4.1.3. Synthesis of Imidazo[2,1-b][1,3,4]thiadiazole Derivatives
Synthesis of 5-(4-substituted phenyl)-1,3,4-thiadiazole-2-amine 3a–l
0.1 M of aromatic carboxylic acid 1a–l was refluxed with 0.2 M of thiosemicarbazide 2 and 5 mL of phosphorous oxytrichloride for 2 h. After 2 h the mixture was cooled and diluted with 10 mL of water and again refluxed for additional 4 h. Then the mixture was filtered hot and the filtrate was neutralized with a solution of 10% potassium hydroxide. The formed precipitate was filtered off and recrystallized from absolute ethanol.
General procedure for the synthesis of 6-(4-substituted phenyl)-2-(4-substituted phenyl)imidazo[2,1-b][1,3,4]thiadiazole 5a–l
To a solution of 5-(4-substituted phenyl)-1,3,4-thiadiazole-2-amine 3a–l (0.01 mol) in 10 mL absolute ethanol, the corresponding phenacyl bromide was added (0.02 mol). The mixture was refluxed for 18 h or more, depending of the reaction progress, monitored by TLC. After the reaction was complete, the mixture was filtered and the solid hydrobromide was collected. The precipitate was neutralized by aqueous sodium carbonate solution, filtered and purified by recrystallization or by column chromatography to remove unwanted products. The purification method is indicated below for each individual compound.
2,6-Diphenylimidazo[2,1-
b][1,3,4]thiadiazole (
5a) [
28]: Yield 53% (0.146 g); purified by column chromatography, eluent dichloromethane: acetone 25:1
v/
v; m.p. 200–202 °C; cristaline white powder; FT-IR (solid state, υ cm
−1): 3094, 3049, 3026 (CH aromatic);
1H-NMR (600 MHz, DMSO-
d6, CDCl
3) δ 8.53 (s, 1H, CH-5 imidazo[2,1-
b][1,3,4]thiadiazole), 7.93 (dd,
J = 7.6, 2H, CH-2, CH-6), 7.88 (d,
J = 7.2 Hz, 2H, CH-2’, CH-6’), 7.62–7.53 (m, 3H, CH-4, CH-3’, CH-5’), 7.40 (t,
J = 7.7 Hz, 2H, CH-3, CH-5), 7.28 (t,
J = 7.4 Hz, 1H, CH-4’);
13C-NMR (151 MHz, DMSO-
d6, CDCl
3) δ 151.13 (C, C-2 imidazo[2,1-
b][1,3,4]thiadiazole), 135.85 (C, C-8 imidazo[2,1-
b][1,3,4]thiadiazole), 134.54 (C, C-6 imidazo[2,1-
b][1,3,4]thiadiazole), 123.85 (C, C-1), 121.82 (C, C-1’), 119.87 (C, C-4), 119.43 (C, C-3’, C-5’), 118.61 (C, C-3, C-5), 117.36 (C, C-2’, C-6’), 116.65 (C, C-4’), 114.85 (C, C-2, C-6), 100.25 (C, C-5 imidazo[2,1-
b][1,3,4]thiadiazole); ESI
+-MS:
m/z 278.2 [M + H]
+ (calcd. 278.3 for C
16H
11N
3S + H
+).
6-(4-Bromophenyl)-2-phenylimidazo[2,1-
b][1,3,4]thiadiazole (
5b)
[27,28]: Yield 40% (0.140 g); m.p. 240–242 °C; yellow powder; FT-IR (solid state, υ cm
−1): 3095, 3071, 3051 (CH aromatic);
1H-NMR (600 MHz, TFA-
d6, acetone-
d6) δ 7.89 (s, 1H, CH-5 imidazo[2,1-
b][1,3,4]thiadiazole), 7.41 (d,
J = 8.5 Hz, 2H, CH-2, CH-6), 7.23 (m,
J = 7.9, 3.8 Hz, 4H, CH-2’, CH-3’, CH-5’ CH-6’), 7.08 (t,
J = 7.5 Hz, 1H, CH-4), 6.99 (t,
J = 7.7 Hz, 2H, CH-3, CH-5);
13C-NMR (151 MHz, TFA-
d6, acetone-
d6) δ 157.60 (C, C-2 imidazo[2,1-
b][1,3,4]thiadiazole), 157.33 (C, C-8 imidazo[2,1-
b][1,3,4]thiadiazole), 156.89 (C, C-6 imidazo[2,1-
b][1,3,4]thiadiazole), 132.47 (C, C-1), 132.06 (CH, C-3’, C-5’), 131.56 (CH, C-4), 130.44 (C, C-1’), 128.99 (CH, C-3, C-5), 128.62 (CH, C-2’, C-6’), 125.75 (CH, C-2, C-6), 125.52 (C, C-4’), 115.86 (C, C-5 imidazo[2,1-
b][1,3,4]thiadiazole); ESI
+-MS:
m/z 356.2 ([M + H]
+,
79Br), 358.2 ([M + H]
+,
81Br) (calcd. for C
16H
10BrN
3S + H
+: 356.1
79Br, 358.0
81Br).
2-Phenyl-6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole (5c): Yield 38% (0.130 g); purified by column chromatography, eluent dichloromethane; m.p. 218–220 °C; yellow powder; FT-IR (solid state, υ cm−1): 3107, 3084 (CH aromatic); 1H-NMR (600 MHz, TFA-d6, acetone-d6) δ 8.21 (s, 1H, CH-5 imidazo[2,1-b][1,3,4]thiadiazole), 7.83 (t, J = 8.0 Hz, 2H, CH-2, CH-6), 7.71 (m, J = 8.4 Hz, 4H, CH-2’, CH-3’, CH-5’, CH-6’), 7.55 (t, J = 8.5 Hz, 1H, CH-4), 7.48–7.42 (m, 2H, CH-3, CH-5); 13C-NMR (151 MHz, TFA-d6, acetone-d6) δ 172.26 (C, C-2 imidazo[2,1-b][1,3,4]thiadiazole), 161.09 (C, C-8 imidazo[2,1-b][1,3,4]thiadiazole), 147.89 (C, C-6 imidazo[2,1-b][1,3,4]thiadiazole), 140.75 (C, C-1′), 136.89 (q, J2C-F = 34.7 Hz, C, C-4′), 133.22 (CH, C-3, C-5), 132.23 (CH, C-4), 132.04 (C, C-1), 130.74 (q, J3C-F =3 Hz, CH, C-3’, C-5’), 130.19 (CH, C-2, C-6), 129.76 (CH, C-2’, C-6’), 126.9 (q, J1C-F = 272 Hz, C, CF3), 115.65 (C, C-5 imidazo[2,1-b][1,3,4]thiadiazole); 19F-NMR (565 MHz, TFA-d6, acetone-d6): δ -64.05 (s, -CF3); ESI+-MS: m/z 346.3 [M + H]+ (calcd. 346.3 for C17H10F3N3S + H+).
6-(4-Methoxyphenyl)-2-phenylimidazo[2,1-
b][1,3,4]thiadiazole (
5d) [
16,
28]: Yield 27% (0.080 g); m.p. 232–234 °C; gray powder; FT-IR (solid state, υ cm
−1): 3107, 3069 (CH aromatic);
1H-NMR (600 MHz, DMF-
d6) δ 8.93 (s, 1H, CH-5 imidazo[2,1-
b][1,3,4]thiadiazole), 8.08 (d,
J = 6.9 Hz, 2H, CH-2, CH-6), 7.98 (d,
J = 8.8 Hz, 2H, CH-2’, CH-6’), 7.73–7.64 (m, 3H, CH-3, CH-4, CH-5) 7.10 (d,
J = 8.8 Hz, 2H, CH-3’, CH-5’), 3.87 (s, 3H, CH
3);
13C-NMR (151 MHz, DMF-
d6) δ 164.03 (C, C-2 imidazo[2,1-
b][1,3,4]thiadiazole), 160.46 (C, C-4’), 144.50 (C, C-8 imidazo[2,1-
b][1,3,4]thiadiazole ), 142.45 (C, C-6 imidazo[2,1-
b][1,3,4]thiadiazole), 132.88 (C, C-1), 130.03 (CH, C-4), 129.45 (CH, C-3, C-5), 127.39 (CH, C-2’, C-6’), 127.03 (CH, C-2, C-6), 123.49 (C, C-1’), 114.75 (C, C-5 imidazo[2,1-
b][1,3,4]thiadiazole), 110.51 (C, C-3’, C-5’), 55.40 (C, OCH
3); ESI
+-MS:
m/z 308.3 [M + H]
+ (calcd. 308.3 for C
17H
13N
3OS + H
+).
2-(4-Chlorophenyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (5e): Yield 32% (0.100 g); m.p. 220–222 °C; gray powder; FT-IR (solid state, υ cm−1): 3125, 3096 (CH aromatic); 1H-NMR (600 MHz, TFA-d6, acetone-d6) δ 8.42 (s, 1H, CH-5 imidazo[2,1-b][1,3,4]thiadiazole), 8.10 (d, 2H, CH-2, CH-6), 7.87 (d, 2H, CH-2’, CH-6’), 7.77–7.72 (m, 5H, CH-3, CH-4, CH-5, CH-3’, CH-5’); 13C-NMR (151 MHz, TFA-d6, acetone-d6) δ 168.84 (C, C-2 imidazo[2,1-b][1,3,4]thiadiazole), 145.47 (C, C-8 imidazo[2,1-b][1,3,4]thiadiazole), 142.94 (C, C-6 imidazo[2,1-b][1,3,4]thiadiazole), 141.72 (C, C-4), 133.06 (C, C-1), 131.82 (CH, C-3, C-5), 131.32 (CH, C-3’, C-5’), 130.02 (CH, C-2, C-6), 127.38 (CH, C-2’, C-6’), 127.07 (C, C-1’), 126.63 (C, C-4’), 112.58 (CH, C-5 imidazo[2,1-b][1,3,4]thiadiazole); ESI+-MS: m/z 312.6 ([M + H]+, 35Cl), 314.6 ([M + H]+, 37Cl) (calcd. for C16H10ClN3S + H+: 312.8 35Cl, 314.8 37Cl).
6-(4-Bromophenyl)-2-(4-chlorophenyl)imidazo[2,1-
b][1,3,4]thiadiazole (
5f) [
27,
28]: Yield 77% (0.230 g); purified by column chromatography, eluent dichloromethane; m.p. 256–258 °C; gray powder; FT-IR (solid state, υ cm
−1): 3119, 3071, 3047 (CH aromatic);
1H-NMR (600 MHz, TFA-
d6, acetone-
d6) δ 8.11 (s, 1H, CH-5 imidazo[2,1-
b][1,3,4]thiadiazole), 7.77 (d,
J = 8.4 Hz, 2H, CH-2, CH-6), 7.57 (d,
J = 8.3 Hz, 2H, CH-2’, CH-6’), 7.45 (d,
J = 8.4 Hz, 2H, CH-3, CH-5), 7.41 (d,
J = 8.3 Hz, 2H, CH-3’, CH-5’);
13C-NMR (151 MHz, TFA-
d6, acetone-
d6) δ 168.82 (C, C-2 imidazo[2,1-
b][1,3,4]thiadiazole), 145.55 (C, C-8 imidazo[2,1-
b][1,3,4]thiadiazole), 142.94 (C, C-6 imidazo[2,1-
b][1,3,4]thiadiazole), 140.58 (C, C-4), 134.55 (CH, C-3’, C-5’), 131.65 (CH, C-3, C-5), 129.78 (CH, C-2’, C-6’), 128.54 (CH, C-2, C-6), 127.62 (C, C-1), 126.72 (C, C-1’), 125.64 (C, C-4’), 116.28 (CH, C-5 imidazo[2,1-
b][1,3,4]thiadiazole); ESI
+-MS:
m/z 390.2 ([M + H]
+,
79Br), 392.2 ([M + H]
+,
81Br) (calcd. for C
16H
9BrClN
3S + H
+: 390.6
79Br, 392.6
81Br).
2-(4-Chlorophenyl)-6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole (5g): Yield 54% (0.200 g); purified by column chromatography, eluent dichloromethane; m.p. 228–230 °C; yellow powder; FT-IR (solid state, υ cm−1): 3104, 2922 (CH aromatic); 1H-NMR (600 MHz, TFA-d6, acetone-d6) δ 8.20 (s, 1H, CH-5 imidazo[2,1-b][1,3,4]thiadiazole), 7.77 (d, J = 7.0 Hz, 2H, CH-3’, CH-5’), 7.69–7.67 (m, 4H, CH-2, CH-3, CH-5, CH-6), 7.43 (d, J = 6.7 Hz, 2H, CH-2’, CH-6’); 13C-NMR (151 MHz, TFA-d6, acetone-d6) δ 170.88 (C, C-2 imidazo[2,1-b][1,3,4]thiadiazole), 147.89 (C, C-8 imidazo[2,1-b][1,3,4]thiadiazole), 144.66 (C, C-6 imidazo[2,1-b][1,3,4]thiadiazole), 141.73 (C, C-4) 136.89 (q, J2C-F = 34.7 Hz, C, C-4′), 133.63 (CH, C-3, C-5), 132.03 (C, C-1), 131.92 (CH, C-2, C-6), 130.11 (q, J3C-F = 3 Hz, CH, C-3′, C-5′), 129.81 (CH, C-2′, C-6′ ), 128.77 (C, C-1′), 127.07 (q, J1C-F = 272 Hz, C, CF3), 115.71 (CH, C-5 imidazo[2,1-b][1,3,4]thiadiazole); 19F-NMR (565 MHz, TFA-d6, acetone-d6): δ -64.05 (s, -CF3); ESI+-MS: m/z 380.2 ([M + H]+, 35Cl), 382.2 ([M + H]+, 37Cl) (calcd. for C17H9ClF3N3S + H+: 380.7 35Cl, 382.7 37Cl).
2-(4-Chlorophenyl)-6-(4-methoxyphenyl)imidazo[2,1-
b][1,3,4]thiadiazole (
5h) [
8,
16,
27]: Yield 44% (0.150 g); purified by column chromatography, eluent dichloromethane: acetone 25:1
v/
v; m.p. 228–230 °C; gray powder; FT-IR (solid state, υ cm
−1): 3119, 3086 (CH aromatic);
1H-NMR (600 MHz, TFA-
d6, acetone-
d6) δ 8.02 (s, 1H, CH-5 imidazo[2,1-
b][1,3,4]thiadiazole), 7.75 (d,
J = 8.2 Hz, 2H, CH-2’, CH-6’), 7.51 (d,
J = 8.4 Hz, 2H, CH-2, CH-6), 7.42 (d,
J = 8.2 Hz, 2H, CH-3’, CH-5’), 7.02 (d,
J = 8.4 Hz, 2H, CH-3, CH-5), 3.84 (s, 3H, CH
3);
13C-NMR (151 MHz, TFA-
d6, acetone-
d6) δ 168.55 (C, C-2 imidazo[2,1-
b][1,3,4]thiadiazole), 162.39 (C, C-4’), 145.02 (C, C-8 imidazo[2,1-
b][1,3,4]thiadiazole), 142.82 (C, C-6 imidazo[2,1-
b][1,3,4]thiadiazole), 141.17 (C, C-4), 131.67 (CH, C-3, C-5), 129.82 (CH, C-2’, C-6’), 129.24 (CH, C-2, C-6), 126.90 (C, C-1), 120.45 (C, C-1), 117.03 (CH, C-3’, C-5’), 111.94 (CH, C-5 imidazo[2,1-
b][1,3,4]thiadiazole), 56.82 (C, OCH
3); ESI
+-MS:
m/z 342.6 ([M + H]
+,
35Cl), 344.6 ([M + H]
+,
37Cl) (calcd. for C
17H
12ClN
3OS + H
+: 342.8
35Cl, 344.8
37Cl).
2-(4-Methoxyphenyl)-6-phenylimidazo[2,1-
b][1,3,4]thiadiazole (
5i) [
26]: Yield 74% (0.230 g); m.p. 198–200 °C; yellow powder; FT-IR (solid state, υ cm
−1): 3127, 3071 (CH aromatic);
1H-NMR (600 MHz, Acetic acid) δ 8.28 (s, 1H, CH-5 imidazo[2,1-
b][1,3,4]thiadiazole), 7.94 (d,
J = 7.7 Hz, 2H, CH-2, CH-6), 7.82 (d,
J = 6.7 Hz, 2H, CH-2’, CH-6’), 7.47 (t,
J = 6.6 Hz, 2H, CH-3’, CH-5’), 7.39 (t,
J = 6.4 Hz, 1H, CH-4’), 7.12 (d,
J = 7.9 Hz, 2H, CH-3, CH-5), 3.91 (s, 3H, OCH
3);
13C-NMR (151 MHz, Acetic acid) δ 166.00 (C, C-2 imidazo[2,1-
b][1,3,4]thiadiazole), 164.57 (C, C-4), 146.96 (C, C-8 imidazo[2,1-
b][1,3,4]thiadiazole), 145.30 (C, C-6 imidazo[2,1-
b][1,3,4]thiadiazole), 133.28 (C, C-1’), 130.54 (CH, C-3’, C-5’), 130.25 (C, C-2’, C-6’), 129.90 (C, C-1), 126.97 (C, C-2, C-6), 123.68 (CH, C-4’), 116.39 (C, C-3, C-5), 111.73 (CH, C-5 imidazo[2,1-
b][1,3,4]thiadiazole), 56.62 (C, OCH
3); ESI
+-MS:
m/z 308.4 [M + H]
+ (calcd. 308.3 for C
17H
13N
3OS + H
+).
6-(4-Bromophenyl)-2-(4-methoxyphenyl)imidazo[2,1-
b][1,3,4]thiadiazole (
5j) [
26]: Yield 74% (0.280 g); purified by column chromatography, eluent dichloromethane: acetone 25:1
v/
v; m.p. 224–225 °C; yellow powder; FT-IR (solid state, υ cm
−1): 3107, 3084 (CH aromatic);
1H-NMR (600 MHz, DMSO-
d6) δ 8.79 (s, 1H, CH-5 imidazo[2,1-
b][1,3,4]thiadiazole), 7.90 (d, 2H, CH-2, CH-6), 7.84 (d, 2H, CH-3’, CH-5’), 7.63 (d, 2H, CH-3, CH-5), 7.16 (d, 2H, CH-2’, CH-6’), 3.86 (s, 3H, OCH
3);
13C-NMR (151 MHz, DMSO-
d6) δ 162.22 (C, C-2 imidazo[2,1-
b][1,3,4]thiadiazole), 161.40 (C, C-4), 144.50 (C, C-8 imidazo[2,1-
b][1,3,4]thiadiazole), 144.07 (C, C-6 imidazo[2,1-
b][1,3,4]thiadiazole), 133.14 (C, C-1’), 131.64 (CH, C-3’, C-5’), 128.48 (CH, C-2’, C-6’), 126.62 (CH, C-2, C-6), 121.94 (C, C-1), 120.18 (C, C-4’), 115.05 (CH, C-3, C-5), 111.06 (CH, C-5 imidazo[2,1-
b][1,3,4]thiadiazole), 55.64 (C, OCH
3); ESI
+-MS:
m/z 386.1 ([M + H]
+,
79Br), 388.1 ([M + H]
+,
81Br) (calcd. for C
16H
9BrClN
3S + H
+: 386.2
79Br, 388.2
81Br).
2-(4-Methoxyphenyl)-6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole (5k): Yield 59% (0.220 g); m.p. 228–230 °C; yellow powder; FT-IR (solid state, υ cm−1): 3087, 3024 (CH aromatic); 1H-NMR (600 MHz, TFA-d6, acetone-d6) δ 8.16 (s, 1H, CH-5 imidazo[2,1-b][1,3,4]thiadiazole), 7.80 (d, J = 8.8 Hz, 2H, CH-2, CH-6), 7.66-7.69 (m, 4H, CH-2’, CH-3’, CH-5’, CH-6’), 7.01 (d, J = 8.8 Hz, 2H, CH-3, CH-5), 3.84 (s, 3H, OCH3); 13C-NMR (151 MHz, TFA-d6, acetone-d6) δ 171.58 (C, C-2 imidazo[2,1-b][1,3,4]thiadiazole), 167.09 (C, C-8 imidazo[2,1-b][1,3,4]thiadiazole), 147.68 (C, C-6 imidazo[2,1-b][1,3,4]thiadiazole), 141.32 (C, C-4), 136.86 (q, J2C-F = 34.7 Hz, C, C-4’), 132.86 (C, C-2, C-6), 132.14 (C, C-1), 130.10 (q, J3C-F = 3 Hz, C, C-3’, C-5’), 129.79 (C, C-2’, C-6’), 127.09 (q, J1C-F = 270.3 Hz, C, CF3), 123.39 (C, C-1′), 118.84 (C, C-3, C-5), 115.59 (CH, C-5 imidazo[2,1-b][1,3,4]thiadiazole), 58.65 (C, OCH3); 19F-NMR (565 MHz, TFA-d6, acetone-d6): δ -64.03 (s, -CF3); ESI+-MS: m/z 376.4 [M + H]+ (calcd. 376.3 for C18H12F3N3OS + H+).
2,6-Bis(4-methoxyphenyl)imidazo[2,1-
b][1,3,4]thiadiazole (
5l) [
26]: Yield 60% (0.200 g); purified by column chromatography, eluent dichloromethane; m.p. 242–244 °C; yellow powder; FT-IR (solid state, υ cm
−1): 3124, 3047 (CH aromatic);
1H-NMR (600 MHz, CDCl
3) δ 7.94 (s, 1H, CH-5 imidazo[2,1-
b][1,3,4]thiadiazole), 7.82 (d,
J = 8.8 Hz, 2H, CH-2, CH-6), 7.77 (d,
J = 8.7 Hz, 2H, CH-2’, CH-6’), 7.03 (d,
J = 8.8 Hz, 2H, CH-3, CH-5), 6.98 (d,
J = 8.7 Hz, 2H, CH-3’, CH-5’), 3.89 (s, 3H, CH
3), 3.83 (s, 3H, OCH
3);
13C-NMR (151 MHz, CDCl
3) δ 164.73 (C, C-2 imidazo[2,1-
b][1,3,4]thiadiazole), 163.21 (C, C-4), 160.50 (C, C-4’), 150.09 (C, C-8 imidazo[2,1-
b][1,3,4]thiadiazole) 143.69 (C, C-6 imidazo[2,1-
b][1,3,4]thiadiazole), 128.78 (CH, C-2’, C-6’), 126.97 (CH, C-2, C-6), 124.74 (C, C-1), 120.95 (C, C-1’), 114.98 (CH, C-3’, C-5’), 114.63 (CH, C-3, C-5), 108.42 (CH, C-5 imidazo[2,1-
b][1,3,4]thiadiazole), 55.59 (C, OCH
3), 55.33 (C, OCH
3). ESI
+-MS:
m/z 338.4 [M + H]
+ (calcd. 338.3 for C
17H
13N
3OS + H
+).