Article
5-(4-Bromobenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (1f).
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 279
General Procedure for the Synthesis of 2-Iminothiazolidin-4-
ones (3, 4). Aromatic aldehydes (3 mmol), 10 mL glacial acetic
acid, β-alanine (3.6 mmol), and 2-(imino)thiazolidin-4-one
(3 mmol) were mixed in parallel in 12 test tubes with reflux
condensers and stirred at 1400 rpm in tubes at 120 °C for 3 h.
Then a small portion of water was added and the precipitated
solids were collected by sucking filtration and washed with
glacial acetic acid (3 ꢀ 15 mL) and distilled water (3 ꢀ
15 mL). The solids obtained were dried in vacuum at 60 °C
for 24 h.
Yield, 90%; HPLC, 99.2%. 1H NMR (DMSO-d6, 400 MHz)
δ: 7.68 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 8.23 (s,
1H), 11.42 (s, 1H), 11.27 (s, 1H). MS (ES) m/z: 293.1 (ES-).
5-(4-Methoxybenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione
(1g). Yield, 95%; HPLC, 98.9%. 1H NMR (DMSO-d6, 400
MHz) δ: 3.88 (s, 3H), 7.06 (d, J = 8.8 Hz, 2H), 8.25 (s, 1H), 8.37
(d, J = 8.8 Hz, 2H), 11.18 (s, 1H), 11.30 (s, 1H). MS (ES) m/z:
247.5 (ESþ), 245.1 (ES-).
5-(4-(Dimethylamino)benzylidene)pyrimidine-2,4,6(1H,3H,5H)-
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trione (1h). Yield, 93%; HPLC, 98.5%. H NMR (DMSO-d6,
(Z)-5-Benzylidene-2-iminothiazolidin-4-one (3a). Yield, 24%;
HPLC, 99.6%. 1H NMR (400 MHz, DMSO-d6) δ: 7.43 (1H, t),
7.50-7.60 (5H, m), 9.19 (1H, s), 9.46 (1H, s). MS (ES): m/z,
203.1 (ES-); m/z, 205.1 (ESþ).
400 MHz) δ: 3.13 (s, 6H), 6.85 (d, J = 8.8 Hz, 2H), 8.15 (s, 1H),
8.43 (d, J = 9.2 Hz, 2H), 10.93 (s, 1H), 11.05 (s, 1H). MS (ES) m/z:
258.2 (ESþ), 260.2 (ES-).
5-(4-Hydroxy-3-methoxybenzylidene)pyrimidine-2,4,6(1H,3H,
5H)-trione (1i). Yield, 95%; HPLC, 98.4%. 1H NMR (DMSO-
d6, 400 MHz) δ: 3.83 (s, 3H), 6.91 (d, 1H), 7.81 (q, 1H), 8.23
(s, 1H), 8.48 (d, 1H), 10.56 (s, 1H), 11.14 (s, 1H), 11.27 (s, 1H).
MS (ES) m/z: 261.2 (ES-).
(Z)-5-(3-Hydroxybenzylidene)-2-iminothiazolidin-4-one (3b).
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Yield, 35%; HPLC, 99.4%. H NMR (400 MHz, DMSO-d6)
δ: 7.50-6.82 (4H, m), 7.53 (1H, m), 9.76 (2H, m), 12.29 (1H, s).
MS (ES) m/z, 219.2 (ES-).
(Z)-5-(4-Hydroxybenzylidene)-2-iminothiazolidin-4-one (3c).
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5-(3,4-Dimethoxybenzylidene)pyrimidine-2,4,6(1H,3H,5H)-
trione (1j). Yield, 96%; HPLC, 98.7%. 1H NMR (DMSO-d6,
400 MHz) δ: 3.81 (s, 3H), 3.89 (s, 3H), 7.12 (d, 1H), 7.91 (d,
1H), 8.26 (s, 1H), 8.41 (s, 1H), 11.19 (s, 1H), 11.31 (s, 1H). MS
(ES) m/z: 275.2 (ES-).
Yield, 63%; HPLC, 97.9%. H NMR (400 MHz, DMSO-d6)
δ: 6.76 (2H, m), 7.22 (1H, s), 7.39 (2H, d, J = 8 Hz), 9.25 (2H, s),
9.99 (1H, s). MS (ES): m/z, 219.1 (ES-); m/z, 221.1 (ESþ).
(Z)-5-(4-Chlorobenzylidene)-2-iminothiazolidin-4-one (3d).
Yield, 52%; HPLC, 99.4%. 1H NMR (400 MHz, DMSO-d6)
δ: 6.77 (2H, m), 7.22 (1H, s), 7.39 (2H, d, J = 8 Hz), 9.24 (1H,
s), 9.51 (1H, s). MS (ES), m/z: 237.7 (ES-).
5-Benzylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-dione
(2a). Yield, 79%; HPLC, 98.5%. 1H NMR (DMSO-d6, 400
MHz) δ: 7.02-7.20 (m, 5H), 8.30 (s, 1H), 11.18 (s, 1H), 11.29
(s, 1H). MS (ES) m/z: 230.8 (ES-).
(Z)-5-(4-Bromobenzylidene)-2-iminothiazolidin-4-one (3e).
Yield, 65%; HPLC, 95.4%. 1H NMR (400 MHz, DMSO-d6)
δ: 7.53 (2H, d), 7.58(1H, d), 7.72 (2H, d), 9.23(1H, s), 9.50 (1H,
s). MS (ES): m/z, 282.9 (ES-); m/z, 281.0 (ESþ).
5-(2-Hydroxybenzylidene)-2-thioxodihydropyrimidine-4,6(1H,5H)-
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dione (2b). Yield, 80%; HPLC, 99.0%. H NMR (DMSO-d6, 400
MHz) δ: 6.90 (m, 2H), 8.23 (s, 1H), 8.39 (m, 2H), 12.25 (s, 1H), 12.34
(s, 1H). MS (ES) m/z: 247.0 (ES-).
5-(3-Hydroxybenzylidene)-2-thioxodihydropyrimidine-4,6-
(1H,5H)-dione (2c). Yield, 84%; HPLC, 98.5%. 1H NMR
(DMSO-d6, 400 MHz) δ: 6.92-7.71 (m, 4H), 8.19 (s, 1H),
9.92 (s, 1H), 12.33 (s, 1H), 12.44 (s, 1H). MS (ES) m/z: 247.1
(ES-).
5-(4-Hydroxybenzylidene)-2-thioxodihydropyrimidine-4,6-
(1H,5H)-dione (2d). Yield, 87%; HPLC, 98.4%. 1H NMR
(DMSO-d6, 400 MHz) δ: 6.90 (d, J = 8.8 Hz, 2H), 8.24 (s,
1H), 8.39 (d, J = 8.8 Hz, 2H), 10.97 (s, 1H), 12.25 (s, 1H),
12.35 (s, 1H). MS (ES) m/z: 247.0 (ES-).
(Z)-5-(4-Methoxybenzylidene)-2-imino-thiazolidin-4-one (3f).
Yield, 71%; HPLC, 98.4%. 1H NMR (400 MHz, DMSO-d6) δ:
3.81 (3H, s), 7.09 (2H, m), 7.51-7.55 (3H, m), 9.15 (2H, br). MS
(ES): m/z, 233.1 (ES-); m/z, 235.1 (ESþ).
(Z)-5-(4-(Dimethylamino)benzylidene)-2-iminothiazolidin-4-one
(3g). Yield, 67%; HPLC, 99.1%. 1H NMR (400 MHz, DMSO-d6)
δ: 2.92 (6H, s), 6.68 (2H, d, J = 8 Hz), 7.20 (1H, s), 7.36 (2H,
d, J = 8 Hz), 9.05 (1H, s), 9.26 (1H, s). MS (ES): m/z, 246.1
(ES-).
(Z)-5-(4-Hydroxy-3-methoxybenzylidene)-2-iminothiazolidin-
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4-one (3h). Yield, 63%; HPLC, 98.4%. H NMR (400 MHz,
DMSO-d6) δ: 3.76 (3H, s), 6.79 (1H, d, J = 8.0 Hz), 7.00 (2H,
m), 7.23 (1H, S), 9.09 (1H, s), 9.37 (1H, s). MS (ES): m/z, 249.4
(ES-); m/z, 251.4 (ESþ).
5-(4-Chlorobenzylidene)-2-thioxodihydropyrimidine-4,6(1H,5H)-
dione (2e). Yield, 93%; HPLC, 99.3%. 1H NMR (DMSO-d6, 400
MHz) δ: 7.56 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H), 8.27 (s,
1H), 12.38 (s, 1H), 12.49 (s, 1H). MS (ES) m/z: 249.2 (ES-).
5-(4-Bromobenzylidene)-2-thioxodihydropyrimidine-4,6(1H,5H)-
dione (2f). Yield, 91%; HPLC, 99.1%. 1H NMR (DMSO-d6, 400
MHz) δ: 7.69 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 8.24 (s,
1H), 12.37 (s, 1H), 12.48 (s, 1H). MS (ES) m/z: 308.9 (ES-).
5-(4-Methoxybenzylidene)-2-thioxodihydropyrimidine-4,6-
(1H,5H)-dione (2g). Yield, 90%; HPLC, 99.5%. 1H NMR
(DMSO-d6, 400 MHz) δ: 7.09 (d, J = 8.8 Hz, 2H), 8.27 (s,
1H), 8.43 (d, J = 8.8 Hz, 2H), 12.29 (s, 1H), 12.39 (s, 1H). MS
(ES) m/z: 261.3 (ES-).
(Z)-5-(3,4-Dimethoxybenzylidene)-2-iminothiazolidin-4-one (3i).
Yield, 65%; HPLC, 97.4%. 1H NMR (400 MHz, DMSO-d6)
δ: 3.82 (6H, s), 7.10-7.16 (3H, m), 7.56 (1H, s), 9.09 (1H, s), 9.37
(1H, s). MS (ES) m/z, 263.3 (ES-).
(Z)-5-Benzylidenethiazolidine-2,4-dione (4a). Yield, 84%;
HPLC, 99.9%. 1H NMR (DMSO-d6) δ: 3.47 (t, J = 12 MHz,
1H), 7.39-7.59 (m, 5H), 7.76 (s, 1H). MS (ES) m/z: 204.0 (ES-).
(Z)-5-(3-Hydroxybenzylidene)thiazolidine-2,4-dione (4b). Yield,
57%; HPLC, 100%. 1H NMR (DMSO-d6) δ: 3.49 (d, 1H),
6.98-7.49 (m, 4H), 9.83 (s, 1H). MS (ES) m/z: 220.0 (ES-).
(Z)-5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione (4c). Yield,
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5-(4-(Dimethylamino)benzylidene)-2-thioxodihydropyrimidine-
77%; HPLC, 100%. H NMR (DMSO-d6) δ: 3.49 (d, 1H), 6.92
(d, 2H), 7.44 (d, 2H), 7.70 (s, 1H), 10.30 (s, 1H). MS (ES) m/z: 220.0
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4,6(1H,5H)-dione (2h). Yield, 92%; HPLC, 98.4%. H NMR
(DMSO-d6, 400 MHz) δ: 3.16 (s, 6H), 6.82 (d, J = 8.8 Hz, 2H),
8.15 (s, 1H), 8.47 (d, J = 8.8 Hz, 2H), 12.04 (s, 1H), 12.14 (s, 1H).
MS (ES) m/z: 274.1 (ES-).
5-(4-Hydroxy-3-methoxybenzylidene)-2-thioxodihydropyri-
midine-4,6(1H,5H)-dione (2i). Yield, 98%; HPLC, 98.9%. 1H
NMR (DMSO-d6, 400 MHz) δ: 3.84 (s, 3H), 6.92 (d, 1H), 7.88
(d, 1H), 8.25 (s, 1H), 8.50 (s, 1H), 10.75 (s, 1H), 12.25 (s, 1H),
12.35 (s, 1H). MS (ES) m/z: 277.0 (ES-).
5-(3,4-Dimethoxybenzylidene)-2-thioxodihydropyrimidine-
4,6(1H,5H)-dione (2j). Yield, 93%; HPLC, 98.8%. 1H NMR
(DMSO-d6, 400 MHz) δ: 3.82 (s, 3H), 3.87 (s, 3H), 7.13 (d,
1H), 7.95 (d, 1H), 8.27 (s, 1H), 8.44 (s, 1H), 12.29 (s, 1H),
12.39 (s, 1H). MS (ES) m/z: 291.2 (ES-).
(ES-).
(Z)-5-(4-Chlorobenzylidene)thiazolidine-2,4-dione (4d). Yield,
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85%; HPLC, 98.5%. H NMR (DMSO-d6, 400 MHz) δ: 7.38
(m, 2H), 7.52 (m, 2H), 7.72 (s, 1H), 12.65 (br, 1H). MS (ES) m/z:
237.9 (ES-).
(Z)-5-(4-Bromobenzylidene)thiazolidine-2,4-dione (4e). Yield,
85%; HPLC, 98.1%. 1H NMR (DMSO-d6) δ: 3.45 (t, 1H), 7.61
(q, 2H), 7.77 (m, 2H), 12.67 (s, 1H). MS (ES) m/z: 281.9, 283.9
(ES-).
(Z)-5-(4-Methoxybenzylidene)thiazolidine-2,4-dione (4f). Yield,
68%; HPLC, 99.5%. H NMR (DMSO-d6, 400 MHz) δ: 3.82
(s, 3H), 7.09 (m, 2H), 7.55 (m, 2H), 7.77 (s, 1H), 12.56 (br, s, 1H).
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MS (ES) m/z: 234.0 (ES-).