All reagents and solvents were purchased from Sigma-Aldrich (St. Louis, MO, USA). All the reactions involving air-sensitive reagents were carried out using anhydrous solvents, in oven-dried glassware and under nitrogen atmosphere. Melting points were recorded on a Buchi M-565 apparatus (Buchi, Flawil, Switzerland), and are uncorrected.
NMR spectra were recorded at room temperature either on a Varian Mercury (Varian, Palo Alto, CA, USA), equipped with an Oxford 300 MHz cryomagnet (Oxford Instruments, Abingdon, UK), operating at 300 MHz for 1H analyses, or on a Bruker Avance 500 (Bruker, Billerica, MA, USA), operating at 500 MHz. DMSO-d6 was used as deuterated solvent for all acquisitions. Chemicals shifts are expressed in ppm (δ) from tetramethylsilane resonance in the indicated solvent; coupling constants (J-values) are given in Hertz (Hz). 1H data are reported in the following order: ppm, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), number of protons and attribution. The APT sequence was used to distinguish methyl and methine signals from those due to methylene and quaternary carbons.
For FT-IR analyses, compounds were mixed in 1:100 w/w ratio with KBr and pressed through a hydraulic press (14 tons) to small tablets; data were recorded on a PerkinElmer SPECTRUM ONE instrument (PerkinElmer, Waltham, MA, USA), in the region between 4000 and 450 cm−1, performing 8 scans at 4 cm−1 resolution.
Mass Spectrometry analyses were carried out on a Thermo Finnigan LCQ Advantage (Thermo Fisher Scientific, Waltham, MA, USA), equipped with an ESI electrospray ionization source and an Ion Trap mass analyzer; ionization: ESI positive or ESI negative; capillary temperature: 250 °C; source voltage: 5.50 kV; source current: 4.00 μA; multipole 1 and 2 offset: −5.50 V and −7.50 V, respectively; intermultipole lens voltage: −16.00 V; trap DC offset voltage: −10.00 V.
3.1.1. 6-Hydroxy-2-methylbenzofuran-4-carboxylic Acid Methyl Ester (2)
Propargyl bromide (0.43 mL, 4.76 mmol), anhydrous K2CO3 (1.65 g. 11.90 mmol), KI (1.68 g, 10.12 mmol) and CuI (0.03 g, 0.18 mmol) were added under nitrogen atmosphere to a solution of 3,5-dihydroxybenzoate (1.00 g, 5.95 mmol) in dry DMF (4 mL), and the mixture was heated at 75 °C for 24 h. The residue obtained by the evaporation in vacuum of DMF was poured in ice-water and then extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure; the crude residue was purified by column chromatography (silica gel ratio 1:60), using hexane/ethyl acetate (8:2 to 7:3), to afford compound 2 as a pale yellow solid (yield: 47%). Rf = 0.32 (hexane/EtOAc 8:2). M.p.: 140–142 °C. 1H-NMR (300 MHz, DMSO): δ 9.75 (s exch D2O, 1H, OH), 7.33 (d, J = 2.2 Hz, 1H, H5), 7.14 (dd, J = 2.2, 0.9 Hz, 1H, H7), 6.86–6.80 (m, 1H, H3), 3.88 (s, 3H, COOCH3), 2.42 (s, 3H, CH3) ppm. 13C-NMR (75 MHz, DMSO): δ 187.61, 166.86, 156.64, 156.46, 154.87, 122.31, 121.68, 113.64, 104.10, 103.41, 52.79, 14.51 ppm. FT-IR (KBr): ν 3405, 3091, 2957, 2919, 2849, 1697, 1623, 1605, 1513, 1441, 1424, 1127, 999 cm−1. ESI-MS (m/z): calcd. for C11H10O4 206,06, found 205.12 m/z [M − H]−.
3.1.2. 6-Hydroxy-2-methylbenzofuran-4-carboxylic Acid (1)
A solution of powdered NaOH (30 mg, 0.75 mmol) in water (1 mL) and methanol (0.4 mL) was added to compound 2 (70 mg, 0.34 mmol). The reaction mixture was stirred at 55 °C for 6 h and then partially concentrated in vacuum to remove methanol. The pH of the solution was adjusted to pH 3–4 by the addition of a few drops of 1 M HCl, thereby inducing the precipitation of the free acid 1, which was collected by filtration as a white solid (yield: 50%). Rf = 0.1 (EtOAc/MeOH 8:2). M.p.: 208–210 °C. 1H-NMR (300 MHz, DMSO): δ 12.88 (s exch D2O, 1H, COOH), 9.67 (s exch D2O, 1H, OH), 7.28 (d, J = 2.2 Hz, 1H, H5), 7.07 (d, J = 2.2, Hz, 1H, H7), 6.80 (s, 1H, H3), 2.39 (s, 3H, CH3) ppm. 13C-NMR (75 MHz, DMSO): δ 167.59, 156.04, 155.81, 154.38, 122.57, 122.07, 113.49, 103.88, 102.52, 14.08 ppm. FT-IR (KBr): ν 3281, 3077, 2962, 2919, 2848,1690, 1626, 1600, 1496, 1439, 1392, 1127 cm−1. ESI-MS (m/z): calcd. for C10H8O4 192.17, found 191.41 m/z [M − H]−.
3.2. Single-Crystal X-ray Diffraction
The slow evaporation of a methanol/water 1:1 solution of 1 afforded diffraction-quality yellow laminar crystals, after about one week at room temperature.
Crystallographic data for 1 were collected at ambient temperature on a Bruker-Axs CCD-based three-circle diffractometer, using graphite-monochromatized Mo-Ka X-radiation (λ = 0.7107 Å).
X-ray diffraction data in the θ
range 2°–25° were collected by acquiring four sets of 600 bidimensional CCD frames with the following operative conditions: omega rotation axis; scan width: 0.3°; acquisition time: 20 s; sample-to-detector distance: 60 mm; φ angle: fixed at four different values (0°, 90°, 180°, 270°) for the four different sets. Omega-rotation frames were processed with SAINT [16
] for data reduction (including intensity integration, background, Lorentz and polarization corrections) and for the determination of accurate unit-cell dimensions, obtained by least-squares refinement of the positions of 1359 independent reflections with I > 10σ(I) in the θ
range 2°–24°. Absorption effects were empirically evaluated with the SADABS software [17
], and absorption correction was applied to the data (0.874 and 0.994 as min and max transmission factor, respectively).
The structures were solved by direct methods using SIR-14 [18
] and completed by iterative cycles of full-matrix least-squares refinement on F02
and DF synthesis using SHELXL-17 [19
] on the WingX.v2014.1 suite [20
]. Hydrogen atoms bonded to carbons were included at geometrically calculated positions and refined using a riding model. The contribution of disordered solvent molecules, embedded in the crystal, to the calculated structure factors was determined with PLATON SQUEEZE [21
], and included in the final steps of the refinement. Graphical representations were rendered with Mercury 4.3.1 [22
]. CCDC entry 2004172 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: [email protected]
Crystal data for compound 1: C10H8O4, Mr = 192.16 g/mol, Triclinic, Space group P-1, a = 3.7850(6) Å, b = 10.1380(16) Å, c = 14.416(2) Å, α = 104.780(2)°, β = 94.920(2)°, γ = 100.720(2)°, V = 520.35(14) Å3, Z = 2, Dcalc = 1.226 Mg/m3, F(000) = 200, R = 0.057 for 1383 reflections with Fo > 4sig(Fo) (R = 0.073 for all 1842 unique/4979 collected reflections), wR2 = 0.172 for reflections with Fo > 4sig(Fo) (wR2 = 0.186 for all unique reflections), T = 293(2) K, GOF = 1.084. The reflections were collected in the range 1.475° ≤ θ ≤ 25.043° (limiting indices = −4 ≤ h ≤ 4, −12 ≤ k ≤ 12, −17 ≤ l ≤ 17) employing a 0.26 × 0.15 × 0.06 mm crystal. The residual positive and negative electron densities in the final map were 0.214 and −0.133 Å−3.