2.4. General Procedure for N′-(2,4-Disubstitutedbenzylidene)-2-(4-(4-nitrophenyl)piperazin-1-yl)acetohydrazide Derivatives (3a–k) 2-[4-(4-Nitrophenyl)piperazin-1-yl]acetohydrazide (0.7 mmol) was dissolved in ethanol (100 mL). After addition of acetic acid (1 mL) and appropriate aldehydes (0.7 mmol), the reaction mixture was refluxed for 8 hours. After TLC screening, at the end of this period, the reaction mixture was cooled, filtered, and recrystallized from ethanol to give the target compounds 3a–k.
2.4.1. N′-(4-Fluorobenzylidene)-2-(4-(4-nitrophenyl)piperazin-1-yl)acetohydrazide (3a) IR (KBr) νmax (cm−1): 3259 (N-H), 3066 (Aromatic C-H), 2885 (Aliphatic C-H), 1695 (C=O), 1597 (C=N), 1581 and 1305 (NO2), 1473 (C=C), 1230 (C-N), 1143, 1076 and 827 (C-H out of plane deformation).
1H-NMR (400 Mhz, DMSO-d6, ppm) δ 2.61 (2H, t, J = 4.4 Hz, piperazine protons), 2.70 (2H, t, J = 4.4 Hz, piperazine protons), 3.15 and 3.61 (2H, two s, CO-CH2), 3.44–3.49 (4H, m, piperazine protons), 6.97 (2H, dd, J1 = 9.2 Hz, J2 = 4 Hz, phenyl protons), 7.20–7.27 (2H, m, phenyl photons), 7.66–7.73 (2H, m, phenyl protons), 7.93 and 8.31 (1H, two s, N=CH), 8.01 (2H, dd, J1 = 9.2 Hz, J2= 3.6 Hz, phenyl protons), 11.23 and 11.32 (1H, two s, NH).
13C-NMR (100 Mhz, DMSO-d6, ppm) δ 46.17 and 46.37 (2CH2), 52.03 and 52.19 (2CH2), 56.85 and 60.07 (COC_H2), 112.47 and 112.55 (2CH), 115.68 and 115.90 (2CH), 125.63 (2CH), 128.75 and 128.83 (CH), 129.07 and 129.16 (CH), 130.71, 130.73 and 130.80, 130.83 (C), 136.72 and 136.83 (C), 141.69 and 146.04 (C=N), 154.64 (C), 161.60, 161.79 and 164.07, 164.25 (C-F), 165.45 and 170.63 (C=O).
HRMS (m/z): [M + H]+ calcd for C19H20FN5O3: 386.1623; found 386.1618.
2.4.2. N′-(4-Methoxybenzylidene)-2-(4-(4-nitrophenyl)piperazin-1-yl)acetohydrazide (3b) IR (KBr) νmax (cm−1): 3271 (N-H), 3070 (Aromatic C-H), 2835 (Aliphatic C-H), 1681 (C=O), 1581 (C=N), 1504 and 1303 (NO2), 1471 (C=C), 1240 (C-N), 1207–1078 (C-O), 1078 and 825 (C-H out of plane deformation).
1H-NMR (400 Mhz, DMSO-d6, ppm) δ 2.64 (2H, t, J = 4.8 Hz, piperazine protons), 2.73 (2H, t, J = 4.8 Hz, piperazine protons), 3.17 and 3.64 (2H, 2s, CO-CH2), 3.48 (2H, t, J = 4.8 Hz, piperazine protons), 3.52 (2H, t, J = 4.8 Hz, piperazine protons), 3.80 (3H, d, J = 3.6 Hz, OCH3), 6.98–7.04 (4H, m, phenyl protons), 7.59–7.65 (2H, m, phenyl protons), 7.92 and 8.28 (1H, two s, N=CH), 8.05 (2H, dd, J1 = 9.2 Hz, J2 = 3.6 Hz, phenyl protons), 11.12 and 11.22 (1H, two s, NH).
13C-NMR (100 Mhz, DMSO-d6, ppm) δ 46.17 and 46.36 (2CH2), 52.03 and 52.18 (2CH2), 55.19 (OCH3), 56.86 and 60.08 (COC_H2), 112.45 and 112.54 (2CH), 114.22 (2CH), 125.63 (2CH), 126.70 and 126.73 (C), 128.20 and 128.55 (2CH), 136.69 and 136.81 (C), 142.71 and 147.04 (C=N), 154.60 and 154.65 (C), 160.49 and 160.71 (C), 165.13 and 170.37 (C=O).
HRMS (m/z): [M + H]+ calcd for C20H23N5O4: 398.1823; found 398.1838.
2.4.3. N′-(4-Hydroxybenzylidene)-2-(4-(4-nitrophenyl)piperazin-1-yl)acetohydrazide (3c) IR (KBr) νmax (cm−1): 3250 (N-H), 3115.04 (Aromatic C-H), 2823 (Aliphatic C-H), 1651 (C=O), 1595 and 1305 (NO2), 1504 (C=N), 1473 (C=C), 1238 (C-N), 1116 and 823 (C-H out of plane deformation).
1H-NMR (400 Mhz, DMSO-d6, ppm) δ 2.64 (2H, t, J = 4.4 Hz, piperazine protons), 2.71–2.76 (2H, m, piperazine protons), 3.15 and 3.62 (2H, two s, CO-CH2), 3.48–3.52 (4H, m, piperazine protons), 6.80–6.85 (2H, m, phenyl protons), 7.00–7.05 (2H, m, phenyl protons), 7.35–7.60 (2H, m, phenyl protons), 7.84 and 8.22 (1H, two s, N=CH), 8.05 (2H, dd, J1 = 9.6 Hz, J2 = 2.4 Hz, phenyl-H), 9.85 (1H, br s, OH), 11.04 and 11.14 (1H, two s, NH).
13C-NMR (100 Mhz, DMSO-d6, ppm) δ 46.16 and 46.35 (2CH2), 52.03 and 52.16 (2CH2), 56.85 and 60.07 (COC_H2), 112.44 and 112.53 (2CH), 115.59 (2CH), 125.10 and 125.13 (C), 125.63 (2CH), 128.33 and 128.70 (2CH), 136.68 and 136.79 (C), 143.15 and 147.45 (C=N), 154.60 and 154.65 (C), 159.05 and 159.29 (C), 165.00 and 170.24 (C=O).
HRMS (m/z): [M + H]+ calcd for C19H21N5O4: 384.1666; found 384.1650.
2.4.4. N′-(4-Ethoxybenzylidene)-2-(4-(4-nitrophenyl)piperazin-1-yl)acetohydrazide (3d) IR (KBr) νmax (cm−1): 3253 (N-H), 3069 (Aromatic C-H), 2976 (Aliphatic C-H), 1693 (C=O), 1598.99 (C=N), 1585 and 1305 (NO2), 1477 (C=C), 1240 (C-N), 1207–1041 (C-O), 829 (C-H out of plane deformation).
1H-NMR (400 Mhz, DMSO-d6, ppm) δ 1.31 (3H, t, J = 7 Hz, CH3), 2.61 (2H, t, J = 4.4 Hz, piperazine protons), 2.70 (2H, t, J = 4.8 Hz, piperazine protons), 3.12 and 3.59 (2H, 2s, CO-CH2), 3.27 (1H, s, piperazine proton), 3.42–3.60 (3H, m, piperazine protons), 4.00–4.06 (2H, m, OCH2), 6.92–7.04 (4H, m, phenyl protons), 7.54–7.62 (2H, m, phenyl protons), 7.88 and 8.24 (1H, two s, N=CH), 8.03 (2H, dd, J1 = 9.6 Hz, J2 = 3.2 Hz, phenyl protons), 11.03 and 11.13 (1H, two s, NH).
13C-NMR (100 Mhz, DMSO-d6, ppm) δ 14.47 (CH3), 46.21 and 46.40 (2CH2), 52.02 and 52.17 (2CH2), 56.84 and 60.07 (COC_H2), 63.17 (OCH2), 112.49 and 112.57 (2CH), 114.65 (2CH), 125.60 (2CH), 126.61 (C), 128.18 and 128.52 (2CH), 136.74 and 136.85 (C), 142.73 and 147.08 (C=N), 154.62 (C), 159.79 and 160.01 (C), 165.08 and 170.33 (C=O).
HRMS (m/z): [M + H]+ calcd for C21H25N5O4: 412.1979; found 412.1971.
2.4.5. N′-(2,4-Dichlorobenzylidene)-2-(4-(4-nitrophenyl)piperazin-1-yl)acetohydrazide (3e) IR (KBr) νmax (cm−1): 3259 (N-H), 3093 (Aromatic C-H), 2862 (Aliphatic C-H), 1683 (C=O), 1597 and 1303 (NO2), 1508 (C=N), 1490 (C=C), 1232 (C-N), 1099 and 821 (C-H out of plane deformation).
1H-NMR (400 Mhz, DMSO-d6, ppm) δ 2.62 (2H, t, J = 4.4 Hz, piperazine protons), 2.64–2.67 (2H, m, piperazine protons), 3.17 and 3.63 (2H, two s, CO-CH2), 3.27 (1H, s, piperazine proton), 3.42–3.52 (3H, m, piperazine protons), 6.99 (2H, dd, J1 =9.6 Hz, J2 = 4 Hz, phenyl protons), 7.42–7.48 (1H, m, phenyl proton), 7.62–7.66 (1H, m, phenyl proton), 7.92 (1H, t, J = 8.4 Hz, phenyl proton), 8.00–8.05 (2H, m, phenyl protons), 8.27 and 8.65 (1H, 2s, N=CH), 11.50 and 11.53 (1H, two s, NH).
13C-NMR (100 Mhz, DMSO-d6, ppm) δ 46.18 and 46.41 (2CH2), 51.97 and 52.17 (2CH2), 56.79 and 60.12 (COC_H2), 112.50 and 112.57 (2CH), 125.60 (2CH), 127.86 (C), 128.00 (C), 129.25 (C), 130.48 and 130.67 (C), 133.44 and 133.71 (C), 134.66 and 134.93 (C), 136.77 and 136.87 (C), 137.87 and 141.90 (CH), 154.61 (C), 165.79 and 170.79 (C).
HRMS (m/z): [M + H]+ calcd for C19H19Cl2N5O3: 436.0938; found 436.0928.
2.4.6. N′-(4-Cyanobenzylidene)-2-(4-(4-nitrophenyl)piperazin-1-yl)acetohydrazide (3f) IR (KBr) νmax (cm−1): 3261 (N-H), 3065 (Aromatic C-H), 2833 (Aliphatic C-H), 2223 (C≡N), 1683 (C=O), 1597 and 1305 (NO2), 1508 (C=N), 1471 (C=C), 1240 (C-N), 1087 and 825 (C-H out of plane deformation).
1H-NMR (400 Mhz, DMSO-d6, ppm) δ 2.66 (2H, t, J = 4.8 Hz, piperazine protons), 2.74 (2H, t, J = 4.8 Hz, piperazine protons), 3.22 and 3.68 (2H, two s, CO-CH2), 3.37 (1H, s, piperazine proton), 3.49–3.58 (3H, m, piperazine protons), 7.03 (2H, dd, J1 = 9.2 Hz, J2 = 4 Hz, phenyl protons), 7.82–7.92 (4H, m, phenyl protons), 8.01 and 8.40 (1H, two s, N=CH), 8.05 (2H, dd, J1 = 9.2 Hz, J2 = 3.2 Hz, phenyl protons), 11.51 and 11.59 (1H, two s, NH).
13C-NMR (100 Mhz, DMSO-d6, ppm) δ 46.15 and 46.35 (2CH2), 51.98 and 52.15 (2CH2), 56.80 and 60.02 (COC_H2), 111.50 and 111.78 (CN), 112.47 and 112.54 (2CH), 118.56 and 118.61 (C), 125.62 (2CH), 127.21 and 127.48 (2CH), 132.62 (2CH), 136.71 and 136.82 (C), 138.54 and 138.70 (C), 140.89 and 145.14 (C=N), 154.58 and 154.64 (C), 165.84 and 170.95 (C=O). HRMS (m/z): [M + H]+ calcd for C20H20N6O3: 393.1670; found 393.1654.
2.4.7. 2-(4-(4-Nitrophenyl)piperazin-1-yl)-N′-(4-(trifluoromethyl)benzylidene)acetohydrazide (3g) IR (KBr) νmax (cm−1): 3267 (N-H), 3035 (Aromatic C-H), 2835 (Aliphatic C-H), 1683 (C=O), 1597 and 1303 (NO2), 1506 (C=N), 1473 (C=C), 1242 (C-N), 1116, 1083 and 825 (C-H out of plane deformation).
1H-NMR (400 Mhz, DMSO-d6, ppm) δ 2.67 (2H, t, J = 4.8 Hz, piperazine protons), 2.75 (2H, t, J = 4.4 Hz, piperazine protons), 3.22 and 3.69 (2H, two s, CO-CH2), 3.38 (1H, s, piperazine proton), 3.46–3.56 (3H, m, piperazine protons), 7.01–7.06 (2H, m, phenyl protons), 7.79 (2H, t, J = 8.4 Hz, phenyl protons), 7.86–8.09 (2H, m, phenyl protons), 8.06 (2H, dd, J1 = 9.2 Hz, J2 = 3.6 Hz, phenyl protons), 8.43 (1H, s, C=N), 11.47 and 11.56 (1H, two s, NH).
13C-NMR (100 Mhz, DMSO-d6, ppm) δ 46.19 and 46.40 (2CH2), 52.02 and 52.21 (2CH2), 56.86 and 60.08 (COC_H2), 112.51 and 112.59 (2CH), 122.69 (CF3), 125.40 and 125.60 (2CH), 125.65 (2CH), 127.24 and 127.55 (2CH), 129.22, 129.45, 129.53, 129.77 (C), 136.76 and 136.87 (C), 138.09 and 138.25 (C), 141.20 and 145.41 (C=N), 154.64 and 154.69 (C), 165.81 and 170.91 (C=O).
HRMS (m/z): [M + H]+ calcd for C20H20F3N5O3: 436.1591; found 436.1577.
2.4.8. N′-(4-(Dimethylamino)benzylidene)-2-(4-(4-nitrophenyl)piperazin-1-yl)acetohydrazide (3h) IR (KBr) νmax (cm−1): 3250 (N-H), 3078 (Aromatic C-H), 2962 (Aliphatic C-H), 1681 (C=O), 1583 and 1315 (NO2), 1595 (C=N), 1477 (C=C), 1232 (C-N), 1114, 1093 and 827 (C-H out of plane deformation).
1H-NMR (400 Mhz, DMSO-d6, ppm) δ 1.21 (6H, dd, J1 = 7.2 Hz, J2 = 2.8 Hz, N(CH3)2), 2.65 (2H, t, J = 4.8 Hz, piperazine protons), 2.74 (2H, t, J = 4.8 Hz, piperazine protons), 3.18 and 3.65 (2H, two s, CO-CH2), 3.39 (1H, s, piperazine proton), 3.44–3.56 (3H, m, piperazine protons), 7.00–7.05 (2H, m, phenyl protons), 7.30 (2H, t, J = 8.2 Hz, phenyl protons), 7.58 (1H, d, J = 8 Hz, phenyl protons), 7.62 (1H, d, J = 8 Hz, phenyl proton), 7.96 and 8.32 (1H, two s, N=CH), 8.05 (2H, dd, J1 = 9.2 Hz, J2 = 3.6 Hz, phenyl protons), 11.21 and 11.31 (1H, two s, NH).
13C-NMR (100 Mhz, DMSO-d6, ppm) δ 23.56 and 33.29 (2CH3), 46.18 and 46.38 (2CH2), 52.03 and 52.20 (2CH2), 56.87 and 60.09 (COC_H2), 112.47 and 112.55 (2CH), 125.63 (2CH), 126.69 and 126.73 (2CH), 127.07 (C), 131.81 and 131.89 (2CH), 136.71 and 136.83 (C), 142.91 and 147.20 (C=N), 150.26 and 150.54 (C), 154.61 and 154.66 (C), 165.33 and 170.51 (C).
HRMS (m/z): [M + H]+ calcd for C22H28N6O3: 424.4961; found 424.4967.
2.4.9. N′-(4-(Diethylamino)benzylidene)-2-(4-(4-nitrophenyl) piperazin-1-yl)acetohydrazide (3i) IR (KBr) νmax (cm−1): 3203 (N-H), 3049 (Aromatic C-H), 2985 (Aliphatic C-H), 1660 (C=O), 1587 and 1315 (NO2), 1548 (C=N), 1494 (C=C), 1240 (C-N), 1195, 1097, 815 (C-H out of plane deformation).
1H-NMR (400 Mhz, DMSO-d6, ppm) δ 2.60 (2H, t, J = 4.8 Hz, piperazine protons), 2.70 (2H, t, J = 4.8 Hz, piperazine protons), 3.09 and 3.56 (2H, two s, CO-CH2), 3.28–3.38 (10H, m, N(C2H5)2), 3.43–3.55 (4H, m, piperazine protons), 6.65 (2H, t, J = 9.2 Hz, phenyl protons), 7.01 (2H, dd, J1 = 9.2 Hz, J2 = 3.2 Hz, phenyl protons), 7.38–7.45 (2H, m, phenyl protons), 7.78 and 8.10 (1H, two s, N=CH), 8.03 (2H, dd, J1 = 9.6 Hz, J2 = 3.2 Hz, phenyl protons), 10.86 and 10.98 (1H, two s, NH).
13C-NMR (100 Mhz, DMSO-d6, ppm) δ 12.31 (2CH3), 43.58 (2CH2), 46.20 and 46.39 (2CH2), 52.00 and 52.14 (2CH2), 56.83 and 60.08 (COC_H2), 111.00 and 111.06 (2CH), 112.45 and 112.53 (2CH), 120.54 and 120.61 (C), 125.57 (2CH), 128.17 and 128.57 (2CH), 136.71 and 136.83 (C), 143.69 and 148.04 (C=N), 148.54 and 148.76 (C), 154.60 and 154.65 (C), 164.58 and 169.91 (C=O).
HRMS (m/z): [M + H]+ calcd for C23H30N6O3: 439.2452; found 439.2436.
2.4.10. N′-(4-Methylbenzylidene)-2-(4-(4-nitrophenyl)piperazin-1-yl)acetohydrazide (3j) IR (KBr) νmax (cm−1): 3255 (N-H), 3082 (Aromatic C-H), 2829 (Aliphatic C-H), 1683 (C=O), 1589 and 1319 (NO2), 1508 (C=N), 1489 (C=C), 1240 (C-N), 1089, 823 (C-H out of plane deformation).
1H-NMR (400 Mhz, DMSO-d6, ppm) δ 2.31 (3H, s, CH3), 2.62 (2H, t, J = 4.8 Hz, piperazine protons), 2.71 (2H, t, J = 4.8 Hz, piperazine protons), 3.14 and 3.61 (2H, two s, CO-CH2), 3.45 (2H, t, J = 4.8 Hz, piperazine protons, 3.49 (2H, t, J = 4.8 Hz, piperazine protons), 6.99 (2H, dd, J1 = 9.6 Hz, J2 = 4 Hz, phenyl protons), 7.21 (2H, t, J = 7.2 Hz, phenyl protons), 7.50–7.57 (2H, m, phenyl protons), 7.91 and 8.27 (1H, two s, N=CH), 8.02 (2H, dd, J1 = 9.2 Hz, J2 = 3.6 Hz, phenyl protons), 11.11 and 11.19 (1H, two s, NH).
13C-NMR (100 Mhz, DMSO-d6, ppm) δ 20.87 (CH3), 46.18 and 46.38 (2CH2), 51.96 and 52.13 (2CH2), 56.79 and 60.04 (COC_H2), 112.45 and 112.53 (2CH), 125.56 (2CH), 126.57 and 126.88 (2CH), 129.27 (2CH), 131.38 and 131.48 (C), 136.73 and 136.85 (C), 139.37 and 139.68 (C), 142.90 and 147.19 (C=N), 154.58 and 154.63 (C), 165.23 and 170.44 (C=O).
HRMS (m/z): [M + H]+ calcd for C20H23N5O3: 382.1874; found 382.1885.
2.4.11. N′-(4-(Methylthio)benzylidene)-2-(4-(4-nitrophenyl)piperazin-1-yl)acetohydrazide (3k) IR (KBr) νmax (cm−1): 3244 (N-H), 3055 (Aromatic C-H), 2833 (Aliphatic C-H), 1683 (C=O), 1593 and 1307 (NO2), 1508 (C=N), 1471 (C=C), 1242 (C-N), 1116, 1087, 819 (C-H out of plane deformation).
1H-NMR (400 Mhz, DMSO-d6, ppm) δ 2.51 (3H, s, SCH3), 2.63–2.68 (2H, m, piperazine protons), 2.72–2.76 (2H, m, piperazine protons), 3.18 and 3.65 (2H, 2s, CO-CH2), 3.33 (1H, br s, piperazine proton), 3.44–3.56 (3H, m, piperazine protons), 7.01 (2H, dd, J1 = 9.6 Hz, J2 = 4 Hz, phenyl protons), 7.30 (2H, t, J = 7.6 Hz, phenyl protons), 7.57–7.64 (2H, m, phenyl protons), 7.94 and 8.30 (1H, two s, N=CH), 8.05 (2H, dd, J1 = 9.6 Hz, J2 = 3.6 Hz, phenyl protons), 11.17 and 11.26 (1H, two s, NH).
13C-NMR (100 Mhz, DMSO-d6, ppm) δ 14.40 (CH3), 46.18 and 46.37 (2CH2), 51.97 and 52.13 (2CH2), 56.80 and 60.04 (COC_H2), 112.42 and 112.50 (2CH), 125.55 and 125.58 (C), 125.63 (2CH), 127.00 and 127.31 (2CH), 130.60 and 130.65 (2CH), 136.74 and 136.85 (C), 140.40 and 140.77 (C), 142.43 and 146.76 (C=N), 154.56 and 154.60 (C), 165.24 and 170.44 (C=O). HRMS (m/z): [M + H]+ calcd for C20H23N5O3S: 414.1594; found 414.1589.