Materials and Methods
Commercial chemicals were of the highest grade available and were used without further purification. Reagent-grade solvents were used for all of the extractions and workup procedures. Distilled water was used for all of the aqueous solutions.
NMR spectra of dry samples were recorded on a Bruker Avance II 400 instrument (Rheinstetten, Germany) with a resonance frequency of 400.13 MHz for
1H and 100.62 MHz for
13C. The samples were dissolved in perdeuterated solvents chloroform, DMSO or pyridine (99.8%D, Euriso-top, Saint-Aubin, France). Raw data processing was carried out with ACD/NMR Processor Academic Edition. Signal assignment was accomplished using attached proton test (APT) and 2D NMR techniques (COSY, HSQC and HMBC) (Bennett et al.
1995). The chemical shift values are given in δ ppm values relative to TMS, coupling constants are given in Hz.
FTIR experiments were performed on a Perkin-Elmer Frontier IR Single-Range spectrometer (Waltham, Massachusetts, USA) in ATR mode (diamond/ZnSe crystal, LiTaO3 detector, KBr windows). Elemental analyses were done on a EURO EA 3000 CHNS-O instrument from HEKAtech (Wegberg, Germany) at the Microanalytical Laboratory of Vienna University. Halide contents (Cl) were determined by argentometry.
TLC was performed on Silica gel 60 F254 pre-coated glass plates (Merck). Flash column chromatography was performed on Silica gel 60 from Merck (Darmstadt, Germany). Solvents were purchased in synthesis grade from Roth, Sigma-Aldrich and VWR and were used as received. Reagents were obtained from Sigma-Aldrich, TCI and Fluka. Melting points were determined on a Kofler hot stage with a Reichert-Biovar microscope microscope and are uncorrected.
X-ray data collection was performed with a Bruker AXS Smart APEX CCD diffractometer and graphite monochromatized Mo-Kα radiation; corrections for absorption with the program SADABS, structure solution with direct methods, structure refinement on F2 (Bruker AXS, 2001: programs SMART, version 5.626; SAINT, version 6.36A; SADABS version 2.05; XPREP, version 6.12; SHELXTL, version 6.10. Bruker AXS Inc., Madison, WI, USA).
The supplementary crystallographic data for this paper can be obtained free of charge via
www.ccdc.cam.ac.uk/data_re-quest/cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
2,5-Diacetoxy-[1,4]-benzoquinone (4). 2,5-Dihydroxy-[1,4]-benzoquinone (1, 3.57 mmol, 500 mg) was dissolved in glacial acetic acid (10 mL) and concentrated sulfuric acid (0.05 mL) was added. The mixture was stirred at room temperature for 3 min, neutralized by a saturated aqueous NaHCO3 solution and extracted with CH2Cl2. Upon evaporation of the solvent, a crystalline residue appeared which was recrystallized from glacial acetic acid to provide compound 4 in 85% yield (680 mg) as colorless plates. 1H NMR (CDCl3): δ = 2.08 (s, 6H, 2 × CH3, OAc), 6.16 ppm (s, 2H, H-3, H-6). 13C NMR (CDCl3): δ = 20.12 (2 × CH3, OAc), 122.5 (C-3, C-6), 148.4 (C-2, C-5.), 167.5 (2 × C=O, OAc), 175.8 ppm (2 × C = O, C-1, C-4).
3-(4-Pyridyl)-1,2,4,5-benzenetetrol tetraacetate (5). 2,5-Dihydroxy-[1,4]-benzoquinone (1, 3.57 mmol, 500 mg) was dissolved in pyridine (36 mmol, 2.88 mL) and stirred at room temperature under argon for 1 h. Acetic anhydride (17 mmol, 1.7 mL) was added. The reaction mixture was stirred under reflux for 2 h and at room temperature for 27 h under argon atmosphere, neutralized by a saturated aqueous NaHCO3 solution and extracted with CH2Cl2. The residue was purified by column chromatography (CH2Cl2/n-hexane, v/v = 1:1, + 5% MeOH) to yield 5 in 68% yield (940 mg). The compound was purified by recrystallization from DMF. 1H NMR (CDCl3): δ = 2.0 (s, 6H, 2 × CH3, OAc), 2.27 (s, 6H, 2 × CH3, OAc), 7.20–7.73 (m, 2H, H-3, H-5, py), 7.28 (s, 1H, H-4′), 8.64–8.66 ppm (m, H-2, H-6, py). 13C NMR (CDCl3): δ = 20.1 (2 × CH3, OAc), 20.7 (2 × CH3, OAc), 118.6 (C-4′), 124.4 (C-3, C-5, py), 128.8 (C-1′), 137.6 (C-4, py), 140.23 (C-3′, C-5′), 140.64 (C-2′, C-6′), 149.74 (C-2, C-6, py), 167.54 (2 × C=O, OAc), 167.65 ppm (2 × C=O, OAc).
1,2,4,5-
Tetraacetoxybenzene (
6). 2,5-Dihydroxy-[1,4]-benzoquinone (
1, 3.57 mmol, 500 mg) was dissolved in glacial acetic acid (10 mL) and zinc powder (2.0 g) was added. The mixture was refluxed for 10 min and stirred at 50 °C for an additional hour. The warm mixture was filtered and the residue washed with glacial acetic acid (5 mL). The combined organic phases were evaporated and the residue recrystallized from
n-heptane to afford compound
6 (1.06 g, 96%) as white crystals, the analytical data being identical to those provided by Crosby and Lutz (
1956).
3,6-Bis(dimethyl-λ4-sulfaneylidene)cyclohexane-1,2,4,5-tetraone (8). Representative protocol: 2,5-Dihydroxybenzoquinone (1, 1.40 g, 10 mmol) was dissolved in DMSO (5 mL), acetic anhydride (20 mL) was added, and the mixture heated under stirring to 100 °C for 1 h. A yellow solid precipitated, which was collected by filtration after cooling to room temperature and additional stirring for 3 h at r.t. The solid was thoroughly washed with ethyl acetate and dried in vacuo to provide 8 (1.87 g, 72%). M.p. > 300 °C. 1H NMR (D2O): δ = 3.08 ppm (s, 12H, Me). 13C NMR (D2O): δ = 25.4 (Me), 94.4 (C-S), 177.0 ppm (C–O). Anal. calcd. for C10H12O4S2 (260.33): C 46.14, H 4.65, S 24.63. Found: C 46.05, H 4.72, S 24.73. Recrystallization from glacial acetic acid provided the bis(acetic acid) adduct as yellow needles, m.p. 182–184 °C.
3-(Dimethyl-λ4-sulfaneylidene)naphthalene-1,2,4(3H)-trione (9). Representative protocol: Compound 9 was obtained according to the above procedure, employing 2-hydroxy-naphthoquinone (7, 1.74 g, 10 mmol) instead of starting compound 1. Yield: 1.97 g, 84%. M.p. (H2O) = 263–265 °C. 1H NMR (DCOOD): δ = 3.30 (s, 6H, Me), 7.82 (t, 1H, ArH), 7.92 (t, 1H, ArH), 8.11 ppm (t, 2H, ArH). 13C NMR (DCOOD): δ = 25.7 (Me), 98.5 (C–S), 127.5 (C), 128.3 (C), 131.3 (CH), 134.1 (CH), 134.3 (CH), 136.5 (CH), 172.2, 181.6, 182.4 ppm. Anal. calcd. for C12H10O3S (234.28): C 61.52, H 4.30, S 13.69. Found: C 61.42, H 4.33, S 13.52.
DHAP monoacetate, 2-hydroxy-5-acetoxy-acetophenone (11). 2,5-Dihydroxyacetophenone (3, 3.29 mmol, 500 mg) was dissolved in pyridine (3 mL) and stirred at room temperature under argon for 1 h. Acetic anhydride (3 mL) was added. The reaction mixture was stirred at room temperature for 2 h under argon atmosphere, neutralized by a saturated aqueous NaHCO3 solution and extracted with CH2Cl2. The residue was purified by column chromatography (CH2Cl2/n-heptane, v/v = 1:1, + 5% MeOH) to yield monoacetate 11 in 82% yield (523 mg) as colorless needles. 1H NMR (CDCl3): δ = 2.21 (s, 3H, CH3 in OAc), 2.50 (s, 3H, CH3 in Ac), 6.88 (d, 1H, 3J = 9.3 Hz, H-3), 7.13 (dd, 1H, 3J = 9.3 Hz, 4J = 1.6 Hz, H-4), 7.38 (d, 1H, 4J = 1.6 Hz, H-6), 12.06 ppm (s, 1H, OH). 13C NMR (CDCl3): δ = 20.7 (CH3 in OAc), 26.3 (CH3 in Ac), 119.0 (CH), 119.2 (C), 122.7 (CH), 130.0 (CH), 142.0 (C), 159.8 (C), 169.5 (CO in OAc), 203.6 ppm (CO in Ac). Anal. calcd. for C10H10O4 (194.19): C 61.85, H 5.19. Found: C 61.80, H 5.32.
2-Hydroxy-6-acetoxy-acetophenone (13) was obtained as white powder according to the same protocol in 74% yield (472 mg), starting from 2,6-dihydroxyacetophenone (10) (3.29 mmol, 500 mg).
DHAP diacetate, 2,5-diacetoxy-acetophenone (12). 2,5-Dihydroxyacetophenone (3, 3.29 mmol, 500 mg) was dissolved in freshly distilled glacial acetic acid (10 mL) and trimethylsilyl chloride (0.1 mL) was added. The reaction mixture was stirred at room temperature for 2 h under argon atmosphere, neutralized by a saturated aqueous NaHCO3 solution and extracted with CH2Cl2. The residue formed upon evaporation of the solvent was recrystallized from glacial acetic acid to yield DHAP diacetate (12) in 78% yield (606 mg) as colorless needles. 1H NMR (CDCl3): δ = 2.16 (s, 3H, CH3 in OAc), 2.20 (s, 3H, CH3 in OAc), 2.46 (s, 3H, CH3 in Ac), 6.88 (d, 1H, 3J = 9.0 Hz, H-3), 7.16 (dd, 1H, 3J = 9.0 Hz, 4J = 1.2 Hz, H-4), 7.40 (d, 1H, 4J = 1.2 Hz, H-6), 12.22 ppm (s, 1H, OH). 13C NMR (CDCl3): δ = 20.4 (CH3 in OAc), 20.7 (CH3 in OAc), 26.0 (CH3 in Ac), 119.2 (C), 119.6 (CH), 123.2 (CH), 130.8 (CH), 142.6 (C), 159.3 (C), 168.3 (CO in OAc), 169.4 (CO in OAc), 182.4 ppm (CO in Ac). Anal. calcd. for C12H12O5 (236.22): C 61.02, H 5.12. Found: C 60.93, H 5.24.
2,6-Diacetoxy-acetophenone (14) was obtained as colorless plates according to the same protocol in 58% yield (528 mg), starting from 2,6-dihydroxyacetophenone (10, 3.29 mmol, 500 mg).
2,5-Di(morpholin-1-yl)-benzo-[1,4]-quinone (19). 2,5-Dihydroxy-[1,4]-benzoquinone (1, 3.57 mmol, 500 mg) was dissolved in acetonitrile (10 mL) and morpholine (1 mL) was added. The mixture was stirred at room temperature for 15 min, and the solvents were evaporated. The residue was recrystallized from 1,4-dioxane to provide compound 19 in quantitative yield (680 mg) as orange, amorphous solid. 1H NMR (CDCl3): δ = 3.53 (s, 8H, 4 × N–CH2), 3.79 (s, 8H, 4 × O–CH2), 5.53 ppm (s, 2H, CH). 13C NMR (CDCl3): δ = 49.3 (N–CH2), 66.6 (O–CH2), 107.2, (CH), 152.4 (C–N), 182.9 ppm (C=O). Anal. calcd. for C14H18N2O4 (278.31): C 60.42, H 6.52, N 10.07. Found: C 60.30, H 6.64, N 9.94.
2,5-Di(1H-imidazol-1-yl)-benzo-[1,4]-quinone (20). 2,5-Dihydroxy-[1,4]-benzoquinone (1, 3.57 mmol, 500 mg) was dissolved in chloroform (20 mL) and imidazole (2.5 mL) was added. The mixture was stirred at room temperature for 15 min, washed three times with water (3 × 5 mL), and dried over anhydrous MgSO4. After removal of the solids by filtration, the solvent was evaporated and the residue was recrystallized from 1,4-dioxane to provide compound 20 in 92% yield (789 mg) as red amorphous solid. 1H NMR (CDCl3): δ = 5.60 (s, 2H, CH), 6.84 (s, 2H, H-5´), 6.98 (s, 2H, H-4´), 7.36 ppm (s, 2H, H-2´). 13C NMR (CDCl3): δ = 109.5, (CH), 120.4 (C-4´), 128.7 (C-5´), 137.9 (C-2´), 154.8 (C-N), 180.8 ppm (C=O). Anal. calcd. for C12H8N4O2 (240.22): C 60.00, H 3.36, N 23.32. Found: C 60.08, H 3.42, N 23.48.
2-(1-Hydroxyethyl)benzene-1,4-diol (21). 2,5-Dihydroxyacetophenone (3, 3.29 mmol, 500 mg) was dissolved in 1,4-dioxane (5 mL) and aqueous sodium bisulfite solution (2 M, 20 mL) was added. The mixture was vigorously stirred at room temperature for 1 h, and extracted with chloroform (3 × 20 mL). The combined organic phases were washed with water (5 mL) and dried over anhydrous MgSO4. After filtration the solvent was evaporated and the residue was purified by column chromatography (CHCl3/MeOH, v/v = 15:1) to provide compound 21 in 92% yield (789 mg) as a yellow solid. 1H NMR (CDCl3): δ = 1.38 (d, 3H, CH3, 3J = 6.8 Hz), 3.96 (s, 1H, OH), 4.96 (q, 1H, CH(OH), 3J = 6.8 Hz), 6.53–6.64 (m, 4H, OH, 3 × ArH), 7.47 (s, 1H, OH). 13C NMR (CDCl3): δ = 24.0 (CH3), 68.8 (CH(OH)), 113.9 (CH), 115.3 (CH), 117.4 (CH), 132.4 (C), 148.5 (C), 150.6 ppm (C). Anal. calcd. for C8H10-O3 (254.17): C 62.33, H 6.54. Found: C 62.20, H 6.72.
4-Acetoxyphenol, hydroquinone monoacetate (22). 2,5-Dihydroxyacetophenone (3, 3.29 mmol, 500 mg) was dissolved in dry 1,4-dioxane (10 mL) and BF3·Et2O (varying amounts, between 0.01 and 2 eq.) was added. The mixture was vigorously stirred at room temperature for 1 h, and extracted three times with saturated aqueous NaHCO3 solution. TLC control (CHCl3/MeOH, v/v = 15:1) showed a product at Rf = 0.58. The organic phase was dried over anhydrous MgSO4. After filtration the solvent was evaporated and the residue purified by column chromatography (CHCl3/MeOH, v/v = 15:1) to provide hydroquinone monoacetate (22) in 16% yield (81 mg) as colorless solid. 1H NMR (CDCl3): δ = 2.28 (s, 3H, CH3), 5.62 (s, br, 1H, OH), 6.72 (d, 2H, 3J = 8.8 Hz), 6.89 ppm (d, 2H, 3J = 8.8 Hz). 13C NMR (CDCl3): δ = 21.3 (CH3), 116.2 (CH), 122.4 (CH), 144.1 (C), 153.7 (C), 170.9 ppm (C = O). Anal. calcd. for C8H8O3 (252.15): C 63.15, H 5.30. Found: C 63.02, H 5.45.
The yield of 22 remained largely constant, between 10 and 20%, also when the amount of BF3·Et2O was varied, and was also not significantly affected by changing the Lewis acid to AlCl3 or SnCl4.
Rhodizonic acid (26)/sodium rhodizonate (26a). 2,5-Dihydroxy-[1,4]-benzoquinone (1, 3.57 mmol, 500 mg) was dissolved in 0.1 M aqueous NaOH (50 mL). Aqueous sodium hypochlorite solution (13% active chlorine, 5 mL) was added, and the mixture stirred for 10 min at room temperature. To destroy excess bleach, concentrated aqueous sodium thiosulfate was added until the KI/starch test was negative. The mixture was acidified to a pH of about 4 with 1 M HCl, and brought to dryness by rotavaporation in vacuo at a bath temperature of 80 °C. The solid residue was triturated with isopropanol (50 mL) and solids were removed by filtration. Evaporation of the solvent provided a residue which was recrystallized from ethanol/water (v/v = 9:1) to provide rhodizonic acid dihydrate (26) as yellow solid (602 mg, 82%). 1H NMR (DMSO-d6): no non-exchanging protons. 13C NMR (DMSO-d6): δ = 94.5 (C(OH)2), 141.5 (= C(OH)), 191.0 ppm (C = O). 1H NMR (DMSO-d6/1 M NaOD in D2O, v/v = 5:1): no non-exchanging protons. 13C NMR (DMSO-d6/1 M NaOD in D2O, v/v = 5:1): δ = 178.4 ppm. An aqueous solution of the product gives intensively colored precipitates with barium(II), lead(II) or copper(II) ions.
5,8-Dihydroxy-1H-benzo[f]indazole-4,9-dione (29). Working in an efficient fume hood at room temperature, a solution of diazomethane in Et2O freshly prepared from Diazald® was added dropwise to a solution of 2,5-dihydroxy-[1,4]-naphthoquinone (2.63 mmol, 500 mg) in freshly distilled and dried dioxane (5 mL) until the yellow color persisted. CAUTION: diazomethane is known to be toxic, explosive and cancerogenic! Two drops of glacial acetic acid were added and the solvents were evaporated. The red, waxy residue was purified by column chromatography (CHCl3/n-heptane, v/v = 1:1) to provide heterocycle 29 in 90% yield (546 mg) as red rhombic plates. 1H NMR (CDCl3): δ = 7.23 (s (m), 2H, CH), 7.40 (s, 1H, NH), 7.88 (s, 1H, CH–N), 11.41 (s, 1H, OH), 12.66 ppm (s, 1H, OH). 13C NMR (CDCl3): δ = 108.8 (C), 111.5 (C), 122.7 (C), 129.4 (CH), 130.9 (CH), 134.1 (C), 142.0 (CH–N), 152.9 (C–O), 156.5 (C-O), 182.4 (C=O), 183.0 ppm (C=O). Anal. calcd. for C11H6N2O4 (230.18): C 57.40, H 2.63, N 12.17. Found: C 57.22, H 2.90, N 12.03.