Chemistry
All reactions were performed with commercially available reagents and solvents without further purification. All reactions were monitored by thin-layer chromatography (TLC). 1H and 13C NMR spectra were recorded on Bruker AVANCE-III HD 400MHz or NEO 500MHz (Bruker Daltonics Inc., Germany) spectrometers using TMS as a reference. Mass spectra were recorded on a Bruker APEXII49e spectrometer (Bruker Daltonics Inc., Germany) with ESI source as ionization.
General procedure for the synthesis of gallic hydrazones 1-17.
The reaction route is outlined in Scheme 1. The intermediate compounds gallic hydrazide was prepared according to the reported methods [20]. Briefly, the gallic acid esters were prepared from gallic acid in refluxing methanol and the presence of H2SO4 as catalyst. The reaction of esters with hydrazine hydrate in ethanol afforded hydrazides. Finally, condensation of hydrazide with different aromatic aldehydes in methanol produced the desired gallic hydrazones analogues 1-17 in 68−85% yield.
(E)-N'-benzylidene-3, 4, 5-trihydroxybenzohydrazide (1). white solid; yield: 85%; 1H NMR (400 MHz, DMSO) δ: 11.54 (s, 1H, NH), 9.17 (s, 2H, OH), 8.85 (m, 1H, OH), 8.42 (s, 1H, =CH), 7.70 (d, 2H, Ar-H), 7.45 (d, 2H, Ar-H), 6.93(s, 2H, Ar-H); 13C NMR (100 MHz, DMSO) δ: 164.20, 146.74, 146.02, 136.80, 134.18, 130.26, 129.28, 126.26, 123.81, 106.88; ESI-MS: m/z 273.10 [M+H]+.
(E)-3, 4, 5-trihydroxy-N'-(4-hydroxybenzylidene) benzohydrazide (2). yellow solid; yield: 80%; 1H NMR (400 MHz, DMSO) δ: 11.53 (s, 1H, NH), 9.16 (s, 2H, OH), 8.82 (s, 2H, OH), 8.42 (s, 1H, =CH), 7.70 (m, 2H, Ar-H), 7.45 (m, 2H, Ar-H), 6.93(s, 2H, Ar-H); 13C NMR (100 MHz, DMSO) δ: 163.88, 147.64, 146.02, 138.00, 135.00, 130.70, 129.27, 128.07, 124.22, 121.89, 117.82, 107.66; ESI-MS: m/z 273.10 [M+H]+; ESI-MS: m/z 289.07 [M+H]+.
(E)-3, 4, 5-trihydroxy-N'-(3-hydroxybenzylidene) benzohydrazide (3). yellow solid; yield: 76%; 1H NMR (400 MHz, DMSO) δ: 11.52 (s, 1H, NH), 10.24 (s, 2H, OH), 9.17 (s, 1H, OH), 8.73 (s, 1H, =CH), 7.82 (m, 2H, Ar-H), 7.24-7.56 (m, 2H, Ar-H), 6.96(s, 2H, Ar-H), 2.56 (s, 3H, CH3); 13C NMR (100 MHz, DMSO) δ: 163.46, 145.31, 140.59, 137.42, 137.11, 134.36, 133.03, 129.50, 126.60, 125.73, 123.84, 107.50, 19.41; ESI-MS: m/z 287.12 [M+H]+.
(E)-3, 4, 5-trihydroxy-N'-(3-hydroxybenzylidene) benzohydrazide (4). white solid; yield: 80%; 1H NMR (400 MHz, DMSO) δ: 11.56 (s, 1H, NH), 10.21 (s, 1H, OH), 9.18 (s, 2H, OH), 8.86 (s, 1H, OH), 8.72 (s, 1H, =CH),7.81 (s, 2H, Ar-H), 7.23-1.55 (m, 2H, Ar-H), 7.01(s, 2H, Ar-H); 13C NMR (100 MHz, DMSO) δ: 163.50, 146.44, 144.41, 137.44, 135.09, 131.23, 129.27, 126.86, 123.40, 116.92, 107.66; ESI-MS: m/z 273.10 [M+H]+; ESI-MS: m/z 289.07 [M+H]+.
(E)-3, 4, 5-trihydroxy-N'-(3-methylbenzylidene) benzohydrazide (5). yellow solid; yield: 70%; 1H NMR (400 MHz, DMSO) δ: 11.52 (s, 1H, NH), 9.17 (s, 2H, OH), 8.83 (s, 1H, OH), 8.38 (s, 1H, =CH), 7.82 (m, 2H, Ar-H), 7.22-7.53 (m, 4H, Ar-H), 6.94(s, 2H, Ar-H), 2.50 (s, 3H, CH3); 13C NMR (100 MHz, DMSO) δ: 163.50, 146.07, 140.58, 137.12, 134.77, 133.03, 132.15, 129.95, 126.10, 125.73, 123.85, 107.28, 19.41; ESI-MS: m/z 287.12 [M+H]+.
(E)-3, 4, 5-trihydroxy-N'-(3-methylbenzylidene) benzohydrazide (6). yellow solid; yield: 71%; 1H NMR (400 MHz, DMSO) δ: 11.57 (s, 1H, NH), 9.14 (s, 2H, OH), 8.82 (s, 1H, OH), 8.74 (s, 1H, =CH), 7.37 (d, 2H, Ar-H), 6.94-7.06 (m, 4H, Ar-H), 3.81(s, 3H, CH3); 13C NMR (100 MHz, DMSO) δ: 163.08, 154.36, 152.66, 145.99, 137.42, 123.70, 117.75, 113.90, 109.64, 107.28, 56.75; ESI-MS: m/z 287.12 [M+H]+.
(E)-3, 4, 5-trihydroxy-N'-(4-hydroxybenzylidene) benzohydrazide (7). white solid; yield: 68%; 1H NMR (400 MHz, DMSO) δ: 11.67 (s, 1H, NH), 11.63 (s, 1H, OH), 9.93 (s, 1H, OH), 9.18 (s, 2H, 2OH), 8.45 (s, 1H, =CH),7.24 (d, 2H, Ar-H), 6.92 (s, 2H, Ar-H), 6.34(m, 2H, Ar-H); 13C NMR (100 MHz, DMSO) δ: 163.07, 161.35, 148.97, 145.61, 137.54, 133.04, 123.34, 112.85, 108.03, 103.16; ESI-MS: m/z 273.10 [M+H]+; ESI-MS: m/z 289.07 [M+H]+.
(E)-N'-(2, 4-dihydroxybenzylidene)-3, 4, 5- trihydroxybenzohydrazide (8). white solid; yield: 75%; 1H NMR (400 MHz, DMSO) δ: 11.40 (s, 1H, NH), 9.14 (s, 2H, OH), 8.95 (s, 1H, OH), 8.85 (s, 1H, OH), 8.29 (s, 1H, =CH), 6.91-6.95 (m, 4H, Ar-H); 13C NMR (100 MHz, DMSO) δ: 163.38, 148.61, 147.64, 146.00, 138.11, 137.27, 135.37, 133.56, 125.73, 124.08, 107.28, 104.96; ESI-MS: m/z 305.06 [M+H]+.
(E)-N'-(2, 5-dihydroxybenzylidene)-3, 4, 5- trihydroxybenzohydrazide (9). white solid; yield: 69%; 1H NMR (400 MHz, DMSO) δ:11.83 (s, 1H, NH), 11.41 (s, 1H, OH), 9.21 (s, 1H, OH), 9.12 (s, 1H, OH), 8.89 (s, 1H, OH), , 9.12 (s, 1H, =CH), 7.36 (d, 2H, Ar-H), 7.05 (d, 1H, Ar-H), 6.98 (m, 1H, Ar-H), 6.94(d, 2H, Ar-H),13C NMR (100 MHz, DMSO) δ: 163.30, 148.72, 146.49, 146.11, 146.01, 137.74, 123.08, 120.72, 119.53, 119.21, 117.65, 107.66; ESI-MS: m/z 305.06 [M+H]+.
(E)-N'-(2, 5-dimethoxybenzylidene) -3, 4, 5- trihydroxybenzohydrazide (10). white solid; yield: 76%; 1H NMR (400 MHz, DMSO) δ: 11.57 (s, 1H, NH), 9.14 (s, 2H, OH), 8.82 (s, 1H, OH), 8.74 (s, 1H, =CH), 7.36 (d, 2H, Ar-H), 7.05 (d, 1H, Ar-H), 6.98 (m, 1H, Ar-H), 6.94(d, 2H, Ar-H), 3.75 (s, 3H, -OCH3), 3.81 (s, 3H, -OCH3 ); 13C NMR (100 MHz, DMSO) δ: 163.38, 153.73, 152.63, 141.77, 137.41, 123.77, 118.13, 114.92, 113.88, 110.71, 109.58, 107.28, 56.73, 55.91; ESI-MS: m/z 301.11[M+H]+.
(E)-3, 4, 5-trihydroxy-N'-(2, 3, 4-trihydroxybenzylidene) benzohydrazide (11). white solid; yield: 75%; 1H NMR (400 MHz, DMSO) δ: 11.71 (s, 1H, NH), 11.65 (s, 1H, OH), 9.40 (s, 1H, OH), 9.19 (s, 1H, OH), 8.85 (s, 1H, OH), 8.42 (s, 1H, =CH), 6.93 (s, 2H, Ar-H), 6.73 (d, 1H, Ar-H) , 6.38 (d, 1H, Ar-H); 13C NMR (100 MHz, DMSO) δ: 163.06, 149.75, 148.94, 147.90, 146.09, 137.56, 133.15, 123.30, 121.58, 111.41, 108.00, 107.56; ESI-MS: m/z 321.05 [M+H]+.
(E)-N'-(3, 4-dihydroxybenzylidene)-3, 4, 5- trihydroxybenzohydrazide (12). white solid; yield: 72%; 1H NMR (400 MHz, DMSO) δ:11.71 (s, 1H, NH), 11.65 (s, 1H, OH), 9.40 (s, 1H, OH), 9.19 (s, 2H, 2OH), 8.85 (s, 1H, OH), 8.42 (s, 1H, =CH), 6.93 (s, 2H, Ar-H), 6.73 (d, 1H, Ar-H), 6.38(d, 1H, Ar-H),13C NMR (100 MHz, DMSO) δ: 163.06, 149.75, 148.94, 147.90, 146.09, 137.55, 133.15, 123.30, 121.58, 111.41, 118.00, 107.56. ; ESI-MS: m/z 305.06 [M+H]+.
(E)-N'-(3, 4-dimethoxybenzylidene) -3, 4, 5- trihydroxybenzohydrazide (13). white solid; yield: 70%; 1H NMR (400 MHz, DMSO) δ: 11.57 (s, 1H, NH), 9.16 (s, 2H, OH), 8.83 (s, 1H, OH), 8.34 (s, 1H, =CH), 7.02 (s, 4H, Ar-H), 6.98 (m, 2H, Ar-H), 3.84 (s, 6H, 2-OCH3 ); 13C NMR (100 MHz, DMSO) δ: 163.38, 153.73, 152.63, 141.77, 137.41, 123.77, 118.13, 114.92, 113.88, 110.71, 109.58, 107.28, 56.73, 55.91; ESI-MS: m/z 301.11[M+H]+ ; ESI-MS: m/z 333.13 [M+H]+.
(E)-3, 4, 5-trihydroxy-N'-(3, 4, 5-trimethoxybenzylidene) benzohydrazide (14). white solid; yield: 78%; 1H NMR (400 MHz, DMSO) δ: 11.54 (s, 1H, NH), 9.89 (s, 1H, OH), 9.17 (s, 1H, OH), 8.84 (s, 1H, OH), 8.34 (s, 1H, =CH), 7.26 (s, 2H, Ar-H), 6.99 (s, 2H, Ar-H), 3.85 (s, 6H, 2-OCH3), 3.71 (s, 3H, -OCH3 ); 13C NMR (100 MHz, DMSO) δ: 163.68, 153.80, 146.44, 143.29, 139.45, 132.13, 130.83, 123.87, 107.20, 104.95, 60.69, 57.06; ESI-MS: m/z 363.11[M+H]+.
(E)-3, 4, 5-trihydroxy-N'-(3, 4, 5-trihydroxybenzylidene) benzohydrazide (15). Yellow solid; yield: 72%; 1H NMR (400 MHz, DMSO) 1H NMR (400 MHz, DMSO) δ: 11.32 (s, 1H, NH), 9.33-9.09 (m, 4H, OH), 8.75 (s, 1H, OH), 8.57 (s, 1H, OH), 8.08 (s, 1H, =CH), 6.86 (s, 2H, Ar-H), 6.60 (s, 2H, Ar-H); 13C NMR (100 MHz, DMSO) δ: 163.35, 147.95, 147.04, 145.88, 137.10, 135.37, 125.38, 124.02, 107.50, 106.15; ESI-MS: m/z 321.05 [M+H]+.
(E)-3, 4, 5-trihydroxy-N'-(3, 4, 5-trimethoxybenzylidene) benzohydrazide (16). white solid; yield: 72%; 1H NMR (400 MHz, DMSO) 1H NMR (400 MHz, DMSO) δ: 11.35 (s, 1H, NH), 9.20 (s, 2H, OH), 8.79 (s, 1H, OH), 8.25 (s, 1H, =CH), 7.23 (s, 1H, Ar-H), 6.90-7.00 (m, 4H, Ar-H), 3.80 (s, 3H, -OCH3 ); 13C NMR (100 MHz, DMSO) δ: 163.42, 150.01, 147.31, 146.00, 137.25, 127.95, 124.06, 120.46, 112.71, 112.33, 107.54, 56.03; ESI-MS: m/z 319.10[M+H]+.
(E)-3, 4, 5-trihydroxy-N'-(4-hydroxy-3, 5-dimethoxybenzylidene) benzohydrazide (17). white solid; yield: 74%; 1H NMR (400 MHz, DMSO) δ: 11.41 (s, 1 H, NH), 9.14 (s, 2H, OH), 8.85 (s, 2 H, OH), 8.29 (s, 1 H, =CH), 6.93 (d, m, 4H, Ar-H), 3.82 (s, 6H, 2-OCH3 ); 13C NMR (100 MHz, DMSO) δ: 163.49, 148.60, 147.75, 146.00, 138.15, 137.26, 125.36, 124.07, 107.56, 104.91, 56.48; ESI-MS: m/z 349.09 [M+H]+.