This section may be divided by subheadings. It should provide a concise and precise description of the experimental results, their interpretation as well as the experimental conclusions that can bedrawn.
2.1. Chemistry
1-(Substituted phenylamino methyl)-3-(2-(4-(2-oxochroman-3-yl) thiazol-2-yl) hydrazono) indolin-2-ones were synthesized by treating 3-(2-(4-(2-oxochroman-3-yl) thiazol-2-yl)hydrazono )indolin-2-one (
3) with substituted aromatic amines and formaldehyde in ethylene glycol as depicted in
Figure 1. Prepared compounds were elucidated by FT-IR,
1H-NMR,
13C-NMR, mass and elemental analysis. In general, absorption bands due to two -NH group appeared in the IR spectra at around 3200 cm
−1. Other bands due to -C=N and two -C=O functional groups were found at around 1600 cm
−1 and 1700cm
−1, respectively. In the
1H-NMR spectra, two -NH peak appeared at around 9 and 10 ppm. The lower value provides information as a singlet due to -NH attached as -CH
2NH with indolinone nitrogen as a characteristic peak. Value at δ 5 ppm confirms the presence of -CH
2 which is another important peak for identification. Further, characteristics peak of -CH
2 of -CH
2NH was confirmed by
13C-NMR around δ 69 ppm.
The characterization data of all the synthesized compounds are provided below.
2-(2-Oxoindolin-3-ylidene)hydrazine carbothioamide (2): M.P.: 222–224°C; %Yield: 72; IR (KBr) cm−1: 3413, 3352 and 3216 (N-H), 1693 (C=O).1H-NMR (CDCl3, DMSO-d6) ppm: 6.72 (s, 1H, NH), 6.92 (d, J=12Hz, 1H, Ar-H), 7.03 (t, J=8Hz, 1H, Ar-H), 7.34 (t, J=8Hz, 1H, Ar-H), 8.04 (d, J=12Hz 1H, Ar-H), 9.99 (s, 1H, NH), 10.55 (s, 2H, NH); Elemental Analysis: Calcd. For (C9H8N4OS), Found % (Calculated %): C, 49.07 (49.08); H, 3.65 (3.66); N, 25.43 (25.44).
3-(2-(4-(2-Oxo-2H-chromen-3-yl)-4,5-dihydrothiazol-2-yl)hydrazono)indolin-2-one(3): M.P.: 240–242 °C; % Yield: 95; IR (KBr) cm−1: 1692 and 1703 (C=O), 3315 and 3253 (N-H), 1612 (C=N), 1543 (C=C).1H-NMR (CDCl3, DMSO-d6) ppm: 7.03 (t, J=8Hz, 1H, Ar-H), 7.39 (m, 8H, Ar-H, NH), 8.28 (s, 2H, Ar-H), 10.25 (s, 1H, -NH=N-); Elemental Analysis: Calcd. For (C20H12N4O3S), Found % (Calculated %): C, 61.84 (61.85); H, 3.10 (3.11); N, 14.42 (14.43).
3-{[4-(2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1-phenylaminomethyl-1,3-dihydro-indol-2-one (4a): M.P.: 245–247 °C; %Yield: 85; IR (KBr) cm−1: 1683 and 1710 (C=O), 3309 and 3251 (N-H), 1613 (C=N), 1546 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 5.13 (s, 2H, CH2), 7.44-8.10 (m, 13H, Ar-H), 9.35 (s, 1H, NH), 10.53 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 171.0 (C=N, thiazolidine),159 and 162 (2CO), 156 (1C, C=N),143.4, 140.9, 139.07, 139.0, 138.6, 131.0,129.8, 129.5, 127.8, 126.8, 125.5, 124.3,123.4, 121.2, 117.1, 112.4, (Ar-C), 69.3 (1C, CH2); Elemental Analysis: Calcd. For (C27H19N5O3S), Found % (Calculated %): C, 65.70 (65.71); H, 3.87 (3.88); N, 14.18 (14.19). Mass (m/z): 493 (M+, C27H19N5O3S), 200 (C11H6NOS), 175 (C10H7OS), 168 (C12H10N), 159 (C8H7N4), 132 (100%, C7H6N3), 106 (C7H8N).
1-[(4-Fluoro-phenylamino)-methyl]-3-{[4-(2-oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1,3-dihydro-indol-2-one (4b): M.P.: 242–244 °C;%Yield: 82; IR (KBr) cm−1: 1683 and 1704 (C=O), 3312 and 3264 (N-H), 1613 (C=N), 1543 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 5.10 (s, 2H, CH2), 7.42 (m, 14H, Ar-H), 9.15 (s, 1H, NH), 10.55 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 172.0 (C=N, thiazolidine),160 and 161 (2CO), 155 (1C, C=N),145.2, 143.1, 140.2, 139.0, 138.4, 132.5,130.7, 129.3, 128.9, 127.6, 125.3,124.4, 122.2, 118.3, 114.3, (Ar-C), 68.9(1C, CH2); MS (m/z): 511 (M+), 513 (M++2); Elemental Analysis: Calcd. For (C27H18N5O3SF), Found % (Calculated %): C, 63.38 (63.40); H, 3.55 (3.55); N, 13.68 (13.69).
1-[(4-Chloro-phenylamino)-methyl]-3-{[4-(2-oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1,3-dihydro-indol-2-one (4c): M.P.: 233–235 °C; %Yield: 85; IR (KBr) cm−1: 1689 and 1705 (C=O), 3309 and 3251 (N-H), 1613 (C=N), 1544 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 5.14 (s, 2H, CH2), 7.39 (m, 14H, Ar-H), 9.25 (s, 1H, NH), 10.50 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 170.0 (C=N, thiazolidine), 161 and 162 (2C, C=O), 157 (1C, C=N), 146.1, 143.1, 140.3, 139.1, 138.6, 133.5, 131.7, 129.2, 128.4, 127.7, 126.3, 125.2, 123.1, 117.9, 112.8, (Ar-C), 68.6(1C, CH2); MS(m/z): 528 (M+), 530 (M++2); Elemental Analysis: Calcd. For (C27H18N5O3SCl), Found % (Calculated %): C, 61.41 (61.42); H, 3.44 (3.44); N, 13.25 (13.26).
1-[(4-Bromo-phenylamino)-methyl]-3-{[4-(2-oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1,3-dihydro-indol-2-one (4d): M.P.:241–243 °C; %Yield: 80; IR (KBr) cm−1: 1685 and 1704 (C=O), 3313 and 3251 (N-H), 1611 (C=N), 1547 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 5.14 (s, 2H, CH2), 7.40 (m, 14H, Ar-H), 9.30 (s, 1H, NH), 10.51 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 171.0 (C=N, thiazolidine), 162 and 163 (2C, C=O), 156 (1C, C=N),145.5, 143.6, 140.3, 139.8, 138.3, 133.6,131.4, 129.7, 128.1, 127.7, 126.9, 123.6, 118.9, 112.9, (Ar-C), 69.3(1C, CH2); MS(m/z): 572 (M+), 574 (M++2); Elemental Analysis: Calcd. For (C27H18N5O3SBr), Found % (Calculated %): C, 56.64 (56.65); H, 3.16 (3.17); N, 12.22 (12.23).
1-[(2-Nitro-phenylamino)-methyl]-3-{[4-(2-oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1,3-dihydro-indol-2-one (4e): M.P.: 244–246 °C; %Yield: 85; IR (KBr) cm−1: 1684 and 1705 (C=O), 3310 and 3255 (N-H), 1613 (C=N), 1543 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 5.07 (s, 2H, CH2), 7.42 (m, 14H, Ar-H), 9.15 (s, 1H, NH), 10.48 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 170.0 (C=N, thiazolidine), 163 and 164 (2CO), 157 (1C, C=N), 146.4, 143.8, 141.6, 140.4, 139.7, 135.6, 133.4, 130.7, 128.5, 127.5, 126.4, 124.6, 118.6, 112.3, (Ar-C), 70.1(1C, CH2); MS (m/z): 538 (M+), 540 (M++2); Elemental Analysis: Calcd. For (C27H18N6O5S), Found % (Calculated %): C, 60.21 (60.22); H, 3.36 (3.37); N, 15.60 (15.61).
1-[(2-chloro-phenylamino)-methyl]-3-{[4-(2-oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1,3-dihydro-indol-2-one (4f): M.P.: 239–241 °C; %Yield: 83; IR (KBr) cm−1: 1689 and 1707 (C=O), 3311 and 3252 (N-H), 1613 (C=N), 1545 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 5.10 (s, 2H, CH2), 7.36 (m, 14H, Ar-H), 9.36 (s, 1H, NH), 10.55 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 172.0 (C=N, thiazolidine), 161 and 162 (2CO), 157 (1C, C=N), 146.5, 143.9, 140.8, 140.1, 138.7, 135.4, 133.7, 129.7, 128.8, 127.6, 126.3, 124.7, 119.3, 114.1, (Ar-C), 68.3(1C, CH2); Elemental Analysis: Calcd. For (C27H18N5O3SCl), Found % (Calculated %): C, 61.41 (61.42); H, 3.43 (3.44); N, 13.25 (13.26). Mass (m/z): 527 (M+, C27H18N5O3SCl), 528 (M++1), 202 (C12H9NCl), 175 (C10H7OS), 132 (100%, C7H6N3), 111 (C6H4Cl), 59 (C2H3S).
1-[(2,4-Dinitro-phenylamino)-methyl]-3-{[4-(2-oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1,3-dihydro-indol-2-one (4g): M.P.: 247–249 °C; %Yield: 80; IR (KBr) cm−1: 1686 and 1704 (C=O), 3292 and 3252 (N-H), 1612 (C=N), 1544 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 5.15 (s, 2H, CH2), 7.45 (m, 13H, Ar-H), 9.33 (s, 1H, NH), 10.51 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 169.0 (C=N, thiazolidine), 159 and 161 (2CO), 155 (1C, C=N), 145.7, 142.5, 140.2, 139.1, 137.4, 135.7, 133.5, 129.6, 128.6, 127.3, 124.7, 118.9, 112.3, (Ar-C), 69.7(1C, CH2); MS(m/z): 583 (M+), 585 (M++2); Elemental Analysis: Calcd.For(C27H17N7O7S), Found % (Calculated %): C, 55.56 (55.57); H, 2.94 (2.94); N, 16.79 (16.80).
3-{[4-(2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1-([
1,
2,
4]triazol-4-ylaminomethyl)-1,3-dihydro-indol-2-one (
4h): M.P.: 236–238 °C; %Yield: 80; IR (KBr) cm
−1: 1685 and 1706 (C=O), 3253 and 3279 (N-H), 1613 (C=N), 1543 (C=C);
1H-NMR (CDCl
3, DMSO-d
6) ppm: 5.17 (s, 2H, CH
2), 7.48 (m, 12H, Ar-H), 9.42 (s, 1H, NH), 10.47 (s, 1H, NH);
13C-NMR (125 MHz, DMSO-d
6); 170.0 (C=N, thiazolidine), 161 and 161 (2CO), 157 (1C, C=N), 144.8, 140.2, 137.4, 135.9, 132.4, 129.4, 128.7, 127.5, 124.3, 116.9, 112.3, (Ar-C), 70.2(1C, CH
2); MS(m/z): 484 (M
+), 486 (M
++2); Elemental Analysis: Calcd. For (C
23H
16N
8O
3S), Found % (Calculated %): C, 57.01 (57.02); H, 3.32 (3.33); N, 23.12 (23.13).
1-[(3-Chloro-4-fluoro-phenylamino)-methyl]-3-{[4-(2-oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1,3-dihydro-indol-2-one (4i): M.P.: 246–248 °C; %Yield: 85; IR (KBr) cm−1: 1684 and 1703 (C=O), 3240 and 3273 (N-H), 1612 (C=N), 1544 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 5.05 (s, 2H, CH2), 7.41 (m, 13H, Ar-H), 9.31 (s, 1H, NH), 10.55 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 171.0 (C=N, thiazolidine), 161 and 163 (2CO), 156 (1C, C=N), 146.9, 143.4, 140.6, 139.2, 137.6, 135.7, 133.8, 129.3, 128.3, 127.6, 124.2, 117.4, 112.3, (Ar-C), 68.6(1C, CH2); MS(m/z): 546 (M+), 548 (M++2); Elemental Analysis: Calcd. For (C27H17N5O3SClF), Found % (Calculated %): C, 59.38 (59.40); H, 3.14 (3.14); N, 12.82 (12.83).
3-{[4-(2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1-(pyridine-4-ylaminomethyl)-1,3-dihydro-indol-2-one (4j):M.P.: 237–239 °C; %Yield: 88; IR (KBr) cm−1: 1687 and 1705 (C=O), 3244 and 3268 (N-H), 1613 (C=N), 1545 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 5.17 (s, 2H, CH2), 7.45 (m, 14H, Ar-H), 9.38 (s, 1H, NH), 10.57 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 172.0 (C=N, thiazolidine), 161 and 163 (2CO), 156 (1C, C=N),144.8, 143.5, 140.4, 139.0, 138.3, 132.5,130.9, 129.3, 128.8, 127.6, 125.1,124.7, 122.9, 116.9, 112.6, (Ar-C), 68.3(1C, CH2); MS (m/z): 594 (M+), 596 (M++2); Elemental Analysis: Calcd. For (C26H18N6O3S), Found % (Calculated %): C, 63.14 (63.15); H, 3.66 (3.67); N, 16.98 (16.99).
3-{[4-(2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1-(pyridine-3-ylaminomethyl)-1,3-dihydro-indol-2-one (4k):M.P.: 231–233 °C; %Yield: 85; IR (KBr) cm−1: 1686 and 1706 (C=O), 3251 and 3277 (N-H), 1612 (C=N), 1543 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 5.15 (s, 2H, CH2), 7.47 (m, 14H, Ar-H), 9.35 (s, 1H, NH), 10.55 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 172.0 (C=N, thiazolidine),161 and 162 (2CO), 156 (1C, C=N),144.9, 143.6, 140.2, 139.0, 138.5, 132.3,130.7, 129.5, 128.7, 127.3, 125.5,124.9, 122.8, 116.6, 112.4, (Ar-C), 68.3(1C, CH2); MS (m/z): 594 (M+), 596 (M++2); Elemental Analysis: Calcd.For(C26H18N6O3S), Found % (Calculated %): C, 63.14 (63.15); H, 3.66 (3.67); N, 16.98 (16.99).
1-[(4-Nitro-phenylamino)-methyl]-3-{[4-(2-oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1,3-dihydro-indol-2-one (4l):M.P.: 241–243 °C; %Yield: 90; IR (KBr) cm−1: 1684 and 1702 (C=O), 3255 and 3278 (N-H), 1612 (C=N), 1544 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 5.18 (s, 2H, CH2), 7.46 (m, 14H, Ar-H), 9.32 (s, 1H, NH), 10.54 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 170.0 (C=N, thiazolidine), 163 and 164 (2CO), 158 (1C, C=N), 146.6, 143.7, 141.9, 140.5, 139.7, 135.2, 133.5, 130.1, 128.2, 127.7, 126.1, 124.3, 116.9, 112.3, (Ar-C), 70.2(1C, CH2); MS (m/z): 538 (M+), 540 (M++2); Elemental Analysis: Calcd. For (C27H18N6O5S), Found % (Calculated %): C, 60.21 (60.22); H, 3.36 (3.37); N, 15.60 (15.61).
3-{[4-(2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1-(p-tolylamino-methyl)-1,3-dihydro-indol-2-one (4m): M.P.: 244–246 °C; %Yield: 84; IR (KBr) cm−1: 1685 and 1706 (C=O), 3252 and 3273 (N-H), 1608 (C=N), 1544 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 2.23 (s, 3H, CH3), 5.11 (s, 2H, CH2), 7.41 (m, 14H, Ar-H), 9.31 (s, 1H, NH), 10.48 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 172.0 (C=N, thiazolidine), 160 and 163 (2CO), 156 (1C, C=N), 146.8, 144.2, 142.4, 140.6, 139.9, 135.3, 133.8, 130.5, 128.8, 127.1, 126.3, 124.8, 117.4, 114.1, (Ar-C), 70.3(1C, CH2); MS (m/z): 507 (M+), 509 (M++2); Elemental Analysis: Calcd. For (C28H21N5O3S), Found % (Calculated %): C, 66.25 (66.26); H, 4.16 (4.17); N, 13.79 (13.80).
3-{[4-(2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-hydrazono}-1-(o-tolylamino-methyl)-1,3-dihydro-indol-2-one (4n):M.P.: 237–239 °C; %Yield: 86; IR (KBr) cm−1: 1686 and 1703 (C=O), 3251 and 3282 (N-H), 1612 (C=N), 1543 (C=C); 1H-NMR (CDCl3, DMSO-d6) ppm: 2.21 (s, 3H, CH3), 5.13 (s, 2H, CH2), 7.43 (m, 14H, Ar-H), 9.34 (s, 1H, NH), 10.53 (s, 1H, NH); 13C-NMR (125 MHz, DMSO-d6); 171.0 (C=N, thiazolidine), 161 and 162 (2CO), 157 (1C, C=N), 145.9, 144.2, 142.6, 140.3, 139.2, 135.6, 133.5, 130.2, 128.9, 127.6, 126.1, 124.9, 118.2, 112.3, (Ar-C), 68.3(1C, CH2); Elemental Analysis: Calcd. For (C28H21N5O3S), Found % (Calculated %): C, 66.25 (66.26); H, 4.16 (4.17); N, 13.80 (13.80); Mass (m/z): 507 (M+, C28H21N5O3S), 387 (C20H11N4O3S), 200 (C11H6NOS), 132 (100%, C7H6N3), 120 (C8H10N), 90 (C6H4N), 59 (C2H3S).
2.1.1. Significance of DES and Ultrasound Blend of Techniques to the Synthesis of Key Intermediate 3-(2-(4-(2-Oxochroman-3-Yl) Thiazol-2-Yl) Hydrazono) Indolin-2-One
To develop the efficient method as compared to conventional, we have conducted the synthesis of key intermediate (3) utilizing biocompatible deep eutectic solvent (DES) and ultrasound blend of technique. As a result of combined use of DES and ultrasound, there have been found an increase in % yield of key intermediate as high as 95% with the expense of 1hr only. Whereas, a similar type of organic transformations using dioxane and another organic solvent together with conventional heating were reported to have % yield around 44–68% in 3–4 hrs. [
36,
37,
38]. Further, we have also found 80–88% of all final compounds (4a–n) utilizing ultrasound as a source of heating. Some of our earlier work and other related literature also mentioned the significance DES and ultrasound technology as an energy saving process [
29,
39,
40] which is certainly a good favor of our present work.
2.1.2. Plausible Mechanism Involved to the Formation of Key Intermediate,3-(2-(4-(2-Oxochroman-3-Yl) Thiazol-2-Yl) Hydrazono) Indolin-2-One
The exact mechanism of formation of the desired intermediate compound is not yet clear. But it was suggested by some researchers that urea part of DES (Choline chloride: urea, 1:2) catalyze the reaction by making hydrogen bond. Thus, urea in deep eutectic solvent involved to stabilize the acetyl moiety of 3-bromoacetylcoumarin via hydrogen bonding, which was further attacked by amide functional group of hydrazine thioamide to form key intermediate, 3-(2-(4-(2-oxochroman-3-yl)thiazol-2-yl)hydrazono) indolin-2-one through cyclization and dehydration process (
Scheme 1).
Moreover, ultrasound also played a significant role in the formation of the desired compound. Under the influence of sonic waves inside the reaction vessel, there was the formation of microscopic bubbles, as a result of high temperature and pressure [
28,
29,
30,
31]. These tiny microscopic bubbles also help in the cyclization process.