Arch. Pharm. Chem. Life Sci. 2011, 11, 170–177
Bioactive thiazolidine and thiazolidinone derivatives
175
Synthesis of (Z)-ethyl 2-(2-cyano-2-(5-oxo-3-
phenylthiazolidin-2-ylidene)acetamido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate 4
Synthesis of ethyl 2-((Z)-2-cyano-2-((E)-5-oxo-3-phenyl-4-
(2-p-tolylhydrazono) thiazolidin-2-ylidene)acetamido)-
4,5,6,7-tetrahydrobenzo-[b]thiophene-3-carboxylate 6
To a well stirred cooled solution of p-toluidine (0.43 g, 4 mmol)
in conc. HCl (1.5 mL) and H2O (2 mL)], a solution of NaNO2
(0.28 g, 4.1 mmol in 5 mL H2O) was added drop wise. The
above cooled diazonium solution was added slowly to a well
stirred solution of 4 (1.87 g, 4 mmol) in pyridine (10 mL). The
reaction mixture was stirred for 2 h. The crude product was
filtered off, dried well and recrystallized from the EtOH/
benzene to give 6.
To a cold suspension of finely divided KOH (0.11 g, 2 mmol) in
dry dimethylformamide (10 mL), the cyanoacetamide derivative
2 (0.58 g, 2 mmol) followed by phenyl isothiocyanate (0.27 g,
2 mmol) was added. The mixture was stirred at room tempera-
ture for 12 h, and then cooled again to 08C, treated with the
chloroacetyl chloride (0.22 g, 2 mmol) and left to stand at room
temperature for 24 h, the mixture was poured into ice cold
water. The resulting precipitate was filtered off, dried and crys-
tallized from DMF/ethanol to afford compound 4.
Reddish brown powder. Yield, 76%, mp: 3108C, IR (KBr):
White powder. Yield, 75%, mp: >3208C, IR (KBr): nmax, cmꢀ1
:
3159 (NH); 2198 (CN); 1739, 1660, 1643 (3 C O). H-NMR (DMSO-
n
max, cmꢀ1: 3436 (br, NH); 2202 (CN); 1704, 1643 (br, 3
–
1
C O), 1506 (N ¼ N). 1H-NMR (DMSO-d6): d 1.19 (t, 3H, CH3,
–
–
–
d6): d 1.20 (t, 3H, CH3, J ¼ 6.9), 1.66–1.68 (m, br., 4H, C5-2H, C6-2H),
2.57–2.66 (m, 4H, C4-2H, C7-2H), 4.03 (s, 2H, C4-2H-thiazolidi-
none), 4.17 (q, 2H, CH2O, J ¼ 6.9), 7.41–7.5 (m, 5H, Ar-H), 11.57
(s, 1H, NH-CO). MS: m/z (%) ¼ 469 (Mþ þ 2, 5.8), 468 (Mþ þ 1, 9.3),
467 (Mþ, 30.4), 421 (4.0), 348 (2.9), 243 (26.0), 215 (78), 179 (17.6),
132 (38.3), 77 (100). Anal. calcd. for C23H21N3O4S2 (467.56): C,
59.08; H, 4.53; N, 8.99. Found: C, 59.15; H, 4.61; N, 9.07.
J ¼ 6.5), 1.67–1.69 (m, 4H, C5-2H, C6-2H), 2.46 (s, 3H, CH3-aryl),
2.63–2.73 (m, 4H, C4-2H, C7-2H), 4.17 (q, 2H, CH2O, J ¼ 6.9),
7.04–7.47 (m, 10H, NH, hydrazo, Ar-H), 11.34 (s, 1H, NH-CO).
MS: m/z (%) ¼ 587 (Mþ þ 2, 2.2), 585 (Mþ, 9.5), 361 (11.7), 317
(2.6), 251 (17.1), 206 (11.7), 169 (16.5), 106 (100), 77 (78.8). Anal.
calcd. for C30H27N5O4S2 (585.70): C, 61.52; H, 4.65; N, 11.96.
Found: C, 61.64; H, 4.73; N, 12.05.
General procedure for compounds 5a and 5b
Synthesis of (Z)-ethyl 2-(2-cyano-3-mercapto-3-
(phenylamino)acrylamido)-4,5,6,7-tetrahydrobenzo-
[b]thiophene-3-carboxylate 7
To a cold suspension of finally divided KOH (0.22 g, 4 mmol) in
dry dimethylformamide (10 mL) was added the cyanoacetamide
derivative 2 (1.17 g, 4 mmol) followed by phenyl isothiocyanate
(0.54 g, 4 mmol). The mixture was stirred at room temperature
over night, then poured into ice cold-water and acidified with
0.1 N HCl to a pH of 3 to 4. The resulting precipitate was filtered
off, dried and crystallized from ethanol-benzene to give com-
pound 7.
To a well stirred solution of compound 4 (1.87 g, 4 mmol) in DMF
(20 mL), TEA (0.2 mL) and 4-(dimethylamino)benzaldehyde
(0.60 g, 4 mmol) or 4-(piperidin-1-yl)benzaldehyde (0.76 g,
4 mmol) were added. The reaction mixture was stirred at 808C
for 3 h. The separated crystals was filtered, dried, and recrystal-
lized from a mixture of MeOH/DMF to give compounds 5a and 5b,
respectively.
Ethyl 2-((Z)-2-cyano-2-((Z)-4-(4-(dimethylamino)-
benzylidene)-5-oxo-3-phenylthiazolidin-2-
ylidene)acetamido)-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxylate 5a
Pale yellow powder. Yield, 67%, mp: 1518C, IR (KBr): nmax
,
cmꢀ1: 3315 (2 NH); 2190 (CN); 1662, 1617 (2 C O). 1H-NMR
–
–
Purple crystals. Yield, 85%, mp: >3208C, IR (KBr): nmax, cmꢀ1
:
3300 (NH); 2198 (CN); 1704, 1641, 1614 (3 C O). H-NMR (DMSO-
(CDCl3-d6): d 1.36 (t, 3H, CH3, J ¼ 6.9), 1.78–1.79 (m, 4H, C5-
2H, C6-2H), 2.64–2.79 (m, 4H, C4-2H, C7-2H), 4.34 (q, 2H,
CH2O, J ¼ 6.9), 4.61 (s, 1H, NH-Ph), 11.80 (s, 1H, NH-CO), 12.45
(s, 1H, SH). MS: m/z (%) ¼ 395 (Mþ – S, 9.3), 325 (5.6), 292 (4.5), 255
(5.0), 225 (15.9), 179 (16.9), 135 (15.6), 93 (100), 77 (43.1), 66 (50).
Anal. calcd. for C21H21N3O3S2 (427.54): C, 58.99; H, 4.95; N, 9.83.
Found: C, 59.04; H, 5.06; N, 9.90.
1
–
–
d6): d 1.19 (t, 3H, CH3, J ¼ 6.9), 1.66–1.68 (m, br., 4H, C5-2H,
C6-2H), 2.53–2.60 (m, 4H, C4-2H, C7-2H), 3.21 (s, 3H, N-Me), 3.24 (s,
3H, N-Me), 4.05 (q, 2H, CH2O, J ¼ 6.9), 6.84–7.98 (m, 9H, Ar-H,
¼CH), 11.28 (s, 1H, NH-CO). MS: m/z (%) ¼ 600 (Mþ þ 2, 3.3), 599
(Mþ þ 1, 3.3), 598 (Mþ, 11.1), 552 (7.2), 422 (3.3), 374 (78.4), 177
(90.2), 77 (100). Anal. calcd. for C32H30N4O4S2 (598.74): C, 64.19;
H, 5.05; N, 9.36. Found: C, 64.17; H, 5.01; N, 9.30.
General procedure for compounds 8a, 8b, and 9
To a solution of compound 7 (0.86 g, 2 mmol) in dimethylform-
amide (20 mL), chloroacetone (0.18 g, 2 mmol), 2-bromo-1-p-
tolyl-ethanone (0.44 g, 2 mmol) or ethyl chloroacetate
(0.24 g, 2 mmol) were added. The reaction mixture was heated
under reflux for 6 h, then cooled and neutralized with saturated
sodium acetate solution. The resulting precipitate was filtered
off, dried and crystallized from ethanol/benzene mixture for
compounds 8a and 8b or DMF for compound 9, respectively.
Ethyl 2-((Z)-2-cyano-2-((Z)-5-oxo-3-phenyl-4-(4-(piperidin-
1-yl)benzylidene)thiazolidin-2-ylidene)acetamido)-4,5,6,7-
tetrahydrobenzo[b]- thiophene-3-carboxylate 5b
Scarlet red crystals. Yield, 88%, mp: >3208C, IR (KBr): nmax, cmꢀ1
:
3300 (NH); 2202 (CN); 1702, 1660, 1648 (3 C O). H-NMR (DMSO-d ):
1
–
–
6
d 1.20 (t, 3H, CH3, J ¼ 6.9), 1.57–1.69 (m, 10H, C5-2H, C6-2H, C3,4,5
-
2H, piperidine), 2.60–2.67 (m, 4H, C4-2H, C7-2H), 3.24–3.30 (m, 4H,
piperidine), 4.18 (q, 2H, CH2O, J ¼ 6.9), 7.10 (d, 2H, p-disubstituted
benzene, J ¼ 8.5), 7.35–7.58 (m, 5H, N-phenyl), 7.6 (d, 2H, p-disub-
stituted benzene, J ¼ 8.5), 7.73 (s, 1H, ¼CH), 11.65 (s, 1H, NH-CO).
MS: m/z (%) ¼ 640 (Mþ þ 2, 3.2), 639 (Mþ þ 1, 9.7), 638 (Mþ, 16.5),
592 (10.7), 414 (100), 217 (42.3), 174 (50.6), 77 (84.1). Anal. calcd.
for C35H34N4O4S2 (638.80): C, 65.81; H, 5.36; N, 8.77. Found: C,
65.94; H, 5.42; N, 8.84.
(Z)-ethyl 2-(2-cyano-2-(4-methyl/p-tolyl-3-phenylthiazol-
2(3H)-ylidene)acetamido)-4,5,6,7-tetrahydrobenzo-
[b]thiophene-3-carboxylates 8a and 8b
8a: Pale yellow powder. Yield, 85%, mp: 2058C, IR (KBr): nmax, cmꢀ1
:
1
–
–
3222 (NH); 2181 (CN); 1660, 1621 (2 C O). H-NMR (DMSO-d ): d 1.19
6
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