A convenient method for the synthesis of 2-[(5-benzyl-1,3-thiazol-2-yl) imino]-1,3-thiazolidin-4-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.11.093

It was found that the reaction of 2-chloroacetamido/chloropropioamido-5- benzylthiazole with potassium thiocyanate gave, via rearrangement, 2-[(5-benzyl-1,3-thiazol-2-yl)imino]-1,3-thiazolidin-4-ones.

Full text of DOI:10.1016/j.tetlet.2011.11.093

Tetrahedron Letters 53 (2012) 543–545
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convenient method for the synthesis of
2-[(5-benzyl-1,3-thiazol-2-yl)imino]-1,3-thiazolidin-4-one derivatives
Yuri V. Ostapiuk a, Mykola D. Obushak a, , Vasyl S. Matiychuk a, Marek Naskrent b, Andrzej K. Gzella c,d
⇑
a Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya St. 6, Lviv 79005, Ukraine
b Faculty of Physics, Adam Mickiewicz University, ul. Umultowska 85, 61-614 Poznan´, Poland
c Department of Organic Chemistry, Poznan University of Medical Sciences, ul. Grunwaldzka 6, 60-780 Poznan´, Poland
d Faculty of Pharmacy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, ul. M. Curie Skłodowskiej 9, 85-094 Bydgoszcz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
It was found that the reaction of 2-chloroacetamido/chloropropioamido-5-benzylthiazole with potas-
sium thiocyanate gave, via rearrangement, 2-[(5-benzyl-1,3-thiazol-2-yl)imino]-1,3-thiazolidin-4-ones.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 25 September 2011
Revised 31 October 2011
Accepted 18 November 2011
Available online 27 November 2011
Keywords:
Thiazole derivatives
Thiazolidin-4-ones
Thiocyanates
Chloroacetamides
Meerwein reaction
4-Thiazolidinones are a class of important heterocycles that
have attracted considerable attention because of their biological
Clarification of this problem is very important especially for
drug development. If the structures of compounds are not identi-
fied correctly, lead optimisation techniques such as SAR, QSAR,
docking, etc can lead to false results.
properties. They are represented in
a well-known group of
patented drugs and substances which possess hypoglycaemic,
anti-inflammatory, choleretic, antitumor, diuretic and immuno-
stimulant amongst other activities.1,2
General synthetic strategies for the preparation of this heterocy-
cle include cyclisation reactions of thioureas or thiosemicarbazide
Our interest in the synthesis of heterocyclic compounds of bio-
logical importance encouraged us to study the synthesis of new 2-
iminothiazolidin-4-ones from 2-amino-5-benzylthiazoles 6. It
should be noted that thiazole derivatives bearing a substituted
acylamino chain at C-2 and an arylmethyl moiety at C-5 have been
the subject of research in recent years. They are reported as inhib-
itors of stearoyl-CoA desaturase-17 and demonstrate antiprolifera-
tive activity on the DU-145 human prostate carcinoma cell line.8
Some new potentially active compounds were identified by
application of a computer-aided drug design protocol based on a
pharmacophoric model and docking simulations of the interactions
between the ligands and the target protein.9
The starting 2-amino-5-benzylthiazoles 6a–c were prepared
by reaction of 3-aryl-2-chloropropanals 5a–c with thiourea10
(Table 1). Aldehydes 5 were synthesized from arenediazonium
salts 4a–c and acrolein under Meerwein reaction conditions.
Aminothiazoles 6 reacted with chloroacetyl chlorides 7a,b to form
chloroacetamides 8a–f.11
derivatives, and cyclocondensation reactions of imines with
capto acids.2,3 In addition, recyclisation strategies have been repor-
ted.3a A method based on cyclisation of
-thiocyanatoamides has
a-mer-
a
also been described.3a,4 However, in this case, the structures of the
products of the reaction were not discussed in detail. In particular,
2-[(thiazol-2-yl)imino]thiazolidin-4-ones and 2-imino-3-(thiazol-
2-yl)thiazolidin-4-ones have been studied in recent years for the
treatment of tumours and microbial diseases.5,6 They have been
prepared from chloroacetyl derivatives of 2-aminothiazoles 1 and
the synthetic procedures were almost identical. Accordingly,6
2-imino-3-(thiazol-2-yl)thiazolidin-4-ones derivatives
2
are
formed via the procedure shown in Scheme 1. The syntheses of
a
-thiocyanatoamides by way of a similar cyclisation were described
earlier.4 On the other hand, Geronikaki5 reported the synthesis of
compounds of type 3 using similar chemistry.
We next examined the reactions of compounds 8a–f with
potassium thiocyanate in acetonitrile, methanol, ethanol, acetone,
DMF and DMSO. It was established that in all cases the reaction
did not stop at the nucleophilic substitution stage. The
atoamides 9 underwent spontaneous cyclization/rearrangement to
a-thiocyan-
⇑
Corresponding author. Tel.: +380 322728062; fax: +380 322616048.
E-mail address: obushak@in.lviv.ua (M.D. Obushak).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.093

544
Y. V. Ostapiuk et al. / Tetrahedron Letters 53 (2012) 543–545
H
N
N
Cl
R
S
O
1
R'
R
_
SCN
R'
N
R
S
H
O
S
O
N
N
N
N
R'
SCN
HN
R
S
O
HN
N
3
S
S
R'
2
Scheme 1. Cyclisation of
a-thiocyanatoamides.
Table 1
Preparation of N-(5-benzyl-1,3-thiazol-2-yl)-2-chloroacetamides 8a–f
S
O
H2N NH2
Cl
5a-c
R1
R1
N2+Cl_
CuCl2, acetone, r.t.
O
EtOH, reflux, 1 h
4a-c
O
R2
Cl
7a, b
R1
R1
O
R2
Cl
N
N
NH2
N
S
S
Cl
H
6a-c
8a-f
Compound
R1
R2
Yield (%)
Mp (°C)
8a
8b
8c
8d
8e
8f
H
H
H
H
Me
Me
Me
80
82
85
70
65
73
171
131
159
141
145
158
3-Me
4-Cl
H
3-Me
4-Cl
give thiazolidin-4-one derivatives 11a–f (Scheme 2, Table 2).12
Compounds 10 were not found.
Table 2
2-[(5-Benzyl-1,3-thiazol-2-yl)imino]-1,3-thiazolidin-4-ones 11
The structure of compound 11f was established by X-ray crys-
Compound
R1
R2
Yield (%)
Mp (°C)
tallography (Fig. 1).13
11a
11b
11c
11d
11e
11f
H
H
H
H
Me
Me
Me
74
71
75
78
63
70
206
177
200
154
138
176
The X-ray analysis of 11f showed that a hydrogen atom was
attached to N3 which is in agreement with the structure containing
a secondary amide in the thiazolidin-4-one ring and an exocyclic
imine nitrogen. This finding is consistent with the crystallographic
structure of compound 1 obtained both at 130 K and at room
temperature. The appropriateness of this observation is supported
3-Me
4-Cl
H
3-Me
4-Cl
R1
O
R2
N
+
KSCN
N
S
H
Cl
8a-f
R1
O
R2
N
N
S
H
SCN
9a-f
O
S
R1
O
R2
R1
N
HN
R2
N
N
S
N
S
S
10
11a-f
HN
Scheme 2. Reactions of N-(5-benzyl-1,3-thiazol-2-yl)-2-chloroacetamides with potassium thiocyanate.

Y. V. Ostapiuk et al. / Tetrahedron Letters 53 (2012) 543–545
545
Figure 1. X-ray crystal structure (ORTEP plot) of 11f.
7. (a) Uto, Y.; Ogata, T.; Harada, J.; Kiyotsuka, Y.; Ueno, Y.; Miyazawa, Y.; Kurata,
H.; Deguchi, T.; Watanabe, N.; Takagi, T.; Wakimoto, S.; Okuyama, R.; Abe, M.;
Kurikawa, N.; Kawamura, S.; Yamato, M.; Osumi, J. Bioorg. Med. Chem. Lett.
2009, 19, 4151–4158; (b) Uto, Y.; Ogata, T.; Kiyotsuka, Y.; Miyazawa, Y.; Ueno,
Y.; Kurata, H.; Deguchi, T.; Yamada, M.; Watanabe, N.; Takagi, T.; Wakimoto, S.;
Okuyama, R.; Konishi, M.; Kurikawa, N.; Kono, K.; Osumi, J. Bioorg. Med. Chem.
Lett. 2009, 19, 4159–4166.
8. Krasavin, M.; Karapetian, R.; Konstantinov, I.; Gezentsvey, Y.; Bukhryakov, K.;
Godovykh, E.; Soldatkina, O.; Lavrovsky, Y.; Sosnov, A. V.; Gakh, A. A. Arch.
Pharm. Chem. Life Sci. 2009, 342, 420–427.
9. Manetti, F.; Falchi, F.; Crespan, E.; Schenone, S.; Maga, G.; Botta, M. Bioorg. Med.
Chem. Lett. 2008, 18, 4328–4331.
10. (a) Obushak, N. D.; Matiichuk, V. S.; Vasylyshin, R. Ya.; Ostapyuk, Yu. V. Russ. J.
Org. Chem. 2004, 40, 383–389 (English translation from Zh. Org. Khim. 2004, 40,
412–417).
by the values of the interatomic distances N3–C4 and C2–N3
[1.379(4) and 1.380(4) Å] as well as C2@N6 [1.292(4) Å] which
are close to the mean values for the single bonds (O@)C–NH
[1.357(2) Å] and NH–C(@N) [1.377(10) Å] as well as the double
bond C@N [1.280(2) Å], respectively, acquired from two structures
containing a 2-imino-1,3-thiazolidin-4-one moiety.14,15
The 1H NMR spectra correlate with the crystallographically ob-
served geometry. The spectra of the compounds 11a–f showed a
signal for the CH2 protons at 3.96–4.20 ppm and a signal for the
NH proton at 11.81–12.15 ppm. It should be noted that the reso-
nance for the proton of the imino group at position 2 of the thiazo-
lidinone ring for compounds 10 would be expected to occur at
ꢀ9 ppm.16
11. Typical procedure for the synthesis of N-(5-benzyl-1,3-thiazol-2-yl)-2-
chloroacetamides 8a–f. Chloroacetyl chloride
7 (0.05 mol) was added
dropwise to a stirred solution of 2-amino-5-(arylmethyl)thiazole 6 (0.05 mol)
and Et3N (7 mL, 0.05 mol) in dry 1,4-dioxane (100 mL) at rt. The resulting
solution was stirred for 1 h and then diluted with H2O. The solid product was
filtered, washed with H2O and dried. Recrystallization from EtOH gave 2-
chloroacetamido-5-(arylmethyl)thiazole 8 as a pale-yellow solid.
In summary, we have synthesized 2-[(5-benzyl-1,3-thiazol-2-
yl)imino]-1,3-thiazolidin-4-ones by spontaneous cyclization/rear-
rangement of the intermediate a-thiocyanatoamides.
12. Typical procedure for the synthesis of compounds 11a–f.
A mixture of 2-
chloroacetamido-5-(arylmethyl)thiazole 8a–f (0.03 mol), KSCN (6.0 g,
0.06 mol) and dry acetone (100 mL) was stirred at room temperature for
20 h and then diluted with H2O. The solid product was filtered, washed with
H2O and dried. Recrystallization from EtOH gave thiazolidinone 11 as a yellow
solid. 2-[5-(4-Chlorophenyl)methyl-1,3-thiazol-2-ylimino]-5-methyl-thiazolidin-
4-one (11f): Yield 70%, mp 176 °C (EtOH); 1H NMR (600 MHz, DMSO-d6):
1.51 (d, 3H, J = 7.2, CH3), 4.10 (s, 2H, CH2), 4.27 (q, 1H, J = 7.2, CH), 7.29 (d, 2H,
J = 8.4, 2,6-C6H4), 7.38 (d, 2H, J = 8.4, 3,5-C6H4), 7.39 (s, 1H, 4-H thiazole), 12.00
(br s, 1H, NH); 13C NMR (150 MHz, DMSO-d6): 18.0 (CH3), 31.7 (CH), 43.8 (CH2),
128.5, 130.2, 131.2, 134.4, 137.3, 139.0, 160.3, 168.5, 177.0; Anal. Calcd for
Acknowledgment
The authors are grateful to the State fund for fundamental
research of Ukraine for the financial support (Project F41.3/008).
References and notes
1. (a) Siddiqui, N.; Arshad, M. F.; Ahsan, W.; Alam, M. S. Int. J. Pharm. Sci. Drug Res.
2009, 1, 136–143; (b) Vinícius, M.; de Souza, N. J. Sulfur Chem. 2005, 26,
429–449.
2. Lesyk, R. B.; Zimenkovsky, B. S. Curr. Org. Chem. 2004, 8, 1547–1577.
3. (a) Singh, S. P.; Parmar, S. S.; Raman, K.; Stenberg, V. I. Chem. Rev. 1981, 81, 175–
203; (b) Metwally, M. A.; Farahat, A. A.; Abdel-Wahab, B. F. J. Sulfur Chem. 2010,
31, 315–349.
4. Newcome, G. R.; Nayak, A. Adv. Heterocycl. Chem. 1979, 25, 93.
5. (a) Vicini, P.; Geronikaki, A.; Anastasia, K.; Incerti, M.; Zani, F. Bioorg. Med. Chem.
2006, 14, 3859–3864; (b) Geronikaki, A.; Eleftheriou, P.; Vicini, P.; Alam, I.;
Dixit, A.; Saxena, A. K. J. Med. Chem. 2008, 51, 5221–5228; (c) c) Vicini, P.;
Geronikaki, A.; Incerti, M.; Zani, F.; Dearden, J.; Hewitt, M. Bioorg. Med. Chem
2008, 16, 3714–3724.
6. (a) Zheng, W.; Degterev, A.; Hsu, E.; Yuan, J.; Yuan, Ch. Bioorg. Med. Chem. Lett.
2008, 18, 4932–4935; (b) Liu, H.-L.; Li, Z.; Anthonsen, T. Molecules 2000, 5,
1055–1061.
C14H12ClN3OS2: C, 49.77; H, 3.58; N, 12.44. Found: C, 49.87; H, 3.52; N, 12.50.
13. Crystallographic data for 11f: Empirical formula: 14H12ClN3OS2, formula
C
weight: 337.84, colorless lath crystals, crystal system: monoclinic, space
group: C2/c, a = 32.0442(18), b = 5.4312(2), c = 18.6559(11) Å, b = 115.152(7)°,
V = 2939.0(3) Å3, Z = 8, Dcalc = 1.527 g/cm3.
A
colorless crystal (EtOH)
-radiation,
(0.25 Â 0.21 Â 0.02 mm) was used to record 26307 (CuK
a
hmax = 75.6°) intensities on a SuperNova diffractometer. The supplementary
crystallographic data have been deposited at the Cambridge Crystallographic
Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ (UK), Tel.: (+44) 1223/
336 408, Fax: (+44) 1223/336 033, e-mail: deposit@ccdc.cam.ac.uk, http://
www.ccdc.cam.ac.uk (deposition No. CCDC 791941).
14. Entenmann, G.; Eckle, E.; Stezowski, J. J. Phosphorus Sulfur 1978, 4, 303.
15. Ramachandran, R.; Rani, M.; Kabilan, S. Acta Cryst. 2009, E65, o584.
16. Obushak, N. D.; Matiichuk, V. S.; Ganushchak, N. I. Russ. J. Org. Chem. 1998, 34,
239–244 (English translation from Zh. Org. Khim. 1998, 34, 266–271).