One pot synthesis of 1,3,4-thiadiazole thiazolidinone derivatives

Article abstract of DOI:10.3184/030823409X12559727242438

One pot synthesis of 2-(substitutedphenyl)-3-[5-(substitutedphenyl)-1,3,4- thiadiazol-2-yl]thiazolidin-4-one was developed by the reaction of 1,3,4-thiadiazole, substituted benzaldehyde and mercaptoacetic acid. These compounds were identified by IR,

Full text of DOI:10.3184/030823409X12559727242438

JOURNAL OF CHEMICAL RESEARCH 2009
NOVEMBER, 671–673
RESEARCH PAPER 671
One pot synthesis of 1,3,4-thiadiazole thiazolidinone derivatives
Peng Wang, Rong Wan*, Fen Han and Yao Wang
College of Sciences, Nanjing University of Technology, Nanjing 210009, P.R. China
One pot synthesis of 2-(substitutedphenyl)-3-[5-(substitutedphenyl)-1,3,4-thiadiazol-2-yl]thiazolidin-4-one was
developed by the reaction of 1,3,4-thiadiazole, substituted benzaldehyde and mercaptoacetic acid. These compounds
1
were identified by IR, H NMR, elemental analyses and 2-(4-methoxyphenyl)-3-[5-(3-methylphenyl)-1,3,4-thiadiazol-
2-yl]thiazolidin-4-one was confirmed by single-crystal X-ray diffraction.
Keywords: thiazolidin-4-one, 1,3,4-thiadiazole, one pot synthesis, crystal structure
Among various biological heterocyclic compounds, the
1,3,4-thiadiazole derivatives have attracted specific interest
due to their promising biological activity. For example,
some 1,3,4-thiadiazole derivatives have been reported to
possess anti-inflammatory, antiproliferative, antibacterial and
fungicidal activities.1-5
Thiazolidinones are of considerable importance as
pharmacophoric groups due to their well known biological
activities including bactericidal, pesticidal, anticonvulsant,
anti-inflammatory and antithyroidal activities.6 For instance,
some 2,3-diaryl-1,3-thiazolidin-4-ones have been reported to
show strong and selective anti-HIV activities.7-11 Therefore,
studies of the synthesis and pharmacology of thiazolidinone
derivatives have attracted more interest in recent years.12
In connection with our research programme directed
toward the synthesis of novel thiazolidinone derivatives,
we have designed and synthesised a series of new compounds
containing the 1,3,4-thiadiazole and thiazolidin-4-one.
Table 1 Synthesis of compounds 3a–g
No.
R1
R2
Yield/%
3a
3b
3c
3d
3e
3f
m-Methyl
p-Methoxy
55
63
57
61
56
77
70
p-Fluoro
H
3,5-Dimethyl
2,4-Dichloro
m-Trifluoromethyl
p-Methoxy
p-Methoxy
p-Methoxy
H
H
p-Chloro
p-Fluoro
3g
analyses were performed on a Elementer Vario EL III elementary
analysis instrument. Crystal structure determination was carried out
on a Enraf-Nonius CAD-4 diffractometer.
General synthetic procedure for the preparation of 2a–g
To a mixture of substituted benzoic acid 1(0.1 mol) and thio-
semicarbazide (0.1 mol) was added POCl3 (0.3 mol) dropwise at
0–5°C and maintained for 30 min. The reaction mixture was heated
until reflux and stirred for 4 h. After cooling, 50 mL water was
added to the reaction mixture. The pH of the reaction solution was
adjusted to the range of 8–9 with the solution of 50% NaOH. The
crude product precipitated, filtered, washed with water, dried, and
recrystallised from ethanol to afford compound 2a–g.
Results and discussion
Previously the thiazolidin-4-ones were synthesised by the two-step
process. First the Schiff bases were designed and prepared by the
reaction of substituted amine and substituted benzaldehydes. Second
the thiazolidin-4-ones were synthesised by the reaction of the Schiff
bases and mercaptoacetic acid.13
In this study, the 2-(substitutedphenyl)-3-[5-(substitutedphenyl)-
1,3,4-thiadiazol-2-yl] thiazolidin-4-one (3a–g) was designed and
prepared by the reaction of 5-(substitutedphenyl)-1,3,4-thiadiazol-
2-amine (2a–g), substituted benzaldehyde and mercaptoacetic acid
via a one-pot three-component reaction as shown in Scheme 1.
The results are reported in Table 1.
General synthetic procedure for the preparation of 3a–g
An equimolar mixture (5 mmol) of substituted benzaldehydes and
2a–g in dry toluene (50 mL) was refluxed until no more water was
collected in a Dean–Stark water separator. Mercaptoacetic acid
(6 mmol) was added, dropwise, to this crude mixture, and the reaction
was carried out at reflux temperature until stoichiometric water was
collected. After the reaction the mixtures cooled, precipitated, filtered,
washed with ethanol, dried, and recrystallised from acetone to afford
compound 3a–g. Crystals of (3a) suitable for X-ray diffraction were
obtained by slow evaporation of ethanol-acetone mixture solution.
2-(4-Methoxyphenyl)-3-[5-(3-methylphenyl)-1,3,4-thiadiazol-2-yl]
thiazolidin-4-one (3a): (55%) M.p. 243–244°C. 1H NMR (500 MHz,
DMSO-d6) d(ppm): 2.38 (s, 3H, CH3), 3.75 (s, 3H, –OCH3), 3.84,
4.16 (d, 2H, CH2), 6.71 (s, 1H, CH), 6.83–7.73 (m, 8H, Ph). IR (KBr)
n: 3045, 2962, 2839, 1689, 1652, 1506, 1463, 1303, 1251, 1020,
Instrumentation and chemicals
Melting points were reconded on an X-4 binocular microscope
melting point apparatus. 1H NMR spectra were recorded on an
Avance Bruker-500 instrument and chemical shifts in ppm are
reported with TMS as the internal standard. IR spectra in KBr were
recorded by a Perkin-Elmer PE-683 infrared spectrometer. Elemental
O
NH
NH2
O
H
H2N
S
N
NH2
NH
OH
N
H
-H2O
S
N
N
S
POCl3
R1
2
R1
R1
2
1
O
S
NH2
S
O
O
S
Dean-Stark
-H2O
+
HS
+
N
N
N
R2
N
N
R1
R2
R1
OH
2
3
Scheme 1 Synthesis route of compounds 3a–g
* Correspondent. E-mail: rwan@njut.edu.cn
PAPER: JC090684

672 JOURNAL OF CHEMICAL RESEARCH 2009
690 cm-1. Anal. Calcd for C19H17N3O2S2: C, 59.51; H, 4.47; N, 10.96;
S, 16.72. Found: C, 59.40; H, 4.35; N, 10.82; S, 16.52%.
2-Phenyl-3-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl]thiazolidin-
4-one (3b): (63%) M.p. 240–242°C. 1H NMR (500 MHz, DMSO-d6)
d(ppm): 3.84, 4.16 (d, 2H, CH2), 6.74 (s, 1H, CH), 7.11–7.91 (m,
9H, Ph). IR (KBr) n: 3074, 2902, 2898, 1683, 1652, 1506, 1456,
1303, 1220, 1103, 705 cm-1. Anal. Calcd for C17H12FN3OS2: C,
57.13; H, 3.38; N, 11.76; S, 17.94. Found: C, 56.96; H, 3.15; N,
11.58; S, 17.66%.
2-(4-Methoxyphenyl)-3-[5-(3,5-dimethylphenyl)-1,3,4-thiadiazol-
1
2-yl]thiazolidin-4-one (3c): (57%) M.p. 190–192°C. H NMR (500
MHz, DMSO-d6) d(ppm): 2.35 (s, 6H, CH3), 3.80 (s, 3H, –OCH3),
3.86, 4.17 (d, 2H, CH2), 6.71 (s, 1H, CH), 6.84–7.53 (m, 7H, Ph).
IR (KBr) n: 3049, 2962, 2835, 1683, 1652, 1506, 1456, 1299, 1242,
1039, 692 cm-1. Anal. Calcd for C20H19N3O2S2: C, 60.43; H, 4.82; N,
10.57; S, 16.13. Found: C, 60.25; H, 4.69; N, 10.38; S, 16.02%.
2-Phenyl-3-[5-(2,4-dichlorophenyl)-1,3,4-thiadiazol-2-yl]
thiazolidin-4-one (3d): (61%) M.p. 199–200°C. 1H NMR (500 MHz,
DMSO-d6) d(ppm): 3.84, 4.18 (d, 2H, CH2), 6.75 (s, 1H, CH),
6.28–8.19 (m, 8H, Ph). IR (KBr) n: 3064, 2985, 1704, 1652, 1506,
1456, 1315, 1107, 1060, 707 cm-1. Anal. Calcd for C17H11Cl2N3OS2:
C, 50.01; H, 2.72; N, 10.29; S, 15.70. Found: C, 49.86; H, 2.66; N,
10.12; S, 15.54%.
Fig. 1 A view of the molecular structure of 3a, showing atom
displacement ellipsoids at the 50% level.
2-phenyl-3-[5-(3-trifluoromethylphenyl)-1,3,4-thiadiazol-2-yl]
thiazolidin-4-one 3e: (56%) M.p. 203–204°C. H NMR (500 MHz,
DMSO-d6) d(ppm): 3.88, 4.20 (d, 2H, CH2), 6.76 (s, 1H, CH),
7.26–8.20 (m, 9H, Ph). IR (KBr) n: 3078, 2979, 1697, 1652, 1506,
1448, 1330, 1311, 1130, 685 cm-1. Anal. Calcd for C18H12F3N3OS2:
C, 53.06; H, 2.97; N, 10.31; S, 15.74. Found: C, 52.91; H, 2.82; N,
10.16; S, 15.65%.
6.67 (s, 1H, CH), 6.67–7.84 (m, 8H, Ph). IR (KBr) n: 3082, 2947,
1683, 1652, 1506, 1463, 1309, 1253, 1180, 1081, 603 cm-1. Anal.
Calcd for C18H14ClN3O2S2: C, 53.53; H, 3.49; N, 10.40; S, 15.88.
Found: C, 53.35; H, 3.18; N, 10.18; S, 15.63%.
1
2-(4-Fluorophenyl)-3-[5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl]
1
thiazolidin-4-one 3g: (70%) M.p. 176–178°C. H NMR (500 MHz,
DMSO-d6) d(ppm): 3.84 (s, 3H, –OCH3), 3.86, 4.15 (d, 2H, CH2),
6.70 (s, 1H, CH), 6.94–7.85 (m, 8H, Ph). IR (KBr) n: 3024, 2985,
1689, 1652, 1506, 1463, 1309, 1253, 1220, 1031, 669 cm-1. Anal.
Calcd for C18H14FN3O2S2: C, 55.80; H, 3.64; N, 10.85; S, 16.55.
Found: C, 55.66; H, 3.45; N, 10.69; S, 16.35%.
2-(4-Chlorophenyl)-3-[5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl]
1
thiazolidin-4-one 3f: (77%) M.p. 213–214°C. H NMR (500 MHz,
DMSO-d6) d(ppm): 3.83 (s, 3H, –OCH3), 3.88, 4.12 (d, 2H, CH2),
Table 2 Crystal data and structure refinement for C19H17N3O2S2
The compound (3a) was subjected to single crystal X-ray
crystallography and intensity data were collected at 298(2) K
on an Enraf-Nonius CAD-4 diffractometer and use graphite
Monochromated MoKa adiation (l = 0.71073Å). The structure was
solved by a direct method using the SHELXL-97 program14 and
refined with the SHELXL-97 program.15 All H atoms bonded to the
C atoms were placed geometrically at the distances of 0.93–0.97 Å
and included in the refinement in riding motion approximation with
Uiso(H) = 1.2 or 1.5Ueq of the carrier atom. The thermal ellipsoids
were plotted with the SHELXL-97 program at 50% probability. The
molecular structure is shown in Fig. 1. Selected crystal data and
structure refinement details are presented in Table 2. Selected bond
distances and angles are listed in Table 3.
Empirical formula
Formula weight
Temperature
C19H17N3O2S2
383.48 g mol-1
298(2) K
0.71073 Å
Monoclinic
P 21
Wavelength
Crystal system
Space group
8.5850(17)Å
7.3680(15)Å
b = 95.35(3)
14.067(3)Å
885.9(3) Å-3
2
Unit cell dimensions
Volume
Z
Absorption correction
F(000)
Absorption coefficient
θrange for entire data collection
Reflections collected
Independent reflections
Data/restraints/parameters
Final R indices [I>2σ>(I)]
Psi-scan
400
0.302 mm-1
1.45°to 25.97°
2344
This work was supported by the Jiangsu High-Tech Research
Project (Agriculture) (BG2007329) from the Science and
Technology Department of Jiangsu Province. We also thank
the Science and Technology Department of Jiangsu Province
for financial support.
2168 (Rint = 0.0189)
2168/1/235
R1 = 0.0515,
wR2 = 0.1358
R1 = 0.0615,
wR2 = 0.1460
1.066
Received 14 July 2009; accepted 29 September 2009
Paper 09/0684 doi: 10.3184/030823409X12559727242438
Published online: 16 November 2009
Goodness-of-fit on F2
Final residual electron density
0.343 and –0.435 e. Å-3
Table 3 Selected bond distances (Å) and angles (°) for compound (3a)
S1 C8 1.719(5)
N1 N2 1.366(7)
C2 C3 1.395(8)
S1 C9 1.722(5)
N1 C8 1.299(6)
C2 C7 1.364(9)
S2 C11 1.798(6)
S2 C12 1.840(5)
N2 C9 1.294(5)
N3 C9 1.377(6)
N3 C10 1.360(5)
N3 C12 1.458(6)
C1 C2 1.494(9)
S1 C8 N1 113.8(4)
S1 C8 C4 121.7(4)
N1 C8 C4 124.4(4)
S1 C9 N2 115.8(4)
S1 C9 N3 123.5(3)
N2 C9 N3 120.7(4)
O1 C10 N3 123.7(5)
O1 C10 C11 124.5(4)
C3 C4 1.395(8)
C4 C5 1.376(8)
O1 C10 1.224(6)
O2 C16 1.346(6)
O2 C19 1.413(8)
C8 S1 C9 85.9(2)
C11 S2 C12 91.8(2)
C16 O2 C19 117.9(4)
N2 N1 C8 113.8(4)
N1 N2 C9 110.6(4)
C9 N3 C10 121.6(4)
C9 N3 C12 119.1(3)
C10 N3 C12 118.3(4)
C4 C8 1.451(7)
C5 C6 1.367(10)
C6 C7 1.375(10)
N3 C10 C11 111.8(4)
S2 C11 C10 108.1(4)
S2 C12 N3 103.1(3)
S2 C12 C13 113.9(3)
N3 C12 C13 112.7(4)
O2 C16 C15 115.1(4)
O2 C16 C17 124.6(5)
C15 C16 C17 120.2(4)
PAPER: JC090684

JOURNAL OF CHEMICAL RESEARCH 2009 673
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PAPER: JC090684