Regioselective synthesis of new 2,5,6-trisubstituted 5,6-dihydro-2H-pyrazolo[3,4-d]thiazoles from 5-dimethylaminoethylene-thaozolidin-4-thiones

Article abstract of DOI:10.1080/17415993.2014.944912

Thiazolidin-4-ones assembled through one-pot three-component (carbonyl compound, amine and ethyl mercaptoacetate) reactions in the presence of dicyclohexyl carbodiimide, on simultaneous treatment with dimethyl formamide dimethylacetal and Lawesson's reage

Full text of DOI:10.1080/17415993.2014.944912

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Regioselective synthesis of new
2,5,6-trisubstituted 5,6-dihydro-2H-
pyrazolo[3,4-d]thiazoles from 5-
dimethylaminoethylene-thaozolidin-4-
thiones
Poonam Gautama, Deepika Gautama & R.P. Chaudharya
a Department of Chemistry, Sant Longowal Institute of Engineering
& Technology, Longowal (Sangrur), Punjab-148106, India
Published online: 04 Aug 2014.
To cite this article: Poonam Gautam, Deepika Gautam & R.P. Chaudhary (2014) Regioselective
synthesis of new 2,5,6-trisubstituted 5,6-dihydro-2H-pyrazolo[3,4-d]thiazoles from 5-
dimethylaminoethylene-thaozolidin-4-thiones, Journal of Sulfur Chemistry, 35:6, 628-640, DOI:
10.1080/17415993.2014.944912
To link to this article: http://dx.doi.org/10.1080/17415993.2014.944912
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Journal of Sulfur Chemistry, 2014
Vol. 35, No. 6, 628–640, http://dx.doi.org/10.1080/17415993.2014.944912
Regioselective synthesis of new 2,5,6-trisubstituted
5,6-dihydro-2H-pyrazolo[3,4-d]thiazoles from
5-dimethylaminoethylene-thaozolidin-4-thiones
Poonam Gautam, Deepika Gautam and R.P. Chaudhary∗
Department of Chemistry, Sant Longowal Institute of Engineering & Technology, Longowal (Sangrur),
Punjab-148106, India
(Received 28 April 2014; accepted 10 July 2014)
Thiazolidin-4-ones assembled through one-pot three-component (carbonyl compound, amine and ethyl
mercaptoacetate) reactions in the presence of dicyclohexyl carbodiimide, on simultaneous treatment
with dimethyl formamide dimethylacetal and Lawesson’s reagent furnished 5-dimethylaminomethylene
thiazolidin-4-thiones. These thiones on condensation with hydrazine derivatives afforded 2,5,6-
trisubstituted-5,6-dihydro-2H-pyrazolo[3,4-d]thiazoles 4 and not their possible 1,5,6-trisubstituted regioi-
somers 5. Results of single-crystal X-ray diffraction studies of thiazolidin-4-one 1b have been reported.
The structures of all the synthesized compounds were established by spectral data. DFT studies on regioi-
somers were carried out using B3LYP with the 6-31G∗∗ basis set and carbon NMR shifts of 4 show good
correlation with experimental values.
Keywords: pyrazolo [3,4-d]thiazole; thiazolidin-4-one; Lawesson’s reagent; DMF-DMA; thiazolidin-4-
thione; spectral data; DFT
1. Introduction
Heterocyclic compounds have a wide variety of applications and represent about three-fourth
of commercially available pharmaceuticals and agrochemicals. Pyrazoles and thiazoles are
important classes of heterocycles possessing a wide variety of biological activities [1–3] and
their utility as medicines is well established. During the last few decades the chemistry of
fused bicyclic scaffolds has attracted remarkable attention due to their biological activities
∗Corresponding author. Email: rpchaudhary65@gmail.com
This article makes reference to supplementary material available on the publisher’s website at http://dx.doi.org/
10.1080/17415993.2014.944912.
c
ꢀ 2014 Taylor & Francis

Journal of Sulfur Chemistry 629
such as pyrazolopyridines as potential antihypertensive [4] and anti-inflammatory agents,[5]
pyrazolopyrimidines as antiviral [6] and antitumor agents,[7] pyrazolo[5,1-c][1,2,4]triazines as
cytotoxic agents,[8] thieno[2,3-e]indazole derivatives as IkB kinase inhibitors, [9] etc. This
bioactive profile of bicyclic scaffolds prompted us to undertake the synthesis of pyrazolo[3,4-
d]thiazole ring system. Despite a number of general methods available for pyrazole and thiazole
derivatives, it is difficult to construct the bicyclic scaffolds with these moieties. Due to the lack
of general synthetic methods only a few reports on the synthesis of pyrazolo[3,4-d]thiazole have
appeared in the literature.[10–14] In continuation of our work on the synthesis of biologically
active heterocycles,[15,16] we report herein an interesting route to the regioselective synthe-
sis of 1,3,5-trisubstituted-5,6-dihydro-2H-pyrazolo[3,4-d]thiazoles starting with the reaction of
enaminones of thiazolidin-4-ones with hydrazine derivatives.
2. Result and discussion
The synthesis of thiazolidin-4-ones 1 is described in the literature from carbonyl compounds,
amines and mercaptoacetic acid using various dehydrating agents such as molecular sieves,
anhyd. ZnCl2,[17] sodium sulfate,[18] N,N-dicyclohexylcarbodiimide (DCC), [19] etc. Recently
several publications have reported environment-friendly methods for their synthesis such as
microwave irradiation,[20] ultrasonication [21] and the use of ionic liquids.[22,23] Herein, we
have assembled thiazolidin-4-one rings in one-pot cyclocondensations of aldehydes, amines and
ethyl mercaptoacetate in the presence of DCC in just 40 min in quantitative yields. The structure
of this ring system is well established in the literature by spectral data. We report here single-
crystal X-ray diffraction studies of 2-(4-chlorophenyl)-3-phenylthiazolidin-4-one 1b in the crys-
tallographic section. Thiazolidin-4-one 1 on treatment with N, N-dimethylformamide-dimethyl
acetal (DMF-DMA) generated 5-dimethylaminomethylene derivatives 2. Condensations of com-
pound 2 with hydrazine derivatives was attempted to synthesize the pyrazolo[3,4-d]thiazole
Scheme 1. Synthetic route to the synthesis of 5,6-dihydro-2H-pyrazolo[3,4-d]thiazoles.

630 P. Gautam et al.
system 4 (Scheme 1). Unfortunately, several attempts with acidic as well as basic reagents did not
result in the ring closure reaction. In the literature, the synthesis of pyrazolo[3,4-d]thiazole ring
system has been reported from condensation of 5-arylidene-4-thiazolidinones with hydrazine
and its derivatives.[24,25] We also made several unsuccessful attempts to achieve the synthe-
sis of pyrazolo[3,4-d]thiazole ring 7 from the reaction of 5-arylidene-4-thiazolidinones 6 with
phenyl hydrazine under acidic as well as basic conditions. In a recent report,[26] 5-arylidene-4-
thiazolidinones have been converted to more reactive thiazolidine-thione and then condensed
with hydrazine derivatives to achieve the synthesis of pyrazolo[3,4-d]thiazoles. Based upon
the same idea, 5-dimethylaminomethylene thiazolidin-4-one 2 was converted into thiazolidine-
thione 3 by Lawesson’s reagent according to the reported procedure [27] in anticipation that it
would enhance the reactivity of the lactam function (Scheme 1). Compound 3 was also obtained
in a single step on simultaneous treatment of thiazolidin-4-one 1 with DMF-DMA and Lawes-
son’s reagent in toluene. Thiazolidine-thione 3 on condensation with hydrazine derivatives in
DMF furnished a single product (TLC) 4 and not its possible regioisomer 5. This cyclocon-
densation of 3 with hydrazine derivatives can possibly proceed via route a (via hydrazone
formation) or b (Scheme 2) leading to the synthesis of 4 and 5, respectively. There is no direct
evidence to support route a mechanism in this case but several reports in the literature [25,26]
have reported the condensation of hydrazine and its derivatives with 5-arylidene-thiazolidin-
4-one or 5-arylidene-thiazolidine-4-thione through hydrazone formation (route a). Based upon
these findings it is presumed that in the present case the reaction proceeds through route a
mechanism and consequently isomer 4 is formed. We tried to obtain crystals of compounds
4a–i in different solvents and we succeeded only for 4c. Unfortunately, the crystals of 4c,
were of poor quality and did not show reflection even after a long exposure time to X-rays
and as a consequence we could not obtain the crystal structure. Since the crystal structure
of the product 4 is not available and to validate our claim for structure 4, DFT studies on
the regioisomers (4a and 5a) were carried out using B3LYP with a 6-31G∗∗ basis set to give
carbon NMR shifts that show good correlation with experimental results (computational stud-
ies section). The structure of compound 4 is also corroborated by additional analytical and
spectral data. For example, the methine proton of the pyrazole ring in compound 4 appears
1
between δ 8.44 and 8.68 in H NMR spectra. The structures of 4a–i are also supported by
their molecular ion peaks [M + H+] in their mass spectra. Finally, the elemental analysis data
of the synthesized compounds are in good agreement with calculated values (within the range
of 0.4%).
Scheme 2. Plausible mechanism to the synthesis of 5,6-dihydro-2H- pyrazolo[3,4-d]thiazole
ring.

Journal of Sulfur Chemistry 631
2.1. Crystallographic studies
X-ray diffraction measurements were performed on X Calibur EOS OXFORD Diffractometer
at 293 (2) K. The intensity data were collected using graphite monochromated Mo-Kα radiation
(λ = 0.71073 Å). The structure was solved by a direct method using the SHELX-97 software
package [28] and refined by full-matrix least-squares procedures on F2. All non-hydrogen atoms
were refined with anisotropic thermal parameters. The compound 1b crystallizes in space group
Figure 1. An ORTEP diagram of 2-(4-chlorophenyl)-3-phenylthiazolidin-4-one (1b) with non-hydrogen ellipsoids
drawn at 50% probability level.
Table 1. Crystal data and structure refinement parameters of
2-(4-chlorophenyl)-3-phenylthiazolidin-4-one (1b).
CCDC no.
943547
Empirical formula
Formula weight
C15H12ClNOS
289.03
Temperature (K)
293 (2)
Wavelength (Å)
Space group
0.71073 Å
P-1
Unit cell dimensions
a (Å)
b (Å)
9.7330 (4)
13.7316 (7)
10.3892 (5)
90.00
97.973 (4)
90.00
c (Å)
α (◦)
β (◦)
γ (◦)
Volume (Å3)
1375.09 (11)
4
Z
Density (calculated) (Mg/m3)
1.255 Mg/m3
0.265 mm−1
3.07–29.27
6310
Absorption coefficient (mm−1
)
Theta range for data collection
Reflections collected
Independent reflections
2308
Data/restraints/parameters
3158/0/173
1.067
Goodness of fit on F2
Final R indices [I > 2σ(I) = 2591 data]
R indices (all data)
R1 = 0.0457, wR2 = 0.0993
R1 = 0.0698, wR2 = 0.1134
−0.457, 0.398
Largest diff. peak and hole (eÅ−3
)

632 P. Gautam et al.
P-1 with Z = 4 and cell parameters a = 9.7330 (4) Å, b = 13.7316 (7) Å, c = 10.3892 (5) Å,
α = 90.00◦, β = 97.973(4)◦, γ = 90.00◦. The ORTEP diagram obtained from the X-ray struc-
ture of 1b is shown in Figure 1. The crystallographic data and refinement parameters of 1b
are reported in Table 1. CCDC 943547 contains the supplementary crystallographic data and
these data can be obtained free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
2.2. Computational studies
The molecular geometry optimization and carbon NMR spectrum calculations were performed
with the Jaguar software package version 7.6 by using DFT methods with B3LYP (Becke
three parameter Lee–Yang–Parr) exchange correlation functional, which combines the hybrid
exchange functional of Becke, with the gradient-correlation functional of Lee, Yang and Parr.[29]
The 6-31G∗∗ basis set was used for gas phase calculations of the regioisomeric structures 4a and
5a. These calculations compensate for the lack of X-ray structures for 4a or 5a. The optimized
4a and 5a structures with atom numbering schemes are shown in Figures 2 and 3.
Shielding tensors for structures 4a and 5a were evaluated by using B3LYP functional with
the basis set given above. In order to express the chemical shifts in ppm, the geometry of
tetramethylsilane (TMS) and chloroform molecules were optimized and then the carbon NMR
Figure 2. Optimized structure of 4a.
Figure 3. Optimized structure of 5a.

Journal of Sulfur Chemistry 633
spectra were calculated. Using the 13C NMR shielding of TMS of δ 202.8593 the calculated
isotropic shielding constants σi were then transformed to chemical shifts relative to TMS by the
equation δi = σTMS − σi.
A comparison of experimental and calculated 13C NMR chemical shifts (ppm) of compounds
4a and 5a is reported in Table 2. Since field effects are prominent in carbon NMR, it is found that
correlation between theoretical and experimental 13C NMR of isomer 4a is 0.9506 and isomer 5a
is 0.9113 (Figure 4). The correlation is good for structure 4a and not for isomer 5a. Frequency
calculations of optimized structures 4a and 5a did not show any negative frequency and this
verifies that there are no stationary points. The Z-matrix (X, Y, Z coordinates of minimized struc-
tures 4a and 5a) are reported as supplementary information (Tables S1 and S2, http://dx.doi.org/
10.1080/17415993.2014.944912). Zero point energies of 4a and 5a are 214.64 and
215.53 kcal/mol, respectively. This shows that compound 4a is more stable than isomer 5a.
Table 2. Experimental and calculated 13C NMR chemical
shifts (ppm) of compound 4a and isomer 5a.
Compound 4a
Compound 5a
Expt.
Calc.
Calc.
Calc.
Calc.
Entry NMR
Shield
NMR Entry Shield NMR
C2
C4
C5
C8
C10
63.92 134.5292 71.41 C2
163.72 45.2233 164.75 C4
122.20 97.8303 109.77 C5
137.29 78.7371 129.72 C8
152.14 59.0237 150.33 C10
125.6302 80.71
55.0144 154.52
98.2488 109.33
68.071 140.87
57.2478 152.18
Structure 4a
Structure 5a
B3LYP/6-31G**
170
160
150
140
130
120
110
100
90
R2 (Structure 4a) = 0.95065
R2 (Structure 5a) = 0.91134
80
70
60
60
80
Experimental 13C NMR Shifts (ppm)
Figure 4. Plot of the calculated vs. experimental 13C NMR chemical shifts (ppm) of 4a and 5a.
100
120
140
160
180

634 P. Gautam et al.
3. Experimental
3.1. Instrumentations
Melting points were determined in sulfuric acid bath and are reported uncorrected. TLC was
performed on silica gel G plates using pet ether–ethyl acetate (4:1) as eluent and iodine vapors
as visualizing agent. IR spectra were recorded on an ABB FTIR spectrometer and the results are
reported in cm−1. 1H NMR and 13C NMR were recorded in CDCl3 and DMSO-d6 on a BRUKER
ADVANCE II 400 NMR spectrometer using TMS as an internal standard (chemical shift in δ,
ppm). Mass spectra were recorded on a WATERS, Q-TOF MICROMASS (LC-MS) instrument.
The elemental analyses of the compounds were performed on Euro EA 3000 Elemental Analyzer.
X-ray diffraction was performed on X Calibur EOS OXFORD Diffractometer.
3.2. General procedure for the synthesis of 1a–c
Compounds 1a–c were synthesized by slight modification (using ethyl mercapto acetate in place
of mercapto acetic acid) in the reported procedure.[19] To an ice cold solution of an alde-
hyde (1.0 mmol) and an amine (2.0 mmol) in THF (15 mL), ethyl mercaptoacetate (2.5 mmol)
was added. After 5 min DCC (1.5 mmol) was added to the reaction mixture and the mix-
ture was stirred for 40 min at room temperature. N, Nꢁ-dicyclohexylurea was then removed
by filtration and THF was removed completely under reduced pressure. The residue was
extracted with ethyl acetate and organic layer was washed successively with (5%) aq. citric acid,
(5%) aq. sodium bicarbonate and finally with brine. The organic layer was dried over anhyd.
sodium sulfate and solvent was removed under reduced pressure. The crude solid obtained was
recrystallized from ethyl acetate.
3.2.1. 2,3-Diphenylthiazolidin-4-one (1a)
White solid, yield 85%, mp 128–130◦C, lit. [22] mp 131–132◦C.
3.2.2. 2-(4-Chlorophenyl)-3-phenylthiazolidn-4-one (1b)
White crystalline solid, yield 87%, mp 124–126◦C, lit. [19] mp 124–127◦C.
3.2.3. 2,3-Di-p-tolylthiazolidin-4-one (1c)
White solid, yield 86%, mp 112–114◦C, lit. [22] mp 119–120◦C.
3.3. General procedure for the synthesis of 2(a–c)
A mixture of thiazolidin-4-one 1 (1.0 mmol) and DMF-DMA (10 mmol) in DMF (5.0 mL) was
refluxed for 50 min. The reaction mixture was then cooled and extracted with ethyl acetate (2 ×
25 mL). The organic layer was washed with brine solution and dried over anhydrous Na2SO4.
The excess ethyl acetate was then removed under reduced pressure and the solid obtained was
filtered and recrystallized from ethanol.

Journal of Sulfur Chemistry 635
3.3.1. 5-[(Dimethylamino)methylene]-2,3-diphenylthiazolidin-4-one (2a)
1
White crystalline solid, yield 85%, mp 198–200◦C. IR (cm−1): 1697 (C O), 1490 (C C); H
=
=
NMR (400 MHz, DMSO-d6): δ 3.02 (s, 6H, NMe2), 6.40 (s, 1H, H-2), 7.03–7.07 (t, 1H, C6H5,
=
J = 7.32 Hz), 7.19–7.28 (m, 6H, C6H5), 7.31–7.33 (m, 4H, C6H5 and CH). Anal. Calcd for
C18H18N2OS: C, 69.65; H, 5.84; N, 9.02; S, 10.33; found: C, 69.86%; H, 5.95%; N, 9.14%; S,
10.48%.
3.3.2. 2-(4-Chlorophenyl)-5-[(dimethylamino)methylene]-3-phenylthiazolidin-4-one (2b)
1
Yellow solid, yield 90%, mp 166–168◦C. IR (cm−1): 1705 (C O), 1495 (C C); H NMR
=
=
(400 MHz, CDCl3): δ 3.03 (s, 6H, NMe2), 6.10 (s, 1H+, H-2), 7.10 (m, 1H, C6H5), 7.20–7.27 (m,
=
8H, C6H5), 7.34 (s, 1H, CH); mass m/z 345 (M + H , 100%). Anal. Calcd for C18H17ClN2OS:
C, 62.69; H, 4.97; N, 8.12; S, 9.30; found: C, 62.86%; H, 5.04%; N, 8.32%; S, 9.48%.
3.3.3. 5-[(Dimethylamino)methylene]-2,3-di-p-tolylthiazolidin-4-one (2c)
1
White solid, yield 90%, mp 148–150◦C. IR (cm−1): 1695 (C O), 1485 (C C); H NMR
=
=
(400 MHz, DMSO-d6): δ 2.22 (s, 3H, CH3), 2.25 (s, 3H, CH3), 3.00 (s, 6H, NMe2), 6.33
=
(s, 1H, H-2), 7.01–7.06 (m, 4H, C6H5), 7.16–7.20 (m, 5H, C6H5 and CH). Anal. Calcd for
C20H22N2OS: C, 70.97; H, 6.55; N, 8.28; S, 9.47; found: C, 70.82%; H, 6.68%; N, 8.42%; S,
9.62%.
3.4. General procedure for the synthesis of 3(a–c)
(a) A mixture of 2 (1.0 mmol) and Lawesson’s reagent (1.0 mmol) in dry toluene (20 mL) was
refluxed for 2 h. The solvent was removed under reduced pressure. The solid obtained on cooling
was recrystallized from ethanol–DMF (3:1) mixture.
(b) A mixture of 1 (1.0 mmol) and DMF-DMA (1.5 mmol) in dry toluene was heated under
reflux for 1–2 h (progress of the reaction was monitored by TLC). After completion of the
reaction, Lawesson’s reagent (1.0 mmol) was added to the reaction mixture and continued reflux-
ing for 2 h. Toluene was removed completely under reduced pressure. The semisolid material
obtained was extracted with ethyl acetate (2 × 15 mL). The extract was washed with brine
(5%) solution and dried over anhydrous Na2SO4. The solid obtained on removal of solvent was
crystallized from DMF-ethanol (1:3) mixture.
3.4.1. 5-[(Dimethylamino)methylene]-2,3-diphenylthiazolidine-4-thione (3a)
1
Light brown solid, yield 65%, mp 108–110◦C. IR (cm−1): 1252 (C S), 1490 (C C); H NMR
=
=
(400 MHz, DMSO-d6): δ 3.00 (s, 6H, NMe2), 6.47 (s, 1H, H-2), 7.05–7.06 (t, 1H, C6H5, J =
=
7.36 Hz), 7.20–7.28 (m, 6H, C6H5), 7.31–7.35 (m, 4H, C6H5 and CH); Mass m/z 327.1(M +
H+, 100%); Anal. Calcd. For: C18H18N2S2: C, 66.22; H, 5.56; N, 8.58; S, 19.64; found: C,
66.46%; H, 5.64%; N, 8.72%; S, 19.48%.
3.4.2. 2-(4-Chlorophenyl)-5-[(dimethylamino)methylene]-3-phenylthiazolidine-4-thione (3b)
1
Light brown solid, yield 65%, mp 120–122◦C. IR (cm−1): 1240 (C S), 1490 (C C); H NMR
=
=
(400 MHz, DMSO-d6): δ 3.00 (s, 6H, NMe2), 6.55 (s, 1H, H-2), 7.06 (m, 1H, C6H5), 7.23–7.27

636 P. Gautam et al.
=
(m, 3H, C6H5), 7.30–7.35 (m, 6H, C6H5 and CH); Anal. Calcd. For: C18H17ClN2S2: C, 59.90;
H, 4.75; N, 7.76%; S, 17.77%; found: C, 60.01%; H, 4.94%; N, 7.92%; S, 17.98%.
3.4.3. 5-[(Dimethylamino)methylene]-2,3-di-p-tolylthiazolidine-4-thione (3c)
Brown solid, yield 65%, mp 158–60◦C. IR (cm−1): 1210 (C S), 1490 (C C); 1H NMR
(400 MHz, DMSO-d6): δ 2.21 (s, 3H, CH3), 2.23 (s, 3H, CH3), 2.99 (s, 6H, NMe2), 6.38 (s,
=
=
=
1H, H-2), 7.01–7.06 (m, 4H, C6H5), 7.17–7.19 (m, 5H, C6H5 and CH ); Anal. Calcd. for:
C20H22N2S2: C, 67.76; H, 6.25; N, 7.90; S, 18.09; found: C, 67.92%; H, 6.40%; N, 8.03%; S,
18.28%.
3.5. General procedure for the synthesis of 4(a–i)
A solution of phenyl hydrazine hydrochloride (0.75 mmol), in ethanol (25 mL) was added while
stirring to a solution of compound 3 (0.5 mmol) in DMF (5.0 mL). The reaction mixture was
refluxed for 10–12 h. Evolution of hydrogen sulfide gas continues for 5–6 h. The progress of
reaction was monitored by TLC. The reaction mixture was then cooled to room temperature and
poured into ice cold water and separated solid was filtered, dried and recrystallized from ethanol.
3.5.1. 2,5,6-Triphenyl-5,6-dihydro-2H-pyrazolo[3,4-d]thiazole (4a)
1
Orange solid, yield 40%, mp 188–190◦C. IR (cm−1): 1659 (C N), 1489 (C C); H NMR
=
=
(400 MHz, DMSO-d6): δ 6.80 (s, 1H, H-5), 7.18–7.22 (m, 1H, C6H5), 7.25–7.31 (m, 5H, C6H5),
=
7.38–7.41 (m, 2H, C6H5), 7.46–7.52 (m, 5H, C6H5), 7.78–7.81 (m, 2H, C6H5), 8.47 (s, 1H, CH
of pyrazole ring); 13C NMR (100 MHz, DMSO-d6) δ: 163.7, 152.1, 137.2, 137.1, 136.7, 131.3,
129.1, 128.7, 128.6, 127.0, 126.8, 125.3, 122.2, 63.9; mass m/z 356.1 (M + H+, 90%). Anal.
Calcd for C22H17N3S: C, 74.34; H, 4.82; N, 11.82; S, 9.02; found: C, 74.42%; H, 5.01%; N,
11.96%; S, 9.18%.
3.5.2. 2-(4-Chlorophenyl)-5,6-diphenyl-5,6-dihydro-2H-pyrazolo[3,4-d]thiazole (4b)
1
Yellow solid, yield 44%, mp 138–140◦C. IR (cm−1): 1645 (C N), 1485 (C C); H NMR
(400 MHz, DMSO-d6): δ 6.88 (s, 1H, H-5), 7.18–7.22 (m, 1H, C6H5), 7.25–7.36 (m, 5H, C6H5),
7.39–7.42 (m, 2H, C6H5), 7.48–7.51 (dd, 2H, C6H5, J = 1.16 Hz, J = 7.56 Hz), 7.55–7.58 (m,
=
=
=
2H, C6H5), 7.79–7.81 (dd, 2H, C6H5, J = 2.0 Hz, J = 4.8 Hz), 8.48 (s, 1H, CH of pyrazole
ring); 13C NMR (100 MHz, DMSO-d6) δ: 163.5, 150.6, 137.2, 137.0, 136.7, 136.2, 135.0, 129.5,
128.9, 128.8, 128.7, 127.1, 126.9, 125.4, 123.7, 63.9; mass m/z 390.2 (M + H+, 35%). Anal.
Calcd for C22H16ClN3S: C, 67.77; H, 4.14; N, 10.78; S, 8.22; found: C, 67.52%; H, 4.31%; N,
10.87%; S, 8.38%.
3.5.3. 5,6-Diphenyl-2-(o-tolyl)-5,6-dihydro-2H-pyrazolo[3,4-d]thiazole (4c)
1
Red needles, yield 42%, mp 188–190◦C. IR (cm−1): 1656 (C N), 1484 (C C); H NMR
(400 MHz, DMSO-d6): δ 2.60 (s, 3H, CH3), 6.83 (s, 1H, H-5), 7.19–7.23 (t, 1H, C6H5, J =
7.52 Hz), 7.24–7.28 (m, 4H, C6H5), 7.30–7.35 (m, 2H, C6H5), 7.37–7.39 (m, 4H, C6H5), 7.46–
=
=
=
7.48 (d, 2H, C6H5, J = 7.56 Hz), 7.58–7.60 (d, 1H, C6H5, J = 8.0 Hz), 8.68 (s, 1H, CH of
pyrazole ring); 13C NMR (100 MHz, DMSO-d6) δ: 163.8, 150.7, 137.7, 137.3, 136.8, 131.3,
128.8, 128.7, 127.1, 126.8, 125.4, 114.8, 63.9, 18.3; mass m/z 370.1 (M + H+, 100%); Anal.

Journal of Sulfur Chemistry 637
Calcd for C23H19N3S: C, 74.77; H, 5.18; N, 11.37; S, 8.68; found: C, 74.89%; H, 5.31%; N,
11.51%; S, 8.82%.
3.5.4. 5-(4-Chlorophenyl)-2,6-diphenyl-5,6-dihydro-2H-pyrazolo[3,4-d]thiazole (4d)
1
Orange solid, yield 48%, mp 156–158◦C. IR (cm−1): 1652 (C N), 1481 (C C); H NMR
=
=
(400 MHz, DMSO-d6): δ 6.23 (s, 1H, H-5), 7.23–7.28 (m, 6H, C6H5), 7.32–7.36 (t, 2H, C6H5,
=
J = 7.48), 7.45–7.48 (m, 3H, C6H5), 7.83–7.86 (m, 2H, C6H5), 8.65 (s, 1H, CH of pyrazole
ring); 13C NMR (100 MHz, DMSO-d6) δ: 163.5, 150.6, 137.2, 137.0, 136.7, 136.2, 135.0, 129.5,
128.9, 128.8, 128.7, 127.1, 126.9, 125.4, 123.7, 63.9; mass m/z 390.1 (M + H+, 21%). Anal.
Calcd for C22H16ClN3S: C, 67.77; H, 4.14; N, 10.78; S, 8.22; found: C, 67.42%; H, 4.31%; N,
11.01%; S, 8.38%.
3.5.5. 2,5-bis(4-chlorophenyl)-6-phenyl-5,6-dihydro-2H-pyrazolo[3,4-d]thiazole (4e)
1
Orange solid, yield 52%, mp 160–162◦C. IR (cm−1): 1654 (C N), 1481 (C C); H NMR
(400 MHz, DMSO-d6): δ 6.87 (s, 1H, H-5), 7.19–7.23 (t, 1H, C6H5, J = 7.40 Hz), 7.31–7.37
(m, 4H, C6H5), 7.43–7.49 (m, 4H, C6H5), 7.53–7.56 (m, 2H, C6H5), 7.78–7.82 (m, 2H, C6H5),
=
=
8.49 (s, 1H, CH of pyrazole ring); 13C NMR (100 MHz, DMSO-d6) δ: 163.4, 150.6, 137.1,
136.5, 136.3, 136.1, 134.5, 133.7, 129.4, 129.0, 128.8, 128.7, 127.0, 125.4, 123.7, 63.1; mass
m/z 424.1 (M + H+, 30%). Anal. Calcd for C22H15Cl2N3S: C, 62.27; H, 3.56; N, 9.90; S, 7.56;
found: C, 62.42%; H, 3.71%; N, 10.08%; S, 7.68%.
=
3.5.6. 5-(4-Chlorophenyl)-6-phenyl-2-(o-tolyl)-5,6-dihydro-2H-pyrazolo[3,4-d]thiazole (4f)
1
Orange solid, yield 41%, mp 152–154◦C. IR (cm−1): 1649 (C N), 1480 (C C); H NMR
=
=
(400 MHz, CDCl3): δ 2.41 (s, 3H, CH3), 6.22 (s, 1H, H-5), 7.22–7.34 (m, 11H, C6H5), 7.74–
7.76 (d, 2H, C6H5, J = 8.32 Hz), 8.60 (s, 1H, CH of pyrazole ring); 13C NMR (100 MHz,
=
CDCl3) δ: 163.4, 150.6, 137.1, 136.5, 136.3, 136.1, 134.5, 133.7, 129.4, 129.0, 128.8, 128.7,
127.0, 125.4, 123.7, 63.1; mass m/z 404.1 (M + H+, 15%). Anal. Calcd for C23H18ClN3S: C,
68.39; H, 4.49; N, 10.40; S, 7.94; found: C, 68.52%; H, 4.71%; N, 10.61%; S, 8.08%.
3.5.7. 2-Phenyl-5,6-di-p-tolyl-5,6-dihydro-2H-pyrazolo[3,4-d]thiazole (4g)
1
Orange solid, yield 40%, mp 128–130◦C. IR (cm−1): 1652 (C N), 1485 (C C); H NMR
(400 MHz, DMSO-d6): δ 2.22 (s, 6H, 2CH3), 6.74 (s, 1H, H-5), 7.04–7.11 (m, 4H, C6H5), 7.21–
7.23 (m, 2H, C6H5), 7.27–7.32 (m, 2H, C6H5), 7.34–7.38 (m, 1H, C6H5), 7.43–7.47 (m, 2H,
=
=
C6H5), 7.77–7.80 (m, 2H, C6H5), 8.44 (s, 1H, CH of pyrazole ring); 13C NMR (100 MHz,
DMSO-d6) δ: 163.5, 152.1, 138.3, 136.9, 136.3, 134.3, 134.1, 131.4, 129.3, 129.2, 127.0, 125.3,
122.2, 63.8, 20.7, 20.5; mass m/z 384.1 (M + H+, 52%). Anal. Calcd for C24H21N3S: C, 75.16;
H, 5.52; N, 10.96; S, 8.36; found: C, 75.32%; H, 5.71%; N, 11.12%; S, 8.48%.
=
3.5.8. 2-(4-Chlorophenyl)-5,6-di-p-tolyl-5,6-dihydro-2H-pyrazolo[3,4-d]thiazole (4h)
1
Brown solid, yield 46%, mp 134–136◦C. IR (cm−1): 1654 (C N), 1490 (C C); H NMR
(400 MHz, DMSO-d6): δ 2.25 (s, 6H, 2CH3), 6.79 (s, 1H, H-5), 7.05–7.10 (m, 2H, C6H5), 7.12–
7.16 (m, 2H, C6H5), 7.25–7.32 (m, 2H, C6H5), 7.34–7.38 (m, 2H, C6H5), 7.40–7.48 (m, 2H,
=
=
C6H5), 7.59–7.65 (m, 2H, C6H5), 8.44 (s, 1H, CH of pyrazole ring); 13C NMR (100 MHz,
=

638 P. Gautam et al.
DMSO-d6) δ: 163.6, 152.3, 138.5, 136.9, 136.5, 134.5, 134.1, 131.5, 129.4, 129.3, 127.1, 125.4,
122.3, 63.9, 20.8, 20.6; mass m/z 418.1 (M + H+, 10%). Anal. Calcd for C24H20ClN3S: C, 68.97;
H, 4.82; N, 10.05; S, 7.67; found: C, 69.18%; H, 4.71%; N, 10.21%; S, 7.48%.
3.5.9. 2-(o-tolyl)-5,6-di-p-tolyl-5,6-dihydro-2H-pyrazolo[3,4-d]thiazole (4i)
1
Orange solid, yield 40%, mp 158–160◦C. IR (cm−1): 1656 (C N), 1484 (C C); H NMR
(400 MHz, DMSO-d6): δ 2.22 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.59 (s, 3H, CH3), 6.74 (s, 1H,
H-5), 7.07–7.09 (d, 2H, C6H5, J = 8.0 Hz), 7.11–7.13 (d, 2H, C6H5, J = 8.32 Hz), 7.23–7.28
(m, 3H, C6H5), 7.31–7.33 (d, 2H, C6H5, J = 8.36 Hz), 7.38–7.39 (d, 2H, C6H5, J = 4.04 Hz),
=
=
7.57–7.59 (d, 1H, C6H5, J = 8.0 Hz), 8.66 (s, 1H, CH of pyrazole ring); 13C NMR (100 MHz,
=
DMSO-d6) δ: 163.5, 152.4, 138.6, 136.4, 136.3, 134.5, 134.2, 131.6, 129.5, 129.2, 127.2, 125.5,
122.4, 63.8, 20.9, 20.5, 20.1; mass m/z 398.1 (M + H+, 40%). Anal. Calcd for C25H23N3S: C,
75.53; H, 5.83; N, 10.57; S, 8.07; found: C, 75.68%; H, 5.91%; N, 10.71%; S, 8.18%.
3.6. General procedure for the synthesis of 6
A mixture of compound 1 (0.5 mmol), aromatic aldehyde (0.5 mmol) and sodium ethoxide
(0.02 g of sodium in 2.0 mL of absolute ethanol) in dry benzene (20 mL) was heated under reflux
for 10–12 h. The progress of reaction was monitored by TLC. After completion, the reaction mix-
ture was cooled and poured into ice cold water. The organic layer was separated and dried over
fused calcium chloride. The solvent was removed under reduced pressure. The solid obtained
was recrystallized from ethanol.
3.6.1. (E)-5-(4-chlorobenzylidene)-2,3-di-p-tolylthiazolidin-4-one (6a)
1
Yellow solid, yield 75%, mp 188–190◦C. IR (cm−1): 1696 (C O); H NMR (400 MHz, DMSO-
=
d6): δ 2.22 (s, 3H, CH3), 2.23 (s, 3H, CH3), 6.82 (s, 1H, H-5), 7.09–7.15 (m, 4H, C6H5), 7.25–
7.27 (d, 2H, C6H5, J = 8.12 Hz), 7.31–7.33 (d, 2H, C6H5, J = 8.36 Hz), 7.52–7.54 (t, 3H, C6H5,
=
J = 6.0 Hz), 7.58–7.60 (t, 2H, C6H5 and CH, J = 2.04 Hz). Anal. Calcd for C24H20ClNOS: C,
71.01; H, 4.97; N, 3.45; S, 7.90; found: C, 71.22%; H, 5.12%; N, 3.58%; S, 8.07%.
3.6.2. (E)-2-(4-chlorophenyl)-5-(4-methylbenzylidene)-3-phenylthiazolidin-4-one (6b)
1
Yellow solid, yield 72%, mp 170–172◦C. IR (cm−1): 1698 (C O); H NMR (400 MHz, DMSO-
=
d6): δ 2.36 (s, 3H, CH3), 6.71 (s, 1H, H-5), 7.17–7.21 (t, 1H, C6H5, J = 7.36 Hz), 7.24–7.43 (m,
=
12H, C6H5), 7.52 (s, 1H, CH); Anal. Calcd for C23H18ClNOS: C, 70.49; H, 4.63; N, 3.57; S,
8.18; found: C, 70.61%; H, 4.87%; N, 3.69%; S, 8.31%.
3.7. Attempted synthesis of 7
A mixture of 6 (0.5 mmol), phenyl hydrazine (0.75 mmol) and anhydrous sodium acetate
(1.0 mmol) in absolute ethanol (15 mL) was heated under reflux for 24–30 h. The progress of
the reaction was monitored by TLC. Unfortunately, the reaction did not happen after 30 h and
starting material was obtained. The reaction was attempted under acidic conditions (acetic acid)
and basic conditions (piperidine). The starting material was obtained in all above cases.
Supplemental data
Supplemental data for this article can be accessed at 10.1080/17415993.2014.944912.

Journal of Sulfur Chemistry 639
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