 MHz NMR spectrometers. HRESIMS was recorded in positive ion mode on a UPLC−MS/MS system (Orbitrap mass spectrometer). For microwave reactions, a monomode microwave synthesizer equipped with infrared and optic fiber temperature measurement was employed. Yields refer to weighed chromatographically homogeneous samples. Synthetic Procedures. Compounds 1a,8 4,7 6a,21 8,19 and 910 were prepared as described in the literature. 1H-Phenalen-1-one (1). In a 35 mL microwave vial were mixed glycerol (664.5 mg, 7.2 mmol), 2-naphtol (469.8 mg, 3.2 mmol), boric acid (283.1 mg, 4.6 mmol), sodium 3-nitrobenzenesulfonate (731.9 mg, 3.2 mmol), iron(II) sulfate heptahydrate (188.3 mg, 0.7 mmol), and concentrated sulfuric acid (1.6 mL, 98% w/v) in that order. The mixture was heated at 80 °C for 20 min under microwave radiation. The crude was then slowly diluted with KOH (50 mL, 20% w/v) and partitioned with AcOEt (3 × 100 mL) followed by flash chromatography of the concentrated organic phase (n-hexane, bp 55−68 °C) to afford 1: 182.7 mg (31% yield); yellow solid; mp: 149− 151 °C; Rf (CH2Cl2) = 0.3. Compound 1 was identical in all respects with a commercial material.

EXPERIMENTAL SECTION

General Experimental Procedures. All reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm 3875


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The Journal of Organic Chemistry 2-Phenyl-1H-phenalen-1-one (2). In a 10 mL microwave vial were mixed 2-bromo-1H-phenalen-1-one (50.2 mg, 0.2 mmol), PEPPSI-IPr catalyst (4.2 mg, 0.006 mmol), K3PO4 (59.3 mg, 0.3 mmol), phenylboronic acid (34.7 mg, 0.3 mmol), and dioxane (1.5 mL) in that order. The mixture was then heated at 80 °C under microwave radiation for 20 min. Partition of the crude reaction mixture between CH2Cl2 (2 × 50 mL)/H2O (50 mL) followed by flash column chromatography of the concentrated organic phase (n-hexane/CH2Cl2 1:1) produced the desired 2-phenylphenalenone (2).11 47.1 mg (96% yield); yellow solid; mp: 139−140 °C; Rf (CH2Cl2) = 0.6; 1H NMR (C2D6CO) δ 7.40 (1H, tt, J = 7.5 and 1.5 Hz, H-4′), 7.46 (2H, m, H3′-5′), 7.74 (3H, m, H-5 and H-2′-6′), 7.91 (1H, dd, J = 7.3 and 8.1 Hz, H-8), 8.04 (1H, d, J = 6.9 Hz, H-4), 8.07 (1H, s, H-3), 8.21 (1H, ∼ d, J = 8.2 Hz, H-6), 8.41 (1H, dd, J = 1.1 and 8.1 Hz, H-7), 8.62 (1H, dd, J = 1.1 and 7.3 Hz, H-9); 13C NMR (C2D6CO) δ 128.7 (C9b), 129.0 (C-5), 129.2 (C-8), 129.71 (C-4′), 129.76 (C-3′-5′), 129.9 (C-3a), 130.9 (C-2′-6′), 131.6 (C-9a), 132.0 (C-9), 133.3 (C-6), 133.7 (C-4), 134.0 (C-6a), 136.6 (C-7), 138.6 (C-1′), 140.6 (C-2), 141.4 (C-3), 184.8 (C-1); HRMS (ESI) [M+H]+ calcd for C19H13O m/z 257.0961, found m/z 257.0961. 3-Hydroxy-1H-phenalen-1-one (3a). A small-scale version of the protocol reported by Eistert and co-workers was followed.9 In an open test tube were mixed naphtalic anhydride (635.5 mg, 3.2 mmol), ZnCl2 (861.5 mg, 6.3 mmol) and diethylmalonate (1 mL, 6.6 mmol). The mixture was heated at 155 °C for 2 h, (color change from white to brown). At that point the tube was heated to 175 °C for another hour. The resulting sticky mixture was then cooled and adsorbed in silica. Purification by column chromatography (n-hexane) afforded 3a: 545.5 mg (87% yield); yellow solid, mp: 255−256 °C (decompose); Rf (nhexane/AcOEt 1:1) = 0.4. Compound 3a was identical in all respects with a commercial material. 1-Oxo-1H-phenalen-3-yl trifluoromethanesulfonate (3b). A solution of 3-hydroxy-1H-phenalen-1-one (1002.6 mg, 5.1 mmol), dimethyl amino pyridine (DMAP, 20.8 mg, 0.2 mmol) in dry pyridine (10 mL) was stirred at −10 °C in a 25 mL rounded bottomed flask. Addition of trifluoromethanesulfonic anhydride (1735 μL, 10.3 mmol) followed, and the mixture was stirred under argon atmosphere for 6 h (the solution turned dark red). Partition of the crude extract between AcOEt (80 mL)/CuSO4 1 M aqueous solution (3 × 100 mL) and extraction of the aqueous phase with AcOEt (200 mL) afforded compound 3b as a brown sticky solid (1250.3 mg, 74% crude yield). The crude product was employed directly for the synthesis of compound 3. For identification purposes, an aliquot was purified via preparative thin layer chromatography (n-hexane/CH2Cl2 1:1). yellow solid mp: 127−128 °C; Rf (CH2Cl2) = 0.7; 1H NMR (CDCl3, 300 MHz) δ 6.77 (1H, s, H-2), 7.71 (1H, dd, J = 7.3 and 8.2 Hz), 7.82 (1H, dd, J = 7.3 and 8.0 Hz), 8.09 (1H, d, J = 7.3 Hz), 8.17 (1H, d, J = 8.2 Hz), 8.27 (1H, d, J = 8.0 Hz), 8.63 (1H, dd, J = 1.1 and 7.3 Hz); 13 C NMR (CDCl3, 300 MHz) δ 118.5 (q, J = 320.3 Hz -CF3), 118.8 (C-2), 122.5, 126.5, 126.6, 127.2, 127.6, 128.4, 131.2, 132.1, 134.1, 136.0, 157.0 (C-3), 184.1 (C-1); HRMS (ESI) [M+H]+ calcd for C14H8F3O4S m/z 329.0095, found m/z 329.0120 3-Phenyl-1H-phenalen-1-one (3). In a 50 mL flask were mixed 1oxo-1H-phenalen-3-yl trifluoromethanesulfonate (3b) (500.0 mg, 1.6 mmol), phenylboronic acid (192.4 mg, 1.6 mmol), bis(triphenylphosphine) palladium(II) dichloride (55.45 mg, 0.08 mmol), a solution of Na2CO3 2 M (2.4 mL), and dioxane (20 mL). The solution was refluxed under argon atmosphere for 18 h, time at which a second addition of phenylboronic acid (190.0 mg, 1.6 mmol) was repeated. The reaction was kept under reflux for another 18 h. Partition of the crude product between AcOEt/H2O and CH2Cl2/ H2O, evaporation of the organic phases and preparative TLC of the organic extracts (n-hexane/ethoxyethane 8:1) afforded 3-phenylphenalenone (3): 227 mg (56% yield); yellow solid; mp: 139−141 °C;17,18 Rf (CH2Cl2) = 0.4; 1H NMR (C2D6CO) δ 6.57 (1H, s, H-2), 7.57 (5H, m, -Ph), 7.67 (1H, dd, J = 7.3 and 8.2 Hz, H-5), 7.73 (1H, dd, J = 0.9 and 7.3 Hz, H-4), 7.91 (1H, dd, J = 7.3 and 8.1 Hz, H-8), 8.23 (1H, dd, J = 0.9 and 8.2 Hz, H-6), 8.43 (1H, dd, J = 1.2 and 8.1 Hz, H-7), 8.59 (1H, dd, J = 1.2 and 7.3 Hz, H-9); 13C NMR (C2D6CO) δ 128.5 (C-5), 128.9 (C-8), 129.6 (C-9b), 129.7 (C-6a),

130.2 (C-2), 130.4 (C-3′-5′), 130.5 (C-4′), 130.9 (C-2′-6′), 131.2 (C9), 131.3 (C-9a), 133.2 (C-4), 134.1 (C-6), 134.6 (C-3a), 137.1 (C-7), 139.7 (C-1′), 155.3 (C-3), 185.416 (C-1); HRMS (ESI) [M+H]+ calcd for C19H13O m/z 257.09609, found m/z 257.09568. 2-Methoxy-6-phenylnaphthalene (5a). In a 10 mL flask were mixed 2-bromo-6-methoxynaphthalene (224.7 mg, 0.9 mmol), phenylboronic acid (140.5 mg, 1.1 mmol), K3PO4 (620.9 mg, 2.9 mmol), bis(triphenylphosphine) palladium(II) dichloride (30.2 mg, 0.04 mmol), and dioxane (7 mL). The mixture was refluxed under argon for 16 h. Partition of the crude reaction between CH2Cl2 (2 × 80 mL)/H2O (100 mL) followed by dryness of the organic phase afforded 2-methoxy-6-phenylnaphthalene (5a)23 after column chromatography (n-hexane): 176.1 mg (79% yield); white solid; mp: 147− 148 °C; Rf (n-hexane/AcOEt 6:1) = 0.5; 1H NMR (C2D6CO) δ 3.94 (3H, s, -OMe), 7.19 (1H, dd, J = 2.6 and 8.8 Hz, H-3), 7.33 (1H, d, J = 2.6 Hz, H-1), 7.37 (1H, tt, J = 1.3 and 7.3 Hz, H-4′), 7.49 (2H, t, J = 7.3 Hz, H-3′-5′), 7.78 (3H, m, H-7 and H-2′-6′), 7.89 (1H, d, J = 8.8 Hz, H-8), 8.10 (1H, d, J = 1.5 Hz, H-5); 13C NMR (C2D6CO) δ 56.6 (2-OMe), 107.4 (C-1), 120.9 (C-3), 127.2 (C-5), 127.5 (C-7), 128.7 (C-2′/6′), 128.9 (C-4′), 130.7 (C-3′/5′), 131.2 (C-4a), 131.5 (C-4), 136.0 (C-8a), 137.9 (C-6), 142.8 (C-1′), 159.9 (C-2); HRMS (ESI) [M+H]+ calcd for C17H15O m/z 235.1122, found m/z 235.1117. 9-Methoxy-5-phenyl-2,3-dihydro-1H-phenalen-1-one (5b). In a 25 mL round bottomed flask, a solution of 2-methoxy-6-phenylnaphthalene (418.8 mg, 1.8 mmol) in CH2Cl2 (12 mL) was cooled to −10 °C. AlCl3 (359.8 mg, 2.7 mmol) was then slowly added and the mixture agitated for 10 min (solution turns brown). To this mixture, acryloyl chloride (168.8 μL, 1.9 mmol) was added (solution turns dark red), after 30 min the reaction mixture was allowed to warm to room temperature with further stirring (5 h). The crude was passed through a column of silica (previously packaged using n-hexane) employing an isocratic system (n-hexane/CH2Cl2 2:1). Compound 5b was further purified via preparative TLC (n-hexane/CH2Cl2 1:2 × 2): 112.7 mg (22% yield, 40% brsm); brown oil; Rf (CH2Cl2) = 0.6; 1H-NMR (C2D6CO) δ 2.89 (2H, t, J = 7.3 Hz, H-2), 3.37 (2H, t, J = 7.3 Hz, H3), 4.03 (3H, s, -OMe), 7.40 (1H, tt, J = 1.1 and 7.5 Hz, H-4′), 7.51 (2H, ∼ d, J = 7.5 Hz, H-3′-5′), 7.53 (1H, d, J = 8.9 Hz, H-8), 7.80 (2H, ∼ dd, J = 1.1 and 7.5 Hz, H-2′-6′), 8.01 (1H, d, J = 8.9 Hz, H-7), 8.34 (1H, d, J = 1.8 Hz, H-6), 8.38 (1H d, J = 1.8 Hz, H-4); 13C NMR (C2D6CO) δ 23.1 (C-3), 39.2 (C-2), 57.6 (9-OMe), 115.9 (C-8), 119.2 (C-9a), 125.7 (C-4), 128.7 (C-2′/6′), 129.4 (C-4′), 130.0 (C-7), 130.9 (C-3′/5′), 131.2 (C-6a), 131.4 (C-3a), 132.9 (C-6), 133.8 (C9b), 137.2 (C-5), 141.9 (C-1′), 156.7 (C-9), 199.0 (C-1); HRMS (ESI) [M+H]+ calcd for C20H17O2 m/z 289.1228, found m/z 289.1224. 9-Methoxy-5-phenyl-2,3-dihydro-1H-phenalen-1-ol (5c). In a 15 mL flask, cerium(III) chloride heptahydrate (140.9 mg, 0.4 mmol) was added to a dispersion of 9-methoxy-5-phenyl-2,3-dihydro-1Hphenalen-1-one (72.1 mg, 0.2 mmol) in methanol (5 mL). Slow addition of NaBH4 (164.6 mg, 4.3 mmol) followed, and the mixture was stirred for 4 h. Partition with CH2Cl2 (50 mL x 2)/H2O (50 mL) followed by column chromatography (n-hexane/AcOEt 5:1), afforded 9-methoxy-5-phenyl-2,3-dihydro-1H-phenalen-1-ol (5c): 47.8 mg (66% yield); pale brown oil; Rf (n-hexane/AcOEt 6:1) = 0.1; 1HNMR (C2D6CO) δ 2.05 (1H, m, H-2), 2.19 (1H, dddd, J = 3.8, 4.8, 7.5, and 12.5 Hz; H-2), 2.99 (1H, ddd, J = 4.8, 8.4, and 13.4 Hz; H-3), 3.21 (1H, ddd, J = 4.8, 7.5, and 12.5 Hz; H-3), 3.97 (3H, s, -OMe), 5.06 (1H, m, H-1), 7.36 (1H, tt, J = 1.3 and 7.3 Hz, H-4′), 7.40 (1H, d, J = 9.0 Hz, H-8), 7.49 (2H, dd, J = 7.3 and 7.8 Hz, H-3′-5′), 7.78 (2H, m, H-2′-6′), 7.86 (1H, d, J = 9.0 Hz, H-7), 7.90 (1H, d, J = 1.8, H-4), 8.00 (1H, d, J = 1.8 Hz, H-6); 13C NMR (C2D6CO) δ 20.8 (C-3), 31.8 (C-2), 56.5 (9-OMe), 69.2 (C-1), 114.0 (C-8), 120.7 (C-9a), 123.4 (C-4), 125.3 (C-6), 127.8 (C-2′-6′), 127.9 (C-4′), 128.1 (C-7), 129.8 (C-3′-5′), 130.1 (C-6a), 130.2 (C-9b), 136.3 (C-5), 139.6 (C-3a), 142.1 (C-1′), 154.2 (C-9); HRMS (ESI) [M−H2O]+ calcd for C20H17O m/z 273.1273, found m/z 273.1274. 5-Phenyl-1H-phenalen-1-one (5). 9-Methoxy-5-phenyl-2,3-dihydro-1H-phenalen-1-ol (5c) (45.5 mg, 0.2 mmol) was dissolved with benzene (6 mL) in a 10 mL flask. The resulting pale yellow solution was treated with silica sulfuric acid10 (SSA) (61.9 mg, solution turns 3876


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The Journal of Organic Chemistry orange) and then refluxed for 9 h. The benzene was then evaporated and the crude submitted to two consecutive preparative TLC (petroleum-ether/AcOEt 8:12) to afford 5-phenyl-1H-phenalen-1one (5): 19.1 mg (47% yield); yellow solid; mp: 151−152 °C; Rf (CH2Cl2) = 0.3; 1H NMR (C2D6CO) δ 6.69 (1H, d, J = 9.7 Hz, H-2), 7.46 (1H, tt, J = 7.3 and 1.3 Hz, H-4′), 7.56 (2H, m, H-3′-5′), 7.89 (3H, m, H-8 and H-2′-6′), 8.03 (1H, d, J = 9.7 Hz, H-3), 8.29 (1H, d, J = 1.6 Hz, H-4), 8.456 (1H, d, J = 1.6 Hz, H-6), 8.453 (1H, dd, J = 1.3 and 7.9 Hz, H-7), 8.50 (1H, dd, J = 1.3 and 7.3 Hz, H-9); 13C NMR (C2D6CO) δ 128.4 (C-9b), 129.0 (C-2′-6′), 129.4 (C-8), 129.9 (C4′), 130.3 (C-9a), 130.91 (C-6), 130.97 (C-3′-5′), 131.04 (C-2), 131.09 (C-3a), 131.1 (C-9), 132.7 (C-4), 134.7 (C-6a), 137.0 (C-7), 141.3 (C-1′), 143.5 (C-3 and C-5), 186.3 (C-1); HRMS (ESI) [M +H]+ calcd for C19H13O m/z 257.09609, found m/z 257.09596. 1-Bromo-4-phenylnaphthalene (6b). In a 50 mL round bottomed flask were mixed 1,4-dibromonaphtalene (1151.0 mg, 4.0 mmol), phenylboronic acid (2 60. 0 m g, 2. 0 mmol ) and b i s(triphenylphosphine)palladium(II) dichloride (71.8 mg, 0.1 mmol), aqueous sodium carbonate (2M, 12 mL), and dioxane (20 mL). The mixture was refluxed under argon for 2.5 h. Partition of the crude reaction between AcOEt (2 × 50 mL)/H2O (100 mL) followed by column chromatography (n-hexane) afforded 1-bromo-4-phenylnaphthalene (6b): 357 mg (62% yield); white solid; mp: 73−74 °C; Rf (nhexane) = 0.6; 1H-NMR (C2D6CO) δ 7.34 (1H, d, J = 7.7 Hz, H-3), 7.52 (6H, m, H-6 and -Ph), 7.69 (1H, ddd, J = 1.3, 7.0, and 8.4 Hz, H7), 7.87 (1H, d, J = 8.4 Hz, H-5), 7.92 (1H, d, J = 7.7 Hz, H-2), 8.30 (1H, d, J = 8.4, H-8); 13C NMR (C2D6CO) δ 123.4 (C-1), 128.3 (C5), 128.9 (C-6 and C-8), 129.2 (C-3), 129.4 (C-7), 129.5 (C-4′), 130.3 (C-2′-6′), 131.5 (C-2), 131.7 (C-3′-5′), 133.8 (C-8a′), 134.7 (C-4a′), 141.6 (C-1′), 142.4 (C-4); HRMS (GC-EI) [M]+ Calc. for C16H11Br m/z 282.0044, found m/z 282.0031. Ethyl (E)-3-(4-Phenylnaphthalen-1-yl)acrylate (6c). Compound 6b (451.6 mg, 1.6 mmol) was mixed with bis(triphenylphosphine)palladium(II) dichloride (56.9 mg, 0.08 mmol), dioxane (25 mL) and a solution of sodium carbonate (2M, 2.4 mL). Then an excess of ethyl acrylate was added (1.2 mL, 10.9 mmol) and the mixture was refluxed under argon. After 16 h, a second addition of ethyl acrylate (0.5 mL, 4.5 mmol) was made and the reaction was further refluxed for another 28 h. The mixture was partitioned with AcOEt (2 × 50 mL)/H2O (100 mL). Adsorption on silica gel, followed by column chromatography (n-hexane until the starting material was separated then nhexane/CH2Cl2 2:1) furnished ethyl (E)-3-(4-phenylnaphthalen-1yl)acrylate (6c): 223.2 mg (46% yield; 85% brsm); white solid; mp: 107−108 °C; Rf (n-hexane/CH2Cl2 2:1) = 0.6; 1H-NMR (C2D6CO) δ 1.34 (3H, t, J = 7.1 Hz, H-2 Et), 4.28 (2H, q, J = 7.1 Hz, H-1 Et), 6.65 (1H, d, J = 15.8 Hz, H-2), 7.52 (7H, m, -Ph, H-3′ and H-6′), 7.67 (1H, ddd, J = 1.2, 7.0, and 8.3 Hz, H-7′), 7.92 (1H, d, J = 8.4 Hz, H-5′), 7.99 (1H, d, J = 7.5 Hz, H-2′), 8.32 (1H, d, J = 8.3 Hz, H-8′), 8.57 (1H, d, J = 15.8 Hz, H-3); 13C NMR (C2D6CO) δ 15.6 (2-OEt), 61.9 (1-OEt), 122.9 (C-2), 125.4 (C-8′), 126.6 (C-2′), 128.3 (C-6′), 128.4 (C-5′), 128.5 (C-3′), 128.7 (C-7′), 129.5 (C-4″), 130.3 (C-2″-6″), 131.6 (C-3″-5″), 133.0 (C-1′), 133.65 (C-4a′), 133.67 (C-8a′) 142.1 (C-1″), 142.7 (C-3), 144.4 (C-4′), 167.9 (C-1); HRMS (ESI) [M +H]+ calcd for C21H19O2 m/z 303.1385, found m/z 303.1379. Ethyl 3-(4-Phenylnaphthalen-1-yl)propanoate (6d). A solution of 6c (196.1 mg, 0.6 mmol) in acetone (7 mL) was treated with 19.5 mg of palladium on activated charcoal catalyst (10% Pd basis). The mixture was stirred under an atmosphere of hydrogen (balloon with a needle in contact with the solution) at room temperature for 4 h. The crude was filtered through a pad of silica-gel (1 g) employing CH2Cl2. The solvent was evaporated to furnish ethyl 3-(4-phenylnaphthalen-1yl)propanoate (6d): 197.2 mg (99% yield); pale yellow oil; Rf (nhexane) = 0.6; 1H-NMR (C2D6CO) δ 1.21 (3H, t, J = 7.1 Hz, H-2 Et), 2.79 (2H, t, J = 7.7 Hz, H-2), 3.46 (2H t, J = 7.7 Hz, H-3), 4.12 (2H, t, J = 7.1 Hz, H-1 Et), 7.35 (1H, d, J = 7.5 Hz, H-3′), 7.49 (7H, m, -Ph, H-2′ and H-7′), 7.59 (1H, dd ∼ t, J = 7.5 and 8.4 Hz, H-6′), 7.88 (1H, d, J = 8.4 Hz, H-5′), 8.19 (1H, d, J = 8.4 Hz, H-8′); 13C NMR (C2D6CO) δ 15.5 (2-OEt), 29.7 (C-3), 36.6 (C-2), 61.7 (1-OEt), 125.7 (C-8′), 127.5 (C-2′), 127.6 (C-6′), 127.8 (C-7′), 128.4 (C3′and C-5′), 129.1 (C-4″), 130.2 (C-2″-6″), 131.8 (C-3″-5″), 133.8

(C-4a′), 133.9 (C-8a′), 138.3 (C-1′), 141.0 (C-4′), 142.7 (C-1″), 174.0 (C-1); HRMS (ESI) [M+H]+ calcd for C21H21O2 m/z 305.1541, found m/z 305.1560. 3-(4-Phenylnaphthalen-1-yl)propanoic Acid (6e). Compound 6d (171.1 mg, 0.6 mmol) was dissolved in a mixture of MeOH/THF (3.5 mL, 1:2) and treated with a KOH solution (5 M, 0.6 mL) at room temperature for 1 h. The crude was acidulated with HCl (12% w/v, 12 mL), diluted with H2O (20 mL), and partitioned with ethyl ether (50 mL). Evaporation of the organic phase afforded 3-(4-phenylnaphthalen-1-yl)propanoic acid (6e): 142.3 mg (91% yield); pale brown solid; mp: 139−140 °C; Rf (AcOEt) = 0.8; 1H-NMR (C2D6CO) δ 2.81 (2H, t, J = 7.7, H-2), 2.86 (1H, brs, −OH), 3.46 (2H, t, J = 7.7, H-3), 7.35 (1H, d, J = 7.1 Hz, H-3′), 7.49 (7H, m, HPh, H-2′ and H-6′), 7.59 (1H, ddd, J = 1.3, 7.0, and 8.4 Hz, H-7′), 7.88 (1H, d, J = 8.4 Hz, H-5′), 8.21 (1H, d, J = 8.4 Hz, H-8′); 13C NMR (C2D6CO) δ 29.7 (C-3), 36.1 (C-2), 125.7 (C-8′), 127.4 (C-6′), 127.5 (C-2′), 127.8 (C-7′), 128.4 (C-3′and C-6′), 129.1 (C-4″), 130.2 (C2″-6″), 131.8 (C-3″-5″), 133.8 (C-4a′), 133.9 (C-8a′), 138.5 (C-1′), 140.9 (C-4′), 142.7 (C-1″), 174.9 (C-1); HRMS (ESI) [M+H]+ calcd for C19H17O2 m/z 277.1228, found m/z 277.1223. 6-Phenyl-1H-phenalen-1-one (6). Compound 6e (124.5 mg, 0.4 mmol) was treated with SOCl2 (0.5 mL) and the flask was air-dried after gas evolution. This process was repeated twice. After dryness, the resulting product was dissolved in CH2Cl2 (1.5 mL), treated with AlCl3 (93.8 mg, 0.7 mmol) and then stirred at room temperature for 1 h. Addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 105.1 mg, 0.5 mmol) and CH2Cl2 (2.5 mL) followed, and the mixture was refluxed for 2.5 h. The reaction crude was adsorbed on silica gel and then purified by column chromatography (CH2Cl2) to give 6Phenyl-1H-phenalen-1-one (6): 52 mg (45% yield); orange solid; mp: 139−140 °C; Rf (CH2Cl2) = 0.4; 1H-NMR (C2D6CO) δ 6.68 (1H, d, J = 9.9 Hz, H-2), 7.56 (5H, m, -Ph), 7.63 (1H, d, J = 7.3, Hz, H-5), 7.84 (1H, dd, J = 7.3 and 8.2 Hz, H-8), 7.99 (1H, d, J = 9.9 Hz, H-3), 8.01 (1H, d, J = 7.3 Hz, H-4), 8.28 (1H, dd, J = 1.1 and 8.2 Hz, H-7), 8.56 (1H, dd, J = 1.1 and 7.3 Hz, H-9); 13C NMR (C2D6CO) δ 128.9 (C3a), 129.0 (C-8), 129.5 (C-9b), 129.7 (C-5), 129.9 (C-4′), 130.1 (C9a), 130.2 (C-2), 130.4 (C-3′-5′), 131.4 (C-9), 131.9 (C-2′-6′), 132.4 (C-6a), 133.3 (C-4), 135.0 (C-7), 141.1 (C-1′), 143.8 (C-3), 146.3 (C-6), 186.5 (C-1); HRMS (ESI) [M+H]+ calcd for C19H13O m/z 257.09609, found m/z 257.09586. 1-Bromo-5-nitronaphthalene (7a‑2). In a 50 mL round bottomed flask were mixed 1-nitronaphthalene (8.8331 g, 50.9 mmol) and FeCl3 (54.2 mg, 0.3 mmol). The mixture was stirred at 90 °C until the melt (dark mixture) and bromine (3.9 mL) was added. After 1.5 h, additional bromine (1.3 mL) was added and the reaction was let at 90 °C for another 2.5 h. The crude was then purified by recrystallization with ethanol affording 1-bromo-5-nitronaphthalene (7a‑2): 3.9212 g (30% yield); yellow solid; mp: 113−114 °C; Rf (n-hexane) = 0.5; 1HNMR (C2D6CO) δ 7.69 (1H, dd, J = 7.5 and 8.8 Hz, H-3), 7.87 (1H, dd, J = 7.7 and 8.6 Hz, H-7), 8.07 (1H, dd, J = 0.9 and 7.5 Hz, H-2), 8.33 (1H, dd, J = 1.1 and 7.7 Hz, H-6), 8.37 (1H, dt, J =0.9 and 8.8 Hz, H-4), 8.62 (1H, dt, J = 1.1 and 8.6 Hz, H-8); 13C NMR (C2D6CO) δ 124.5 (C-4), 124.7 (C-1), 126.1 (C-6), 127.8 (C-4a), 128.2 (C-7), 131.5 (C-3), 133.7 (C-2), 134.2 (C-8a), 134.5 (C-8), 149.3 (C-5); HRMS (ESI) [M+H]+ calcd for C10H7BrNO2 m/z 251.9660, found m/z 251.9658. 5-Bromonaphthalen-1-amine (7a‑1). In a 100 mL round bottomed flask were mixed 1-bromo-5-nitronaphthalene (3.7817 g, 15.0 mmol), iron wire (cut in small pieces 8.3810 g, 150.1 mmol), ethanol (15 mL), dioxane (15 mL), acetic acid (15 mL), H2O (7.5 mL), and HCl (2M, 187.5 μL). The mixture was refluxed for 1.6 h, the iron removed with a magnet and the resulting crude washed with CH2Cl2 and AcOEt. Purification by column chromatography (n-hexane) afforded 5bromonaphthalen-1-amine (7a‑1): 3.019 g (90% yield); gray solid; mp: 63−65 °C; Rf (n-hexane/CH2Cl2 1:1) = 0.3; 1H-NMR (CDCl3) δ 4.14 (2H, bs, -NH2), 6.79 (1H, d, J = 7.5 Hz, H-2), 7.22 (1H, dd ∼ t, J = 7.7 and 8.1 Hz, H-7), 7.36 (1H, dd, J = 7.5 and 8.4 Hz, H-3), 7.69 (1H, d, J =8.4 Hz, H-4), 7.74 (2H, d overlapped, J = 7.8 Hz, H-6 and H-8); 13C NMR (CDCl3) δ 110.6 (C-2), 118.0 (C-7), 120.6 (C-8), 123.5 (C-5), 124.6 (C-8a), 124.8 (C-4), 127.7 (C-3), 130.0 (C-6), 3877


Note


hexane/CH2Cl2 2:1) = 0.4; 1H-NMR (C2D6CO) δ 1.20 (3H, t, J = 7.1 Hz, H-2-Et), 2.79 (2H, t, J = 7.7 Hz, H-2), 3.46 (2H, t, J = 7.7 Hz, H3), 4.11 (2H, q, J = 7.1 Hz, H-1-Et), 7.39 (1H, dd, J = 7.1 and 8.2 Hz, H-3′), 7.47 (7H, m, H-2′, H-6′ and -Ph), 7.62 (1H, dd, J = 7.1 and 8.4 Hz, H-7′), 7.73 (1H, d, J = 8.2 Hz, H-4′), 8.16 (1H, d, J = 8.4 Hz, H8′); 13C NMR (C2D6CO) δ 15.5 (2-OEt), 30.0 (C-3), 36.7 (C-2), 61.7 (1-OEt), 125.0 (C-8′), 126.6 (C-4′), 127.4 (C-7′), 127.5 (C-3′), 127.9 (C-2′), 128.5 (C-6′), 129.1 (C-4″), 130.1 (C-2″-6″), 131.8 (C3″-5″), 133.95 (C-4a′), 133.98 (C-8a′), 139.0 (C-1′), 142.94 (C-5′), 142.96 (C-1″), 174.0 (C-1); HRMS (ESI) [M+H]+ calcd for C21H21O2 m/z 305.15415, found m/z 305.15375. 3-(5-Phenylnaphthalen-1-yl)propanoic Acid (7e). Compound 7d (219.8 mg, 0.7 mmol) was dissolved in a mixture of MeOH/THF (4 mL, 1:2) and treated with a KOH solution (5 M, 0.7 mL) at room temperature for 1 h. The crude was acidulated with HCl (12% w/v, 12 mL), diluted with H2O (25 mL), and partitioned with ethyl ether (2 × 25 mL). Evaporation of the organic phase afforded 3-(5-phenylnaphthalen-1-yl)propanoic acid (7e): 190.5 mg (95% yield); pale yellow solid; mp: 180−181 °C; Rf (AcOEt) = 0.7; 1H-NMR (C2D6CO) δ 2.79 (2H, d, J = 7.8 Hz, H-2), 2.89 (2H, d, J = 7.8 Hz, H-3), 7.38 (1H, dd, J = 6.9 and 8.4 Hz, H-3′), 7.43 (1H, dd, J = 1.1 and 6.9 Hz, H-6′), 7.49 (6H, m, -Ph and H-2′), 7.63 (1H, dd, J = 6.9 and 8.6 Hz, H-7′), 7.73 (1H, d, J = 8.4 Hz, H-4′), 8.18 (1H, d, J = 8.6 Hz, H-8′); 13C NMR (C2D6CO) δ 30.0 (C-3), 36.2 (C-2), 125.0 (C-8′), 126.5 (C-4′), 127.4 (C-7′), 127.5 (C-3′), 127.8 (C-2′), 128.5 (C-6′), 129.1 (C-4″), 130.1 (C-2″-6″), 131.7 (C-3″-5″), 133.94 (C4a′), 133.99 (C-8a′), 139.2 (C-1′), 142.91 (C-5′), 142.96 (C-1″), 174.9 (C-1); HRMS (ESI) [M+H]+ calcd for C19H17O2 m/z 277.1228, found m/z 277.1226. 7-Phenyl-1H-phenalen-1-one (7). Compound 7e (160.8 mg, 0.6 mmol) was treated with SOCl2 (1.0 mL) and the flask was air-dried after gas evolution. This process was repeated twice (0.2 mL of SOCl2 per addition). After dryness, the resulting product was dissolved in CH2Cl2 (2 mL), slowly treated with AlCl3 (120.9 mg, 0.9 mmol), and then stirred at room temperature for 1 h. Addition of 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ, 136.0 mg, 0.6 mmol) and CH2Cl2 (2.5 mL) followed, and the mixture was refluxed for 2.5 h. The crude was adsorbed on silica gel and then purified by column chromatography (CH2Cl2) to give 7-Phenyl-1H-phenalen-1-one (7): 46 mg (31% yield); yellow solid; mp: 107−108 °C;18 Rf (CH2Cl2) = 0.4; 1H-NMR (C2D6CO) δ 6.67 (1H, d, J = 9.9 Hz, H-2), 7.58 (5H, m, -Ph), 7.67 (1H, dd, J = 6.9 and 8.6 Hz, H-5), 7.81 (1H, d, J = 7.7 Hz, H-8), 7.97 (1H, d, J = 6.9 Hz, H-4), 7.98 (1H, d, J = 9.9 Hz, H-3), 8.08 (1H, dd, J = 1.1 and 8.6 Hz, H-6), 8.57 (1H, d, J = 7.7 Hz, H-9); 13 C NMR (C2D6CO) δ 128.8 (C-5), 129.6 (C-9b), 129.9 (C-3a), 130.1 (C-8 and C-4′), 130.4 (C-3′-5′), 130.52 (C-9a), 130.54 (C-2), 131.0 (C-9), 131.95 (C-6), 131.97 (C-2′-6′), 132.2 (C-6a), 133.4 (C4), 141.2 (C-1′), 143.8 (C-3), 149.2 (C-7), 186.0 (C-1); HRMS (ESI) [M+H]+ calcd for C19H13O m/z 257.0961, found m/z 257.0965.

132.8 (C-4a), 142.3 (C-1); HRMS (ESI) [M+H]+ calcd for C10H9BrN m/z 221.9918, found m/z 221.9920. 1,5-Dibromonaphthalene (7a). In a 100 mL plastic beaker were stirred at 45 °C 5-bromonaphthalen-1-amine (2.0013 g, 9.0 mmol) and HBF4 [30% w/w, 35 mL, prepared by slow addition (1 h) of H3BO3 (37.2 g) to a cooled (0 °C) HF solution (136.1 g, 40% w/v)] until a fine dispersion formed. The suspension was then cooled at −10 °C for 25 min and a slow addition of NaNO2 (940.7 mg, 13.2 mmol, 20 min) followed. The diazotization reaction was led for another 40 min under stirring at −10 °C after which a CuBr/HBr solution (2.0023 g of CuBr in 20 mL HBr 40% w/v) was slowly incorporated (reaction turns dark) and further stirred for 40 min. The reaction was then left at r.t. for 85 min and finally heated at 45 °C for 40 min. The crude was partitioned between AcOEt (175 mL) and H2O (350 mL) and purified by column chromatography (n-hexane) to furnish 1,5dibromonaphthalene (7a):21 1.1025 g (42% yield); white solid; mp: 128−129 °C; Rf (n-hexane) = 0.7; 1H-NMR (C2D6CO) δ 7.59 (2H, dd, J = 7.5 and 8.4 Hz, H-3−7), 7.98 (2H, d, J = 7.5 Hz, H-2−6), 8.28 (2H, d, J = 8.4 Hz, H-4−8); 13C NMR (C2D6CO) δ 124.3 (C-1−5), 128.9 (C-4−8), 129.9 (C-3−7), 133.1 (C-2−6), 134.7 (C-4a-8a); HRMS (GC-EI) [M]+ calcd for C10H6Br2 m/z 283.8836, found m/z 283.8847. 1-Bromo-5-phenylnaphthalene (7b). In a round bottomed flask were mixed 1,5-dibromonaphtalene (875.5 mg, 3.1 mmol), phenylboronic acid (199 mg, 1.6 mmol) and bis(triphenylphosphine)palladium(II) dichloride (54.9 mg, 0.08 mmol), aqueous sodium carbonate (2M, 9 mL), and dioxane (22 mL). The mixture was refluxed under argon for 2.5 h. Partition of the crude reaction between AcOEt (2 × 50 mL)/H2O (100 mL) followed by column chromatography (n-hexane) afforded 1-bromo-5-phenylnaphthalene (7b): 253 mg (55% yield); pale yellow oil; Rf (n-hexane) = 0.5; 1HNMR (C2D6CO) δ 7.39 (1H, dd, J = 7.3 and 8.6, H-3), 7.48 (3H, m, H-4′ and H-2′-6′), 7.54 (3H, m, H-6 and H-3′-5′), 7.73 (1H, dd, J = 7.1 and 8.6 Hz, H-7), 7.86 (1H, dt, J =1.1 and 8.6 Hz, H-4), 7.89 (1H, dd, J = 1.1 and 7.3 Hz, H-1), 8.28 (1H, dt, J = 1.1 and 8.6 Hz, H-8); 13 C NMR (C2D6CO) δ 124.4 (C-1), 127.9 (C-4), 128.2 (C-8), 128.4 (C-3), 128.9 (C-7), 129.4 (C-2′-6′), 129.8 (C-6), 130.3 (C-3′-5′), 131.7 (C-4′), 132.0 (C-2), 133.9 (C-8a′), 134.7 (C-4a′), 141.9 (C-1′), 142.7 (C-5); HRMS (ESI) [M+H]+ calcd for C16H12Br m/z 283.0122, found m/z 283.0121. Ethyl (E)-3-(5-Phenylnaphthalen-1-yl)acrylate (7c). Compound 7b (397.9 mg, 1.6 mmol) was mixed with bis(triphenylphosphine)palladium(II) dichloride (51.8 mg, 0.07 mmol), dioxane (17 mL), and a solution of sodium carbonate (2M, 2 mL). Then an excess of ethyl acrylate was added (1.0 mL, 9.1 mmol) and the mixture was refluxed under argon for 24 h. The mixture was partitioned with AcOEt (2 × 50 mL)/H2O (100 mL) followed by dryness of the organic phase. Adsorption of the crude on silica gel followed by column chromatography (n-hexane until the starting material was separated then n-hexane/CH2Cl2 3:1) afforded ethyl (E)-3-(5-phenylnaphthalen-1-yl)acrylate (7c): 300.0 mg (71% yield); pale yellow oil; Rf (nhexane/CH2Cl2 2:1) = 0.4; 1H-NMR (C2D6CO) δ 1.34 (3H, t, J = 7.1 Hz, H-2-Et), 4.28 (2H, q, J = 7.1 Hz, H-1-Et), 6.62 (1H, d, J = 15.7 Hz, H-2), 7.51 (7H, m, -Ph, H-3′ and H-8′), 7.69 (1H, dd, J = 7.1 and 8.4 Hz, H-7′), 7.92 (2H, d, J = 7.9 Hz, H-2′ and H-4′), 8.26 (1H, d, J = 8.4 Hz, H-6′), 8.57 (1H, d, J = 15.7 Hz, H-3); 13C NMR (C2D6CO) δ 15.6 (2-OEt), 61.9 (1-OEt), 123.2 (C-2), 124.6 (C-6′), 127.0 (C-2′), 127.6 (C-4″), 128.3 (C-7′), 129.1 (C-8′), 129.3 (C-3′), 130.0 (C-4′), 130.2 (C-2″-6″), 131.8 (C-3″-5″), 133.6 (C-8a′), 133.7 (C-4a′), 133.9 (C-5′), 142.4 (C-1′), 142.9 (C-1″), 143.1 (C-3), 167.8 (C-1); HRMS (ESI) [M+H]+ calcd for C21H19O2 m/z 303.13850, found m/z 303.13855. Ethyl 3-(5-Phenylnaphthalen-1-yl)propanoate (7d). A solution of 7c (237.4 mg, 0.8 mmol) in acetone (7 mL) was treated with 23.8 mg of palladium on activated charcoal catalyst (10% Pd basis). The mixture was stirred under hydrogen atmosphere (balloon with a needle in contact with the solution) at room temperature for 4 h. The crude was filtered through a pad of silica-gel (1 g) employing CH2Cl2. The solvent was evaporated to furnish ethyl 3-(5-phenylnaphthalen-1yl)propanoate (7d): 236.3 mg (99% yield); pale yellow oil; Rf (n-

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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.6b02985. 1

H and 13C NMR spectra for all products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Felipe Otálvaro: 0000-0002-3905-4650 Notes

The authors declare no competing financial interest. 3878


Note


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ACKNOWLEDGMENTS We thank Emily Wheeler for editorial assistance. This research was financially supported by Universidad de Antioquia, COLCIENCIAS (grant 111565842551) and the Max-PlanckInstitut für Chemische Ö kologie.

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REFERENCES

(1) Silverman, R. B.; Holladay, M. W.; Lead discovery and lead modification. The organic chemistry of drug design and drug action, Third ed.; Elsevier: USA, 2014; pp 19−122. (2) Altmann, K. -H. Preclinical pharmacology and structure-activity studies of epothilones. In The epothilones: an outstanding family of anti-tumor agents. Progress in the chemistry of organic natural products; Kinghorn, A. D., Falk, H., Kobayashi, J., Eds.; SpringerWienNewYork: Germany, 2009; Vol. 90, pp 157−220. (3) See for example: (a) Gong, B.; Hong, F.; Kohm, C.; Jenkins, S.; Tulinsky, J.; Bhatt, R.; de Vries, P.; Singer, J. W.; Klein, P. Bioorg. Med. Chem. Lett. 2004, 14, 2303−2308. (b) Ranjith, P. K.; Rajeesh, P.; Haridas, K. R.; Susanta, N. K.; Guru Row, T. N.; Rishikesan, R.; Kumari, N. S. Bioorg. Med. Chem. Lett. 2013, 23, 5228−5234. (c) Chen, Y.; Li, Y.; Pan, L.; Liu, J.; Wan, Y.; Chen, W.; Xiong, L.; Yang, N.; Song, H.; Li, Z. Bioorg. Med. Chem. 2014, 22, 6366−6379. (4) Gutiérrez, D.; Flores, N.; Abad-Grillo, T.; McNaughton-Smith, G. Exp. Parasitol. 2013, 135, 456−458. (5) Rosquete, L. I.; Cabrera-Serra, M. G.; Piñero, J. E.; MartínRodriguez, P.; Fernández-Perez, L.; Luis, J. G.; McNaughton-Smith, G.; Abad-Grillo, T. Bioorg. Med. Chem. 2010, 18, 4530−4534. (6) Cooke, R.; Dagley, I. Aust. J. Chem. 1978, 31, 193−197. (7) Cano, M.; Rojas, C.; Hidalgo, W.; Sáez, J.; Gil, J.; Schneider, B.; Otálvaro, F. Tetrahedron Lett. 2013, 54, 351−354. (8) Hidalgo, W.; Duque, L.; Saez, J.; Arango, R.; Gil, J.; Rojano, B.; Schneider, B.; Otálvaro, F. J. Agric. Food Chem. 2009, 57, 7417−7421. (9) Koelsch, C.; Anthes, J. J. Org. Chem. 1941, 06, 558−565. (10) Otálvaro, F.; Quiñones, W.; Echeverri, F.; Schneider, B. J. Labelled Compd. Radiopharm. 2004, 47, 147−159. (11) Asscher, Y.; Agranat, I. J. Org. Chem. 1980, 45, 3364−3366. (12) Brkljaca, R.; White, J. M.; Urban, S. J. Nat. Prod. 2015, 78, 1600−1608. The structure of fuliginone has been revised, see Brkljaca, R.; Schneider, B.; Hidalgo, W.; Otálvaro, F.; Ospina, F.; Lee, S.; Hoshino, M.; Fujita, M.; Urban, S. Molecules 2017, 22, 211. (13) Imanzadeh, G. K.; Zamanloo, M. R.; Eskandari, H.; Shayesteh, K. J. Chem. Res. 2006, 2006, 151−153. (14) Eistert, B.; Eifler, W.; Göth, H. Chem. Ber. 1968, 101, 2162− 2175. (15) Luis, J. G.; Fletcher, W. Q.; Echeverri, F.; Grillo, T. A. Tetrahedron 1994, 50, 10963−10970. (16) Pfeiffer, V. P.; Jenning, W.; Stöcker, H. Justus Liebigs Ann. Chem. 1949, 563, 73−85. (17) Nonaka, T.; Asai, M. Bull. Chem. Soc. Jpn. 1978, 51, 2976−2982. (18) Solodar, S. L.; Vinogradov, L. M. Zh. Org. Khim. 1980, 16, 2120−2123. (19) Ospina, F.; Hidalgo, W.; Cano, M.; Schneider, B.; Otálvaro, F. J. Org. Chem. 2016, 81, 1256−1262. (20) Nanclares, J.; Gil, J.; Rojano, B.; Sáez, J.; Schneider, B.; Otálvaro, F. Tetrahedron Lett. 2008, 49, 3844−3847. (21) Cakmak, O.; Demirtas, I.; Balaydin, H. T. Tetrahedron 2002, 58, 5603−5609. (22) Pinto-Bazurco Mendieta, M. A. E.; Jagusch, C.; Hille, U. E.; Müller-Vieira, U.; Schmidt, D.; Hansen, K.; Hartmann, R. W.; Negri, M. Bioorg. Med. Chem. Lett. 2008, 18, 267−273. (23) Cassirame, B.; Condon, S.; Pichon, C. J. Mol. Catal. A: Chem. 2016, 425, 94−102.

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Synthesis of Positional Isomeric Phenylphenalenones - The Journal of

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