550
R. A. ALHAMEED ET AL.
2.2. General procedure for the synthesis of 2,4-dioxothiazolidin
acid derivatives 3a–g
2-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)acetic acid (3c).
2/
3/
S
1/
The target products 3a–g were prepared in three steps as follow:
O
6/
Cl
4/
N
O
5/
OH
i. Synthesis of thiazolidine-2,4-dione (TZD) was prepared
according to the reported method39–41: A mixture of chloro-
acetic acid (0.1 mol) and thiourea (0.1 mol) in water (10 ml)
were placed in a 100 ml round bottom flask, the reaction
mixture was stirred at rt for 30 min and then cooled down to
0 ꢁC. To the reaction mixture, 8 ml of conc. HCl was added
dropwise and after complete addition, the reaction mixture
O
The product was obtained as light-yellow crystals in yield 92%,
mp: 250–252 ꢁC. IR (KBr, cmꢀ1): 3383 (OH of COOH), 3008 (CH-aro-
matic), 1738, 1690, 1607 (CO). 1H-NMR (DMSO-d6, d ppm): 4.42
(2H, s, CH2-COOH), 7.59–8.00 (4H, m, Ar-H), 8.03 (1H, s,
was refluxed for 16–18 h. The white solid was obtained after CH ¼ C).13C-NMR (DMSO-d6,
d ppm): 42.2 (CH2-COOH), 114.6,
cooling, filtered and washed with water several times to
remove the acid traces, dried and then the product TZD 1
was recrystallised from ethanol to afford white crystals mp
123–124 ꢁC, in 91% yield (literature m.p. 123–125 ꢁC)39.
ii. A solution of TZD 1 was treated with various appropriate
aldehydes via refluxing in ethanol for 24 h in the presence of
piperidine as a catalyst. The reaction mixture was poured
into water followed by acidification with acetic acid to afford
the products 2a–g. The compounds 2a–g were used directly
to the next step without further purification for preparation
of 3a–g.
121.3, 129.3, 131.5, 131.7, 132.4, 135.3, 142.1, 164.8, 166.5, 167.8
(CO). Anal. Calc. for C12H8ClNO4S (297.7): C, 48.40; H, 2.70; N, 4.70.
Found C, 48.61; H, 2.83; N, 4.81
2-(5-(2-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)acetic acid (3d).
Cl
2/
3/
S
1/
O
4/
6/
N
5/
O
OH
O
iii. A mixture of 2a–g (1 mmol) and ethyl 2-bromoacetate
(2 mmol) was refluxed for 24 h in acetone in presence of
potassium carbonate (2 mmol) to furnish the target products
obtained as white solid after evaporation of the solvent. The
crude product was used directly to next step for preparation
of the free carboxylic acid derivatives 3a–g where the solid
product was refluxed with glacial acetic acid and HCl in ratio
(4:1) for 2 h to afford the pure (2,4-dioxothiazolidin-3-yl)
acetic acid derivatives 3a–g after evaporation of the solvent
and then crystallised with ethanol. The spectral data for com-
pounds 3a, 3f, and 3g were in agreement with the
The product was obtained as white crystals in 90% yield, mp:
223–225 ꢁC. IR (KBr, cmꢀ1): 3364 (OH of COOH), 3064 (CH-aro-
matic), (2940) CH-aliphatic, 1490 (C ¼ C), 1722, 1691, 1608 (CO).
1H-NMR (DMSO-d6, d ppm): 4.43 (2H, s, CH2COOH), 7.55–7.69 (4H,
m, Ar-H), 8.09 (1H, s, CH ¼ C).13C-NMR (DMSO-d6, d ppm): 42.0
(CH2COOH), 114, 124.1, 128.0, 130.8, 132.0, 137.4, 147.4, 164.3,
166.3, 167.6 (CO). Anal. Calc. for C12H8ClNO4S (297.7): C, 48.41; H,
2.71; N, 4.70. C, 48.65; H, 2.84; N, 4.95.
reported ones42–45
.
2-(5-(4-bromobenzylidene)-2,4-dioxothiazolidin-3-yl)acetic acid (3e).
2/
3/
S
1/
O
2.2.1. General procedure for the synthesis of 2,4-dioxothiazolidin-
acetic acid derivatives
Br
6/
4/
N
O
5/
OH
2-(5-benzylidene-2,4-dioxothiazolidin-3-yl)acetic acid (3a).
2/
O
3/
S
1/
The product was obtained as yellowish white crystals in yield
94%, mp: 260–262 ꢁC. IR (KBr, cmꢀ1): 3371 (OH of COOH), 2948
(CH-aliphatic), 1696, 1606 (CO).1H-NMR (DMSO-d6, d ppm): 4.37
(2H, s, CH2COOH), 7.56, (2H, d, J ¼ 6.6 Hz, Ar-H, H2ꢀ& H6ꢀ), 7.73 (2H,
d, J ¼ 6 Hz, Ar-H, H3ꢀ & H5ꢀ); 7.95(1H, s, CH ¼ C). 13C-NMR (DMSO-d6,
d ppm): 42.8 (CH2-COOH), 114.2, 121.9, 124.9, 132.4, 132.8, 133.1,
142.4, 165.3, 167.1, 168.4 (CO). Anal. Calc. for C12H8BrNO4S
(342.16): C, 42.12; H, 2.36; N, 4.09. Found C, 42.45; H, 2.59; N, 4.25.
O
4/
6/
N
O
5/
OH
O
The product was obtained as a white crystal in 93% yield, mp:
214–216 ꢁC. IR (KBr, cmꢀ1): 3423 (OH of COOH), 2940 (CH-aliphatic),
1744, 1686, 1602 (CO). 1H-NMR (DMSO-d6, d ppm): 4.40 (2H, s,
CH2COOH), 7.51–8.00 (5H, m, Ar-H), 8.05 (1H, s, CH ¼ C). 13C-NMR
(DMSO-d6, d ppm): 42.0 (CH2COOH), 114.3, 120.8, 130.0, 130.6,
133.7, 141.6, 163.1, 166.6, 167.4 (CO). Anal. Calc. for C19H9NO4S
(263.27): C, 54.75; H, 3.45; N, 5.32. Found C, 54.96; H, 3.61; N, 5.53.
The product was obtained as light-yellow crystals in 96% yield,
mp: 226–228 ꢁC. IR (KBr, cmꢀ1): 3371 (OH of COOH), 2950 (CH-ali-
phatic), 1733, 1685, 1600 (CO). 1H-NMR (DMSO-d6, d ppm): 2.34
(3H, s, CH) , 4.36 (2H, s, CH2COOH), 7.33 (2H, d, J ¼ 6.6 Hz, Ar-H, H3ꢀ
& H5ꢀ), 7.51 (2H, d, J ¼ 7.2 Hz, Ar-H, H2ꢀ & H6ꢀ), 7.92 (1H, s,
CH ¼ C).13C-NMR (DMSO-d6, d ppm): 21.6 (CH3), 42.7 (CH2-COOH),
113.9, 119.8, 130.5, 130.7, 134.4, 141.7, 165.5, 167.4, 168.4 (CO).
Anal. Calc. for C13H11NO4S (277.3): C, 56.31; H, 4.00; N, 5.05. Found
C, 56.44; H, 4.12; N, 5.26.
2-(5-(4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl) acetic acid (3f).
2/
3/
S
1/
O
6/
O
4/
N
5/
OH
O
O
The product was obtained as yellowish white crystals in yield
91%, mp: 223–225 ꢁC. IR (KBr, cmꢀ1): 3368 (OH of COOH),
2926(CH-aliphatic), 1684, 1589 (CO). 1H-NMR (DMSO-d6, d ppm):
3.81 (3H, s, OCH3), 4.35 (2H, 2, CH2COOH), 7.10 (2H, d, J ¼ 7.2 Hz,