Chemistry
All solvents and reagents were from Sigma Aldrich and used without further purification. All melting points are uncorrected and were determined on a Büchi Melting Point M-560 apparatus. FTIR spectra were recorded by a Perkin Elmer FTIR Spectrum One by using ATR system (4000–650 cm−1). The 1H and 13C NMR spectra were recorded at 298 K on a JEOL ECA 400 MHz or Bruker Advance 500 MHz spectrometer equipped with a z-gradient, triple-resonance (1H, 13C, 15N) cryoprobe, using DMSO-d6 as solvent. The 19F-NMR spectra were acquired on an Oxford Instruments Pulsar benchtop NMR 60 MHz Spectrometer. Chemical shifts are expressed in ppm with tetramethylsilane (TMS, δ = 0 ppm) as an internal reference for protons and trifluoroacetic acid (TFA, δ = − 75.39 ppm) for fluorine. Accurate mass data were obtained using a Waters (Waltham, MA) model LCT Premiere time-of-flight (TOF) mass spectrometer. Reactions were monitored by TLC on silica gel using ethyl acetate/hexane mixtures as a solvent and compounds visualized by UV lamp. The reported yields are for the purified material and are not optimized.
General procedure for the synthesis of 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) 3a–q
To a solution of 0.4 mmol aldehyde 2a–q and 0.8 mmol pyrazole 1 in 4 mL of 70% EtOH at room temperature, 40.2 μL of 1 M NaOAc were added and the mixture was stirred until the reaction was complete (see Table 1). Water was added to obtain 50% EtOH and the mixture was filtered, washed with 50% EtOH and dried to obtain pure product.
4,4ʹ-[(2-Hydroxyphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3a
Yield 98% as a white solid; mp 219.5–220.6 °C [Lit. 218–220 [39]]; 1H-NMR (400 MHz, DMSO-d6) δ: 14.30 (br. s., 1 H, OH), 12.38 (br. s., 1 H, OH), 9.51 (br. s., 1 H, OH), 7.70 (d, J = 8.0 Hz, 4 H, Ar–H), 7.56 (d, J = 7.6 Hz, 1 H, Ar–H), 7.43 (t, J = 7.6 Hz, 4 H, Ar–H), 7.24 (t, J = 6.7 Hz, 2 H, Ar–H), 6.97 (t, J = 7.6 Hz, 1 H, Ar–H), 6.75 (d, J = 7.9 Hz, 1 H, Ar–H), 6.71 (t, J = 7.6 Hz, 1 H, Ar–H), 5.18 (s, 1 H, CH), 2.29 (s, 6 H, CH3).
4,4ʹ-(Phenylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3b
Yield 97% as a white solid; mp 159.5–161.1 °C [Lit. 161–163 [40]]; 1H-NMR (400 MHz, DMSO-d6) δ: 13.94 (br. s., 1 H, OH), 12.44 (br. s., 1 H, OH), 7.71 (d, J = 7.9 Hz, 4 H, Ar–H), 7.44 (t, J = 7.9 Hz, 4 H, Ar–H), 7.31–7.21 (m, 6 H, Ar–H), 7.20–7.14 (m, 1 H, Ar–H), 4.96 (s, 1 H, CH), 2.32 (br. s., 6 H, CH3).
4,4'-[(2-Nitrophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3c
Yield 95% as a yellow solid; mp 210.0–211.0 °C [Lit. 218–220 [41]]; 1H-NMR (400 MHz, DMSO-d6) δ: 13.35 (br. s., 1 H, OH), 12.60 (br. s., 1 H, OH), 7.72 (d, J = 7.9 Hz, 1 H, Ar–H), 7.66 (d, J = 7.9 Hz, 4 H, Ar–H), 7.62 (m, 2 H, Ar–H), 7.48 (m, 1 H, Ar–H), 7.43 (t, J = 7.9 Hz, 4 H, Ar–H), 7.25 (t, J = 7.3 Hz, 2 H, Ar–H), 5.43 (s, 1 H, CH), 2.24 (br. s., 6 H, CH3).
4,4'-[(3-Nitrophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3d
Yield 95% as a white solid; mp 150.7–152.0 °C [Lit. 150–152 [42]]; 1H-NMR (400 MHz, DMSO-d6) δ: 13.87 (br. s., 1 H, OH), 12.64 (br. s., 1 H, OH), 8.09 (s, 1 H, Ar–H), 8.08 (d, J = 8.6 Hz, 1 H, Ar–H), 7.74 (d, J = 7.9 Hz, 1 H, Ar–H), 7.70 (d, J = 8.5 Hz, 4 H, Ar–H), 7.61 (t, J = 8.6, 7.9 Hz, 1 H, Ar–H), 7.45 (t, J = 7.9 Hz, 4 H, Ar–H), 7.26 (d, J = 7.4 Hz,, 2 H, Ar–H), 5.15 (s, 1 H, CH), 2.35 (br. s., 6 H, CH3).
4,4'-[(3-Fluorophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3e
Yield quantitative as a white solid; mp 178.0–179.0 °C [Lit. 183–184 [40]]; 1H-NMR (500 MHz, DMSO-d6) δ: 7.70 (d, J = 8.0 Hz, 4H, Ar–H), 7.44 (t, J = 7.8 Hz, 4H, Ar–H), 7.29–7.36 (m, 1H, Ar–H), 7.21—7.28 (m, 2H, Ar–H), 7.10 (d, J = 8.2 Hz, 1H, Ar–H), 6.98–7.04 (m, 2H, Ar–H), 4.97 (s, 1H, CH), 2.31 (br. s., 6H, CH3).
4,4'-[(3-Hydroxyphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3f
Yield 98% as a white solid; mp 165.0–167.0 °C [Lit. 164–166 [43]]; 1H-NMR (400 MHz, DMSO-d6) δ: 13.95 (br. s., 1H, OH), 9.21 (s, 1H, Ar–H), 7.71 (d, J = 7.9 Hz, 4H, Ar–H), 7.44 (t, J = 7.8 Hz, 4H, Ar–H), 7.24 (t, J = 7.3 Hz, 2H, Ar–H), 7.04 (t, J = 7.8 Hz, 1H, Ar–H), 6.68 (br. s, 1H, OH), 6.65 (d, J = 7.7 Hz, 1H, Ar–H), 6.55 (dd, J = 7.9, 1.5 Hz, 1H, Ar–H), 4.86 (s, 1H), 2.30 (br. s., 6H).
4,4'-[(3-Hydroxy-4-nitrophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3g
Yield 99% as a yellow solid; mp 202.0–204.0 °C (d); FTIR (cm−1): 3616 (OH), 1604 (C=C), 1600 (C=N), 1577 (NO2), 1499 (C=C), 1353 (OH), 1331 (NO2), 1233 (OH), 1120 (C–OH); 1H-NMR (500 MHz, DMSO-d6) δ: 13.84 (br. s., 1 H, OH), 10.84 (s, 1 H, OH), 7.83 (d, J = 8.2 Hz, 1 H, Ar–H), 7.71 (d, J = 8.2 Hz, 4 H, Ar–H), 7.45 (t, J = 8.0 Hz, 4 H, Ar–H), 7.26 (t, J = 7.4 Hz, 2 H, Ar–H), 7.04 (s, 1 H, Ar–H), 6.81 (dd, J = 1.9, 8.5 Hz, 1 H, Ar–H), 5.00 (s, 1 H, CH), 2.33 (br. s., 6 H, CH3); 13C-NMR (126 MHz, DMSO-d6) δ: 152.1, 150.5, 146.3, 134.7, 129.0, 125.7, 125.2, 120.6, 118.7, 118.4, 117.5, 33.0; ESI–MS m/z 497.8 [M]+.
4,4'-[(3-Hydroxy-4-methoxyphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3h
Yield 91% as a white solid; mp 200.0–202.0 °C [Lit. 201–203 [44]]; 1H-NMR (500 MHz, DMSO-d6) δ: 13.90 (br. s., 1 H, OH), 12.38 (br. s., 1 H, OH), 8.82 (br. s., 1 H, OH), 7.71 (d, J = 8.23 Hz, 4 H, Ar–H), 7.44 (t, J = 7.68 Hz, 4 H, Ar–H), 7.24 (t, J = 6.86 Hz, 2 H, Ar–H), 6.79 (d, J = 8.78 Hz, 1 H, Ar–H), 6.69 (d, J = 1.65 Hz, 1 H, Ar–H), 6.59 (dd, J = 8.23, 1.65 Hz, 1 H, Ar–H), 4.83 (s, 1 H, CH), 3.70 (s, 3 H, OCH3), 2.30 (br. s., 6 H, CH3).
4,4'-[(3,4-Dihydroxyphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3i
Yield 93% as a cream solid; mp 182.7–184.0 °C; FTIR (cm−1): 3206 (OH), 1598(C=N), 1568 (C=C), 1501 (C=C), 1368 (OH), 1291 (OH), 1191 (C-O); 1H-NMR (500 MHz, DMSO-d6) δ: 13.90 (br. s., 1 H, OH), 12.34 (br. s., 1 H, OH), 8.74 (s, 1 H, OH), 8.60 (br. s., 1 H, OH), 7.72 (d, J = 7.7 Hz, 4 H, Ar–H), 7.44 (t, J = 7.7 Hz, 4 H, Ar–H), 7.24 (t, J = 7.1 Hz, 2 H, Ar–H), 6.66 (d, J = 1.6 Hz, 1 H, Ar–H), 6.61 (d, J = 8.2 Hz, 1 H, Ar–H), 6.47 (dd, J = 1.6, 8.2 Hz, 1 H, Ar–H), 4.80 (s, 1 H, CH), 2.29 (br. s., 6 H, CH3); 13C-NMR (126 MHz, DMSO-d6) δ: 146.2, 144.8, 143.4, 132.9, 128.9, 125.5, 120.5, 117.8, 115.2, 114.8, 32.4, 11.6; HRMS (TOF ES +) m/z calcd for C27H25N4O4 (M+H)+: 469.1870; found: 469.1876.
4,4'-[(4-Hydroxyphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3j
Yield 97% as a white solid; mp 217.2–218.9 °C [Lit. 214–216 [45]]; 1H-NMR (400 MHz, DMSO-d6) δ: 13.93 (br. s., 1H, OH), 9.17 (s, 1H, OH), 7.70 (d, J = 7.7 Hz, 4H, Ar–H), 7.43 (t, J = 7.8 Hz, 4H, Ar–H), 7.24 (t, J = 7.3 Hz, 2H, Ar–H), 7.04 (d, J = 8.4 Hz, 2H, Ar–H), 6.65 (d, J = 8.6 Hz, 2H, Ar–H), 4.84 (s, 1H, CH), 2.29 (br. s., 6H, CH3).
4,4'-[(4-Methoxyphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3k
Yield 92% as a white solid; mp 176.0–177.0 °C [Lit. 176–177 [46]]; 1H-NMR (400 MHz, DMSO-d6) δ: 13.92 (br. s., 1 H, OH), 12.39 (br. s., 1 H, OH), 7.70 (d, J = 7.9 Hz, 4 H, Ar–H), 7.44 (t, J = 7.3, 7.9 Hz, 4 H, Ar–H), 7.24 (d, J = 7.3 Hz, 2 H, Ar–H), 7.16 (d, J = 8.5 Hz, 2 H, Ar–H), 6.83 (d, J = 8.5 Hz, 2 H, Ar–H), 4.89 (s, 1 H, CH), 3.70 (s, 3 H, OCH3), 2.30 (br. s., 6 H, CH3).
4,4'-[(4-Nitrophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3l
Yield 97% as a yellow solid; mp 218.0–219.0 °C [Lit. 219–220 [47]]; 1H-NMR (500 MHz, DMSO-d6) δ: 8.17 (d, J = 8.9 Hz, 2 H, Ar–H), 7.69 (dd, J = 1.0, 8.6 Hz, 4 H, Ar–H), 7.51 (d, J = 8.9 Hz, 2 H, Ar–H), 7.45 (t, J = 8.0 Hz, 4 H, Ar–H), 7.26 (t, J = 7.4 Hz, 2 H, Ar–H), 5.13 (s, 1 H, CH), 2.34 (s, 6 H, CH3).
4,4'-[(4-Fluorophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3m
Yield 87% as a white solid; mp 183.8–185.8 °C [Lit. 181–183 [48]]; 1H-NMR (500 MHz, DMSO-d6) δ: 7.59—7.65 (m, 4H, Ar–H), 7.42 (dd, J = 8.3, 7.4 Hz, 4H, Ar–H), 7.24 (t, J = 7.2 Hz, 4H, Ar–H), 7.06 (t, J = 8.9 Hz, 2H, Ar–H), 4.91 (s, 1H, CH), 2.27 (s, 6H, CH3).
Methyl 4-[bis(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]benzoate 3n
Yield quantitative as a white solid; mp 217.2–218.7 °C¸ FTIR (cm−1): 1720 (C=O), 1595 (C=N), 1569 (C=C), 1499 (C=C), 1286 (C-O), 1118 (C-O); 1H-NMR (400 MHz, CDCl3) δ: 7.89 (d, J = 8.2 Hz, 2H, Ar–H), 7.60 (d, J = 7.9 Hz, 4H, Ar–H), 7.29 (t, J = 7.7 Hz, 4H, Ar–H), 7.26 (d, J = 7.6 Hz, 2H, Ar–H), 7.12 (t, J = 7.4 Hz, 2H, Ar–H), 4.80 (s, 1H, CH), 3.86 (s, 3H, COOCH3), 2.12 (s, 6H, CH3); 13C-NMR (101 MHz, CDCl3) δ: 167.2, 146.8, 146.1, 129.9, 129.1, 128.5, 128.2, 128.1, 127.5, 126.4, 121.4, 52.2, 34.1, 12.0; ESI–MS m/z 494.8 [M]+.
4,4'-[(4-Trifluoromethylphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3o
Yield 96% as a white solid; mp 203.0–205.0 °C; FTIR (cm−1): 1600 (C=N), 1583 (C=C), 1500 (C=C), 1320 (CF3), 1115 (CF3); 1H-NMR (400 MHz, DMSO-d6) δ: 13.88 (s, 1H, OH), 7.70 (d, J = 7.7 Hz, 4H, Ar–H), 7.65 (d, J = 8.3 Hz, 2H, Ar–H), 7.46 (d, J = 8.4 Hz, 2H, Ar–H), 7.44 (t, J = 8.1 Hz, 4H, Ar–H), 7.25 (t, J = 7.3 Hz, 2H, Ar–H), 5.06 (d, J = 8.4 Hz, 1H, CH), 2.33 (s, 6H, CH3); 13C-NMR (101 MHz, DMSO-d6) δ: 147.1, 146.3, 128.9, 128.1, 126.7 (q, J = 31.5 Hz), 125.7 (m), 125.1 (q, J = 4.0 Hz), 124.5 (q, J = 271.9 Hz), 120.6, 33.0, 11.6; 19F-NMR (56.17 MHz, DMSO-d6) δ: − 60.12 (s, CF3); ESI–MS m/z 504.8 [M]+.
4,4'-[(4-Trifluoromethoxyphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3p
Yield quantitative as a white solid; mp 174.5–176.0 °C; FTIR (cm−1): 1596 (C=N), 1579 (C=C), 1501 (C=C), 1253 (C–OCF3), 1226 (CF3), 1167 (CF3); 1H-NMR (500 MHz, DMSO-d6) δ: 7.70 (d, J = 7.8 Hz, 4H, Ar–H), 7.44 (t, J = 7.8 Hz, 4H, Ar–H), 7.35 (d, J = 8.6 Hz, 2H, Ar–H), 7.27 (d, J = 8.5 Hz, 2H, Ar–H), 7.25 (t, J = 7.3 Hz, 2H, Ar–H), 5.00 (s, 1H, CH), 2.32 (br. s., 6H, CH3); 13C NMR (126 MHz, DMSO-d6) δ: 147.1, 146.8, 141.9, 137.4, 137.2, 129.5, 129.4, 126.4, 121.2, 33.0, 11.8; 19F-NMR (56.17 MHz, DMSO-d6) δ: − 56.02 (s, OCF3); ESI–MS m/z 520.8 [M]+.
4,4'-[(4-Thiomethylphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 3q
Yield 60% as a white solid; mp 209.1–211.3 °C [Lit. 205–207 [49]]; 1H-NMR (400 MHz, DMSO-d6) δ: 13.91 (br. s., 1H, OH), 7.70 (d, J = 7.9 Hz, 4H, Ar–H), 7.44 (t, J = 7.8 Hz, 4H, Ar–H), 7.24 (t, J = 7.3 Hz, 2H, Ar–H), 7.18 (s, 4H, Ar–H), 4.91 (s, 1H, CH), 2.42 (s, 3H, SCH3), 2.31 (br. s., 6H, CH3).