Synthesis of some new 2,4-disubstituted hydrazinothiazoles and 2,5-disubstituted thiazolidinones

Article abstract of DOI:10.1080/10426500802625404

A series of hydrazinothiazoles has been synthesized by the condensation of thiosemicarbazones and α-bromoketones. Similarly the hydrazinothiazolidiones were prepared by the condensation of thiosemicarbazone and α-bromoesters. The newly synthesized compounds were characterized by NMR and LCMS studies.

Full text of DOI:10.1080/10426500802625404

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Synthesis of Some
New 2,4-Disubstituted
Hydrazinothiazoles and 2,5-
Disubstituted Thiazolidinones
P. Manivel a b & F. Nawaz Khan a
a Chemistry Division, School of Science and
Humanities , VIT University , Vellore, Tamil Nadu,
India
b Syngene International Limited , Bangalore, India
Published online: 03 Nov 2009.
To cite this article: P. Manivel & F. Nawaz Khan (2009) Synthesis of Some New
2,4-Disubstituted Hydrazinothiazoles and 2,5-Disubstituted Thiazolidinones,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:11, 2910-2922, DOI:
10.1080/10426500802625404
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Phosphorus, Sulfur, and Silicon, 184:2910–2922, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802625404
Synthesis of Some New 2,4-Disubstituted
Hydrazinothiazoles and 2,5-Disubstituted Thiazolidinones
P. Manivel1,2 and F. Nawaz Khan1
1Chemistry Division, School of Science and Humanities, VIT University,
Vellore, Tamil Nadu, India
2Syngene International Limited, Bangalore, India
A series of hydrazinothiazoles has been synthesized by the condensation of thiosemi-
carbazones and α-bromoketones. Similarly the hydrazinothiazolidiones were pre-
pared by the condensation of thiosemicarbazone and α-bromoesters. The newly
synthesized compounds were characterized by NMR and LCMS studies.
Keywords α-Haloketones; hydrazine; thiazole; thiazolidinones; thiosemicarbazone
INTRODUCTION
Thiazole and thiazolidinone derivatives find applications in many fields
of chemistry including medicine and agriculture. Thiazoles and thiazo-
lidinones find applications in drug development for the treatment of in-
flammation,1 hypertension,2 bacterial infections,3–9 HIV infections,10–16
allergies,17 schizophrenia,18 and as hypnotics.19,20 They are also used as
fungicides, as an ingredient of herbicides, and as schistosomicidal and
anthelmintic drugs,21–24 as anti-inflammatory agents, and they possess
anti-tubercular properties.25–27 In addition, thiazoles are also synthetic
intermediates and common substructures in numerous biologically ac-
tive compounds. Thus the thiazole and thiazolidinone nucleus has been
much studied in the fields of organic and medicinal chemistry.28–31 The
azo derivatives of thiazoles also have wide applications in the dyeing
of synthetic fibers.32,33
Therefore, a general, simple, and efficient method for rapid synthe-
sis of thiazoles and thiazolidinones would be greatly advantageous and
Received 18 September 2008; accepted 3 November 2008.
We wish to thank Syngene International Limited for the generous support of spectral
analysis. The author F. N. K. thanks DST, India, for their support of SERC–Fast Track
Proposal funding.
Address correspondence to F. Nawaz Khan, Chemistry Division, School of Sci-
ence and Humanities, VIT University, Vellore 632 014, Tamil Nadu, India. E-mail:
nawaz f@yahoo.co.in
2910

New Hydrazinothiazoles and Thiazolidinones
2911
warrants further investigations in drug discovery. Hantzsch, Tcher-
nic, Cook-Heilborn, Gabriel, and other groups have developed several
methods for the synthesis of thiazole derivatives.34–36 The most wildly
used method is Hantzsch synthesis,34–36 which originated in 1887, in-
volving the reaction of α-halo carbonyl compounds with thioureas or
thioamides. Among the various methodologies reported for the prepa-
ration of thiazoles, solid supported syntheses have been used to gener-
ate small organic libraries,37 and solution-phase preparations of com-
binatorial libraries have been prepared in DMF,38 as well as in 1,4-
dioxane.39 These methods require high temperatures, long reaction
times, hazardous solvents, and often produce low yields. Recently, thi-
azole derivatives were synthesized by using catalysts such as ammo-
nium molybdophosphate, cyclodextrin, iodine, and silica chloride in or-
ganic solvents at elevated temperature and solvents such as 1-methyl-
2-pyrrolidinone, and with the use of microwave.40–45 However, in spite
of their potential utility, many of these reported methods suffer from
drawbacks such as harsh reaction conditions and remain unsatisfac-
tory.
Prompted by these reports and in continuation of our search for
bioactive molecules,46–51 we report in this article the Hanzch synthesis
of some new thiazole, thiazolidinone derivatives starting from 1-(3-
phenylisoquinolin-1-yl) thiosemicarbazide 1.
RESULTS AND DISCUSSION
The synthetic strategies adopted to obtain the target compounds are
depicted in Scheme 1. The key intermediate was prepared in an ex-
cellent yield in three sequential steps. 1-(3-phenylisoquinolin-1-yl)
thiosemicarbazide 1 was synthesized by the reaction of 1-chloro-3-
phenylisoquinoline 2 and thiosemicarbazide. Compound 1 was then
treated with substituted α-haloketones, 3, to yield 2,4 disubstituted
hydrazinothiazoles 4.
The results of the synthesis of thiazoles 4a–i are given in Table I.
The formation of the thiazoles was confirmed by the 1H NMR, 13C NMR,
and LCMS of the compounds. The IR spectrum of 4a showed absorption
bands at 3384, 3058, 2921, 1574, 1543, 823, and 695 cm−1 due to NH,
C–H aromatic (str), aliphatic C–H, C = /N, C = C, C–H aromatic (ben),
and C–S–C groups, respectively. The IR spectra of other thiazoles of the
series showed similar absorption bands, and the data are presented in
1
Table I. The H NMR spectrum of 4a showed a sharp singlet at δ 7.1
corresponding to C-5 proton of the thiazole ring. The 13C NMR spectrum

2912
P. Manivel and F. N. Khan
SCHEME 1 Synthesis of hydrazinothiazoles and thiazolidinones.
showed the presence of a thiazole ring, i.e., (d CHS), (s, N=CS), and (s,
NC=CH) (see data in the Experimental section).
We have also cyclized the thiosemicarbazone, 1, functionality into
thiazolidinone, 6, and 7. Thus, treatment of thiosemicarbazone deriva-
tive 1 with one equivalent of ethyl bromoacetate or other α-bromoesters,
5, in refluxing ethanol containing three equivalents of freshly fused
sodium acetate afforded a single product, 6 (Table II, entries 1–4).
However, if excess bromoesters were used, the N-alkylated product, 7,
formed as a major product with only trace of compounds 5, (Table II,
entries 5–8).
CONCLUSION
In conclusion, the condensation of α-bromoketones with thiosemicar-
bazide were effected by following a Hantzsch method to provide an
excellent route to highly functionalized 2-hydrazinothiazoles. A new
scheme for the formation of thiazolidinone and its N-alkylated product

New Hydrazinothiazoles and Thiazolidinones
2913
TABLE I Synthesis of Hydrazinothiazoles from Isoquinoline
Thiosemicarbazonea
Substrate 3 and Product 4
Yieldb
Entry
R1
H
H
H
H
H
H
H
F
R2
H
CN
F
H
H
H
H
H
CF3
R3
CH3
H
Cl
CF3
Cl
CN
F
Cl
R4
H
H
H
H
H
H
H
H
R5
H
H
H
H
H
H
H
H
H
%
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
80
82
85
76
83
87
85
83
81
H
H
CF3
aAll products were identified by 1H, 13C NMR, LCMS.
bIsolated Yields.
by treatment with α-bromoesters has also been reported. These reac-
tions are simple and effective, and also possess interesting potential as
a new method in hydrazinothiazoles synthesis.
EXPERIMENTAL
The materials were purchased from Sigma-Aldrich and Merck, and
were used without any additional purification. All reactions were mon-
itored by thin layer chromatography (TLC) on gel F254 plates. The
silica gel (230–400 meshes) for column chromatography was purchased

2914
P. Manivel and F. N. Khan
TABLE II Synthesis of Hydrazinothiazolidinones from Isoquinoline
Thiosemicarbazonea
Substrates 5, Product 6
Yieldb
Entry
R1
H
H
CH3
R2
H
CH3
%
1
2
3
4
a
b
c
74
71
69
73
CH3
d
H
CH(CH3)2
Substrates 5, Product 7
5
6
7
8
a
b
c
H
H
CH3
H
H
CH3
CH3
79
82
81
80
d
CH(CH3)2
aProducts 6b, 6c, 7a, 7b were identified by 1H, 13C NMR, LCMS.
bIsolated Yields.
from Spectrochem Pvt. Ltd., India. Melting points were taken in open
capillary tubes and are corrected with reference to benzoic acid. IR
spectra in KBr pellets were recorded on a Nucon Infrared spectropho-
1
tometer. H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a Bruker 400 MHz spectrometer in CDCl3 or DMSO (with
TMS for 1H and DMSO for 13C NMR as internal references).
Preparation of 3-Phenylisoquinolin-1(2H)-one
3-Phenylisocoumarin (20 g, 90 mmol) was dissolved in THF (100 mL),
and to this, liq. ammonia in excess was added. The mixture was refluxed
overnight in an oil bath until TLC showed completion of the reaction.
Then ice-cold water (500 mL) was added to the reaction mixture, then
it was extracted with ethyl acetate and the extract was dried over

New Hydrazinothiazoles and Thiazolidinones
2915
anhydrous sodium sulfate. Removal of the solvent under vacuum gave
the crude product, which was further purified by column chromatogra-
phy on silica gel (100–200 mesh) with ethyl acetate-hexane (25%) as
an eluent to afford pure product, 3-phenylisoquinolin-1(2H)-one in 70%
yield, and is characterized by its 1H and 13C NMR spectra.
1H NMR (CDCl3): δ 6.79 (s, 1H, NH−C=CH), 7.45–7.55 (m, 4H),
7.60–7.62 (d, 1H), 7.67–7.73 (m, 3H), 8.41–8.44 (d, 1H), 9.68 (s, 1H,
NH). 13C NMR (CDCl3): δ 163.63 (C=O), 139.34 (NH−C=CH), 138.24,
134.37, 132.88, 129.60, 129.31, 127.52, 126.71, 126.56, 126.00, 125.05
(Aromatic Carbons), 104.28 (NH−C=C). LCMS-221.9. C15H11NO re-
quires Mol. Wt.: 221.25.
Preparation of 1-Chloro-3-phenylisoquinoline
To 3-phenylisoquinolin-1(2H)-one (15 g, 68 mmol), phosphoryl chloride
(90 mL) was added. The mixture was refluxed overnight under a ni-
trogen atmosphere in an oil bath until TLC showed completion of the
reaction. Then the reaction mixture was added to ice-cold water, and it
was extracted with ethyl acetate. The extract was dried over anhydrous
sodium sulfate. Removal of the solvent under vacuum gave the crude
product, which was further purified by column chromatography on sil-
ica gel (230–400 mesh) with ethyl acetate-hexane (2%) as an eluent to
afford the pure product 1-chloro-3-phenylisoquinoline, 2, in 92% yield
and was characterized by its 1H and 13C NMR spectra.
1H NMR (CDCl3): δ 8.32–8.34 (d, 1H), 8.11–8.14 (m, 2H), 8.02 (s,
1H, NH−C=CH), 7.88–7.90 (m, 1H), 7.73–7.77 (m, 1H), 7.64–7.68 (m,
1H), 7.49–7.53 (m, 1H), 7.41–7.46 (m, 3H). 13C NMR (CDCl3): δ 163.63
(C-Cl), 139.34 (NH−C=CH), 138.24, 134.37, 132.88, 129.60, 129.31,
127.52, 126.71, 126.56, 126.00, 125.05 (Aromatic carbons), 104.28 (NH-
C=CH). LCMS-240.1. C15H10ClN requires Mol. Wt.: 239.6.
Preparation of Thiosemicarbazide
The thiosemicarbazone derivative was prepared by refluxing an
equimolar ratio of halo derivative of isoquinoline and thiosemicar-
bazide in the presence of ethanol. Removal of the solvent under vac-
uum gave the crude product, which was further purified by wash-
ing with petether to afford the pure product 1-(3-phenylisoquinolin-
1-yl)thiosemicarbazide, 1, in 95% yield and was characterized by its 1H
and 13C NMR spectra.
1H NMR (DMSO): δ 9.49 (s, 1H), 9.22 (s, 1H), 8.26–8.23 (m, 3H),
7.87–7.85 (d, J = 8.08 Hz, 1H), 7.80–7.77 (m, 1H), 7.71–7.61 (m, 2H),
7.53–7.49 (m, 1H), 7.46–7.42 (m, 2H), 7.37–7.34 (m, 1H). 13C NMR

2916
P. Manivel and F. N. Khan
(DMSO): δ 183.75 (C=S), 154.35 (N=C−NH), 147.78 (NH−C=CH),
139.35, 138.17, 130.68, 128.83, 128.75, 127.55, 126.85, 126.30, 123.89,
116.88, 108.65 (NH−C=CH). LCMS-295.1. C16H14N4S requires Mol.
Wt.: 294.3.
General Procedure for the Synthesis of Thiazole Derivatives
(4a–4i)
To a solution of thiosemicarbazide, 1 (0.005 mol) in absolute ethanol
(10 mL), equimolar amounts (0.005 mol) of the appropriate α-
haloketone, 3, were added. The reaction mixture was heated at 50◦C
for 2 h. The separated solid product was filtered, dissolved in chloro-
form, washed with water, dried over anhydrous sodium sulfate, and
concentrated under vacuum to afford the thiazole compounds, 4.
1-(3-Phenylisoquinolin-1-yl)-2-(4-p-tolylthiazol-2-yl)hydrazine,
4a
Brown solid, mp 272◦C, (IR ν cm−1) 3384, 3058, 2921, 1722, 1625,
1574, 1543, 1509, 1377, 1030, 764, 695. 1H NMR (DMSO): δ 9.96 (s, 1H,
NH), 9.42 (s, 1H, NH), 8.32–8.30 (t, J = 1.64 Hz, 1H), 8.08 (d, J = 1.68
Hz, 1H), 8.06 (s, 1H), 7.90–7.88 (d, J = 8.12 Hz, 1H), 7.77–7.69 (m, 4H),
7.59–7.55 (t, J = 7.88 Hz, 1H), 7.32–7.30 (m, 3H), 7.22–7.20 (d, J =
4.04 Hz, 2H), 7.09 (s, 1H, S−CH), 2.32 (s, 3H, CH3). 13C NMR (DMSO):
δ 175.71 (S−C=N), 154.79 (HNNH−C=N isoquinoline ring), 151.17
(N−C=C−S), 147.86 (N−C=CH isoquinoline ring), 139.41, 138.23,
137.03, 132.85, 130.89, 129.58, 128.75, 127.86, 126.83, 126.73, 125.99,
123.20, (Aromatic carbons), 116.88, 108.80 (N−C=CH isoquinoline
ring), 102.71 (S−CH), 21.28 (CH3). LCMS-409.2. C25H20N4S, Mol. Wt.:
408.52, Calculated C, 73.50; H, 4.93; N, 13.71; S, 7.85, found C, 73.42;
H, 4.84; N, 13.66; S, 7.78.
2-(4-(3-Cyanophenyl)thiazol-2-yl)-1-(3-phenylisoquinolin-1-yl)
hydrazine, 4b
Brown solid, mp 292◦C, (IR ν cm−1) 3345, 3061, 2956, 2232, 1625,
1575, 1512, 1381, 1054, 767, 688. 1H NMR (DMSO): δ 9.98 (s, 1H, NH),
9.55 (s, 1H, NH), 8.30–8.27 (m, 2H), 8.20–8.18 (d, J = 6.92 Hz, 1H), 8.03
(s, 2H), 7.89–7.87 (d, J = 7.36 Hz, 1H), 7.77–7.72 (m, 3H), 7.63–7.61 (d,
J = 6.36 Hz, 2H), 7.58–7.56 (d, J = 9.44 Hz, 1H), 7.42–7.27 (m, 3H).
13C NMR (DMSO): δ 176.19 (S−C=N), 154.68 (HNNH−C=N isoquino-
line ring), 148.82 (N−C=C−S), 147.81 (N−C=CH isoquinoline ring),
139.37, 138.22, 136.44, 131.18, 130.92, 130.50, 130.43, 129.29, 128.73,
127.87, 126.77, 123.16, (Aromatic carbons), 119.28, 116.86, 112.20 (CN,

New Hydrazinothiazoles and Thiazolidinones
2917
−C−CN), 108.94 (N−C=CH isoquinoline ring), 105.92 (S−CH). LCMS-
420.0, C25H17N5S, Mol. Wt.: 419.5, Calculated C 71.58; H, 4.08; N,
16.69; S, 7.64, Found C 71.51; H, 4.00; N, 16.62; S, 7.56.
2-(4-(4-Chloro-3-fluorophenyl)thiazol-2-yl)-1-
(3-phenylisoquinolin-1-yl)hydrazine, 4c
Brown solid, mp 146◦C, (IR ν cm−1) 3234, 3062, 2953, 1897, 1623,
1
1574,1377, 1327, 1073, 817, 766, 693. H NMR (DMSO): δ 9.98 (s, 1H,
NH), 9.53 (s, 1H, NH), 8.30–8.28 (d, J = 8.28 Hz, 1H), 8.05–8.03 (m,
2H), 7.89–7.82 (m, 2H), 7.77–7.68 (m, 3H), 7.62–7.54 (m, 2H), 7.37
(s, 1H), 7.31–7.26 (m, 3H). 13C NMR (DMSO): δ 176.04, (S−C=N),
156.64 (HNNH−C=N isoquinoline ring), 148.74 (N−C=C−S), 147.81
(N−C=CH isoquinoline ring), 139.36, 138.22, 136.61, 131.28, 130.91,
128.74, 127.86, 126.78, 123.16 (Aromatic carbons), 118.24, 116.85,
113.98 (C=C−F), 113.76, 108.93, (N−C=CH isoquinoline ring), 105.83
(S−CH). LCMS-447.0, C24H16ClFN4S, Mol. Wt.: 446.93, Calculated C,
64.50; H, 3.61; Cl, 7.93; F, 4.25; N, 12.54; S, 7.17, Found C, 64.42; H,
3.53; Cl, 7.83; F, 4.16; N, 12.46; S, 7.08.
2-(4-(4-(Trifluoromethyl)phenyl)thiazol-2-yl)-1-(3-
phenylisoquinolin-1-yl)hydrazine, 4d
Brown solid, mp 148◦C, (IR ν cm−1) 3224, 3114, 3053, 1626, 1574,
1
1380, 1322, 1202, 1167, 1070, 769, 694. H NMR (DMSO): δ 9.98 (s,
1H, NH), 9.55 (s, 1H, NH), 8.31–8.29 (d, J = 8.40 Hz, 1H), 8.08–8.03
(m, 4H), 7.90–7.88 (d, J = 8.12 Hz, 1H), 7.77–7.68 (m, 4H), 7.58–7.54
(t, J = 8.1 Hz,1H), 7.41 (s, 1H), 7.30–7.25 (m, 3H). 13C NMR (DMSO):
δ 176.12 (S−C=N), 154.67 (HNNH−C=N isoquinoline ring), 149.51
(N−C=C−S), 147.82 (N−C=CH isoquinoline ring), 139.37, 139.10,
138.23, 130.91, 128.74, 127.87, 126.77, 126.52, 126.03, 123.16 (Aro-
matic carbons), 116.86, 108.91 (N−C=CH isoquinoline ring), 106.39
(S−CH). LCMS-463.1, C25H17F3N4S, Mol. Wt.: 462.49, Calculated C,
64.92; H, 3.70; F, 12.32; N, 12.11; S, 6.93, Found C, 64.85; H, 3.64; F,
12.22; N, 12.05; S, 6.84.
2-(4-(4-Chlorophenyl)thiazol-2-yl)-1-(3-phenylisoquinolin-1-yl)
hydrazine, 4e
Brown solid, mp 170◦C, (IR ν cm−1) 3383, 3174, 3059, 2892, 1625,
1
1574, 1377, 1322, 1012, 825, 770, 695. H NMR (DMSO): δ 9.98 (s,
1H, NH), 9.50 (s, 1H, NH), 8.32–8.30 (d, J = 8.28 Hz,1H), 8.07 (d,
J = 1.92 Hz, 1H), 8.05 (d, J = 1.36 Hz, 1H), 7.90–7.88 (d, J = 8.52
Hz, 3H), 7.78 (s, 1H), 7.73–7.69 (t, J = 7.4 Hz, 1H), 7.59–7.55 (t, J
= 7.24 Hz, 1H), 7.47–7.45 (d, J = 8.56 Hz, 3H), 7.32–7.24 (m, 4H).

2918
P. Manivel and F. N. Khan
13C NMR (DMSO): δ 175.28 (S−C=N), 154.73 (HNNH−C=N isoquino-
line ring), 149.81 (N−C=C−S), 147.84 (N−C=CH isoquinoline ring),
139.38, 138.23, 134.31, 132.18, 130.90, 129.04, 128.75, 127.87, 127.73,
126.80, 126.75, 123.18 (Aromatic carbons), 116.87, 108.87 (N−C=CH
isoquinoline ring), 104.42 (S−CH). LCMS-429.0, C24H17ClN4S, Mol.
Wt.: 428.94, Calculated C, 67.20; H, 3.99; Cl, 8.27; N, 13.06; S, 7.48,
Found C, 67.20; H, 3.99; Cl, 8.27; N, 13.06; S, 7.48.
2-(4-(4-Cyanophenyl)thiazol-2-yl)-1-(3-phenylisoquinolin-
1-yl)hydrazine, 4f
Brown solid, mp 180◦C, (IR ν cm−1) 3340, 3178, 3060, 2926, 2224,
1624, 1573, 1409, 1381, 1327, 841, 767, 689. 1H NMR (DMSO): δ
10.01 (s, 1H, NH), 9.59 (s, 1H, NH), 8.32–8.30 (m, 1H), 8.06–8.04
(m, 4H), 7.99–7.86 (m, 3H), 7.79 (s, H), 7.74–7.70 (m, 1H), 7.59–7.56
(m, 1H), 7.50 (s, 1H), 7.30–7.27(m, 3H). 13C NMR (DMSO): δ
176.18 (S−C=N), 154.67 (HNNH−C=N isoquinoline ring), 149.32
(N−C=C−S), 147.66 (N−C=CH isoquinoline ring), 139.52, 139.37,
138.25, 133.15, 130.94, 128.77, 127.90, 126.78, 126.61, 123.18 (Aro-
matic carbons), 109.85 (N−C=CH isoquinoline ring), 107.53 (S−CH).
LCMS-420.0, C25H17N5S, Mol. Wt.: 419.5, Calculated C, 71.58; H, 4.08;
N, 16.69; S, 7.64, Found C, 71.47; H, 4.00; N, 16.57; S, 7.57.
2-(4-(4-Fluorophenyl)thiazol-2-yl)-1-(3-phenylisoquinolin-1-yl)
hydrazine, 4g
Brown solid, mp 194◦C, (IR ν cm−1) 3385, 3174, 3060, 2894, 1625,
1
1573, 1377, 1324, 1216, 770, 695. H NMR (DMSO): δ 9.97 (s, 1H,
NH), 9.46 (s, 1H, NH), 8.32–8.28 (m, 1H), 8.05–8.03 (d, J = 6.32 Hz,
1H), 7.90–7.87 (m, 3H), 7.75 (s, 1H), 7.71–7.68 (m, 1H), 7.57–7.53 (m,
1H), 7.27 (s, 1H), 7.23–7.19 (m, 5H), 7.14 (s, 1H). 13C NMR (DMSO):
δ 175.84 (S−C=N), 163.19, 160.76, 154.73 (HNNH−C=N isoquino-
line ring), 149.97 (N−C=C−S), 138.22 (N−C=CH isoquinoline ring),
132.06, 130.97, 128.76, 128.01, 127.94, 127.88, 126.84, 123.22 (Aro-
matic carbons), 116.86, 115.95, 115.74 (C=C−F), 108.89 (N−C=CH
isoquinoline ring), 103.36 (S−CH). LCMS-413, C24H17FN4S, Mol. Wt.:
412.48, Calculated C, 69.88; H, 4.15; F, 4.61; N, 13.58; S, 7.77, Found C,
69.81; H, 4.07; F, 4.55; N, 13.51; S, 7.69.
2-(4-(4-Chloro-2-fluorophenyl)thiazol-2-yl)-1-(3-
phenylisoquinolin-1-yl)hydrazine, 4h
Brown solid, mp 170◦C, (IR ν cm−1) 3381, 3182, 3060, 2894, 1625,
1574, 1415, 1377, 877, 769, 698. 1H NMR (DMSO): δ 10.05 (s, 1H, NH),
9.55 (s, 1H, NH), 8.32–8.30 (m, 1H), 8.12–8.04 (m, 3H), 7.91–7.89 (d,

New Hydrazinothiazoles and Thiazolidinones
2919
J = 8.08 Hz, 1H), 7.79 (s, 1H), 7.74–7.70 (m, 1H), 7.59–7.50 (m, 2H),
7.42–7.39 (m, 1H), 7.33–7.28(m, 2H), 7.15–7.14 (d, J = 2.52 Hz, 1H). 13
C
NMR (DMSO): δ 174.94 (S−C=N), 160.55, 158.04, 154.28 (HNNH-C=N
isoquinoline ring), 147.41 (N−C=C−S), 143.23 (N−C=CH isoquinoline
ring), 138.96, 137.84, 132.14, 132.04, 130.52, 128.35, 127.48, 126.38,
125.04, 122.77(Aromatic carbons), 121.70, 121.58, 116.77, 116.51,
161.47, 108.52 (N−C=CH isoquinoline ring), 108.42 (S−CH). LCMS-
447.1, C24H16ClFN4S, Mol. Wt.: 446.93, Calculated C, 64.50; H, 3.61;
Cl, 7.93; F, 4.25; N, 12.54; S, 7.17, Found C, 64.42; H, 3.56; Cl, 7.86; F,
4.17; N, 12.43; S, 7.11.
2-(4-(3,5-Bis(trifluoromethyl)phenyl)thiazol-2-yl)-1-(3-
phenylisoquinolin-1-yl) hydrazine, 4i
Brown solid, mp 182◦C, (IR ν cm−1) 3310, 3116, 2914, 1627, 1578,
1377, 1278, 1125, 769, 697. 1H NMR (DMSO): δ 10.04 (s, 1H, NH), 9.69
(s, 1H, NH), 8.52 (s, 2H), 8.32–8.29 (d, J = 10.8 Hz, 1H), 8.06–8.01
(m, 3H), 7.91–7.89 (d, J = 10.6 Hz, 1H), 7.79–7.69 (m, 3H), 7.60–7.55
(m, 1H), 7.27–7.25 (m, 2H). 13C NMR (DMSO): δ 176.60 (S−C=N),
154.66 (HNNH−C=N isoquinoline ring), 147.79 (N−C=C−S), 147.70
(N−C=CH isoquinoline ring), 139.37, 138.25, 137.65, 131.39, 131.06,
130.95, 130.74, 128.74, 128.68, 127.89, 126.78, 126.18, 125.23, 123.16
(Aromatic carbons), 122.52, 120.86, 116.88, 109.04 (N−C=CH iso-
quinoline ring), 107.85 (S−CH).. LCMS-531.1, C26H16F6N4S, Mol. Wt.:
530.49, Calculated C, 58.87; H, 3.04; F, 21.49; N, 10.56; S, 6.04, Found
C, 58.77; H, 2.95; F, 21.41; N, 10.46; S, 5.92.
General Procedure for the Synthesis of Thiazolidinone
Derivatives (6a–6d, 7a–7d)
A mixture of compound 1 (0.01 mol), α-bromoesters 5 (0.01 mol), and
anhydrous sodium acetate (0.03 mol) in ethanol (15 mL) was heated
under reflux for 8 h. The reaction mixture was left to cool, poured
into ice-cold water, extracted with ethyl acetate, dried, and concen-
trated. The crude product was purified by column chromatography to
give compound 6a–d. However if an excess quantity of α-bromoesters
(2.5 eq.) was used, it resulted in the formation of 7a–d.
2-(2-(3-Phenylisoquinolin-1-yl)hydrazono)-5-methylthiazolidin-
4-one, 6b
1H NMR (DMSO): δ 11.59 (s, 1H), 9.14 (s, 1H), 8.12–8.10 (d, J
= 7.64 Hz, 1H), 7.68–7.67 (d, J = 6.4 Hz, 2H), 7.52–7.47 (m, 6H),
7.37–7.34 (m, 1H), 6.60 (s, 1H), 1.48–1.46 (d, J = 7.16 Hz, 3H). 13C

2920
P. Manivel and F. N. Khan
NMR (DMSO): δ 176.72, 148.94, 138.29, 135.63, 134.50, 131.72, 130.02,
129.73, 127.15, 126.95, 125.63, 124.20, 123.91, 101.80, 19.56. LCMS-
349.0, C19H16N4OS, Mol. Wt.: 348.42, Calculated C, 65.50; H, 4.63; N,
16.08; O, 4.59; S, 9.20, Found C, 65.42; H, 4.56; N, 16.01; S, 9.13.
2-(2-(3-Phenylisoquinolin-1-yl)hydrazono)-5,5-
dimethylthiazolidin-4-one, 6c
1H NMR (DMSO): δ 11.59 (s, 1H), 9.16 (s, 1H), 8.11–8.09 (d, J =
8.04 Hz, 1H), 7.69–7.67 (m, 2H), 7.55–7.47 (m, 5H), 7.37–7.34 (m, 1H),
6.60 (s, 1H), 1.54 (s, 6H). 13C NMR (DMSO): δ 179.05, 153.01, 148.90,
138.30, 135.63, 134.50, 131.71, 130.02, 129.72, 127.13, 126.25, 125.64,
124.18, 123.91, 101.81, 51.99, 31.14, 28.42. LCMS-363.0, C20H18N4OS,
Mol. Wt.: 362.45, Calculated C, 66.28; H, 5.01; N, 15.46; O, 4.41; S, 8.85,
Found C, 66.21; H, 4.93; N, 15.37; S, 8.77.
Ethyl 2-(2-(2-(3-Phenylisoquinolin-1-yl)hydrazono)-4-
oxothiazolidin-3-yl)acetate, 7a
1H NMR (DMSO): δ 9.43 (s, 1H), 8.19–8.17 (d, J = 8.28 Hz, 1H),
7.73–7.71 (m, 2H), 7.57–7.51 (m, 5H), 7.42–7.40 (m, 1H), 6.67 (s, 1H),
4.68 (s, 2H), 4.14–4.08 (m, 4H), 1.13–1.10 (t, J = 7.12 Hz, 3H). 13C
NMR (DMSO): δ 171.44, 167.52, 153.84, 149.53, 138.15, 135.29, 134.10,
131.43, 129.52, 129.13, 126.77, 126.53, 125.54, 124.02, 123.40, 101.94,
61.15, 43.80, 40.22, 32.13, 14.01. LCMS-421.3, C22H20N4O3S, Mol. Wt.:
420.48, Calculated C, 62.84; H, 4.79; N, 13.32; O, 11.41; S, 7.63, Found
C, 62.75; H, 4.70; N, 13.24; S, 7.56.
Ethyl 2-(2-(2-(3-Phenylisoquinolin-1-yl)hydrazono)-5-methyl-4-
oxothiazolidin-3-yl)propanoate, 7b
1H NMR (DMSO): δ 9.11 (s, 1H), 8.15–8.13 (d, J = 7.88 Hz, 1H),
7.77–7.74 (m, 2H), 7.55–7.47 (m, 5H), 7.39–7.35 (m, 1H), 6.67–6.64 (d,
J = 10.8 Hz, 1H), 5.34–5.24 (m, 1H), 4.33–4.29 (m, 1H), 4.06–4.04
(m, 1H), 3.98–3.96 (m, 1H), 1.53–1.49 (m, 6H), 1.03–0.97 (m, 3H).
13C NMR (DMSO): δ 174.50, 174.42, 170.20, 170.12, 152.35, 152.32,
149.84, 138.44, 138.25, 135.67, 134.20, 134.08, 131.90, 131.88, 130.00,
129.96, 129.55, 127.22, 126.99, 125.90, 125.76, 124.39, 123.74, 123.70,
102.37, 102.27, 61.40, 61.3, 51.35, 51.29, 41.71, 19.91, 19.82, 14.29,
14.23. LCMS-449.2, C24H24N4O3S, Mol. Wt.: 448.54, Calculated C,
64.27; H, 5.39; N, 12.49; O, 10.70; S, 7.15, Found C, 64.19; H, 5.32; N,
12.39; S, 7.05.

New Hydrazinothiazoles and Thiazolidinones
2921
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