3.1. General
All reagents were obtained from commercial sources. Solvents were either commercially obtained as analytical grade or freshly distilled prior to use. Analytical thin layer chromatography was carried out on precoated silica gel 60F254 plates using either UV absorption or iodine staining for visualization. Column chromatography was carried out using 100–200 mesh silica gel. 1H-NMR and 13C{1H}-NMR spectra were recorded on a Bruker DRX 300 MHz instrument (300/75 MHz); chemical shift values are reported relative to tetramethylsilane as internal standard. The IR spectra were recorded on a Thermo Mattson IR300 and Nicolet 510 PET spectrometers. Elemental microanalysis was carried out using a model 5500-Carlo Erba C.H.N.S.O elemental analyzer instrument.
General procedure for the preparation of ethyl 2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetate (2). A mixture of 7-hydroxy-4-methylcoumarin (5.6 mmol), anhydrous potassium carbonate (5.6 mmol) and ethyl bromoacetate (5.6 mmol) in dry acetone (10 mL) was refluxed with continuous stirring for 12 h. After filtration, the solution was concentrated under reduced pressure, vacuum dried and the solid product was recrystallized from ethanol. m.p. 185–186 °C, yield 92%; IR: νmax CO lactone: 1,714 cm−1, NH: 3,435 cm−1, CO (ketone): 1,606 cm−1; 1H-NMR: δ 7.76 (d, JH5.6 = 14.6 Hz, 1H, H-5), 7.04 (d, JH5.6 = 14.6 Hz, 1H, H-6), 7.02 (s, 1H, H-8), 6.34 (s, 1H, H-3), 4.92 (s, 2H, -OCH2), 4.19 (q, JH2-H3 = 10.6 Hz, 2H, CH2, -CH2CH3), 4.02 (s, 2H, CH2), 1.22 (t, JH2-H3 = 10.6 Hz, 3H, CH3, -CH2CH3); 13C{1H}- NMR: δ 14.2 (CH2CH3), 34.8 (CH2CO), 61.3 (CH2CH3), 65.5 (COCH2O), 109.6 (C-8), 112.8 (C-6), 113.8 (C-3), 114.8 (C-10), 128.3 (C-5), 151.2 (C-9), 155.2 (C-4), 160.3 (C-7), 160.9 (C-2), 168.9 (CO-O), 169.3 (C-CO-C). Found, %: C, 64.12; H, 5.2; O, 30.40. C14H14O5. Calculated, %: C, 64.12; H, 5.38; O, 30.50.
2-(4-Methyl-2-oxo-2H-chromen-7-yloxy)acetohydrazide (3). To a solution of ethanol (15 mL) and hydrazine hydrate (10 mmol), ethyl 2-(4-methyl-2-oxo-2H-chromen-7-yloxy) acetate (2, 10 mmol) was added, and the mixture was refluxed for 4 h. The product precipitated and was collected by suction filtration, washed with methanol and recrystallized from dil. Acetic acid. m.p. = 300 °C, yield 70%; IR: νmax CO lactone: 1,681 cm−1, CONH (amide): 1,612 cm−1, CN: 1,271 cm−1; 1H-NMR: δ 9.41 (s, 1H, NH), 7.76 (d, JH5.6 = 14.6 Hz, 1H, H-5), 7.04 (d, JH5.6 = 14.6 Hz, 1H, H-6), 7.02 (s, 1H, H-8), 6.34 (s, 1H, H-3), 4.94 (s, 2H, -OCH2), 4.34 (s, 2H, NH2). 13C{1H}-NMR: δ 45.8 (CH2), 68.9 (CH2O-), 108.0 (C-8), 111.8 (C-6), 112.9 (C-3), 114.1 (C-10), 128.3 (C-5), 152.2 (C-9), 155.2 (C-4), 160.4 (C-7), 160.9 (C-2), 166.8 (COCH2O), 169.6 (COCH2). Found, %: C, 58.1; H, 4.82; N, 11.1; O, 25.70 C12H12O4N2. Calculated, %: C, 58.06; H, 4.87; N, 11.29; O, 25.78.
General procedure for the preparation of N′-benzylidene-2-(4-methyl-2-oxo-2H-chromen-7-yloxy) acetohydrazide (4). A mixture of 2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetohydrazide (3, 3.06 g, 0.01 mol) and appropriate aromatic aldehyde (Ar/a-d, 0.01 mol) was refluxed in absolute ethanol (30 mL) in the presence of a catalytic amount of glacial acetic for 4 h. The reaction mixture was cooled; the solid separated was filtered and recrystallized from methanol to give compounds 4a–d.
N'-Benzylidene-2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide (4a). m.p. 268–269 °C; yield 74%; IR: νmax CO lactone: 1681 cm−1, CONH (amide): 1610 cm−1, C=N: 1258 cm−1; 1H-NMR: δ 8.30 (s, 1H, HC=N-), 8.02 (s, 1H, NH), 7.76 (d, JH5.6 = 15.6 Hz, 1H, H-5), 7.72–7.31 (m, 10H, arom.), 7.04 (d, JH5.6 = 15.6 Hz, 1H, H-6), 7.02 (s, 1H, H-8), 6.34 (s, 1H, H-3), 4.83 (s, 2H, -OCH2), 13C{1H}-NMR: δ 45.7 (CH2), 69.2 (CH2O-), 108.1 (C-8), 111.6 (C-6), 112.5 (C-3), 114.4 (C-10), 127.9 (C-5), 128.4 (C-3,5, Ar-), 129.0 (C-2,6, Ar-), 131.4 (C-4, Ar-), 133.9 (C-1, Ar-), 143.6 (N=CH-), 151.8 (C-9), 155.2 (C-4), 160.4 (C-7), 160.9 (C-2), 166.9 (COCH2O), 170.0 (CONH-). Found, %: C, 67.75; H, 4.8; N, 8.2; O, 19.1. C19H16O4N2. Calculated, %: C, 67.85; H, 4.79; N, 8.33; O, 19.03.
N′-(3-Methoxybenzylidene)-2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide (4b). m.p. 225–226 °C, yield (76%); IR: νmax CO lactone:1,681 cm−1,CONH (amide): 1,614 cm−1, C=N: 1,255 cm−1; 1H-NMR: δ 8.73 (s, 1H, -HC=N-), 8.45 (s, 1H, NH), 7.72 (d, JH5.6 = 15.5 Hz, 1H, H-5), 7.60–7.30 (m, 8H, arom.), 3.65 (s, 3H, OCH3) ,7.04 (d, JH5.6 = 15.4 Hz ,1H, H-6), 7.02 (s, 1H, H-8), 6.34 (s, 1H, H-3), 4.84 (s, 2H, -OCH2), 13C{1H} NMR: δ 45.6 (CH2), 68.9 (CH2O-), 107.8 (C-8), 111.5(C-6), 112.7 (C-3), 113.9 (C-10), 127.8 (C-5), 129.4 (C-3, Ar-), 130.6 (C-6, Ar-), 132.7 (C-4, Ar-),133.8 (C-1, Ar-), 134.3 (C-2, Ar-), 143.5 (N=CH-), 151.7 (C-9), 155.0 (C-4), 160.3 (C-7), 160.9 (C-2),166.4 (COCH2O), 169.9 (CONH-). Found, %: C, 65.5; H, 4.80; N, 7.6; O, 21.8. C20H18O5N2. Calculated, %: C, 65.57; H, 4.95; N, 7.65; O, 21.84.
N′-(2.3.4-Trimethoxybenzylidene)-2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide (4c). m.p. 259–261 °C, yield 72%; IR: νmax CO lactone: 1,681 cm−1, CONH (amide): ,1618 cm−1, C=N: 1,281 cm−1. 1H-NMR: δ 8.31 (s, 1H, -HC=N-), 7.76 (d, JH5.6 = 15.5Hz, 1H, H-5), 7.67–7.30 (m, 8H, arom.), 7.04 (d, JH5.6 = 15.6 Hz ,1H, H-6), 7.02 (s, 1H, H-8), 6.34 (s, 1H, H-3), 3.78 (s, 9H, 2,3,4 OCH3), 4.84 (s,2H, -OCH2), 13C{1H}-NMR: δ 45.5 (CH2), 69.1 (CH2O-), 107.9 (C-8), 111.4 (C-6),112.5 (C-3), 113.4 (C-10), 127.3 (C-6, Ar-), 127.9 (C-5), 129.3 (C-2, Ar-), 130.3 (C-5, Ar-), 131.2 (C- 4, Ar-), 135.2 (C-1, Ar-), 134.4 (C-3, Ar-), 143.4 (N=CH-), 151.6 (C-9), 155.2 (C-4), 160.6 (C-7), 160.9 (C-2), 166.7 (COCH2O), 169.8 (CONH-). Found, %: C, 61.9; H, 5.1; N, 6.5; O, 26.3. C22H22O7N2. Calculated, %: C, 61.97; H, 5.20; N, 6.57; O, 26.26.
N′-(4-Bromobenzylidene)-2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide (4d). m.p. 273–275 °C, yield 52%; IR: νmax CO lactone: 1,681 cm−1, CONH (amide): 1,612 cm−1, 1H-NMR: 8.30 (s, 1H, -HC=N-), 8.23 (s, 1H, NH), 7.76 (d, JH5.6 = 15.5 Hz, 1H, H-5), 7.61–7.30 (m, 6H, arom.), 7.04 (d, JH5.6 = 15.5 Hz, 1H, H-6), 7.02 (s, 1H, H-8), 6.34 (s, 1H, H-3), 4.82 (s, 2H, -OCH2), 13C{1H}- NMR: δ 45.6 (CH2), 69.2 (CH2O-), 103.8 (C-3, Ar-), 107.6 (C-8), 108.7 (C-5, Ar-),111.3 (C-6), 112.7 (C-3), 113.4 (C-10), 127.2 (C-6, Ar-), 127.9 (C-5), 135.2 (C-1, Ar-), 143.0 (N=CH-), 151.2 (C-9), 155.1 (C-4), 160.5 (C-7), 160.9 (C-2), 162.4 (C-2, Ar-), 162.6 (C-4, Ar-), 166.5 (COCH2O), 169.4 (CONH-). Found, %: C, 54.8; H, 3.6; Br, 19.1; N, 6.7; O, 15.4. C19H15O4N2. Calculated, %: C, 54.96; H, 3.64; Br, 19.24; N, 6.75; O, 15.41.
General procedure for the preparation of 2-(4-methyl-2-oxo-2H-chromen-7-yloxy)-N-(4-oxo-2 arylthiazolidin-3-yl) acetamide (5). A mixture of N′-benzylidene-2-(4-methyl-2-oxo-2H-chromen-7-yloxy) acetohydrazide (4, 0.01 mol) and mercaptoacetic acid (1.82 g, 0.02 mol) in 1,4-dioxane (30 mL) containing a pinch of anhydrous ZnCl2 was refluxed for 6–8 h. The reaction mixture was cooled and poured onto crushed ice. The solid thus obtained was filtered, washed with water and recrystallized from DMF yielding 5a–d.
2-(4-Methyl-2-oxo-2H-chromen-7-yloxy)-N-(4-oxo-2-phenylthiazolidin-3-yl)acetamide (5a). m.p. 202–204 °C, yield 40%; IR: νmax CO lactone: 1,681 cm−1, CONH (amide): 1,615 cm−1; 1H-NMR: 2.15 (s, 3H), 8.12 (s, 1H, -NH), 7.76 (d, JH5.6 = 10.6 Hz, 1H, H-5), 7.71–7.23 (m, 10H, arom.), 7.04 (d, JH5.6 = 10.6 Hz, 1H, H-6), 7.02 (s, 1H, H-8), 6.34 (s, 1H, H-3), 5.92 (s, 1H, -SCHN-), 4.83 (s, 2H, ‑OCH2), 3.38 (s, 2H, COCH2S-); 13C{1H}-NMR: δ 35.8 (COCH2S), 45.5 (CH2), 57.4 (NCHS), 69.1 (CH2O-) 107.6 (C-8), 111.0 (C-6), 112.5 (C-3), 113.4 (C-10), 127.2 (C-4, Ar-), 127.8 (C-5), 128.7 (C-3,5, Ar-),128.8 (C-2,6 Ar-), 139.2 (C-1, Ar-), 151.2 (C-9), 155.0 (C-4), 160.3 (C-7), 160.9 (C-2), 166.4 (COCH2O), 168.8 (SCH2CO-N), 173.3 (CONH-). Found, %: C, 61.3; H, 4.4; N, 6.8; O, 19.5; S, 7.7. C21H18O5N2S. Calculated, %: C, 61.45; H, 4.42; N, 6.83; O, 19.49; S, 7.81.
N-(2-(3-Methoxyphenyl)-4-oxothiazolidin-3-yl)-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetamide (5b). m.p. 184 °C, yield 76%; IR: νmax CO lactone: 1,681 cm−1, CONH (amide): 1,614 cm−1; 1H-NMR: 8.62 (s, 1H, NH-), 2.20 (s, 3H), 7.76 (d, JH5.6 = 10.5 Hz, 1H, H-5), 7.60–7.30 (m, 8H, arom.), 3.67 (s, 3H, OCH3), 7.04 (d, JH5.6 = 10.5 Hz, 1H, H-6), 7.02 (s, 1H, H-8), 6.34 (s, 1H, H-3), 5.92 (s, 1H, NCHS), 4.84 (s, 2H, -OCH2), 3.38 (s, 2H, COCH2S); 13C{1H}-NMR: δ 35.7 (COCH2S), 45.5 (CH2), 57.4(NCHS), 69.10 (CH2O-), 107.6 (C-8), 111.0 (C-6), 112.5 (C-3), 113.4 (C-10), 127.0 (C-5), 129.0 (C-3, Ar-), 130.6 (C-6, Ar-), 132.5 (C-4, Ar-), 133.4 (C-1, Ar-), 134.0 (C-2, Ar-), 143.0 (N=CH-), 151.2 (C-9), 155.0 (C-4), 160.3 (C-7), 160.9 (C-2), 166.4 (COCH2O), 173.0 (CONH-). Found, %: C, 59.9; H, 4.5; N, 6.4; O, 21.8; S, 7.2. C22H20O6N2S. Calculated, %: C, 59.99; H, 4.58; N, 6.36; O, 21.79; S, 7.28.
2-(4-Methyl-2-oxo-2H-chromen-7-yloxy)-N-(4-oxo-2-(2,3,4-trimethoxyphenyl)thiazolidin-3-yl)acetamide (5c). m.p. 239–241 °C, yield 52%; IR: νmax 1,712 (C=O, lactone), 1,624 (C=O, amide) cm−1; 1H-NMR: 2.12 (s, 3H), 8.30 (s, 1H, NH-), 7.76 (d, JH5.6 = 10.4 Hz, 1H, H-5), 7.61–7.30 (m, 6H, arom.), 7.04 (d, JH5.6 = 10.4 Hz, 1H, H-6), 7.02 (s, 1H, H-8), 6.34 (s, 1H, H-3), 5.92 (s, 1H, NCHS), 4.82 (s, 2H, ‑OCH2), 3.75 (s, 9H, 2,3,4 OCH3), 4.28 (s, 2H, CH2), 3.38 (s, 2H, COCH2S); 13C{1H}-NMR: δ 35.7 (COCH2S), 45.5 (CH2), 47.4 (NCHS), 69.10 (CH2O-), 103.7 (C-3, Ar-), 107.6 (C-8), 108.4 (C-5, Ar-), 110.1 (C-1, Ar-), 111.0 (C-6), 112.5 (C-3), 113.4 (C-10), 127.8 (C-5),131.3 (C-6, Ar-), 151.2 (C-9), 157.2 (C-2, Ar-), 158.2 (C-4), 160.3 (C-7), 160.9 (C-2), 166.4 (CONH),168.8 (NCOCH2), 173.3 (CH2CONH). Found, %: C, 57.4; H, 4.75; N, 5.7; O, 25.6; S, 6.5. C24H24O8N2S. Calculated, %: C, 57.59; H, 4.83; N, 5.60; O, 25.57; S, 6.41.
N-(2-(4-Bromophenyl)-4-oxothiazolidin-3-yl)-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetamide (5d). m.p. 240–241 °C, yield 72%; IR: νmax 1,727 (CO, lactone), 1,616 (C=O, amide) cm−1; 1H-NMR: 2.14 (s, 3H), 8.22 (s, 1H, NH-), 7.76 (d, JH5.6 = 10.5 Hz, 1H, H-5), 7.67–7.30 (m, 8H, arom.), 7.04 (d, JH5.6 = 10.5 Hz, 1H, H-6), 7.02 (s, 1H, H-8), 6.34 (s, 1H, H-3), 5.92 (s, 1H, NCHS), 4.84 (s, 2H, -OCH2), 3.38 (s, 2H, COCH2S); 13C{1H}-NMR: δ 35.7 (COCH2S), 45.5 (CH2), 57.4 (NCHS), 69.10 (CH2O-), 107.6 (C-8), 111.0 (C-6), 112.5 (C-3), 113.4 (C-10), 127.3 (C-6, Ar-), 127.8 (C-5), 129.3 (C-2, Ar-), 130.3 (C-5, Ar-), 131.2 (C-4, Ar-), 135.2 (C-1, Ar-), 134.4 (C-3, Ar-), 143.0 (N=CH-), 151.2 (C-9), 155.0 (C-4), 160.3 (C-7), 160.9 (C-2), 173.0 (COCH2O), 173.0 (CONH-). Found, %: C, 51.6; H, 3.4; Br, 16.4; N, 5.75; O, 16.4; S, 6.7. C21H17O5N2BrS. Calculated, %: C, 51.54; H, 3.50; Br, 16.33; N, 5.72; O, 16.35; S, 6.55.