Synthesis of imidazo[2,1-b]thiazoles through the reaction of thiohydantoins and α-bromoketones

Article abstract of DOI:10.1080/17415993.2013.789516

Imidazo-fused heterocycles are used as anticancer agents. In this study, some novel imidazo[2,1-b]thiazoles were synthesized from thiohydantoins and α-bromoketones in good yields. This method has the advantages of simple operation, high yields, and mild r

Full text of DOI:10.1080/17415993.2013.789516

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Synthesis of imidazo[2,1-b]thiazoles
through the reaction of thiohydantoins
and α-bromoketones
Mohammad M. Ghanbari a , Issa Yavari b & Abedin Emadi c
a Chemistry Department, Sarvestan Branch, Islamic Azad
University, Sarvestan, Iran
b Chemistry Department, Science and Research Branch, Islamic
Azad University, Tehran, Iran
c Chemistry Department, Marvdasht Payam Noor University,
Marvdasht, Iran
Published online: 19 Apr 2013.
To cite this article: Mohammad M. Ghanbari , Issa Yavari & Abedin Emadi , Journal of Sulfur
Chemistry (2013): Synthesis of imidazo[2,1-b]thiazoles through the reaction of thiohydantoins and
α-bromoketones, Journal of Sulfur Chemistry, DOI: 10.1080/17415993.2013.789516
To link to this article: http://dx.doi.org/10.1080/17415993.2013.789516
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Journal of Sulfur Chemistry, 2013
http://dx.doi.org/10.1080/17415993.2013.789516
Synthesis of imidazo[2,1-b]thiazoles through the reaction of
thiohydantoins and α-bromoketones
Mohammad M. Ghanbaria*, Issa Yavarib and Abedin Emadic
aChemistry Department, Sarvestan Branch, Islamic Azad University, Sarvestan, Iran;
bChemistry Department, Science and Research Branch, Islamic Azad University, Tehran, Iran;
cChemistry Department, Marvdasht Payam Noor University, Marvdasht, Iran
(Received 13 February 2013; final version received 21 March 2013)
Imidazo-fused heterocycles are used as anticancer agents. In this study, some novel imidazo[2,1-b]thiazoles
were synthesized from thiohydantoins and α-bromoketones in good yields. This method has the advan-
tages of simple operation, high yields, and mild reaction conditions and uses less toxic and low-cost
chemical reagents.
S
S
HN
O
Et2O
Ar
Ar
N
NH
Ar
Ar
+
OH
Br
N
r.t.; 12 h
Z
Z
O
O
74–97%
Z=CO2Et,4-MeO-C6H5,4-Br-C6H5
Ar=Ph,4-Me-C6H5,4-Cl-C6H5,4-Br-C6H5,4-MeO-C6H5
Keywords: imidazo[2,1-b]thiazole; thiohydantoin; α-bromoketones; anticancer; thioxoimidazolidin
1. Introduction
The search for anticancer drugs led to the discovery of several imidazo-fused heterocycles having
anticancer activity (1–5). Imidazo[2,1-b][1,3,4]thiadiazole, imidazo[2,1-b][1,3]-thiazoles, and
diazepinone-fused derivatives occupy a prominent place in medicinal chemistry because of their
significant properties as therapeutics (6). As part of our current studies on the development
of new routes in heterocyclic synthesis (7–9), we now report an efficient one-pot synthesis of
imidazo[2,1-b]thiazoles 4 (Scheme 1).
*Corresponding author. Email: m.mehdi.ghanbari@gmail.com
© 2013 Taylor & Francis

2
M.M. Ghanbari et al.
S
S
HN
Ar
O
Et2O
N
NH
Ar
Ar
+
OH
Br
N
r.t.; 12 h
Ar
O
Z
Z
O
3
Ar
Z
1
Ar
2
Z
a
b
c
d
e
f
C6H5
CO2Et
CO2Et
a
b
c
C6H5
4-Me-C6H5
4-Cl-C6H5
a
b
c
CO2Et
4-MeO-C6H5
4-Br-C6H5
4-Me-C6H5
4-Cl-C6H5
C6H5
CO2Et
4-MeO-C6H5
4-Br-C6H5
4-MeO-C6H5
4-Br-C6H5
C6H5
4-Me-C6H5
4-Me-C6H5
g
Scheme 1. The one-pot synthesis of imidazo[2,1-b]thiazole 3.
2. Results and discussion
The reaction shown in Scheme 1 proceeded spontaneously in diethyl ether and was completed after
a few hours. The 1H and 13C NMR spectra of the crude products clearly indicated the formation
of 3. The structures of compounds 3a–3g were deduced from their elemental analyses and their
IR, 1H NMR, and 13CNMR spectra. The mass spectra of these compounds displayed molecular
and fragmentation ion peaks at appropriate m/z values.
The 1H NMR spectrum of 3a exhibited five sharp singlets readily recognized as arising from a
methyl group (δ = 1.25 ppm), a methylene group (δ = 3.65 and 4.15 ppm), and CH2O (δ = 4.25–
4.49 ppm) protons, along with a multiplet for the aromatic (δ = 7.24–7.52 ppm) protons. The 1H
and 13C NMR spectra of 3b–3g are similar to those of 3a except for the alkoxy and aromatic
moieties, which exhibited characteristic signals with appropriate chemical shifts. The structural
assignments of compounds 3a–3g made on the basis of their NMR spectra were supported by their
IR spectra. Of special interest are the alcohol absorption bands, observed in all of the compounds 3,
at approximately 3440 cm−1
.
A plausible mechanism for the formation of imidazo[2,1-b]thiazoles 3a–3g is shown in
Scheme 2. The reaction proceeds by addition of the thiohydantoins to the α-bromoketones
to produce intermediate 4. Finally, the negatively charged ion collapses by attack at the car-
bonyl group to produce 3 (Scheme 2). The absence of a strong ketone carbonyl signal at
about 190 ppm in all the compounds and the presence of a peak at about 90 ppm indicative
of a C–OH carbon in 13C-NMR indicate conversion of the intermediate 4 to the imidazo[2,1-b]
thiazole 3.
O
S
NH
Z
O
S
HN
N
O
Ar
Ar
Ar
Ar
3
+
Br
Z
NH
O
4
Scheme 2. Proposed mechanism for the formation of imidazo[2,1-b]thiazole 3.

Journal of Sulfur Chemistry
3
3. Conclusions
The reaction between thiohydantoins and α-bromoketones provides a simple one-pot synthesis of
imidazo[2,1-b]thiazoles of potential synthetic and pharmaceutical interest. The present procedure
has the advantage that the reaction is performed under neutral conditions, and the starting material
can be used without any activation or modification.
4. Experimental
4.1. General
Melting points were measured on an Electrothermal 9100 apparatus. Elemental analyses for C,
H, and N were performed using a Heraeus CHNO-Rapid analyzer. IR spectra were measured on a
Shimadzu IR-460 spectrometer. 1H and 13C NMR spectra were measured with a Bruker DRX-300
Avance instrument with CDCl3 as the solvent at 300.1 and 75.1 MHz, respectively. Mass spectra
were recorded on a Finnigan-Matt 8430 mass spectrometer operating at an ionization potential of
70 eV. Isocyanides and dialkyl acetylenedicaboxylates were obtained from Fluka and were used
without further purification. 5,5-Diaryl-2-thioxoimidazolidin-4-ones 1 were prepared by known
methods (10, 11).
4.2. Typical procedure for the preparation of ethyl-2,3,5,6-tetrahydro-2-hydroxy-5-oxo-6,
6-diphenylimidazo[2,1-b]thiazole-2-carboxylate (3a)
A solution of 0.390 g 2a (2 mmol) in 3 ml of ether was added dropwise to a stirred solution of
0.537 g of 1a (2 mmol) in 3 ml of ether at room temperature over a period of 10 min. The reaction
mixture was left to stand for 12 h and the resulting product was filtered off and washed with cold
diethyl ether.
4.2.1. Ethyl-2,3,5,6-tetrahydro-3-hydroxy-5-oxo-6,6-diphenylimidazo[2,1-b]thiazole-3-
carboxylate (3a)
White powder; mp: 202–203◦C; yield: 0.73 g (95%); IR (KBr) (νmax/cm−1): 3442 (OH), 1750
(C9O), 1448 (C9C); 1H NMR (300 MHz, CDCl3): δ = 1.25 (3 H, t, 3JHH = 7.1, Me), 3.65 (1 H, d,
2JHH = 11.7, CH), 4.15 (1 H, d, 2JHH = 11.7, CH), 4.25–4.49 (2 H, m, ABX3system, JAX = 7.1,
JBX = 7.1, JAB = 10.6 Hz, CH2O), 4.99 (1 H, br s, OH), 7.24–7.52 (10 H, m, 2 C6H5) ppm;
13C NMR (75 MHz, CDCl3): δ = 14.3 (Me), 45.7 (CH2), 64.7 (CH2), 83.2 (C), 87.4 (C), 127.2
(2 CH), 127.4 (2 CH), 127.5 (2 CH), 128.4 (2 CH), 128.9 (CH), 129.2 (CH), 139.6 (C), 140.2 (C),
166.9 (C9O), 168.2 (C9O), 176.0 [NC(S)N] ppm. Anal. Calcd (%) for C20H18N2O4S (382.43):
C, 62.81; H, 4.74; N, 7.33; S, 8.38. Found: C, 62.60; H, 4.82; N, 7.16; S, 8.57; EI-MS: m/z(%),
382 (M+, 15), 364 (78), 337 (75), 266 (20), 166 (100), 77 (26), 59 (14), 45 (84).
4.2.2. Ethyl-2,3,5,6-tetrahydro-3-hydroxy-5-oxo-6,6-dip-tolylimidazo[2,1-b]thiazole-3-
carboxylate (3b)
White powder; mp: 148–150◦C; yield: 0.70 g (85%); IR (KBr) (νmax/cm−1): 3440 (OH), 1750
(C9O), 1447 (C9C); 1H NMR (300 MHz, CDCl3): δ = 1.22 (3 H, t, 3JHH = 7.1, Me), 2.29 (3 H,
S, Me), 2.36 (3 H, S, Me), 3.64 (1 H, d, 2JHH = 11.7, CH), 4.14 (1 H, d, 2JHH = 11.7, CH), 4.25–
4.38 (2 H, m,ABX3 system, JAX = 7.1, JBX = 7.1, JAB = 10.6 Hz, CH2O), 4.98 (1 H, br s, OH),

4
M.M. Ghanbari et al.
7.12–7.35 (8 H, m, 2 C6H4) ppm; 13C NMR (75 MHz, CDCl3): δ = 14.3 (Me), 21.5 (Me), 21.6
(Me), 50.3 (CH2), 65.2 (CH2), 82.6 (C), 87.1 (C), 126.9 (2 CH), 127.0 (2 CH), 127.7 (2 CH), 130.4
(2 CH), 130.5 (C), 132.4 (C), 140.3 (C), 140.4 (C), 165.8 (C9O), 167.6 (C9O), 176.8 [NC(S)N]
ppm. Anal. Calcd (%) for C22H22N2O4S (410.49): C, 64.37; H, 5.40; N, 6.82; S, 7.81. Found: C,
64.50; H, 5.52; N, 6.70; S, 8.01.
4.2.3. Ethyl-6,6-bis(4-chlorophenyl)-2,3,5,6-tetrahydro-3-hydroxy-5-oxoimidazo[2,1-b]
thiazole-3-carboxylate (3c, C20H16Cl2N2O4S)
White powder; mp: 208–210◦C; yield: 0.68 g (75%); IR (KBr) (νmax/cm−1): 3440 (OH), 1751
(C9O), 1448 (C9C); 1H NMR (300 MHz, CDCl3): δ = 1.29 (3 H, t, 3JHH = 7.1, Me), 3.69 (1 H, d,
2JHH = 11.7, CH), 4.17 (1 H, d, 2JHH = 11.7, CH), 4.26–4.52 (2 H, m, ABX3 system, JAX = 7.1,
JBX = 7.1, JAB = 10.5 Hz, CH2O), 4.97 (1 H, br s, OH), 7.24–7.45 (8 H, m, 2 C6H4) ppm; 13
C
NMR (75 MHz, CDCl3): δ = 14.5 (Me), 50.6 (CH2), 65.4 (CH2), 82.5 (C), 87.1 (C), 129.3 (2CH),
129.5 (2CH), 129.8 (2CH), 129.9 (2CH), 131.5 (C), 131.6 (C), 138.4 (C), 138.5 (C), 165.8 (C9O),
167.8 (C9O), 176.9 [NC(S)N] ppm.
4.2.4. 2,3-Dihydro-3-hydroxy-3-(4-methoxyphenyl)-6,6-diphenylimidazo
[2,1-b]thiazol-5(6H)-one (3d, C24H20N2O3S)
White powder; mp: 232–234◦C; yield: 0.89 g (97%); IR (KBr) (νmax/cm−1): 3442 (OH), 1750
(C9O), 1448 (C9C); 1H NMR (300 MHz, CDCl3): δ = 3.92 (3 H, S, MeO), 3.96 (1 H, br s, OH),
4.72 (1 H, d, 2JHH = 14.5, CH), 4.39 (1 H, d, JHH = 14.5, CH), 7.04–8.31 (14 H, m, 2 C6H5,
2
C6H4) ppm; 13C NMR (75 MHz, CDCl3): δ = 47.7 (CH2), 54.7 (Me), 64.7 (CH2), 83.0 (C), 87.4
(C), 114.4 (C), 127.4 (2 CH), 127.5 (2 CH), 127.8 (CH), 127.9 (CH), 128.8 (2 CH), 128.9 (2 CH),
129.0 (2 CH), 129.1 (2 CH), 131.5 (C), 139.1 (C), 139.2 (C), 166.9 (C9O), 176.1 [NC(S)N] ppm.
Anal. Calcd (%) for C24H20N2O3S (416.49): C, 69.21; H, 4.84; N, 6.73; S, 7.70. Found: C, 69.30;
H, 4.72; N, 6.58; S, 7.81.
4.2.5. 3-(4-Bromophenyl)-2,3-dihydro-3-hydroxy-6,6-diphenylimidazo[2,1-b]thiazol-5(6H)-
one (3e, C23H17BrN2O2S)
White powder; mp: 225–227◦C; yield: 0.70 g (75%); IR (KBr) (νmax/cm−1): 3441 (OH), 1750
(C9O), 1452 (C9C); 1H NMR (300 MHz, CDCl3): δ = 4.37 (1 H, d, 2JHH = 14.8, CH), 4.75 (1 H,
d, 2JHH = 14.8, CH), 4.99 (1 H, br s, OH), 7.24–8.10 (14 H, m, 2 C6H5, C6H4) ppm; 13C NMR
(75 MHz, CDCl3): δ = 52.2 (CH2), 83.2 (C), 87.4 (C), 127.3 (2 CH), 127.5 (2 CH), 127.8 (CH),
127.9 (CH), 128.3 (C), 128.8 (2 CH), 128.9 (2 CH), 130.7 (2 CH), 132.3 (2 CH), 131.5 (C), 141.0
(C), 141.1 (C), 166.9 (C9O), 176.2 [NC(S)N] ppm.
4.2.6. 4-Methoxyphenyl 2,3,5,6-tetrahydro-3-hydroxy-5-oxo-6,6-dip-tolylimidazo
[2,1-b]thiazole-3-carboxylate (3f, C26H24N2O3S)
White powder; mp: 194–196◦C; yield: 0.66 g (74%); IR (KBr) (νmax/cm−1): 3442 (OH), 1750
(C9O), 1450 (C9C); 1H NMR (300 MHz, CDCl3): δ = 2.29 (3 H, S, Me), 2.36 (3 H, S, Me), 3.92
(3 H, S, MeO), 3.96 (1 H, br s, OH), 4.72 (1 H, d, 2JHH = 14.5, CH), 4.39 (1 H, d, 2JHH = 14.5,
CH), 7.00–8.31 (14 H, m, 3 C6H4) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (Me), 21.6 (Me),
54.8 (Me), 47.7 (CH2), 83.2 (C), 87.4 (C), 114.4 (C), 126.9 (2 CH), 127.0 (2 CH), 127.7 (2 CH),
128.7 (2 CH), 128.9 (2 CH), 130.4 (2 CH), 130.5 (C), 131.5 (C), 132.4 (C), 140.3 (C), 140.4 (C),
166.9 (C9O), 176.0 [NC(S)N] ppm.

Journal of Sulfur Chemistry
5
4.2.7. 4-Bromophenyl 2,3,5,6-tetrahydro-3-hydroxy-5-oxo-6,6-dip-tolylimidazo
[2,1-b]thiazole-3-carboxylate (3g, C25H21BrN2O2S)
White powder; mp: 180–182◦C; yield: 0.76 g (77%); IR (KBr) (νmax/cm−1): 3441 (OH), 1750
1
(C9O), 1452 (C9C); H NMR (300 MHz, CDCl3): δ = 2.29 (3 H, S, Me), 2.36 (3 H, S, Me),
4.37 (1 H, d, 2JHH = 14.8, CH), 4.75 (1 H, d, 2JHH = 14.8, CH), 4.99 (1 H, br s, OH), 7.12–8.10
(14 H, m, 2 C6H4) ppm; 13C NMR (75 MHz, CDCl3): δ = 21.5 (Me), 21.6 (Me), 52.2 (CH2),
83.0 (C), 87.4 (C), 126.9 (2 CH), 127.0 (2 CH), 127.7 (2 CH), 128.3 (C), 128.5 (2 CH), 128.7
(2 CH), 130.5 (2 CH), 131.5 (C), 131.7 (C), 132.3 (C), 141.0 (C), 141.1 (C), 166.7 (C9O), 176.0
[NC(S)N] ppm.
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