Note pubs.acs.org/joc
Synthetic Method to Form 2,2′-Bis(naphthoquinone) Compounds Vishwajeet Jha,† Navneet Goyal,† Cheryl K. Stevens,‡ Edwin Stevens,‡ and Jayalakshmi Sridhar*,† †
Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, Louisiana 70125, United States Department of Chemistry, Western Kentucky University, Bowling Green, Kentucky 42101, United States
‡
S Supporting Information *
ABSTRACT: We have discovered a transition-metal-free approach to the synthesis of 2,2′-bis(naphthoquinones) using a Diels−Alder reaction of conjugated ketene silyl acetals with benzoquinone. Its monomer analogue can also be synthesized by simply increasing the equivalents of benzoquinone.
T
oxidative biaryl coupling of 1-naphthols to 2,2′-bisnaphthols, followed by subsequent oxidation to 2,2′-bisnaphthoquinones.9 Our interest in the design and development of new pharmacotherapeutics as kinase inhibitors prompted an investigation into the synthesis of napthoquinones and anthraquinones, which revealed a series of quinone analogues with an excellent growth inhibition potency for refractive breast tumors and showed a high selectivity for inhibition of the PIM kinases.10 We have previously reported the synthesis of a quinone derivative (compound 1, Figure 1) using the Diels−Alder reaction, which showed a very promising therapeutic potential for cancer in in vitro studies (Scheme 1).11 Docking studies of compound 1 revealed that the methyl side chain was placed in a hydrophobic environment and that an increase in the length and branching of the side chain at C-7 could further enhance its activity. Scheme 1 was employed for the preparation of the designed compounds. The synthetic strategy started with the commercially available 2-heptanone 9a, which upon the Horner− Wadsworth−Emmons (HWE) olefination gave olefin 10a in 87% yield with a Z/E ratio of 1:4 (Scheme 2).12 Olefin 10a was treated with LDA and then trapped with TMSCl to give diene 11a. Diene 11a was then subjected to the Diels−Alder reaction with benzoquinone13 as a dienophile and afforded ketal 12a, and the subsequent cleavage of ketal 12a with 1 N HCl should have yielded product 14a. The 1H NMR of this product did not correspond to the structure of 14a, wherein one proton belonging to the quinone ring was missing (Figure S1, Supporting Information). The 13C and DEPT NMR were not conclusive. The crystallized product was subjected to X-ray crystallographic analysis, which clearly established the product to be the dimerized quinone derivative 13a instead of its monomer analogue 14a (Figure S2, Supporting Information). The overall yield of
he pharmacology of quinone molecules has generated significant interest over the past few years as they serve as electron acceptors in electron transport chains that are essential to nearly every living organism.1 Many of these compounds have been reported in the elucidation of biological mechanisms and help in the development of the lead compounds for different therapeutic agents. Quinone moieties have been found in several natural products2 including sesquiterpenes,3 kinamycins,4 terphenylquinones,5 etc. with several of them showing biological or pharmacological activity. They are key structural components of numerous therapeutic agents impacting many disease conditions, viz antimicrobial, antiparasitic, antitumor, inhibition of PGE2 biosynthesis, and anticardiovascular diseases.6 Additionally, many natural and artificial coloring substances (dyes and pigments) are quinone derivatives. Among naturally occurring quinones,7a 2,2′-bisnaphthoquinones, including bilawsone (2),7b 3,3′-bijuglone (3),7c,d biramentaceone (4),7e 3,3′-biplumbagin (5),7f,g mamegakinone (6),7h etc., were isolated from various plant species and found to exhibit different biological activities (Figure 1). The synthesis of these bisquinone molecules has been a challenge.8a−k Tanoue et al. have reported the synthesis using oxidation of alkoxy-naphthols with AgO and 40% HNO3,8h whereas Takeya et al. have reported the synthesis using oxidative dimerization of 1-naphthols with SnCl4/O2.8i Recently, Tsubaki et al. have shown its synthesis using the Stille-type reaction with vinylstannanes.8k (For the schematic representation of literature precedence of bis(naphthoquinone) syntheses, see Scheme S1 in the Supporting Information). However, all of these reports suffer from one or more drawbacks such as the use of expensive reagents, which require specially modified starting materials (substituted naphthalene derivatives and substituted naphthoquinones), the use of toxic heavy metal catalysts (like Pd, Pb, and Sn catalysts), etc. In addition, they may not always be suitable for large-scale synthesis. The biosynthetic pathway to these classes of compounds involves © 2017 American Chemical Society
Received: October 2, 2017 Published: November 7, 2017 13686
DOI: 10.1021/acs.joc.7b02501 J. Org. Chem. 2017, 82, 13686−13692
Note
The Journal of Organic Chemistry
Figure 1. Structures of quinone and bis(naphthoquinone) derivatives.
Scheme 1. Synthesis of Compound 1 Using a Diels−Alder Reaction
Scheme 2. Synthetic Route for the Formation of Bis(napthoquinones)
the dimer product in this reaction was 67%. Changes to the reaction conditions such as the use of different solvents and increasing/decreasing the reaction time and the concentration of HCl only lead to the formation of the dimerized product (Table 1). The scope of this reaction was examined using various ketones bearing different side chains (Table 2). It was observed that the reaction sequence displayed a wide substrate scope and was compatible with varying side chains that were short, long, or branched. Good yields (60−70%) were obtained for all of the substrates (Table 2). However, in the case of 13b and 13d, we did observe the formation of a monomer analogue as a minor product (6% yield for 14b and 8% yield for 14d). The dimerization of compound 1 was attempted by changing the reaction conditions without any success. Under all of the attempted variations in the reaction conditions, only the monomer derivative was obtained.
We believe that the Diels−Alder reaction between compound 11 and 1,4-benzoquinone takes place in the traditional manner to yield cyclohexene product 12. The addition of 1 N HCl facilitates the cleavage of the ketal and subsequent enol intermediate I (Scheme 3). Aromatization of the cyclohexadiene ring in intermediate I requires the use of oxidizing reagents. It has been shown that the residual excess of benzoquinone present in the reaction medium acts as the oxidizing agent, leading to the formation of intermediate II (Scheme 3, step 1). Intermediate II (NQ) can also act as an auto-oxidizing agent due to the presence of a quinone ring in the structure, and this intermediate can participate in the auto-oxidation of intermediate I to intermediate II (Scheme 3, step 2), resulting in the formation of hydroquinone intermediate III (HNQ). Any protonation of the carbonyls of the quinone will preferably happen on the carbonyl that is on the opposite side of the hydroxyl group of the adjacent ring to give intermediate IV. 13687
DOI: 10.1021/acs.joc.7b02501 J. Org. Chem. 2017, 82, 13686−13692
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The Journal of Organic Chemistry Table 1. Modifications to the Reaction Conditions for the Diels−Alder Reaction and Subsequent Treatment with HCl entry
solvent
reaction time (h)
[hydrochloric acid]
benzoquinone (equiv)
yield of 13a (%)
yield of 14a (%)
1 2 3 4 5 6 7 8 9 10
CH3OH CH2Cl2 CH3OH CH3OH CH3OH CH3OH CH3OH CH3OH CH3OH CH3OH
3 3 3 3 3 1 16 3 3 3
1N 1N 1N 1N 1N 1N 1N 2N neat 1N
1 1 1.25 1.5 2 1.5 1.5 1.5 1.5 5
47 21 56 67 65 64 59 62 34 16
0 0 0 0 0 0 0 0 0 40
Table 2. Substrate Scope of the Dimerization Reaction
equivalents of benzoquinone, the yield of the dimer also increases and finally plateaus at 1.5 equiv of benzoquinone (Table 1). A shortage of benzoquinone might lead to the formed intermediate II to also act as an auto-oxidizing agent. To test this thought, the same reaction was performed with a large excess (5 equiv) of benzoquinone (Table 1, entry 10). When we used a large excess of benzoquinone (5 equiv), most of intermediate I is converted to intermediate II in step 1 and very little intermediate I is present to undergo oxidation with intermediate II in step 2; hence, we get monomer as a major product, which supports the proposed mechanism (Scheme 4). In conclusion, a synthetic method has been discovered for the synthesis of 2,2′-bis(naphthoquinones) using a Diels−Alder reaction of conjugated ketene silyl acetals derived from
This is due to the carbonyl group ortho to the phenolic group having a hydrogen bond with the hydroxyl group. A Michael addition on the protonated intermediate IV by intermediate III will lead to the formation of intermediate VI. A further oxidation of this intermediate with benzoquinone yields the dimerized bisnaphthoquinone product. The plausible mechanism for the synthesis of this dimer is shown in Scheme 3. The proposed mechanism is greatly dependent on the oxidizing property of benzoquinone at multiple points and on the fact that the unreacted benzoquinone present in the reaction medium plays the key role in product formation. It not only acts as a dienophile for the Diels−Alder reaction but also influences the oxidation−reduction process, which could be confirmed by the fact that, by increasing the number of 13688
DOI: 10.1021/acs.joc.7b02501 J. Org. Chem. 2017, 82, 13686−13692
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The Journal of Organic Chemistry Scheme 3. Proposed Mechanism for the Formation of Dimer Bis(naphthoquinone)
Scheme 4. Reaction Using a Large Excess (5 Equiv) of Benzoquinone
All NMR spectra were recorded on an Agilent 400 MHz unit using TMS as an internal solvent reference. High-resolution MS was performed at the University of Texas at Austin on the Agilent 6530 Accurate-Mass Q-TOF LC/MS and Waters Micromass AutoSpec Ultima GC/MS units, giving high-resolution ESI and CI. Aluminumbacked 60 F254 silica plates were used for thin-layer chromatography. Flash chromatography was performed using the Teledyne Isco CombiFlash automated column machine. Melting points were obtained using a Mel-Temp melting point apparatus. The X-ray intensity data were measured with Mo Kα radiation using a Bruker APEX II single-crystal X-ray diffractometer at the Western Kentucky University, Bowling Green, KY. General Procedure for Horner−Wadsworth−Emmons Olefination. To the solution of triethylphosphonoacetate (2.2 mL, 11.01 mmol) and NaH (0.264 g, 11.01 mmol) in tetrahydrofuran (THF) were added ketones (7 mmol) dissolved in THF, and the whole mixture was stirred at 0 °C for 12 h. It was then quenched with an
commercially available ketones and benzoquinone dienophile, which underwent dimerization upon deprotection of the phenolic −OH to give the 2,2′-bis(naphthoquinones) analogues. The bioactivity of these compounds is being investigated.
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EXPERIMENTAL SECTION
All of the reactions were performed in flame-dried glassware. Liquids and solutions were transferred using syringes. Air- and moisturesensitive materials were stored, protected, and handled under an atmosphere of argon, with appropriate glassware. Technical grade solvents for extraction and chromatography (cyclohexane, dichloromethane, and ethyl acetate) were used without purification. All reagents were purchased from standard suppliers (Sigma-Aldrich, Alfa Aesar, and Fisher Scientific). The starting materials, if commercial, were purchased and used as such, provided that adequate checks (NMR) had confirmed the claimed purity. 13689
DOI: 10.1021/acs.joc.7b02501 J. Org. Chem. 2017, 82, 13686−13692
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The Journal of Organic Chemistry aqueous ammonium chloride solution (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. It was then purified by silica gel column chromatography using n-hexane/ethyl acetate (94:06) as an eluent to afford the olefination products (10a−e) in a Z/E ratio of 2:8 (determined by 1H NMR). Ethyl (E)-3-Methyloct-2-enoate (10a). Compound 10a was prepared from compound 9a using the general procedure. The reaction was performed on a 7 mmol scale, and we got ethyl (E)-3methyloct-2-enoate (10a) as a colorless liquid (1.121 g, 87% yield). Rf: 0.30 (EtOAc/hexane 05:95). 1H NMR (CDCl3) (Z/E 2:8): δ 5.65 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.60 (t, J = 7.8 Hz, 0.4H), 2.14−2.09 (m, 4H), 1.87 (s, 0.6H), 1.50−1.43 (m, 2H), 1.32−1.25 (m, 7H), 0.88 (t, J = 6.6 Hz, 3H) ppm. 13C{1H} NMR (CDCl3) (Z/E 2:8): δ 166.9, 166.4, 160.8, 160.3, 115.9, 115.3, 59.4, 40.9, 33.3, 31.8, 31.3, 27.9, 27.0, 25.1, 22.5, 22.4, 18.7, 14.3, 13.9 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H21O2, 185.1536; found, 185.1534. Ethyl (E)-3-Methylpent-2-enoate14 (10b). Compound 10b was prepared from compound 9b using the general procedure. The reaction was performed on a 4 mmol scale, and we got ethyl (E)-3methylpent-2-enoate (10b) as a colorless liquid (0.460 g, 81% yield). Rf: 0.30 (EtOAc/hexane 05:95). 1H NMR (CDCl3) (Z/E 2:8): δ 5.65 (s, 0.8H), 5.62 (s, 0.2H), 4.17−4.12 (m, 2H), 2.62 (q, J = 7.5 Hz, 0.4H), 2.18−2.13 (m, 4H), 1.87 (s, 0.6H), 1.29−1.25 (m, 3H), 1.08− 1.04 (m, 3H) ppm. 13C{1H} NMR (CDCl3) (Z/E 2:8): δ 166.9, 166.3, 162.0, 161.5, 115.4, 114.4, 59.4, 33.7, 26.5, 24.6, 18.7, 14.3, 12.5, 11.9 ppm. Ethyl (E)-3,6-Dimethylhept-2-enoate (10c). Compound 10c was prepared from compound 9c using the general procedure. The reaction was performed on a 4 mmol scale, and we got ethyl (E)-3,6dimethylhept-2-enoate (10c) as a colorless liquid (0.565 g, 83% yield). Rf: 0.30 (EtOAc/hexane 05:95). 1H NMR (CDCl3) (Z/E 2:8): δ 5.64 (s, 0.8H), 5.61 (s, 0.2H), 4.11 (q, J = 7.2 Hz, 2H), 2.61−2.57 (m, 0.4H), 2.13−2.08 (m, 4H), 1.85 (s, 0.6H), 1.57−1.48 (m, 1H), 1.35− 1.29 (m, 2H), 1.26−1.23 (m, 3H), 0.91−0.86 (m, 6H) ppm. 13C{1H} NMR (CDCl3) (Z/E 2:8): δ 166.8, 166.3, 160.9, 160.5, 115.7, 115.2, 59.3, 38.8, 37.2, 36.5, 31.4, 28.4, 27.6, 25.0, 22.4, 18.7, 14.3, 14.1 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H21O2, 185.1542; found, 185.1537. Ethyl (E)-3,5-Dimethylhex-2-enoate (10d). Compound 10d was prepared from compound 9d using the general procedure. The reaction was performed on a 4 mmol scale, and we got ethyl (E)-3,5dimethylhex-2-enoate (10d) as a colorless liquid (0.603 g, 82% yield). Rf: 0.30 (EtOAc/hexane 05:95). 1H NMR (CDCl3) (Z/E 2:8): δ 5.68 (s, 0.2H), 5.61 (s, 0.8H), 4.14−4.09 (m, 2H), 2.54 (d, J = 7.4 Hz, 0.4H), 2.11 (s, 2.4H), 1.97 (d, J = 7.0 Hz, 1.6H), 1.85−1.82 (m, 1.6H), 1.27−1.23 (m, 3H), 0.89−0.85 (m, 6H) ppm. 13C{1H} NMR (CDCl3) (Z/E 2:8): δ 166.7, 166.4, 159.4, 159.1, 117.0, 116.6, 59.3, 50.5, 41.6, 27.3, 26.1, 25.4, 22.3, 18.5, 14.2, 12.5 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H19O2, 171.1380; found, 171.1380. Ethyl (E)-3-Methylnon-2-enoate (10e). Compound 10e was prepared from compound 9e using the general procedure. The reaction was performed on a 3 mmol scale, and we got ethyl (E)-3methylpent-2-enoate (10b) as a colorless liquid (0.504 g, 85% yield). Rf: 0.30 (EtOAc/hexane 05:95). 1H NMR (CDCl3) (Z/E 2:8): δ 5.65 (s, 1H), 4.16−4.11 (m, 2H), 2.60 (t, J = 7.7 Hz, 0.4H), 2.14−2.10 (m, 4H), 1.87 (s, 0.6H), 1.47−1.44 (m, 2H), 1.28−1.25 (m, 9H), 0.89−0.86 (m, 3H) ppm. 13C{1H} NMR (CDCl3) (Z/E 2:8): δ 166.9, 166.4, 160.8, 160.4, 115.9, 115.3, 59.4, 40.9, 33.4, 31.7, 31.6, 29.4, 28.8, 28.2, 27.3, 25.1, 22.6, 22.5, 18.7, 14.3, 14.0 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H23O2, 199.1693; found, 199.1690. General Procedure for the Diels−Alder Reaction. 8,8′Dihydroxy-6,6′-dipentyl-[2,2′-binaphthalene]-1,1′,4,4′-tetraone (13a). A mixture of ethyl 3-methyloct-2-enoate (10a) (0.185 g, 1 mmol) in THF (3 mL) was slowly added dropwise to a 2.0 M solution of lithium diisopropylamide (0.75 mL, 1.5 mmol) in THF cooled to −78 °C under an argon atmosphere. The temperature was allowed to gradually rise to −35 °C in 2 h. After 2 h, chlorotrimethylsilane (0.2 mL, 1.5 mmol) was slowly added, and the mixture was
allowed to stir for 15 min. The cooling bath was removed, and the reaction was allowed to stir for an additional 45 min at room temperature, after which the THF was removed under reduced pressure. The resulting yellow oil was dissolved in hexane, and the lithium salt was removed by filtration. The filtrate was concentrated to afford a bright yellow oil of (E)-((1-ethoxy-3-methyleneoct-1-en-1yl)oxy)trimethylsilane as a crude product, which was used as such for the next step without further purification. To a solution of the above product in dichloromethane (6 mL) at 0 °C was added 1,4-benzoquinone (0.162 g, 1.5 mmol). The reaction mixture was allowed to stir under a nitrogen atmosphere for 16 h. The dichloromethane was evaporated under reduced pressure, and the crude solid was dissolved in methanol (6 mL). The solution was cooled to 0 °C, and a 1 N HCl (4 mL) solution was added. The reaction mixture was allowed to stir for an additional 3 h. After 3 h, the crude mixture was concentrated, extracted with dichloromethane, washed with water, dried over sodium sulfate, and concentrated to afford a solid. Purification of the solid via flash column chromatography using n-hexane/ethyl acetate (95:05) afforded 8,8′-dihydroxy6,6′-dipentyl-[2,2′-binaphthalene]-1,1′,4,4′-tetraone (13a) as a bright orange solid (0.163 g, 67% yield). Rf: 0.25 (EtOAc/hexane 05:95). 1H NMR (CDCl3): δ 11.73 (s, 2H, ArOH), 7.51 (s, 2H, benzene H), 7.12 (s, 2H, benzene H), 6.98 (s, 2H, quinone H), 2.69 (t, J = 7.3 Hz, 4H, CH2), 1.67−1.64 (m, 4H), 1.33 (m, 8H), 0.90 (t, J = 6.3 Hz, 6H, CH3) ppm. 13C{1H} NMR (CDCl3): δ 187.1, 183.6, 162.2, 154.0, 143.2, 138.5, 131.6, 123.9, 120.1, 112.9, 36.4, 31.3, 30.1, 22.4, 13.9 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H31O6, 487.2113; found, 487.2115. Mp 172−174 °C. 6,6′-Diethyl-8,8′-dihydroxy-[2,2′-binaphthalene]-1,1′,4,4′-tetraone (13b). Compound 13b was prepared from compound 10b using the same procedure as reported for 13a. The reaction was performed on a 1 mmol scale, and we got 6,6′-diethyl-8,8′-dihydroxy[2,2′-binaphthalene]-1,1′,4,4′-tetraone (13b) as an orange solid (0.120 g, 60% yield). Rf: 0.25 (EtOAc/hexane 05:95). 1H NMR (CDCl3): δ 11.74 (s, 2H, ArOH), 7.54 (s, 2H, benzene H), 7.15 (s, 2H, benzene H), 6.99 (s, 2H, quinone H), 2.75 (q, J = 7.3 Hz, 4H, CH2), 1.30 (t, J = 7.6 Hz, 6H, CH3) ppm. 13C{1H} NMR (CDCl3): δ 187.1, 183.5, 162.3, 155.2, 143.2, 138.5, 131.7, 123.4, 119.7, 112.9, 29.4, 14.5 ppm. HRMS (ESI-TOF): m/z [M + Na]+ calcd for C24H18O6Na, 425.1003; found, 425.0096. Mp 208−210 °C. 8,8′-Dihydroxy-6,6′-diisopentyl-[2,2′-binaphthalene]-1,1′,4,4′tetraone (13c). Compound 13c was prepared from compound 10c using the same procedure as reported for 13a. The reaction was performed on a 1 mmol scale, and we got 8,8′-dihydroxy-6,6′-diisopentyl[2,2′-binaphthalene]-1,1′,4,4′-tetraone (13c) as an orange solid (0.148 g, 61% yield). Rf: 0.25 (EtOAc/hexane 05:95). 1H NMR (CDCl3): δ 11.74 (s, 2H, ArOH), 7.53 (s, 2H, benzene H), 7.14 (s, 2H, benzene H), 6.99 (s, 2H, quinone H), 2.71 (t, J = 7.3 Hz, 4H, CH2), 1.65−1.60 (m, 2H), 1.56−1.52 (m, 4H), 0.96 (d, J = 6.8 Hz, 12H, CH3) ppm. 13 C{1H} NMR (CDCl3): δ 187.0, 183.5, 162.2, 154.2, 143.2, 138.5, 131.6, 123.9, 120.1, 112.8, 39.6, 34.3, 27.7, 22.4 ppm. HRMS (CImagnetic sector): m/z [M]+ calcd for C30H30O6, 486.2042; found, 486.2036. Mp 204−206 °C. 8,8′-Dihydroxy-6,6′-diisobutyl-[2,2′-binaphthalene]-1,1′,4,4′-tetraone (13d). Compound 13d was prepared from compound 10d using the same procedure as reported for 13a. The reaction was performed on a 1 mmol scale, and we got 8,8′-dihydroxy-6,6′-diisobutyl[2,2′-binaphthalene]-1,1′,4,4′-tetraone (13d) as an orange solid (0.161 g, 70% yield). Rf: 0.25 (EtOAc/hexane 05:95). 1H NMR (CDCl3): δ 11.74 (s, 2H, ArOH), 7.49 (s, 2H, benzene H), 7.11 (s, 2H, benzene H), 6.99 (s, 2H, quinone H), 2.58 (d, J = 7.5 Hz, 4H, CH2), 2.01−1.94 (m, 2H), 0.95 (d, J = 6.7 Hz, 12H, CH3) ppm. 13C{1H} NMR (CDCl3): δ 187.1, 183.6, 162.0, 152.9, 143.2, 138.5, 131.5, 124.7, 120.7, 112.9, 45.7, 29.8, 22.3 ppm. HRMS (CI-magnetic sector) m/z [M]+ calcd for C28H26O6, 458.1729; found, 458.1725. Mp 212−214 °C. 6,6′-Dihexyl-8,8′-dihydroxy-[2,2′-binaphthalene]-1,1′,4,4′-tetraone (13e). Compound 13e was prepared from compound 10e using the same procedure as reported for 13a. The reaction was performed on a 1 mmol scale, and we got 6,6′-dihexyl-8,8′-dihydroxy-[2,2′binaphthalene]-1,1′,4,4′-tetraone (13e) as an orange solid (0.178 g, 13690
DOI: 10.1021/acs.joc.7b02501 J. Org. Chem. 2017, 82, 13686−13692
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The Journal of Organic Chemistry 69% yield). Rf: 0.25 (EtOAc/hexane 05:95). 1H NMR (CDCl3): δ 11.74 (s, 2H, ArOH), 7.52 (s, 2H, benzene H), 7.13 (s, 2H, benzene H), 6.99 (s, 2H, quinone H), 2.70 (t, J = 7.6 Hz, 4H, CH2), 1.69−1.65 (m, 4H), 1.32 (m, 12H), 0.89 (t, J = 6.5 Hz, 6H, CH3) ppm. 13C{1H} NMR (CDCl3): δ 187.1, 183.6, 162.2, 154.0, 143.2, 138.5, 131.6, 123.9, 120.1, 112.8, 36.4, 31.6, 30.4, 28.8, 22.5, 14.0 ppm. HRMS (CI-magnetic sector) m/z [M]+ calcd for C32H34O6, 514.2355; found, 514.2370. Mp 168−170 °C. 5-Hydroxy-7-pentylnaphthalene-1,4-dione (14a). Compound 14a was prepared using the same procedure as reported for 13a using 5 equiv of 1,4-benzoquinone. The reaction was performed on a 1 mmol scale, and we got 5-hydroxy-7-pentylnaphthalene-1,4-dione (14a) as an orange solid (0.098 g, 40% yield). Rf: 0.30 (EtOAc/hexane 05:95). 1H NMR (CDCl3): δ 11.89 (s, 1H), 7.47 (s, 1H), 7.10 (s, 1H), 6.93 (s, 2H), 2.68 (t, J = 7.6 Hz, 2H), 1.65 (m, 2 H), 1.34−1.26 (m, 4H), 0.90 (t, J = 7.1 Hz, 3 H) ppm. 13C{1H} NMR (CDCl3): δ 189.7, 184.7, 161.7, 153.5, 139.4, 138.8, 131.5, 123.6, 119.9, 113.1, 36.4, 31.3, 30.2, 22.4, 13.9 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H17O3, 245.1168; found, 245.1172. Mp 84−86 °C. 7-Ethyl-5-hydroxynaphthalene-1,4-dione (14b). Compound 14b was prepared using the same procedure as reported for 13a. The reaction was performed on a 1 mmol scale, and we got 7-ethyl-5hydroxynaphthalene-1,4-dione (14b) as an orange solid (0.012 g, 6% yield). Rf: 0.30 (EtOAc/hexane 05:95). 1H NMR (CDCl3): δ 11.89 (s, 1H, ArOH), 7.49 (s, 1H, benzene H), 7.12 (s, 1H, benzene H), 6.93 (s, 2H, quinone H), 2.73 (q, J = 7.7 Hz, 2H, CH2), 1.28 (t, J = 7.5 Hz, 3H, CH3) ppm. 13C{1H} NMR (CDCl3): δ 189.7, 184.6, 161.8, 154.6, 139.4, 138.8, 131.6, 122.9, 119.5, 113.0, 29.4, 14.5 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H11O3, 203.0703; found, 203.0701. Mp 108−110 °C. 5-Hydroxy-7-isobutylnaphthalene-1,4-dione (14d). Compound 14d was prepared using the same procedure as reported for 13a. The reaction was performed on a 1 mmol scale, and we got 5-hydroxy7-isobutylnaphthalene-1,4-dione (14d) as an orange solid (0.019 g, 8% yield). Rf: 0.30 (EtOAc/hexane 05:95). 1H NMR (CDCl3): δ 11.87 (s, 1H, ArOH), 7.42 (s, 1H, benzene H), 7.05 (s, 1H, benzene H), 6.91 (s, 2H, quinone H), 2.54 (d, J = 7.3 Hz, 2H, CH2), 1.98−1.91 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H, CH3) ppm. 13C{1H} NMR (CDCl3): δ 189.7, 184.7, 161.5, 152.3, 139.4, 138.8, 131.4, 124.3, 120.4, 113.1, 45.7, 29.8, 22.3 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H15O3, 231.1021; found, 231.1012. Mp 114−116 °C.
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Louisiana Biomedical Research Network NIH (Grant no. 8P20GM103424). We acknowledge the additional support of the NIH BUILD (Grant no. TL4M118968), the Louisiana Cancer Research Consortium, the Cell and Molecular Biology Core NIH-RCMI (Grant no. 2G12MD007595-06), and the Center for Undergraduate Research at Xavier University of Louisiana. We thank the University of Texas at Austin Mass Spectrometry Facility for the HRMS analysis of our samples.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02501. 1 H and 13C NMR spectra of compounds, ORTEP diagram of 13a, crystallography data for compound 13a, 1H NMR comparison of monomer 1 and dimer 13a, schematic representation of literature precedence of bis(naphthoquinone) syntheses (PDF) Crystal data for 13a (CIF)
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REFERENCES
(1) For a recent review, see: (a) Nowicka, B.; Kruk, J. Biochim. Biophys. Acta, Bioenerg. 2010, 1797, 1587−1605. (b) Yu, J. − S. Synlett 2014, 25, 2377−2378. (c) Chaudhary, A.; Khurana, J. M. Curr. Org. Chem. 2016, 20, 1314−1344. (2) (a) The Chemistry of the Quinonoid Compounds, Parts 1 and 2; Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1988; Vol. 2. (b) Thomson, R. H. Naturally Occuring Quinones IV; Blackie Academic: London, 1997. (3) Marcos, I. S.; Conde, A.; Moro, R. F.; Basabe, P.; Diez, D.; Urones, J. G. Mini-Rev. Org. Chem. 2010, 7, 230−254. (4) (a) Gould, S. J. Chem. Rev. 1997, 97, 2499−2510. (b) MarcoContelles, J.; Molina, M. T. Curr. Org. Chem. 2003, 7, 1433−1442. (c) Kumamoto, T.; Ishikawa, T.; Omura, S. Yuki Gosei Kagaku Kyokaishi 2004, 62, 49−58. (5) (a) Cali, C. S. V.; Tringali, C. Stud. Nat. Prod. Chem. 2003, 29, 263−307. (b) Liu, J.-K. Chem. Rev. 2006, 106, 2209−2223. (6) (a) Kayser, O.; Kiderlen, A. F.; Laatsch, H.; Croft, S. L. Acta Trop. 2000, 77, 307−314. (b) Stagliano, K. W.; Emadi, A.; Lu, Z.; Malinakova, H. C.; Twenter, B.; Yu, M.; Holland, L. E.; Rom, A. M.; Harwood, J. S.; Amin, R.; Johnson, A. A.; Pommier, Y. Bioorg. Med. Chem. 2006, 14, 5651−5665. (c) Liu, H.-W. In Extraction and Isolation of Compounds from Herbal Medicines, in Traditional Herbal Medicine Research Methods; Liu, W. J. H., Ed.; John Wiley & Sons: New York, 2011; p 81. (d) Wellington, K. W. RSC Adv. 2015, 5, 20309−20338. (e) Lapidus, R. G.; Carter-Cooper, B. A.; Sadowska, M.; Choi, E. Y.; Wonodi, O.; Muvarak, N.; Natarajan, K.; Pidugu, L. S.; Jaiswal, A.; Toth, E. A.; Rassool, F. V.; Etemadi, A.; Sausville, E. A.; Baer, M. R.; Emadi, A. Pharmaceuticals 2016, 9, 4−18. (f) de Carvalho da Silva, F.; Ferreira, V. F. Curr. Org. Synth. 2016, 13, 334−371. (7) (a) Thomson, R. H. Naturally Occurring quinones; Chapman & Hall: New York, 1987; Vol. 3. (b) Mehendale, A. R.; Thomson, R. H. Phytochemistry 1975, 14, 801−802. (c) Hirakawa, K.; Ogiue, E.; Motoyoshiya, J.; Yajima, M. Phytochemistry 1986, 25, 1494−1495. (d) Pardhasaradhi, M.; Babu, M. H. Phytochemistry 1978, 17, 2042− 2043. (e) Sankaram, A.V. B.; Reddy, V. V. N.; Sidhu, G. S. Phytochemistry 1981, 20, 1093−1096. (f) Sankaram, A. V. B.; Reddy, V. V. N.; Marthandamurthi, M. Phytochemistry 1986, 25, 2867−2871. (g) Higa, M; Ogihara, K.; Yogi, S. Chem. Pharm. Bull. 2002, 50, 590− 593. (h) Laatsch, H. Liebigs Ann. Chem. 1980, 1980, 1321−1347. (8) (a) Brockmann, H.; Greve, H.; Waldmüller, W. Chem. Ber. 1971, 104, 1436−1454. (b) Maiti, B. C.; Musgrave, O. C.; Skoyles, D. J. Chem. Soc., Chem. Commun. 1976, 244−245. (c) Laatsch, H. Tetrahedron Lett. 1976, 17, 3287−3290. (d) Brockmann, H.; Laatsch, H. Liebigs Ann. Chem. 1983, 1983, 433−447. (e) Schutte, J. H. P.; du Plessis, J. A. K.; Lachmann, G.; Viljoen, A. M.; Nelson, H. D. J. Chem. Soc., Chem. Commun. 1989, 1290−1291. (f) Bringmann, G.; Gotz, R.; Keller, P. A.; Walter, R.; Boyd, M. R.; Lang, F.; Garcia, A.; Walsh, J. J.; Tellitu, I.; Bhaskar, K. V.; Kelly, T. R. J. Org. Chem. 1998, 63, 1090−1097. (g) El-Seedi, H. R.; Yamamura, S.; Nishiyama, S. Tetrahedron 2002, 58, 7485−7489. (h) Tanoue, Y.; Sakata, K.; Hashimoto, M.; Morishita, S.; Hamada, M.; Kai, N.; Nagai, T. Tetrahedron 2002, 58, 99−104. (i) Takeya, T.; Doi, H.; Ogata, T.; Okamoto, I.; Kotani, E. Tetrahedron 2004, 60, 9049−9060. (j) Maiti, B. C.; Musgrave, O. C.; Skoyles, D. Tetrahedron 2005, 61, 6568−6574. (k) Azuma, S.; Nishio, K.; Kubo, K.; Sasamori, T.; Tokitoh, N.; Kuramochi, K.; Tsubaki, K. J. Org. Chem. 2012, 77, 4812−4820. (9) (a) Whiting, D. A. Phenols in comprehensive organic chemistry; Barton, D., Ollis, W. D., Eds., Pergamon Press, 1979; Vol. 1.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Phone: 504-520-7519. ORCID
Jayalakshmi Sridhar: 0000-0002-4424-9874 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Dr. Kathleen Morgan, from the chemistry department at Xavier University of Louisiana, for helpful discussions on the proposed mechanism of the dimerization reaction. We acknowledge the financial support for this work by the 13691
DOI: 10.1021/acs.joc.7b02501 J. Org. Chem. 2017, 82, 13686−13692
Note
The Journal of Organic Chemistry (b) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Phytochemistry 1986, 25, 1245. (c) Cheeke, P. R. Toxicants of plant origin; CRC Press: FL, 1989; Vol. 4. (10) Sridhar, J.; Sfondouris, M. E.; Bratton, M. R.; Nguyen, T. K.; Townley, I.; Stevens, C. L. K.; Jones, F. E. Bioorg. Med. Chem. Lett. 2014, 24, 126−131. (11) Schroeder, R. L.; Goyal, N.; Bratton, M. R.; Townley, I.; Pham, N. A.; Tram, P.; Stone, T.; Geathers, J.; Nguyen, K.; Sridhar, J. Bioorg. Med. Chem. Lett. 2016, 26, 3187−3191. (12) The Z/E ratio was determined using 1H NMR data. (13) For the usage of benzoquinones in the Diels−Alder reactions, see: Nawrat, C. C.; Moody, C. J. Angew. Chem. 2014, 126, 2086−2109; Angew. Chem., Int. Ed. 2014, 53, 2056−2077. (14) Tanaka, K.; Yamagishi, N.; Tanikaga, R.; Kaji, A. Bull. Chem. Soc. Jpn. 1979, 52, 3619−3625.
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DOI: 10.1021/acs.joc.7b02501 J. Org. Chem. 2017, 82, 13686−13692
