A. Skrzypek et al. / European Journal of Medicinal Chemistry 62 (2013) 311e319
317
3H, CH3); 13C NMR (125 MHz, DMSO-d6, ppm)
d
: 166.0, 162.3,
EI-MS (m/z, %): 302 (Mþ, 100), 169 (6), 168 (9), 167 (67), 153 (39), 138
(5),137 (5),136 (10),135 (34),121 (11),119 (8),112 (5),108 (7),107 (13),
106 (10), 97 (7), 89 (6), 81 (7), 80 (10), 79 (9), 75 (7), 69 (13), 65 (7), 63
(17), 62 (7), 55 (6), 53 (7), 52 (21), 51 (18), 50 (7), 39 (17), 38 (6).
161.1, 156.3, 150.9, 149.1, 128.9, 122.8, 120.8, 112.0, 109.7, 108.4,
108.3, 102.4, 55.7 (OCH3), 55.6 (OCH3); IR (KBr, cmꢀ1): 3478, 3151
(OH), 2943 (AreH), 2840 (CAreOCH3), 1627 (C]N), 1597 (C]C),
1522 (C]C), 1454 (C]C), 1432 (C]C), 1269 (CeOeC), 1246, 1178
(CeO), 1128, 1095 (N]CeSeC]N), 1020, 985, 967, 859, 805, 756
(AreH), 679, 643 (CeSeC); EI-MS (m/z, %): 330 (Mþ, 100), 329 (5),
315 (12), 301 (4), 287 (9), 181 (7), 180 (5), 167 (14), 165 (7), 164 (5),
163 (14), 153 (8), 152 (4), 148 (6), 137 (4), 136 (4), 135 (6), 120 (7),
107 (4), 94 (5), 65 (4), 39 (4).
5.2.15. 4-(5-(3-Aminophenyl)-1,3,4-thiadiazol-2-yl)benzene-1,3-
diol (18)
Yield: 69%; yellow needles; HPLC (C-18): log k ¼ 0.107; m.p.:
160e162 ꢄC; anal. calc. for C14H11N3O2S (285.32): C, 58.93; H, 3.89;
N, 14.73; found: C, 58.98; H, 3.91; N, 14.68; 1H NMR (500 MHz,
DMSO-d6, ppm) d: 11.14 (s, 1H, HOeC(3)), 10.07 (s, 1H, HOeC(1)),
5.2.12. 4-(5-(2,5-Dimethoxyphenyl)-1,3,4-thiadiazol-2-yl)benzene-
1,3-diol (13)
Yield: 79%; pale yellow plaques; HPLC (C-18): log k ¼ 0.102;
m.p.: 248e249 ꢄC; anal. calc. for C16H14N2O4S (330.36): C, 58.17; H,
4.27; N, 8.48; found: C, 58.23; H, 4.29; N, 11.41; 1H NMR (500 MHz,
8.08 (d, J ¼ 8.68 Hz, 1H, C(5)), 7.88 (m, 2H, HeAr), 7.61 (m, 1H,
HeAr), 6.53 (d, J ¼ 2.34 Hz, 1H, C(2)), 6.47 (dd, J ¼ 8.70 and 2.33 Hz,
1H, C(6)), 6.38 (s, 2H, NH2), 6.36 (d, 1H, HeAr); 13C NMR (125 MHz,
DMSO-d6, ppm) d: 165.5, 161.4, 156.2, 147.5, 133.9, 130.2, 128.9,
120.8, 118.8, 112.0, 109.7, 108.5, 107.9, 102.3; IR (KBr, cmꢀ1): 3433
(OH, NH), 1622 (C]N), 1506 (C]C), 1464 (C]C), 1341, 1234 (CeOe
C), 1171 (CeO), 978, 892, 843, 801, 744, 682 (CeSeC), 649; EI-MS
(m/z, %): 28 (5), 258 (4), 256 (10), 192 (7), 160 (11), 149 (4), 128
(9), 110 (7), 96 (6), 91 (6), 81 (4), 80 (7), 77 (5), 76 (5), 73 (4), 69 (4),
66 (10), 64 (100), 60 (6), 57 (7), 55 (8), 51 (7), 48 (12), 45 (8), 44 (80),
43 (14), 41 (13), 40 (46), 39 (12), 38 (6), 36 (15), 34 (4).
DMSO-d6, ppm) d: 11.03 (s, 1H, HOeC(3)), 10.03 (s, 1H, HOeC(1)),
8.05 (d, J ¼ 8.64 Hz, 1H, HeC(5)), 7.87 (d, J ¼ 3.16 Hz, 1H, He
C(60)), 7.25 (d, J ¼ 9.12, 1H, HeC(30)), 7.11 (dd, J ¼ 9.07 and
3.19 Hz, 1H, HeC(40)), 6.50 (d, J ¼ 2.29 Hz, 1H, HeC(2)), 6.47 (dd,
J ¼ 8.64 and 2.32 Hz, 1H, HeC(6)), 3.97 (s, 3H, OCH3), 3.82 (s, 3H,
OCH3); 13C NMR (125 MHz, DMSO-d6, ppm)
d: 164.5, 161.0, 160.0,
156.4, 153.3, 149.9, 129.1, 119.4, 117.9, 114.0, 111.3, 108.5, 108.3, 102.4,
56.6, 55.6; IR (KBr, cmꢀ1): 3434 (OH), 3001 (AreH), 2938 (AreH),
2836 (CH3), 1629 (C]N), 1598 (C]C), 1503 (C]C), 1465 (C]C),
1427 (C]C), 1402, 1338, 1289 (CeOeC), 1224, 1182 (CeO), 1129,
1047 (N]CeSeC]N), 1018(AreH), 970, 876, 846, 805, 728, 691,
669 (CeSeC), 644, 616; EI-MS (m/z, %): 330 (Mþ, 100), 329 (16), 301
(15), 287 (9), 271 (7), 196 (10), 195 (49), 194 (18), 180 (13), 179 (7),
178 (11), 168 (7), 167 (46), 166 (17), 165 (14), 163 (13), 162 (23), 162
(23), 153 (28), 152 (9), 150 (9), 149 (16), 148 (27), 137 (8), 136 (17),
135 (22), 134 (21), 120 (11), 107 (9), 79 (8), 69 (7).
5.2.16. 4-(5-(2-Nitrophenyl)-1,3,4-thiadiazol-2-yl)benzene-1,3-
diol (19)
Yield: 64%; orange needles; HPLC (C-18): log k ¼ ꢀ0.360; m.p.:
282e284 ꢄC; anal. calc. for C14H9N3O4S (315.30): C, 53.33; H, 2.88; N,
13.33; found: C, 53.41; H, 2.90; N, 13.29; 1H NMR (500 MHz, DMSO-
d6, ppm) d: 11.30 (s, 1H, HOeC(3)), 10.18 (s, 1H, HOeC(1)), 8.14 (d,
J ¼ 8.80 Hz, 1H, HeC(5)), 8.09 (dd, J ¼ 7.80 and 1.28 Hz, 1H, HeC(30)),
7.97 (dd, J ¼ 7.52 and 1.46 Hz, 1H, HeC(60)), 7.85 (td, J ¼ 7.52 and
1.46 Hz,1H, HeC(50)), 7.79 (td, J ¼ 7.70 and 1.47 Hz,1H, HeC(40)), 6.55
(d, J ¼ 2.20 Hz, 1H, HeC(2)), 6.48 (dd, J ¼ 8.70 and 2.33 Hz, 1H, He
5.2.13. 4-(5-(3,4,5-Trimethoxyphenyl)-1,3,4-thiadiazol-2-yl)
benzene-1,3-diol (14)
Yield: 71%; yellow needles; HPLC (C-18): log k ¼ ꢀ0.022; m.p.:
202e204 ꢄC; anal. calc. for C17H16N2O5S (360.38): C, 56.66; H, 4.47;
N, 7.77; found: C, 56.74; H, 4.45; N, 7.80; 1H NMR (500 MHz, DMSO-
C(6)); 13C NMR (125 MHz, DMSO-d6, ppm)
d: 164.1, 161.6, 161.1,
156.5, 148.5, 133.1, 132.0, 131.6, 128.9, 124.6, 123.4, 108.5, 108.1, 102.3;
IR (KBr, cmꢀ1): 3443, 3143 (OH), 3039 (AreH), 1606 (C]N), 1529,
1466 (C]C),1411,1368,1350,1317,1291 (NO2),1216 (CeO), 1109, 1042
(N]CeSeC]N), 984, 852, 812, 771, 745, 719, 684 (CeSeC), 648; EI-
MS (m/z, %): 315 (Mþ, 49), 155 (5), 154 (9), 153 (100), 150 (3), 135 (7),
134 (12), 108 (4), 107 (4), 104 (9), 97 (4), 90 (4), 76 (4), 69 (3).
d6, ppm) d: 11.05 (s, 1H, HOeC(1)), 10.02 (s, 1H, HOeC(3)), 8.08 (d,
J ¼ 8.60 Hz,1H, HeC(5)), 7.85 (d, J ¼ 3.19 Hz, 2H, HeC(20, 60)), 6.50 (d,
J ¼ 2.29 Hz,1H, HeC(2)), 6.48 (dd, J ¼ 8.63 and 2.30 Hz,1H, HeC(6)),
3.90 (s, 6H, OCH3), 3.82 (s, 3H, OCH3); 13C NMR (125 MHz, DMSO-d6,
5.2.17. 4-(5-(3-Methyl-4-nitrophenyl)-1,3,4-thiadiazol-2-yl)
benzene-1,3-diol (21)
ppm) d: 166.0, 162.7, 161.2, 156.3, 156.3, 153.4, 139.5, 128.9, 125.7,
108.4, 108.3, 104.6 (2C), 102.3, 60.2 (OCH3), 56.1 (OCH3, 2C); IR (KBr,
cmꢀ1): 3408 (OH), 2934 (AreH), 2836 (CH3), 1628 (C]N), 1592 (C]
C), 1517 (C]C), 1467 (C]C), 1414, 1332, 1248 (CeOeC), 1172 (CeO),
1130, 1045 (N]CeSeC]N), 1002, 968, 925, 845, 804, 767, 737, 681,
650 (CeSeC), 600; EI-MS (m/z, %): 360 (Mþ, 100), 347 (4), 346 (11),
345 (6), 331 (4), 317 (10), 314 (5), 302 (7), 193 (4), 180 (4), 178 (10),
167 (7), 153 (14), 152 (4), 150 (12), 135 (9), 120 (4), 118 (4).
Yield: 84%; yellow needles; HPLC (C-18): log k ¼ 0.193; m.p.:
295e296 ꢄC; anal. calc. for C15H11N3O4S (329.33): C, 54.71; H, 3.37;
N, 12.76; found: C, 54.62; H, 3.39; N, 12.81; 1H NMR (500 MHz,
DMSO-d6, ppm) d: 11.22 (s, 1H, HOeC(1)), 10.13 (s, 1H, HOeC(3)),
8.15 (m, 2H, HeAr), 8.12 (d, J ¼ 8.71 Hz, 1H, HeC(5)), 8.10 (m, 1H,
HeAr), 6.54 (d, J ¼ 2.3 Hz, 1H, C(2)), 6.48 (dd, J ¼ 8.72 and 2.34 Hz,
1H, C(6)), 2.63 (s, 3H, CH3); 13C NMR (125 MHz, DMSO-d6, ppm)
d:
164.0, 163.7, 161.6, 156.6, 149.5, 134.3, 134.2, 131.2, 128.9, 125.6,
125.5, 108.5, 108.2, 102.3, 19.5 (CH3); IR (ATR, cmꢀ1): 3358 (OH),
2947 (CH), 2835 (CH), 1633 (C]N), 1558 (C]C), 1507 (C]C), 1449,
1424, 1346, 1323, 1284, 1214, 1185 (CeO), 1112, 1023, 865; EI-MS (m/
z, %): 329 (Mþ, 100), 299 (9), 284 (5), 283 (8), 167 (37), 153 (20), 148
(10), 136 (5), 135 (14), 134 (7), 132 (9), 122 (7), 121 (9), 119 (7), 116
(10), 108 (7), 107 (10), 106 (5), 104 (10), 97 (6), 90 (8), 89 (13), 80 (7),
78 (5), 77 (9), 69 (9), 65 (5), 63 (11), 52 (13), 51 (10), 45 (6), 39 (13).
Compounds: 4-[5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl]benzene-
1,3-diol (2), 4-[5-(2-bromophenyl)-1,3,4-thiadiazol-2-yl]benzene-1,3-
diol (4), 4-[5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzene-
1,3-diol (15), 4-[5-(4-hydroxy-3-methoxyphenyl)-1,3,4-thiadiazol-2-
yl]benzene-1,3-diol (17) and 4-[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-
yl]benzene-1,3-diol (20) were prepared according to the procedure
already described [26,32,33].
5.2.14. 4-(5-(3,4-Dihydroxyphenyl)-1,3,4-thiadiazol-2-yl)benzene-
1,3-diol (16)
Yield: 82%; yellow plaques; HPLC (C-18): log k ¼ ꢀ0.293; m.p.:
296e298 ꢄC; anal. calc. for C14H10N2O4S (302.31): C, 55.62; H, 3.33; N,
9.27; found: C, 55.70; H, 3.32; N, 9.31; 1H NMR (500 MHz, DMSO-d6,
ppm) d: 11.03 (s, 1H, HOeC(3)), 10.02 (s, 1H, HOeC(1)), 9.55 (br.s., 2H,
HOeC(30, 40)), 8.00 (d, J ¼ 8.68 Hz,1H, HeC(5)), 7.44 (d, J ¼ 2.14 Hz,1H,
HeC(20)), 7.28 (dd, J ¼ 8.2 and 2.21 Hz, 1H, HeC(60)), 6.88 (d,
J ¼ 8.19 Hz, 1H, HeC(50)), 6.51 (d, J ¼ 2.29 Hz, 1H, HeC(2)), 6.47 (dd,
J ¼ 8.66 and 2.3 Hz, 1H, HeC(6)); 13C NMR (125 MHz, DMSO-d6, ppm)
d
: 166.4, 161.8, 161.0, 156.2, 148.2, 145.8, 128.9, 121.4, 119.5, 116.2, 113.9,
108.4, 108.3, 102.4; IR (KBr, cmꢀ1): 3392 (OH), 1631 (C]N), 1530 (C]
C),1440 (C]C),1335,1292,1228,1185 (CeO), 1141, 1020 (N]CeSeC]
N), 987, 969, 886, 884 (AreH), 805, 772, 745, 728, 686 (CeSeC), 644;