All reagents and organic solvents were purchased from Sigma Chemical Co. (St. Louis, USA) and used without further purification. Thin-layer chromatography (TLC) was carried out on pre-coated silica gel aluminum plates (Merck silica gel 60, F254). Melting points of target compound 8a-o were measured on a Kofler hot stage apparatus and were uncorrected. 1H NMR and 13C NMR spectra were recorded on Bruker FT-500 spectrometer (Bruker, Rheinstetten, Germany) in DMSO-d6 with tetramethylsilane (TMS) as the internal standard. IR spectra were recorded on Nicolet Magna FTIR 550 spectrophotometer (resolution 2 cm − 1) in KBr pellets. Elemental analysis was carried out with an Elemental Analyzer system GmbH VarioEL CHNS mode (Germany).
4.4. General procedure for the preparation of pyrazole-benzofuran hybrids 8a-n
To a mixture of the appropriate pyrazole aldehydes 4 (1 mmol) and catalytic amount of glacial acetic acid (3–4 drops) in absolute ethanol (10 mL), were added hydrazide 7 (1.1 mmol) and refluxed for 12–18 h. As the reaction was completed, the mixture was allowed to cool to room temperature, the precipitate was filtered off and crystallized from ethanol to give the pure final derivatives 8a-n.
4.4.1. N'-((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8a)
Creamish powder; yield: 86%, mp 210–211 ºC. IR (KBr, cm− 1): 3345(N-H), 3080 − 2980 (C-H), 1656(C = O), 15615(C = N), 1435(C = C).1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H, NH), 9.15 (s, 1H, H5-pyr), 8.79 (s, 1H, CH = N), 8.16 (d, J = 7.9 Hz, 2H, Ar-H), 7.88–7.79 (m, 4H, Ar-H), 7.65 (m, 7H, Ar-H), 7.49 (m, 2H, Ar-H). 13C NMR (101 MHz, DMSO) δ 154.35, 154.20, 151.99, 148.06, 142.00, 139.00, 131.89, 129.57, 128.76, 128.61, 128.44, 127.15, 127.12, 127.00, 123.85, 122.85, 118.85, 116.74, 111.82, 110.69. Anal. Calcd for C25H18N4O2: C, 73.88; H, 4.46; N, 13.78. Found: C, 73.21; H, 4.24; N, 13.92.
4.4.2. N'-((1-Phenyl-3-p-tolyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8b)
Creamish powder; yield: 81%, mp 234–235 ºC. IR (KBr, cm− 1): 3385(N-H), 3010 − 2923 (C-H), 1648(C = O), 1555(C = N), 1450(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H, NH), 9.13 (s, 1H, H5-pyr), 8.77 (s, 1H, CH = N), 8.15 (d, J = 7.9 Hz, 2H, Ar-H), 7.93 (m, J = 7.7 Hz ,1H, Ar-H), 7.80–7.82 (m, 2H, Ar-H), 7.76 (d, J = 8.0 Hz, 2H, Ar-H), 7.63 (m, 3H, Ar-H), 7.48 (m, 4H, Ar-H), 2.52 (s, 3H, CH3). 13C NMR (101 MHz, DMSO) δ 154.34, 154.19, 152.04, 148.07, 142.14, 139.02, 138.07, 129.55, 129.31, 129.05, 128.33, 127.15, 127.02, 126.99, 126.93, 123.85, 122.84, 118.81, 116.64, 111.82, 110.67, 20.86. Anal. Calcd for C26H20N4O2: C, 74.27; H, 4.79; N, 13.33. Found: C, 74.83; H, 3.99; N, 13.73.
4.4.3. N'-((3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8c)
White powder; yield: 78%, mp 207–209 ºC. IR (KBr, cm− 1): 3408(N-H), 3214 − 2980 (C-H), 1670(C = O), 1537(C = N), 1446(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H, NH), 9.12 (s, 1H, H5-pyr), 8.77 (s, 1H, CH = N), 8.15 (d, J = 8.0 Hz, 2H, Ar-H), 7.94 (d, J = 7.7 Hz, 1H, Ar-H), 7.81–7.83 (m, 4H, Ar-H), 7.68–7.60 (m, 3H, Ar-H), 7.49 (t, J = 7.4 Hz, 2H, Ar-H), 7.23 (d, J = 8.6 Hz, 2H, Ar-H), 3.96 (s, 3H, OCH3). 13C NMR (101 MHz, DMSO) δ 159.59, 154.34, 154.18, 151.85, 148.08, 142.20, 139.03, 129.76, 129.54, 127.15, 127.00, 126.86, 124.27, 123.85, 122.84, 118.75, 116.46, 114.17, 111.82, 110.67, 55.25. Anal. Calcd for C26H20N4O3: C, 71.55; H, 4.62; N, 12.84. Found: C, 71.83; H, 4.21; N, 12.20.
4.4.4. (E)-N'-((3-(4-hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8d)
Creamish powder; yield: 81%, mp 280–281 ºC. IR (KBr, cm− 1): 3506(N-H), 2996–3195 (C-H), 1646(C = O), 1521(C = N), 1469(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H, NH), 9.09 (s, 1H, H5-pyr), 8.76 (s, 1H, CH = N), [8.14 (d, J = 7.8 Hz, 2H), 7.93 (d, J = 7.8 Hz, 1H), 7.81–7.83 (m, 2H), 7.46–7.70 (m, 6H), 7.46–7.50 (m, 2H), 7.05 (d, J = 8.5 Hz, 2H)] (15H, Ar-H and OH). 13C NMR (101 MHz, DMSO) δ 157.97, 154.34, 154.18, 152.25, 148.09, 142.37, 139.06, 129.75, 129.53, 127.13, 126.99, 126.82, 126.77, 123.84, 122.84, 122.61, 118.69, 116.30, 115.51, 111.82, 110.63. Anal. Calcd for C25H18N4O3: C, 71.08; H, 4.29; N, 13.26. Found: C, 71.68; H, 4.49; N, 13.76.
4.4.5. N'-((3-(4-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8e)
Yellow powder; yield: 73%, mp 241–243 ºC. IR (KBr, cm− 1): 3105(N-H), 2907 (C-H), 1669(C = O), 1552(C = N), 1444(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H, NH), 9.21 (s, 1H, H5-pyr), 8.82 (s, 1H, CH = N), 8.39–8.50 (m, 2H, Ar-H), 8.22–8.05 (m, 3H, Ar-H), 7.93 (d, J = 7.7 Hz, 1H, Ar-H), 7.89–7.75 (m, 2H, Ar-H), 7.75–7.56 (m, 4H, Ar-H), 7.35–7.46 (m, 2H, Ar-H). 13C NMR (101 MHz, DMSO) δ 154.36, 154.27, 149.31, 147.98, 147.15, 141.28, 138.77, 138.41, 129.61, 129.50, 128.55, 127.37, 127.22, 126.98, 123.87, 123.78, 123.53, 122.88, 119.00, 118.76, 117.52, 111.82, 110.90. Anal. Calcd for C25H17N5O4: C, 66.51; H, 3.80; N, 15.51. Found: C, 65.83; H, 3.12; N, 14.93.
4.4.6. N'-((3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8f)
White powder; yield: 88%, mp 243–245 ºC. IR (KBr, cm− 1): 3430(N-H), 2845–3165 (C-H), 1655(C = O), 1538(C = N), 1442(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H, NH), 9.19 (s, 1H, H5-pyr), 8.78 (s, 1H, CH = N), 8.17 (d, J = 7.9 Hz, 2H, Ar-H), 7.95 (d, J = 7.7 Hz, 1H, Ar-H), 7.91–7.81 (m, 6H, Ar-H), 7.82–7.96 (m, 3H, Ar-H), 7.48–7.54 (m, 2H, Ar-H). 13C NMR (101 MHz, DMSO) δ 154.35, 154.20, 150.69, 148.03, 141.72, 138.91, 131.66, 131.12, 130.49, 129.59, 127.69, 127.19, 127.12, 126.98, 123.87, 122.87, 122.07, 118.89, 116.83, 111.83, 110.77. Anal. Calcd for C25H17BrN4O2: C, 61.87; H, 3.53; N, 11.54. Found: C, 61.16; H, 3.21; N, 12.04
4.4.7. N'-((3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8g)
Creamish powder; yield: 81%, mp 241–243 ºC. IR (KBr, cm− 1): 3491(N-H), 2945–3223 (C-H), 1652(C = O), 1553(C = N), 1503(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H, NH), 9.17 (s, 1H, H5-pyr), 8.78 (s, 1H, CH = N), 8.16 (d, J = 7.9 Hz, 2H, Ar-H), 7.92–7.95 (m, 3H, Ar-H), 7.85–7.79 (m, 2H, Ar-H), 7.73 (d, J = 8.4 Hz, 2H), 7.66 (t, J = 8.0 Hz, 3H, Ar-H), 7.47–7.52 (m, 2H, Ar-H). 13C NMR (101 MHz, DMSO) δ 154.34, 150.59, 148.24, 141.66, 138.91, 133.39, 130.79, 130.19, 129.58, 128.74, 127.63, 127.11, 127.01, 123.83, 122.82, 118.86, 116.90, 111.80, 110.64. Anal. Calcd for C25H17ClN4O2: C, 68.11; H, 3.89; N, 12.71. Found: C, 68.53; H, 3.16; N, 12.52.
4.4.8. N'-((3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8h)
White powder; yield: 84%, mp 253–254 ºC. IR (KBr, cm− 1): 3500 (N-H), 2926–3093 (C-H), 1661(C = O), 1553(C = N), 1441(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H, NH), 9.15 (s, 1H, H5-pyr), 8.76 (s, 1H, CH = N), 8.15 (d, J = 7.9 Hz, 2H, Ar-H), 7.92–7.96 (m, 3H, Ar-H), 7.80–7.82 (m, 2H), 7.60–7.67 (m, 3H), 7.53–7.46 (m, 4H). 13C NMR (101 MHz, DMSO) δ 163.58, 161.14, 154.34, 154.20, 150.95, 148.04, 141.82, 138.94, 130.65, 130.57, 129.57, 128.42, 127.41, 127.18, 127.03, 126.98, 123.86, 122.86, 118.84, 116.69, 115.76, 115.55, 111.82, 110.74. Anal. Calcd for C25H17FN4O2: C, 70.75; H, 4.04; N, 13.20. Found: C, 70.26; H, 4.34; N, 13.61.
4.4.9. N'-((1-Phenyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8i)
White powder; yield: 78%, mp 217–218 ºC. IR (KBr, cm− 1): 337 (N-H), 2909–3050 (C-H), 1665(C = O), 1555(C = N), 1442(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H, NH), 9.23 (s, 1H, H5-pyr), 8.80 (s, 1H, CH = N), 8.21–8.13 (m, 4H, Ar-H), 8.04 (d, J = 8.2 Hz, 2H, Ar-H), 7.94 (d, J = 7.8 Hz, 1H, Ar-H), 7.81–7.84 (m, 2H, Ar-H), 7.61–7.70 (m, 3H, Ar-H), 7.47–7.54 (m, 2H, Ar-H). 13C NMR (101 MHz, DMSO) δ 154.35, 154.21, 150.33, 148.00, 141.53, 138.86, 135.96, 129.62, 129.24, 128.94, 128.62, 127.94, 127.26, 127.21, 126.98, 125.59, 125.55, 123.88, 122.87, 118.96, 117.15, 111.82, 110.83. Anal. Calcd for C26H17F3N4O2: C, 65.82; H, 3.61; N, 11.81. Found: C, 65.21; H, 3.32; N, 11.10.
4.4.10. N'-((3-Phenyl-1-p-tolyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8j)
White powder; yield: 81%, mp 255–256 ºC. IR (KBr, cm− 1): 3420(N-H), 2917–3050 (C-H), 1646(C = O), 1537(C = N), 1442(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H, NH), 9.08 (s, 1H, H5-pyr), 8.77 (s, 1H, CH = N), 8.02 (d, J = 8.4 Hz, 2H, Ar-H), 7.87–7.78 (m, 4H, Ar-H), 7.69–7.56 (m, 5H, Ar-H), 7.43–7.49 (m, 3H, Ar-H), 2.46 (s, 3H, CH3). 13C NMR (101 MHz, DMSO) δ 154.34, 154.19, 151.75, 148.08, 142.06, 136.80, 136.42, 131.96, 129.93, 128.74, 128.54, 128.42, 127.14, 126.99, 126.90, 123.84, 122.84, 118.77, 116.51, 111.81, 110.66, 20.47. Anal. Calcd for C26H20N4O2: C, 74.27; H, 4.79; N, 13.33. Found: C, 74.66; H, 4.32; N, 13.91.
4.4.11 N'-((1,3-Dip-tolyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8k)
White powder; yield: 83%, mp 259–261 ºC. IR (KBr, cm− 1): 3450(N-H), 2945–3065 (C-H), 1665(C = O), 1580(C = N), 1455(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H, NH), 9.05 (s, 1H, H5-pyr), 8.76 (s, 1H, CH = N), 8.01 (d, J = 8.2 Hz, 2H, Ar-H), 7.91 (d, J = 7.7 Hz, 1H, Ar-H), 7.79–7.81 (m, 2H, Ar-H), 7.74 (d, J = 7.8 Hz, 2H, Ar-H), 7.60 (t, J = 7.7 Hz, 1H, Ar-H), 7.48–7.38 (m, 5H, Ar-H), 2.50 (s, 3H, CH3), 2.46 (s, 3H, CH3). 13C NMR (101 MHz, DMSO) δ 154.34, 154.18, 151.80, 148.09, 142.20, 137.98, 136.82, 136.33, 129.92, 129.56, 129.28, 129.12, 128.75, 128.30, 127.13, 126.99, 126.80, 123.84, 122.83, 118.72, 116.41, 111.81, 110.64, 20.85, 20.46. Anal. Calcd for C27H22N4O2: C, 74.64; H, 5.10; N, 12.89. Found: C, 74.25; H, 5.42; N, 12.24.
4.4.12 N'-((3-(4-Methoxyphenyl)-1-p-tolyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8l)
White powder; yield: 82%, mp 230–232 ºC. IR (KBr, cm− 1): 3442(N-H), 2890–3120 (C-H), 1670(C = O), 1540(C = N), 1450(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H, NH), 9.06 (s, 1H, H5-pyr), 8.76 (s, 1H, CH = N), 8.03 (d, J = 8.4 Hz, 2H, Ar-H), 7.94 (d, J = 7.7 Hz, 1H, Ar-H), 7.80–7.83 (m, 4H, Ar-H), 7.62 (t, J = 7.5 Hz, 1H, Ar-H), 7.50–7.43 (m, 3H, Ar-H), 7.23 (d, J = 8.7 Hz, 2H, Ar-H), 3.96 (s, 3H, OCH3), 2.48 (s, 3H, CH3). 13C NMR (101 MHz, DMSO) δ 159.55, 154.34, 154.16, 151.62, 148.10, 142.25, 136.83, 136.26, 129.92, 129.73, 127.14, 126.99, 126.80, 124.35, 123.85, 122.84, 118.68, 116.23, 114.15, 111.82, 110.63, 55.25, 20.47. Anal. Calcd for C27H22N4O3: C, 71.99; H, 4.92; N, 12.44. Found: C, 71.43; H, 4.36; N, 12.72.
4.4.13 N'-((3-(4-Hydroxyphenyl)-1-p-tolyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8m)
Creamish powder; yield: 82%, mp 293–295 ºC. IR (KBr, cm− 1): 3460(N-H), 2990–3165 (C-H), 1666(C = O), 1540(C = N), 1430(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H, NH), 9.02 (s, 1H, H5-pyr), 8.75 (s, 1H, CH = N), [8.00 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 7.6 Hz, 1H), 7.80–7.82 (m, 2H), 7.59–7.68 (m, 4H), 7.49–7.40 (m, 3H), 7.04 (d, J = 8.5 Hz, 2H)] (14H, Ar-H and OH), 2.46 (s, 3H, CH3). 13C NMR (101 MHz, DMSO) δ 157.92, 154.33, 154.16, 152.03, 148.10, 142.42, 136.86, 136.16, 129.90, 129.72, 127.12, 126.99, 126.61, 123.84, 122.83, 122.68, 118.62, 116.07, 115.50, 111.82, 110.61, 20.46. Anal. Calcd for C26H20N4O3: C, 71.55; H, 4.62; N, 12.84. Found: C, 71.10; H, 4.15; N, 12.28.
4.4.14 N'-((3-(4-Bromophenyl)-1-p-tolyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8n)
White powder; yield: 75%, mp 258–259 ºC. IR (KBr, cm− 1): 3425(N-H), 2898–3098 (C-H), 1666(C = O), 1535(C = N), 1450(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H, NH), 9.10 (s, 1H, H5-pyr), 8.75 (s, 1H, CH = N), 8.02 (d, J = 8.3 Hz, 2H, Ar-H), 7.92 (d, J = 7.7 Hz, 1H, Ar-H), 7.82–7.85 (m, 5H, Ar-H), 7.61 (t, J = 7.7 Hz, 1H, Ar-H), 7.44–7.50 (m, 4H, Ar-H), 2.47 (s, 3H, CH3). 13C NMR (101 MHz, DMSO) δ 154.34, 154.18, 150.45, 148.04, 141.77, 136.71, 136.55, 131.64, 131.19, 130.45, 129.95, 127.47, 127.18, 126.98, 123.87, 122.86, 121.99, 118.80, 116.61, 111.82, 110.75, 20.47. Anal. Calcd for C26H19BrN4O2: C, 62.54; H, 3.84; N, 11.22. Found: C, 62.91; H, 3.52; N, 11.76.
4.4.15 N'-((3-(4-Chlorophenyl)-1-p-tolyl-1H-pyrazol-4-yl)methylene)benzofuran-2-carbohydrazide (8o)
White powder; yield: 83%, mp 248–249 ºC. IR (KBr, cm− 1): 3435(N-H), 2925–3050 (C-H), 1675(C = O), 1542(C = N), 1438(C = C). 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H, NH), 9.09 (s, 1H, H5-pyr), 8.74 (s, 1H, CH = N), 8.02 (d, J = 8.4 Hz, 2H, Ar-H), 7.90–7.94 (m, 3H, Ar-H), 7.82–7.76 (m, 2H, Ar-H), 7.72 (d, J = 8.4 Hz, 2H, Ar-H), 7.63–7.57 (m, 1H, Ar-H), 7.45–7.49 (m, 3H, Ar-H), 2.48 (s, 3H, CH3). 13C NMR (101 MHz, DMSO) δ 154.30, 150.24, 141.39, 136.74, 136.47, 133.26, 130.93, 130.11, 129.95, 128.71, 127.30, 127.15, 126.82, 123.70, 122.65, 118.74, 116.96, 111.74, 110.10, 20.47. Anal. Calcd for C26H19ClN4O2: C, 68.65; H, 4.21; N, 12.32. Found: C, 68.99; H, 4.53; N, 12.81.