2. Material and Methods
2.1. General Experimental Procedures
Reagents and chemicals used in this study were purchased from Sigma Aldrich via Capital Laboratories, South Africa, and were reagent grade. All organic solvents were redistilled and dried according to standard procedures. NMR spectra were recorded using a Bruker AvanceIII 400 MHz spectrometer at room temperature with chemical shifts (δ) recorded against the internal standard, tetramethylsilane (TMS). 2D NMR spectroscopy (COSY, NOESY, HSQC, and HMBC) were used for the structural elucidation of the synthesised compounds. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer with universal ATR sampling accessory. For GC-MS analyses, the samples were analysed on an Agilent GC-MSD apparatus equipped with DB-5SIL MS (30 m × 0.25 mm i.d., 0.25 μm film thickness) fused-silica capillary column. Helium (at 2 mL min−1) was used as a carrier gas. The MS was operated in the EI mode at 70 eV. Optical rotation was recorded using a Perkin Elmer, Model 341 Polarimeter. Melting points were recorded on an Ernst Leitz Wetzlar microhot stage melting point apparatus.
2.2. Typical Procedure for the Preparation of Cinnamic Acids
For the preparation of the cinnamic acids 2a–c and 2h-i, the procedure in Qian et al. [29] was adopted with slight modifications. The required aromatic aldehydes (3.2 mmol), malonic acid (3.87 mmol), and piperidine (0.387 mmol) were dissolved in pyridine (10 mL) and stirred at 80–90°C for 4-5 hours. The pyridine was removed under vacuum, and the reaction mixture was poured into water (25 mL) and washed with HCl (3 × 10 mL). A precipitate formed which was filtered and washed thrice with hexane (3 × 10 mL), after which it was dried under vacuum to afford the cinnamic acids 2a–c and 2h-i (Figure 1), whose 1H NMR was consistent with that in the literature [30–34]. The cinnamic acids 2d–g and 2j were purchased from Sigma Aldrich via Capital Laboratories, South Africa.
2′-Fluorocinnamic acid (2a) yield 91%; mp 175-176°C (lit. 176.5–177°C [30]); 3′-fluorocinnamic acid (2b) yield 84%, mp 166-167°C (lit. 167°C [35]); 4′-fluorocinnamic acid (2c) yield 88%, mp 206–208°C (lit. 208°C [32]); 4′-methoxycinnamic acid (2h) yield 92%, mp 172-173°C (lit. 173–175°C [33]); 3′,4′-dimethoxycinnamic acid (2i) yield 83%, mp 181–183°C (lit. 182–184°C [36]).
2.3. Typical Procedure for the Synthesis of Substituted 2-(Cinnamoyloxy) Acetophenones (3a–j)
POCl3 (15.6 mmol, 2.39 g) was added to a solution of the appropriate 2-hydroxyacetophenone (12.0 mmol) and the appropriate cinnamic acid (15.6 mmol) in dry pyridine (10 mL). The solution was stirred at 60–70°C for 3 h and then poured into ice and water (20 mL), and the reaction mixture acidified with HCl (pH 3-4). The obtained solid was removed by filtration, dissolved in EtOAc (100 mL), and purified by silica gel column chromatography using a 7 : 3 mixture of EtOAc : n-hexane as the eluent. The solvent was evaporated to dryness, and the residue recrystallized from EtOH, resulting in compounds 3a–j.
2′-(2-Fluorocinnamoyloxy) Acetophenone (3a). Brown solid residue (90% yield); mp 68–70°C; IR (KBr) υmax: 1682 (br C=O), 1627 (C=C), 1612 (aromatic C–C), 1483, 1456, 1284 (C–F), 1227 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.00 (1H, d, J = 16.2 Hz, H-β), 7.85 (1H, dd, J = 7.9, 1.6 Hz, H-6′), 7.59 (1H, td, J = 7.9, 1.7 Hz, H-6′′), 7.54 (1H, td, J = 7.6, 1.6 Hz, H-4′), 7.39-7.40 (1H, m, H-4′′), 7.33 (1H, td, J = 7.6, 0.8 Hz, H-5′), 7.19 (1H, dd, J = 8.0, 0.8 Hz, H-3′), 7.18 (1H, t, J = 7.5 Hz, H-5′′), 7.11 (1H, dd, J = 10.3, 8.8 Hz, H-3′′), 6.76 (1H, d, J = 16.2 Hz, H-α), 2.55 (3H, s, CH3-2); 13C NMR (CDCl3, 100 MHz) δ 197.7 (C-1), 165.1 (C=O), 161.8 (d, JCF = 252.6 Hz, C-2′′), 149.1 (C-2′), 140.0 (d, J = 2.7 Hz, C-β), 133.4 (C-4′), 132.2 (d, J = 14.2 Hz, C-4′′), 131.3 (C-1′′), 130.2 (C-6′), 129.4 (d, J = 2.7 Hz, C-6′′), 126.1 (C-5′), 124.6 (d, J = 3.6 Hz, C-5′′), 123.8 (C-3′), 122.2 (d, J = 11.6 Hz, C-1′′), 119.4 (d, J = 6.9 Hz, C-α), 116.3 (d, J = 21.7 Hz, C-3′′), 29.8 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −113.57; EIMS (probe) 70 eV, m/z (rel. int.): 284 M+ (3), 149 (100), 121 (63), 101 (65), 75 (15); calculated molecular mass: 284.28.
2′-(3-Fluorocinnamoyloxy) Acetophenone (3b). Brown solid residue (68% yield): mp 55-56°C; IR (KBr) υmax: 1733 and 1673 (C=O), 1637 (C=C), 1444, 1136 (C–F), 1073 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.83 (1H, dd, J = 7.6, 1.6 Hz, H-6′), 7.82 (1H, d, J = 16.0 Hz, H-β), 7.55 (1H, td, J = 7.8, 1.6 Hz, H-4′), 7.35–7.37 (2H, m, H-5′, H-6′′), 7.33 (1H, td, J = 7.7, 0.8, H-5′′), 7.27 (1H, d, J = 9.6 Hz, H-2′′), 7.17 (1H, dd, J = 8.0, 0.7 Hz, H-3′), 7.10 (1H, tt, J = 8.2, 2.0 Hz, H-4′′), 6.55 (1H, d, J = 16.0 Hz, H-α), 2.55 (3H, s, CH3-2); 13C NMR (CDCl3, 100 MHz) δ 197.7 (C-1), 164.9 (C=O), 163.0 (d, JCF = 245.6 Hz, C-3′′), 149.0 (C-2′), 145.8 (d, J = 2.7 Hz, C-β), 136.3 (d, J = 7.9 Hz, C-1′′), 133.4 (C-4′), 131.2 (C-1′), 130.6 (d, J = 8.0 Hz, C-5′′), 130.2 (C-6′), 126.2 (C-5′), 124.4 (d, J = 2.9 Hz, C-6′′), 123.8 (C-3′), 118.3 (C-α), 117.7 (d, J = 21.3 Hz, C-4′′), 114.6 (d, J = 21.9 Hz, C-2′′), 30.0 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −112.27; EIMS (probe) 70 eV, m/z (rel. int.): 284 M+ (3), 149 (100), 121 (60), 101 (55), 75 (11); calculated molecular mass: 284.28.
2′-(4-Fluorocinnamoyloxy) Acetophenone (3c). Cream solid residue (72% yield); mp 80–82°C; IR (KBr) υmax: 1729 (C=O), 1670 (C=O), 1624 (C=C), 1590, 1446, 1221 (C–F), 1202, 1159, 1050 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.84 (1H, d, J = 16.0 Hz, H-β), 7.81 (1H, dd, J = 8.0, 1.6 Hz, H-6′), 7.58 (2H, dd, J = 8.6, 5.4 Hz, H-2′′/6′′), 7.53 (1H, dd, J = 8.0, 1.5 Hz, H-4′), 7.33 (1H, td, J = 8.1, 0.7 Hz, H-5′), 7.17 (1H, dd, J = 8.1, 0.7 Hz, H-3′), 7.09 (2H, t, J = 8.6 Hz, H-3′′/5′′), 6.58 (1H, d, J = 16.0 Hz, H-α), 2.54 (s, 3H, CH3-2); 13C NMR (CDCl3, 100 MHz) δ 197.8 (C-1), 165.1 (C=O), 164.3 (d, JCF = 250.7 Hz, C-4′′), 149.1 (C-2′), 146.0 (C-β), 133.4 (C-4′), 131.3 (C-1′), 130.4 (d, J = 8.4 Hz, C-2′′/6′′), 130.32 (d, J = 3.6 Hz, C-1′′), 130.2 (C-6′), 126.1 (C-5′), 123.8 (C-3′), 116.6 (d, J = 2.4 Hz, C-α), 116.2 (d, J = 21.9 Hz, C-3′′/5′′), 29.7 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −108.54; EIMS (probe) 70 eV, (m/z, rel. int.) 284 M+ (21), 149 (100), 121 (25), 101 (20); calculated molecular mass: 284.28.
2′-(3,5-Difluorocinnamoyloxy) Acetophenone (3d). Brown solid residue (70% yield); mp 58-59°C; IR (KBr) υmax: 1729 (C=O), 1682 (C=O), 1249 (C–F), 1201, 1122 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.82 (1H, dd, J = 7.9, 1.0 Hz, H-6′), 7.75 (1H, d, J = 16.0 Hz, H-β), 7.55 (1H, td, J = 7.6, 1.1 Hz, H-4′), 7.34 (1H, t, J = 7.6 Hz, H-5′), 7.16 (1H, dd, J = 7.9, 0.8 Hz, H-3′), 7.08–7.10 (2H, m, H-2′′/6′′), 6.85 (1H, tt, J = 8.7, 2.3 Hz, H-4′′), 6.64 (1H, d, J = 16.0 Hz, H-α), 2.54 (3H, s, CH3-2); 13C NMR (CDCl3, 100 MHz) δ 197.6 (C-1), 164.6 (C=O), 163.2 (dd, JCF = 248.3, 12.8 Hz, C-3′′/5′′), 148.9 (C-2′), 144.5 (t, J = 2.8 Hz, C-β), 137.3 (d, J = 9.5 Hz, C-1′′), 133.5 (C-4′), 131.0 (C-1′), 130.3 (C-6′), 126.3 (C-5′), 123.7 (C-3′), 119.7 (C-α), 111.0 (dd, J = 18.8, 7.2 Hz, C-2′′/6′′), 105.9 (t, J = 25.4 Hz, C-4′′), 29.5 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −108.75; EIMS (probe) 70 eV, (m/z, rel. int.): 302 M+ (3), 167 (100), 139 (79), 119 (60); calculated molecular mass: 302.27.
4′-Fluoro-2′-(4-fluorocinnamoyloxy) Acetophenone (3e). Off-white solid residue (68% yield); mp 60–62°C; IR (KBr) υmax: 1724 (C=O), 1679 (C=O), 1361 (C–O), 1225 (C–F), 1143 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.87 (1H, dd, J = 8.8, 6.3 Hz, H-6′), 7.84 (1H, d, J = 16.0 Hz, H-β), 7.58 (2H, dd, J = 5.4, 2.0 Hz, H-2′′/6′′), 7.10 (2H, dd, J = 8.7, 2.5 Hz, H-3′′/5′′), 7.03 (1H, td, J = 8.8, 2.5 Hz, H-5′), 6.92 (dd, J = 8.9, 2.5 Hz, H-3′), 6.56 (1H, d, J = 16.0 Hz, H-α), 2.53 (3H, s, CH3-2); 13C NMR (CDCl3, 100 MHz) δ 196.1 (C-1), 165.1 (C=O), 165.0 (d, JCF = 254.1 Hz, C-4′), 164.4 (d, JCF = 251.0 Hz, C-4′′), 151.0 (d, J = 11.2 Hz, C-2′), 146.6 (C-β), 132.2 (d, J = 10.1 Hz, C-6′), 130.5 (d, J = 8.5 Hz, C-2′′/6′′), 130.2 (d, J = 3.0 Hz, C-1′′), 127.6 (d, J = 3.5 Hz, C-1′), 116.3 (d, J = 21.9 Hz, C-3′′/5′′), 116.1 (d, J = 2.2 Hz, C-α), 113.3 (d, J = 21.2 Hz, C-5′), 111.7 (d, J = 24.0 Hz, C-3′), 29.7 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −103.81, −103.17; EIMS (probe) 70 eV (m/z, rel. int.) 302 M+ (3), 149 (100), 121 (92), 101 (75); calculated molecular mass: 302.27.
4′-Fluoro-2′-cinnamoyloxy Acetophenone (3f). Brown solid residue (86% yield); mp 98–100°C; IR (KBr) υmax: 1730 (C=O), 1678 (C=O), 1634, 1598, 1247 (C–F), 1100, 886 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.88 (1H, d, J = 15.9 Hz, H-β), 7.86 (1H, dd, J = 8.6, 5.4 Hz, H-6′), 7.58 (2H, dd, J = 7.5, 1.9 Hz, H-2′′/6′′), 7.43–7.45 (3H, m, H-3′′/4′′/5′′), 7.03 (1H, ddd, J = 8.6, 7.9, 2.5 Hz, H-5′), 6.94 (1H, dd, J = 8.9, 2.5 Hz, H-3′), 6.63 (1H, d, J = 15.9 Hz, H-α), 2.53 (3H, s, CH3-2); 13C NMR (CDCl3, 100 MHz) δ 196.1 (C-1), 166.4 (d, JCF = 255.8 Hz, C-4′), 164.8 (C=O), 151.0 (C-2′), 145.4 (C-β), 133.9 (C-1′′), 132.3 (d, J = 10.2 Hz, C-6′), 131.1 (C-4′′), 129.0 (C-2′′/6′′), 128.5 (C-3′′/5′′), 127.0 (C-1′), 116.3 (C-α), 113.4 (d, J = 21.1 Hz, C-3′), 111.7 (d, J = 24.1 Hz, C-5′), 29.8 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −103.91; EIMS (probe) 70 eV (m/z, rel. int.) 284 M+ (3), 131 (100), 103 (71), 77 (39), 51 (11); calculated molecular mass: 284.28.
5′-Fluoro-2′-cinnamoyloxy Acetophenone (3g). Brown solid residue (90% yield); mp 81–83°C; IR (KBr) υmax: 1731 (C=O), 1681 (C=O), 1632, 1581, 1131 (C–F), 983 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.88 (1H, d, J = 15.9 Hz, H-β), 7.58-7.59 (2H, m, H-2′′/6′′), 7.49 (1H, dd, J = 8.7, 3.0 Hz, H-3′), 7.39–7.41 (3H, m, H-3′′/4′′/5′′), 7.23 (1H, dd, J = 7.8, 3.0 Hz, H-4′), 7.15 (1H, dd, J = 8.7, 4.7 Hz, H-6′), 6.64 (1H, d, J = 15.9 Hz, H-α), 2.53 (3H, s, CH3-2); 13C NMR (CDCl3, 100 MHz) δ 196.4 (C-1), 165.2 (C=O), 159.9 (d, JCF = 245.1 Hz, C-5′), 147.8 (C-2′), 145.0 (C-β), 133.9 (C-1′′), 132.6 (d, J = 6.1 Hz, C-1′), 131.0 (C-4′′), 129.0 (C-3′′/5′′), 128.5 (C-2′′/6′′), 125.4 (d, J = 8.0 Hz, C-3′), 120.1 (d, J = 23.3 Hz, C-6′), 116.5 (d, J = 20.5 Hz, C-4′), 116.6 (C-α), 29.8 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −115.35; EIMS (probe) 70 eV (m/z, rel. int.) 284 M+ (30), 266 (8), 145 (25), 131 (100), 103 (44), 77 (21); calculated molecular mass: 284.28.
2′-(4-Methoxycinnamoyloxy) Acetophenone (3h). Off-white solid residue (91% yield); mp 97–99°C (lit. 103–105°C [20]); IR (KBr) υmax: 1711 (C=O), 1680 (C=O), 1600 (C=C), 1509, 1581, 1246, 1189 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.83 (1H, d, J = 15.9 Hz, H-β), 7.80 (1H, dd, J = 8.0, 1.6 Hz, H-6′), 7.53 (2H, d, J = 8.7 Hz, H-2′′/6′′), 7.51 (1H, td, J = 7.6, 1.6 Hz, H-4′), 7.31 (1H, td, J = 8.0, 0.8 Hz, H-5′), 7.17 (1H, d, J = 8.0 Hz, H-3′), 6.91 (dd, J = 8.7, 2.6 Hz, H-3′′/5′′), 6.52 (1H, d, J = 15.9 Hz, H-α), 3.84 (3H, s, OCH3), 2.54 (3H, s, CH3-2); 13C NMR (CDCl3, 100 MHz) δ 197.9 (C-1), 165.5 (C=O), 161.9 (C-4′′), 149.3 (C-2′), 147.2 (C-β), 133.3 (C-4′), 131.5 (C-1′), 130.2 (C-2′′/6′′), 130.0 (C-6′), 126.8 (C-1′′), 126.0 (C-5′), 123.8 (C-3′), 114.5 (C-3′′/5′′), 114.1 (C-α), 55.4 (OCH3), 29.9 (C-2); EIMS (probe) 70 eV (m/z, rel. int.) 296 M+ (7), 161 (100), 133 (49), 118 (16), 90 (15), 77 (16); calculated molecular mass: 296.10.
2′-(3,4-Dimethoxycinnamoyloxy) Acetophenone (3i). Off-white solid residue (56% yield); mp 99–101°C (lit. 97–99°C [37]); IR (KBr) υmax: 1728 (C=O), 1683 (C=O), 1633 (C=C), 1515, 1254 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.82 (1H, d, J = 15.9 Hz, H-β), 7.81 (1H, dd, J =7.8, 1.7 Hz, H-6′), 7.54 (td, J = 7.9, 1.6 Hz, H-4′), 7.31 (1H, td, J = 7.6, 0.9 Hz, H-5′), 7.17 (1H, d, J = 8.0 Hz, H-3′), 7.16 (1H, dd, J = 8.2, 1.9 Hz, H-6′′), 7.10 (1H, d, J = 1.9 Hz, H-2′′), 6.87 (1H, d, J = 8.2 Hz, H-5′′), 6.52 (1H, d, J = 15.9 Hz, H-α), 3.91 (6H, s, 2 x OCH3), 2.55 (3H, s, CH3-2); 13C NMR (CDCl3, 100 MHz) δ 197.9 (C-1), 165.5 (C=O), 151.7 (C-2′), 149.3 (C-4′′), 149.2 (C-3′′), 147.4 (C-β), 133.3 (C-4′), 131.5 (C-1′), 130.1 (C-6′), 127.0 (C-1′′), 126.0 (C-5′), 123.8 (C-3′), 123.3 (C-6′′), 114.4 (C-α), 111.1 (C-5′′), 109.8 (C-2′′), 55.9 (OCH3), 56.0 (OCH3), 29.9 (C-2); EIMS (probe) 70 eV (m/z, rel. int.) 326 M+ (20), 191 (100), 163 (36), 148 (19), 77 (22); calculated molecular mass: 326.10.
2′-(3,4-Methylenedioxycinnamoyloxy) Acetophenone (3j). Off-white solid residue (59% yield), mp 99-100°C, IR (KBr) υmax: 1715 (C=O), 1679 (C=O), 1600 (C=C), 1449, 1202 (C–F), 925 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.80 (1H, dd, J = 7.9, 1.6 Hz, H-6′), 7.78 (1H, d, J = 15.9 Hz, H-β), 7.53 (1H, td, J = 7.9, 1.6 Hz, H-4′), 7.31 (1H, td, J = 7.9, 1.6 Hz, H-5′), 7.16 (1H, d, J = 7.9 Hz, H-3′), 7.08 (1H, dd, J = 7.9, 1.6 Hz, H-6′′), 7.05 (1H, dd, J = 7.9, 1.6 Hz, H-2′′), 6.82 (1H, d, J = 7.9 Hz, H-5′′), 6.47 (1H, d, J = 15.9 Hz, H-α), 6.01 (2H, s, OCH2O), 2.54 (3H, s, CH3-2); 13C NMR (CDCl3, 100 MHz) δ 197.8 (C-1), 165.4 (C=O), 150.2 (C-2′), 149.2 (C-4′′), 148.5 (C-3′′), 147.1 (C-β), 133.3 (C-4′), 131.5 (C-1′), 130.1 (C-6′), 128.5 (C-1′′), 126.0 (C-5′), 125.2 (C-3′), 123.8 (C-6′′), 114.6 (C-α), 108.6 (C-5′′), 106.7 (C-2′′), 101.7 (OCH2O), 29.9 (C-2); EIMS (probe) 70 eV (m/z, rel. int.) 310 M+ (12), 175 (100), 145 (64), 117 (24), 89 (40), 63 (16); calculated molecular mass: 310.30.
2.4. Typical Procedure for the Synthesis of Substituted 3-Hydroxy-1-(2-hydroxyphenyl)-5-(phenyl)-2,4-pentadien-1-ones (4a-j)
KOH powder (0.05 mmol, 2.8 g) was added to a solution of 2-cinnamoyloxy acetophenones 3a–j (10.0 mmol) in Me2SO (15 mL). The solution was stirred at room temperature until complete disappearance of the starting material, which was monitored by TLC. A typical reaction time was 2 h. The solution was then poured into ice water and HCl (20 mL) and the pH adjusted to 5. The obtained solid was removed by filtration, dissolved in EtOAc (150 mL), and purified by silica gel chromatography using EtOAc : n-hexane (7 : 3) as the eluent. The solvent was evaporated to dryness, and the residue recrystallized from EtOH, resulting in 4a-j.
3-Hydroxy-1-(2-hydroxyphenyl)-5-(2-fluorophenyl)-2,4-pentadien-1-one (4a). Pale yellow solid residue (93% yield); mp 158–160°C, IR (KBr) υmax: 1680 (C=O), 1626, 1581, 1483, 1283 (C–F), 1227 (C–O) cm−1; 1H NMR (CDCl3, 400 MHz) δ 14.55 (s, 3-OH), 12.17 (s, 2′-OH), 7.73 (1H, d, J = 16.0 Hz, H-5), 7.69 (1H, dd, J = 8.0, 1.4 Hz, H-6′), 7.54 (1H, td, J = 7.7, 1.5 Hz, H-6′′), 7.43 (1H, ddd, J = 8.5, 7.1, 1.4 Hz, H-4′), 7.31-7.32 (1H, m, H-4′′), 7.16 (1H, t, J = 7.6 Hz, H-5′′), 7.09 (1H, t, J = 8.2 Hz, H-3′′), 6.97 (1H, dd, J = 8.5, 0.7 Hz, H-3′), 6.88 (1H, t, J = 8.1 Hz, H-5′), 6.70 (1H, d, J = 16.0 Hz, H-4), 6.32 (1H, s, H-2); 13C NMR (CDCl3, 100 MHz) δ 196.5 (C-1), 174.0 (C-3), 162.6 (C-2′), 161.4 (d, JCF = 253.8 Hz, C-2′′), 136.1 (C-4′), 132.6 (d, J = 2.2 Hz, C-5), 131.4 (d, J = 8.8 Hz, C-4′′), 129.2 (d, J = 3.0 Hz, C-6′′), 128.6 (C-6′), 124.8 (d, J = 7.8 Hz, C-4), 124.5 (d, J = 3.5 Hz, C-5′′), 123.1 (d, J = 11.5 Hz, C-1′′), 119.06 (C-5′), 119.04 (C-1′), 118.7 (C-3′), 116.3 (d, J = 21.9 Hz, C-3′′), 97.4 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −114.18; EIMS (probe) 70 eV (m/z, rel. int.) 284 M+ (26), 264 (7), 149 (100), 121 (59), 101 (20); calculated molecular mass: 284.28.
3-Hydroxy-1-(2-hydroxyphenyl)-5-(3-fluorophenyl)-2,4-pentadien-1-one (4b). Yellow solid residue (72% yield), mp 115–117°C, IR (KBr) υmax: 1641 (C=O), 1626 (C=C), 1581, 1488, 1429, 1294 (C–F), 1236 cm−1; 1H NMR (CDCl3, 400 MHz) δ 14.55 (s, 3-OH), 12.15 (s, 2′-OH), 7.68 (1H, dd, J = 8.0, 2.0 Hz, H-6′), 7.58 (1H, d, J = 15.8 Hz, 1H, H-5), 7.44 (1H, ddd, J = 8.5, 7.1, 1.5 Hz, H-4′), 7.34 (1H, dd, J = 7.9, 5.7 Hz, H-5′′), 7.30 (1H, d, J = 7.8 Hz, H-6′′), 7.24-7.25 (1H, m, H-2′′), 7.06-7.07 (1H, m, H-4′′), 6.89 (1H, ddd, J = 8.0, 7.1, 0.9 Hz, H-5′), 6.97 (1H, dd, J = 7.9, 0.9 Hz, H-3′), 6.56 (1H, d, J = 15.8 Hz, H-4), 6.32 (1H, s, H-2); 13C NMR (CDCl3, 100 MHz) δ 196.3 (C-1), 173.6 (C-3), 164.9 (d, JCF = 247.2 Hz, C-3′′), 162.7 (C-2′), 138.3 (d, J = 2.5 Hz, C-5), 137.3 (d, J = 7.8 Hz, C-1′′), 136.0 (C-4′), 130.5 (d, J = 8.23 Hz, C-5′′), 128.5 (C-6′), 124.1 (d, J = 2.8 Hz, C-6′′), 123.5 (C-4), 119.1 (C-5′), 119.0 (C-1′), 118.8 (C-3′), 116.9 (d, J = 21.6 Hz, C-4′′), 114.1 (d, J = 20.0 Hz, C-2′′), 97.4 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −112.32; EIMS (probe) 70 eV (m/z, rel. int.) 284 M+ (25), 149 (100), 265 (8), 121 (88), 101 (17); calculated molecular mass: 284.28.
3-Hydroxy-1-(2-hydroxyphenyl)-5-(4-fluorophenyl)-2,4-pentadien-1-one (4c). Pale yellow solid residue (92% yield); mp 130–132°C, IR (KBr) υmax: 1683 (C=O), 1627 (C=C), 1598, 1572, 1489, 1156 (C–F) cm−1; 1H NMR (CDCl3, 400 MHz) δ 14.62 (s, 3-OH), 12.17 (s, 2′-OH), 7.68 (1H, dd, J = 8.0, 1.4 Hz, H-6′), 7.60 (1H, d, J = 16.0 Hz, H-5), 7.52 (2H, dd, J = 8.9, 5.4 Hz, H-2′′/6′′), 7.44 (1H, ddd, J = 8.5, 7.1, 1.4 Hz, H-4′), 7.08 (2H, t, J = 8.9 Hz, H-3′′/5′′), 6.97 (1H, dd, J = 8.5, 0.9 Hz, H-3′), 6.88 (1H, ddd, J = 8.1, 7.1, 0.9 Hz, H-5′), 6.49 (1H, d, J = 16.0 Hz, H-4), 6.29 (1H, s, H-2); 13C NMR (CDCl3, 100 MHz) δ 196.0 (C-1), 174.3 (C-3), 163.8 (d, JCF = 250.3 Hz, C-4′′), 162.6 (C-2′), 138.5 (C-5), 135.9 (C-4′), 130.2 (d, J = 3.5 Hz, C-1′′), 129.8 (d, J = 8.2 Hz, C-2′′/6′′), 128.5 (C-6′), 121.9 (C-4), 119.04 (C-1′/5′), 118.8 (C-3′), 116.2 (d, J = 21.9 Hz, C-3′′/5′′), 97.0 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −109.55; EIMS (m/z, rel. int.) 284 M+ (21), 149 (100), 121 (71), 265 (4), 163 (16), 101 (18); calculated molecular mass: 284.28.
3-Hydroxy-1-(2-hydroxyphenyl)-5-(3,5-difluorophenyl)-2,4-pentadien-1-one (4d). Light brown solid residue (91% yield), mp 130–132°C, IR (KBr) υmax: 1698 (C=O), 1658 (C=C), 1119 (C–F), 962, 843 cm−1; 1H NMR (CDCl3, 400 MHz) δ 14.46 (s, 3-OH), 12.10 (s, 2′-OH), 7.67 (1H, dd, J = 8.0, 1.4 Hz, H-6′), 7.51 (1H, d, J = 15.7 Hz, H-5), 7.45 (1H, ddd, J = 8.5, 7.2, 1.6 Hz, H-4′), 7.04 (1H, dd, J = 8.2, 2.2 Hz, H-2′′/6′′), 6.98 (1H, dd, J = 8.5, 1.1 Hz, H-3′), 6.89 (1H, ddd, J = 8.1, 7.2, 1.1 Hz, H-5′), 6.80 (1H, tt, J = 8.8, 2.2 Hz, H-4′′), 6.55 (1H, d, J = 15.7 Hz, H-4), 6.32 (1H, s, H-2); 13C NMR (CDCl3, 100 MHz) δ 196.4 (C-1), 172.8 (C-3), 163.3 (d, JCF = 247.8 Hz, C-3′′/5′′), 162.7 (C-2′), 138.3 (t, J = 9.5 Hz, C-1′′), 137.0 (C-5), 136.2 (C-4′), 128.6 (C-6′), 124.8 (C-4), 119.1 (C-5′), 118.94 (C-1′), 118.85 (C-3′), 110.5 (dd, J = 18.5, 6.8 Hz, C-2′′/6′′), 105.1 (d, J = 25.6 Hz, C-4′′), 97.9 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −109.10; EIMS (m/z, rel. int.) 302 M+ (28), 167 (100), 121 (76), 285 (10), 139 (29), 121 (76); calculated molecular mass: 302.27.
3-Hydroxy-1-(4-fluoro-2-hydroxyphenyl)-5-(4-fluorophenyl)-2,4-pentadien-1-one (4e). Yellow solid residue (82% yield); mp 143–145°C; IR (KBr) υmax: 1726 (C=O), 1629 (C=C), 1234 (C–F), 1157, 975, 824, 803, 789 cm−1; 1H NMR (CDCl3, 400 MHz) δ 14.42 (s, 3-OH), 12.47 (s, 2′-OH), 7.60 (1H, d, J = 15.9 Hz, H-5), 7.68 (1H, dd, J = 9.0, 6.4 Hz, H-6′), 7.52 (1H, dd, J = 8.7, 5.4 Hz, H-2′′/6′′), 7.08 (2H, t, J = 8.6 Hz, H-3′′/5′′), 6.65 (1H, dd, J = 10.4, 2.5 Hz, H-3′), 6.60 (1H, ddd, J = 8.8, 8.2, 2.2 Hz, H-5′), 6.51 (1H, d, J = 15.9 Hz, H-4), 6.20 (1H, s, H-2); 13C NMR (CDCl3, 100 MHz) δ 194.9 (C-1), 174.2 (C-3), 166.4 (d, JCF = 212.1 Hz, C-4′), 165.2 (d, J = 14.1 Hz, C-2′), 163.0 (d, JCF = 252.6 Hz, C-4′′), 138.7 (C-5), 130.7 (d, J = 11.9 Hz, C-1′′), 130.4 (d, J = 10.8 Hz, C-6′), 129.9 (d, J = 8.6 Hz, C-2′′/6′′), 121.7 (C-4), 116.2 (d, J = 21.9 Hz, C-3′′/5′′), 116.0 (C-1′), 107.3 (d, J = 22.6 Hz, C-5′), 105.3 (d, J = 23.6 Hz, C-3′), 96.7 (C-2); 19F NMR (CDCl3, 376.5 MHz) δ −100.64, −109.57; EIMS (m/z, rel. int.) 302 M+ (41), 149 (100), 283 (18), 207 (11), 163 (35), 139 (95), 121 (37), 101 (35); calculated molecular mass: 302.27.
3-Hydroxy-1-(4-fluoro-2-hydroxyphenyl)-5-phenyl-2,4-pentadien-1-one (4f). Yellow solid residue (64% yield); mp 143–145°C; IR (KBr) υmax: 1632 (C=O), 1579 (C=C), 1178 (C–F) cm−1; 1H NMR (CDCl3, 400 MHz) δ 14.48 (s, 3-OH), 12.55 (s, 2′-OH), 7.68 (1H, dd, J = 8.9, 6.4 Hz, H-6′), 7.64 (1H, d, J = 15.8 Hz, H-5), 7.53 (dd, J = 8.1, 2.1 Hz, H-2′′/6′′), 7.37–7.39 (3H, m, H-3′′/4′′/5′′), 6.65 (dd, J = 10.3, 2.5 Hz, H-3′), 6.60 (1H, td, J = 8.0, 2.50 Hz, H-5′), 6.57 (1H, d, J = 15.8 Hz, H-4), 6.21 (1H, s, H-2); 13C NMR (CDCl3, 100 MHz) δ 194.9 (C-1), 174.4 (C-3), 165.2 (d, JCF = 209.2 Hz, C-4′), 165.1 (d, J = 14.1 Hz, C-2′), 140.1 (C-5), 134.9 (C-1′′), 130.5 (d, J = 11.7 Hz, C-6′), 130.2 (C-4′′), 129.0 (C-3′′/5′′), 128.0 (C-2′′/6′′), 122.0 (C-4), 116.0 (C-1′), 107.3 (d, J = 22.7 Hz, C-5′), 105.3 (d, J = 23.4 Hz, C-3′), 96.8 (C-2); 19F (CDCl3, 376.5 MHz) δ −100.72; EIMS (m/z, rel. int.) 284 M+ (33), 131 (100), 265 (14), 139 (64), 103 (42), 77 (39), 51 (11); calculated molecular mass: 284.28.
3-Hydroxy-1-(5-fluoro-2-hydroxyphenyl)-5-phenyl-2,4-pentadien-1-one (4g). Yellow solid residue (90% yield); mp 118–120°C; IR (KBr): 1632 (C=O), 1550, 1487, 1248, 1180, 960, 781, 754 cm−1; 1H NMR (CDCl3, 400 MHz) δ 14.59 (s, 3-OH), 11.94 (s, 2′-OH), 7.66 (1H, d, J = 15.8 Hz, H-5), 7.54 (2H, dd, J = 7.9, 2.2 Hz, H-2′′/6′′), 7.39–7.41 (3H, m, H-3′′/4′′/5′′), 7.34 (1H, dd, J = 9.0, 3.0 Hz, H-6′), 7.17 (1H, ddd, J = 9.2, 3.0, 1.3 Hz, H-4′), 6.93 (1H, dd, J = 9.1, 4.7 Hz, H-3′), 6.58 (1H, d, J = 15.8 Hz, H-4), 6.20 (1H, s, H-2); 13C NMR (CDCl3, 100 MHz) δ 194.8 (d, J = 2.7 Hz, C-1), 175.2 (C-3), 158.7 (C-2′), 155.1 (d, JCF = 236.8 Hz, C-5′), 140.6 (C-5), 134.8 (C-1′′), 130.4 (C-4′′), 129.0 (C-3′′/5′′), 128.1 (C-2′′/6′′), 123.2 (d, J = 23.4 Hz, C-4′), 121.9 (C-4), 120.0 (d, J = 7.41 Hz, C-3′), 118.7 (d, J = 6.5 Hz, C-1′), 113.46 (d, J = 23.5 Hz, C-6′), 96.8 (C-2); 19F (CDCl3, 376.5 MHz) δ −124.33; EIMS (probe) 70 eV (m/z, rel. int.) 284 M+ (5), 131 (100), 103 (80), 77 (35); calculated molecular mass: 284.28.
3-Hydroxy-1-(2-hydroxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadien-1-one (4h). Yellow solid residue (90% yield); mp 167–169°C (lit. 162–164°C [38]); IR (KBr) υmax: 1645 (C=O), 1599, 1514, 1462, 1258, 963, 828, 749 cm−1; 1H NMR (CDCl3, 400 MHz) δ 14.72 (s, 3-OH), 12.24 (s, 2′-OH), 7.67 (1H, dd, J = 8.0, 1.6 Hz, H-6′), 7.61 (1H, d, J = 15.8 Hz, H-5), 7.49 (2H, d, J = 8.8 Hz, H-2′′/6′′), 7.42 (1H, ddd, J = 8.5, 7.5, 1.6 Hz, H-4′), 6.96 (1H, dd, J = 8.5, 2.1 Hz, H-3′), 6.91 (2H, d, J = 8.8 Hz, H-3′′/5′′), 6.88-6.89 (1H, m, H-5′), 6.45 (d, J = 15.8 Hz, H-4), 6.26 (1H, s, H-2), 3.83 (s, 3H, OCH3); 13C NMR (CDCl3, 100 MHz) δ 195.3 (C-1), 174.9 (C-3), 162.3 (C-2′), 161.1 (C-4′′), 139.5 (C-5), 135.3 (C-4′), 129.8 (C-1′′), 129.4 (C-2′′/6′′), 128.8 (C-6′), 119.4 (C-4), 118.9 (C-1′), 118.7 (C-5′), 118.44 (C-3′), 114.2 (C-3′′/5′′), 96.1 (C-2), 55.2 (OCH3); EIMS (probe) 70 eV (m/z, rel. int.) 296 M+ (14), 161 (100), 207 (18), 133 (77), 118 (29); calculated molecular mass: 296.10.
3-Hydroxy-1-(2-hydroxyphenyl)-5-(3,4-dimethoxyphenyl)-2,4-pentadien-1-one (4i). Yellow solid residue (84% yield); mp 130–132°C (lit. 136–138°C [37]); IR (KBr): 1685 (C=O), 1621, 1564, 1488, 1252, 1161; 1H NMR (CDCl3, 400 MHz) δ 14.71 (s, 3-OH), 12.23 (s, 2′-OH), 7.67 (1H, dd, J = 8.1, 1.5 Hz, H-6′), 7.59 (1H, d, J = 15.8 Hz, H-5), 7.42 (1H, ddd, J = 8.5, 8.3, 1.5 Hz, H-4′), 7.11 (dd, J = 8.3, 1.9 Hz, H-6′′), 7.1 (d, J = 1.8 Hz, H-2′′), 6.96 (1H, dd, J = 8.4, 0.7 Hz, H-3′), 6.87 (1H, d, J = 8.3 Hz, H-5′′), 6.85 (1H, td, J = 8.3, 0.7 Hz, H-5′), 6.45 (1H, d, J = 15.8 Hz, H-4), 6.28 (1H, s, H-2), 3.92 (3H, s, 4′-OCH3), 3.91 (3H, s, 3′-OCH3); 13C NMR (CDCl3, 100 MHz) δ 195.6 (C-1), 175.0 (C-3), 162.5 (C-2′), 151.1 (C-3′′), 149.3 (C-4′′), 140.0 (C-5), 135.6 (C-4′), 128.4 (C-6′), 128.0 (C-1′′), 122.6 (C-6′′), 119.9 (C-4), 119.1 (C-1′), 119.0 (C-5′), 118.7 (C-3′), 111.2 (C-5′′), 109.7 (C-2′′), 96.5 (C-2), 56.0 (3′′-OCH3), 55.93 (4′′-OCH3); EIMS (probe) 70 eV (m/z, rel. int.) 326 M+ (15), 191 (100), 207 (16), 163 (49), 148 (19), 133 (18), 77 (23); calculated molecular mass: 326.12.
3-Hydroxy-1-(2-hydroxyphenyl)-5-(3,4-methylenedioxyphenyl)-2,4-pentadien-1-one (4j). Light yellow solid residue (94% yield); mp 165–167°C; IR (KBr) υmax: 1693 (C=O), 1621, 1602, 1566, 1484, 1446, 1239 (C–O), 1171, 1035, 925 cm−1; 1H NMR (CDCl3, 400 MHz) δ 14.68 (s, 3-OH), 12.21 (s, 2′-OH), 7.66 (1H, dd, J = 8.0, 1.6 Hz, H-6′), 7.55 (1H, d, J = 15.8 Hz, H-5), 7.42 (1H, ddd, J = 8.5, 8.0, 1.6 Hz, H-4′), 7.04 (1H, bd, J = 0.35 Hz, H-2′′), 7.02 (1H, dd, J = 8.0, 1.2 Hz, H-6′′), 6.96 (1H, dd, J = 8.5, 0.5 Hz, H-3′), 6.87 (1H, td, J = 8.0, 0.5 Hz, H-5′), 6.81 (1H, d, J = 8.0 Hz, H-5′′), 6.39 (1H, d, J = 15.8 Hz, H-4), 6.26 (1H, s, H-2), 6.00 (2H, s, OCH2O); 13C NMR (CDCl3, 100 MHz) δ 195.7 (C-1), 174.8 (C-3), 162.6 (C-2′), 149.6 (C-3′′), 148.5 (C-4′′), 139.7 (C-5), 135.7 (C-4′), 129.5 (C-1′′), 128.4 (C-6′), 124.6 (C-6′′), 120.1 (C-4), 119.1 (C-1′), 119.0 (C-5′), 118.73 (C-3′), 108.7 (C-5′′), 106.3 (C-2′′), 101.6 (OCH2O), 96.6 (C-2); EIMS (probe) 70 eV (m/z, rel. int.) 310 M+ (18), 175 (100), 207 (28), 145 (87), 157 (42), 117 (44), 89 (52), 43 (62); calculated molecular mass: 310.30.
2.5. Typical Procedure for the Synthesis of Substituted 2-Styrylchromones (5a–j)
p-Toluenesulfonic acid (3.42 mmol, 0.59 g) was added to a solution of the appropriate 3-hydroxy-1-(2-hydroxyphenyl)-5-(phenyl)-2,4-pentadien-1-ones 4a–j (6.5 mmol) in Me2SO (20 mL). The reaction mixture was heated at 90°C for 2 h and then poured into ice and water (20 mL) and stirred for 10 min. The obtained solid was removed by filtration, dissolved in CHCl3 (100 mL), and washed with a 20% aqueous solution of sodium thiosulphate (3 × 10 mL). The solvent was evaporated to dryness, and the residue was purified by silica gel chromatography, using CHCl3 : n-hexane (7 : 3) as the eluent, to produce 5a–j.
2′-Fluro-2-styrylchromone (5a). Light yellow solid residue (68% yield); mp 150–152°C; UV λmax (CH3OH) nm (log ε): 325 (3.37); IR (KBr) υmax: 1682 (C=O), 1625, 1589 (C–C), 1562, 1464, 1391 (C–F), 1125, 968 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.17 (1H, dd, J = 7.9, 1.6 Hz, H-5), 7.72 (1H, d, J = 16.2 Hz, H-β), 7.66 (1H, ddd, J = 8.6, 7.2, 1.6 Hz, H-7), 7.59 (1H-td, J = 7.6, 1.5 Hz, H-6′), 7.53 (1H, d, J = 8.3 Hz, H-8), 7.37 (1H, td, J = 7.9, 0.8 Hz, H-6), 7.31-7.32 (1H, m, H-4′), 7.17 (1H, t, J = 7.9 Hz, H-5′), 7.11 (1H, ddd, J = 9.2, 8.2, 2.4 Hz, H-3′), 6.87 (1H, d, J = 16.2 Hz, H-α), 6.32 (1H, s, H-3); 13C NMR (CDCl3, 100 MHz) δ 178.5 (C-4), 161.5 (C-2), 161.2 (d, JCF = 253.3 Hz, C-2′), 156.0 (C-9), 133.9 (C-7), 131.3 (d, J = 8.7 Hz, C-4′), 129.5 (d, J = 3.1 Hz, C-β), 128.4 (d, J = 2.7 Hz, C-6′), 125.7 (C-5), 125.1 (C-6), 124.6 (d, J = 3.6 Hz, C-5′), 124.1 (C-10), 123.1 (d, J = 11.7 Hz, C-1′), 122.7 (d, J = 6.5 Hz, C-α), 117.9 (C-8), 116.2 (d, J = 21.8 Hz, C-3′), 111.2 (C-3); 19F NMR (CDCl3, 376.5 MHz) δ −115.39; EIMS (m/z, rel. int.) 265 (M+-1) (100), 237 (12), 207 (20), 146 (36), 92 (25); HRMS (m/z) M+ 266.0733 (calculated for C17H11FO2: 266.0743).
3′-Fluro-2-styrylchromone (5b). Brown solid residue (62% yield), mp 105–108°C; UV λmax (CH3OH) nm (log ε): 325 (3.34); IR (KBr) υmax: 1694 (C=O), 1622, 1579 (C–C), 1465, 1389 (C–F), 1247, 1122, 967, 775 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.18 (dd, J = 7.9, 1.6 Hz, H-5), 7.68 (dt, J = 8.6, 1.6 Hz, H-7), 7.52 (d, J = 8.3 Hz, H-8), 7.55 (1H, d, J = 16.0 Hz, H-β), 7.35–7.37 (3H, m, H-5′/6′/6), 7.26-7.27 (1H, m, H-2′), 7.06 (1H, d, J = 6.8 Hz, H-4′), 6.77 (1H, d, J = 16.0 Hz, H-α), 6.34 (1H, s, H-3); 13C NMR (CDCl3, 100 MHz) δ 178.5 (C-4), 163.2 (d, JCF = 245.5 Hz, C-3′), 161.2 (C-2), 156.0 (C-9), 137.3 (d, J = 7.8 Hz, C-1′), 135.6 (d, J = 2.8 Hz, C-β), 133.9 (C-7), 130.5 (d, J = 8.3 Hz, C-5′), 125.8 (C-5), 125.1 (C-6), 124.1 (C-10), 123.61 (d, J = 2.7 Hz, C-6′), 121.7 (C-α), 117.9 (C-8), 116.7 (d, J = 21.6 Hz, C-4′), 114.0 (d, J = 22.0 Hz, C-2′), 111.2 (C-3); 19F NMR (CDCl3, 376.5 MHz) δ −108.99; EIMS (m/z, rel. int.) 265 (M+-1) (100), 237 (6), 209 (8), 173 (16), 146 (40), 121 (20), 92 (27); HRMS (m/z): 266.0726 M+ (calculated for C17H11FO2: 266.0743).
4′-Fluoro-2-styrylchromone (5c). Off-white solid residue (70% yield), mp 158–160°C; UV λmax (CH3OH) nm (log ε): 328 (3.39); IR (KBr): 1691 (C=O), 1623, 1594, 1506, 1466, 1391 (C–F), 1224, 969, 817 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.01 (1H, dd, J = 7.9, 1.4 Hz, H-5), 7.81-7.82 (1H, m, H-7), 7.79 (2H, m, H-2′/6′), 7.70 (1H, d, J = 16.2 Hz, H-β), 7.69 (1H, d, J = 8.5 Hz, H-8), 7.47 (1H, t, J = 7.4 Hz, H-6), 7.28 (2H, t, J = 8.8 Hz, H-3′/5′), 7.16 (1H, d, J = 16.2 Hz, H-α), 6.46 (1H, s, H-3); 13C NMR (CDCl3, 100 MHz) δ 177.1 (C-4), 162.88 (d, JCF = 240.6 Hz, C4’), 161.7 (C-2), 155.4 (C-9), 135.4 (C-β), 134.4 (C-7), 131.6 (d, J = 3.2 Hz, C-1′), 130.0 (d, J = 8.1 Hz, C-2′/6′), 125.3 (C-6), 124.8 (C-5), 123.4 (C-10), 120.4 (C-α), 118.2 (C-8), 116.0 (d, J = 24.3 Hz, C-3′/5′), 110.1 (C-3); 19F NMR (CDCl3, 376.5 MHz) δ −110.72; EIMS (m/z, rel. int.) 265 (M+-1) (100), 237 (8), 207 (13), 173 (10), 146 (39), 120 (18), 92 (20); HRMS (m/z): 266.0721 M+ (calculated for C17H11FO2: 266.0743).
3′,5′-Difluoro-2-styrylchromone (5d). Light brown solid residue (92% yield); mp 114–116°C; UV λmax (CH3OH) nm (log ε) 322 (3.49); IR (KBr) υmax: 1701 (C=O), 1615, 1586, 1465, 1390 (C–F), 1309, 1272, 1117 (C–F), 966, 847, 751 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.18 (1H, dd, J = 7.9, 1.6 Hz, H-5), 7.72 (1H, ddd, J = 8.5, 7.2, 1.6 Hz, H-7), 7.51 (1H, d, J = 8.3 Hz, H-8), 7.49 (1H, d, J = 16.0 Hz, H-β), 7.39 (1H, td, J = 7.9, 0.7 Hz, H-6), 7.08 (2H, dd, J = 8.1, 1.9 Hz, H-2′/6′), 6.76 (1H, d, J = 16.0 Hz, H-α), 6.81 (1H, tt, J = 8.7, 2.4 Hz, H-4′), 6.34 (1H, s, H-3); 13C NMR (CDCl3, 100 MHz) δ 178.3 (C-4), 163.4 (dd, JCF = 247.8, 12.9 Hz, C3′/5′), 160.6 (C-2), 156.0 (C-9), 138.3 (t, J = 11.2 Hz, C-1′), 134.0 (C-7), 134.2 (t, J = 3.0 Hz, C-β), 125.8 (C-5), 125.3 (C-6), 124.1 (C-10), 123.0 (C-α), 117.9 (C-8), 111.7 (C-3), 110.3 (dd, J = 18.5, 7.2 Hz, C-2′/6′), 105.0 (t, J = 25.4 Hz, C-4′); 19F NMR (CDCl3, 376.5 MHz) δ −109.31; EIMS (m/z, rel. int.) 284 M+ (100), 267 (82), 191 (40), 164 (63), 121 (58), 92 (65), 64 (21); HRMS (m/z): 284.0633 M+ (calculated for C17H10F2O2: 284.0649).
7,4′-Difluoro-2-styrylchromone (5e). Pale yellow solid residue (45% yield); mp 182–184°C; UV λmax (CH3OH) nm (log ε) 322 (3.54); IR (KBr): 1659 (C=O), 1621 (C=C), 1598, 1511, 1438, 1377 (C–F), 1233, 1140, 1112, 967 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.18 (1H, dd, J = 8.8, 6.4 Hz, H-5), 7.56 (2H, dd, J = 8.6, 5.6 Hz, H-2′/6′), 7.53 (1H, d, J = 16.0 Hz, H-β), 7.20 (1H, dd, J = 9.0, 2.4 Hz, H-8), 7.11-7.12 (1H, m, H-6), 7.10 (2H, t, J = 8.6 Hz, H-3′/5′), 6.67 (1H, d, J = 16.0 Hz, H-α), 6.28 (1H, s, H-3); 13C NMR (CDCl3, 100 MHz) δ 177.4 (C-4), 167.1 (d, JCF = 210.1 Hz, C-7), 165.0 (d, JCF = 251.6 Hz, C-4′), 161.8 (C-2), 156.9 (C-9), 135.8 (C-β), 131.2 (d, J = 3.6 Hz, C-1′), 129.5 (d, J = 8.2 Hz, C-2′/6′), 128.2 (d, J = 10.5 Hz, C-5), 121.0 (C-10), 119.7 (C-α), 116.2 (d, J = 21.9 Hz, C-3′/5′), 113.7 (d, J = 22.5 Hz, C-6), 110.6 (C-3), 104.6 (d, J = 25.5 Hz, C-8); 19F NMR (CDCl3, 376.5 MHz) δ −102.96, −109.89; EIMS (m/z, rel. int.) 283 (M+-1) (100), 267 (56), 255 (8), 227 (13), 173 (13), 146 (50), 120 (10); HRMS (m/z): 284.0642 (calculated for C17H10F2O2: 284.0649).
7-Fluoro-2-strychromone (5f). Off-white solid residue (94% yield); mp 116–118°C; UV λmax (CH3OH) nm (log ε) 312 (3.35); IR (KBr) υmax: 1667 (C=O), 1599, 1538, 1438, 1382 (C–F stretch), 1143, 1012, 960 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.19 (1H, dd, J = 8.9, 6.4 Hz, H-5), 7.59 (1H, d, J = 16.0 Hz, H-β), 7.58 (2H, dd, J = 8.1, 1.5 Hz, H-2′/6′), 7.39–7.41 (3H, m, H-3′/4′/5′), 7.21 (1H, dd, J = 9.1, 2.4 Hz, H-8), 7.10 (1H, td, J = 8.6, 2.4 Hz, H-6), 6.76 (1H, d, J = 16.0 Hz, H-α), 6.29 (1H, s, H-3); 13C NMR (CDCl3, 100 MHz) δ 177.5 (C-4), 164.5 (d, JCF = 240.0 Hz, C-7), 162.0 (C-2), 157.1 (d, J = 13.2 Hz, C-9), 137.2 (C-β), 134.9 (C-1′), 130.0 (C-4′), 129.05 (C-3′/5′), 128.2 (d, J = 10.6 Hz, C-5), 127.7 (C-2′/6′), 121.0 (C-10), 119.9 (C-α), 113.7 (d, J = 22.6 Hz, C-6), 110.6 (C-3), 104.6 (d, J = 25.4 Hz, C-8); 19F NMR (CDCl3, 376.5 MHz) δ −103.04; EIMS (m/z, rel. int.) 265 (M+-1) (100), 250 (36), 237 (5), 209 (7), 128 (29), 102 (8); HRMS (m/z): 266.0730 (calculated for C17H11FO2: 266.0743).
6-Fluoro-2-styrylchromone (5g). Light green solid residue (89% yield); mp 108–110°C; IR (KBr): 1710 (C=O), 1628, 1567, 1478, 1445, 1378, 1284, 1172, 967, 818, 751 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.85 (1H, dd, J = 8.2, 3.2 Hz, H-5), 7.60 (1H, d, J = 16.1 Hz, H-β), 7.56 (2H, d, J = 8.0 Hz, H-2′/6′), 7.52 (1H, dd, J = 9.10, 4.15 Hz, H-8), 7.39–7.41 (4H, m, H-3′/4′/5′/7), 6.77 (1H, d, J = 16.1 Hz, H-α), 6.31 (1H, s, H-3); 13C NMR (CDCl3, 100 MHz) δ 177.6 (d, J = 2.3 Hz, C-4), 162.0 (C-2), 159.5 (d, JCF = 245.1 Hz, C-6), 152.20 (C-9), 137.4 (C-β), 134.9 (C-1′), 130.0 (C-4′), 129.1 (C-3′/5′), 127.7 (C-2′/6′), 125.5 (d, J = 7.1 Hz, C-10), 121.8 (d, J = 25.13 Hz, C-7), 120.03 (C-α), 119.9 (d, J = 7.9 Hz, C-8), 110.7 (d, J = 23.4 Hz, C-5), 109.9 (C-3); 19F NMR (CDCl3, 376.5 MHz) δ −115.51; EIMS (m/z, rel. int.) 265 (M+-1) (100), 249 (43), 237 (9), 209 (12), 128 (56); calculated molecular mass: 266.67.
4′-Methoxy-2-styrylchromone (5h). Yellow solid residue (90% yield); mp 140-141°C (lit. 139-140 [11]; UV λmax (CH3OH) nm (log ε) 354 (3.33); IR (KBr) υmax: 1645 (C=O), 1599, 1514, 1462, 462, 1258, 963, 828, 749 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.18 (1H, dd, J = 8.0, 1.6 Hz, H-5), 7.65 (1H, ddd, J = 8.6, 7.1, 1.6 Hz, H-7), 7.55 (1H, d, J = 16.0 Hz, H-β), 7.52 (1H, d, J = 8.6 Hz, H-8), 7.48 (2H, d, J = 8.7 Hz, H-2′/6′), 7.36 (1H, t, J = 8.0 Hz, H-6), 6.92 (2H, d, J = 8.7 Hz, H-3′/5′), 6.64 (1H, d, J = 16.0 Hz, H-α), 6.28 (1H, s, H-3), 3.84 (3H, s, OCH3); 13C NMR (CDCl3, 100 MHz) δ 178.5 (C-4), 162.3 (C-2), 161.1 (C-4′), 156.0 (C-9), 136.7 (C-β), 133.6 (C-7), 131.0 (C-1′), 129.3 (C-2′/6′), 125.7 (C-5), 124.9 (C-6), 124.2 (C-10), 117.90 (C-α), 117.85 (C-8), 114.5 (C-3′/5′), 109.9 (C-3), 55.4 (OCH3); EIMS (m/z, rel. int.) 277 (M+-1) (100), 247 (21), 207 (19), 158 (38), 115 (55); calculated molecular mass: 278.30.
3′,4′-Dimethoxy-2-styrylchromone (5i). Yellow solid residue (55% yield); mp 162-163°C (lit. 163-164°C [11]); UV λmax (CH3OH) nm (log ε) 367 (3.18); IR (KBr) υmax: 1682 (C=O), 1617, 1558, 1509, 1464, 1381, 1261, 1138, 1025, 965, 780, 759 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.01 (1H, dd, J = 7.9, 1.7 Hz, H-5), 7.81 (1H, ddd, J = 8.2, 7.2, 1.7 Hz, H-7), 7.70 (1H, d, J = 8.2 Hz, H-8), 7.65 (1H, d, J = 16.0 Hz, H-β), 7.47 (1H, ddd, J = 7.9, 7.2, 0.7 Hz, H-6), 7.36 (1H, d, J = 1.7 Hz, H-2′), 7.27 (1H, dd, J = 8.3, 1.7 Hz, H-6′), 7.11 (1H, d, J = 16.0 Hz, H-α), 7.02 (1H, d, J = 8.3 Hz, H-5′), 6.40 (1H, s, H-3), 3.80 (3H, s, 3′-OCH3), 3.83 (s, 3H, 4′-OCH3); 13C NMR (CDCl3, 100 MHz) δ 177.0 (C-4), 162.3 (C-2), 155.4 (C-9), 150.5 (C-4′), 149.0 (C-3′), 136.9 (C-β), 134.2 (C-7), 127.8 (C-1′), 125.2 (C-6), 124.7 (C-5), 123.4 (C-10), 122.3 (C-6′), 118.1 (C-8), 118.0 (C-α), 111.7 (C-5′), 109.9 (C-2′), 109.2 (C-3), 55.5 (2 × OCH3); EIMS (m/z, rel. int.) 308 (M+) (100), 277 (22), 250 (10), 221 (14), 188 (70), 121 (19); calculated molecular mass: 308.33.
3′,4′-Methylenedioxy-2-styrylchromone (5j). Yellow solid residue (92% yield); mp 209-210°C (lit. 209-210°C [11]); UV λmax (CH3OH) nm (log ε) 329 (3.36); IR (KBr) υmax: 1694 (C=O), 1625, 1461, 1499, 1447, 1383, 1251, 845 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.17 (1H, d, J = 7.6 Hz, H-5), 7.65 (1H, ddd, J = 8.1, 7.1, 1.0 Hz, H-7), 7.51 (1H, d, J = 7.8 Hz, H-8), 7.50 (1H, d, J = 16.1 Hz, H-β), 7.37 (1H, t, J = 7.5, H-6), 7.08 (1H, s, H-2′), 7.05 (1H, d, J = 8.1 Hz, H-6′), 6.81 (1H, d, J = 8.1 Hz, H-5′), 6.59 (1H, d, J = 16.1, H-α), 6.28 (1H, s, H-3), 6.01 (2H, s, OCH2O); 13C NMR (CDCl3, 100 MHz) δ 178.5 (C-4), 162.0 (C-2), 156.0 (C-9), 149.3 (C-3′), 148.5 (C-4′), 136.7 (C-β), 133.7 (C-7), 129.5 (C-1′), 125.7 (C-5), 125.0 (C-6), 123.9 (C-6′), 123.3 (C-10), 118.4 (C-α), 117.8 (C-8), 110.2 (C-3), 108.7 (C-5′), 106.2 (C-2′), 101.6 (OCH2O); EIMS (m/z, rel. int.) 291 (M+-1) (100), 275 (55), 233 (18), 205 (24), 172 (67), 114 (29); calculated molecular mass: 292.29.
2.6. X-Ray Crystallographic Study
Single-crystal X-ray diffraction data were collected on a Bruker KAPPA APEX II DUO diffractometer using graphite-monochromated Mo-Kα radiation (χ = 0.71073 Å). Data collection was carried out at 173(2) K. Temperature was controlled by an Oxford Cryostream cooling system (Oxford Cryostat). Cell refinement and data reduction were performed using the program SAINT [39]. The data were scaled, and absorption correction was performed using SADABS [40]. The structure was solved by direct methods using SHELXS-97 [40] and refined by full-matrix least-squares methods based on F2 using SHELXL-97 [40] and using the graphics interface program X-Seed [41, 42]. The programs X-Seed and POV-Ray were both used to prepare molecular graphic images. All nonhydrogen atoms were refined anisotropically, and all hydrogen atoms could be found in the difference electron density maps but were placed in idealised positions and refined in riding models with Uiso set at 1.2 times those of their parent atoms and at a distance (C–H) of 0.95 Å. The structure was refined to a R factor of 0.0503.
CCDC 897969 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: deposit@ccdc.cam.ac.uk).
2.7. Antibacterial Assay
In vitro evaluation of antibacterial activity was carried out on all synthesized, fluorinated, and oxygenated 2-styrylchromones by the disc diffusion method as described by Bauer et al. [43] against the Gram-positive bacteria, Bacillus subtilis, Enterococcus faecium, and three Staphylococcus species, aureus, sciuri, and xylosus, and the Gram-negative bacteria, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The standard antibiotics, tetracycline (Te) and ampicillin (Amp), were used as controls and for comparison. Briefly, Mueller Hilton agar was prepared (38 g in 1 L of water) and poured into prelabeled sterile Petri dishes, which were then allowed to set and dry at room temperature. The bacterial organisms were standardized using a 0.5 McFarland standard turbidity and then swabbed onto the agar plates. Paper discs with dissolved sample and a control disc was placed onto the agar plates, which were inverted and incubated at 35–37°C for 24 hours. The diameter of the inhibition zones were then measured in mm. The tests were done in triplicate, and the results were reported as means of at least three determinations. The results are summarized in Tables 2 and 3.
The activity index of the product 2-styrylchromones was calculated as follows: Activity index (A.I.) = zone of inhibition of compound/Zone of inhibition obtained for the standard antibiotic drug.