Microwave-assisted Hantzsch thiazole synthesis of N-phenyl-4-(6- phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines from the reaction of 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones and thioureas

Article abstract of DOI:10.1016/j.tetlet.2012.06.116

N-Phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines (6a-q) have been synthesized by the Hantzsch thiazole reaction of 2-chloro-1-(6- phenylimidazo[2,1-b]thiazol-5-yl)ethanones (4a-e) with suitably substituted thioureas using microwave heating.

Full text of DOI:10.1016/j.tetlet.2012.06.116

Tetrahedron Letters 53 (2012) 4921–4924
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted Hantzsch thiazole synthesis of
N-phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines from the
reaction of 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones and
thioureas
⇑
Sukanta Kamila, Kimberly Mendoza, Edward R. Biehl
Department of Chemistry, Southern Methodist University, Dallas, TX 75275, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines (6a–q) have been synthesized by the
Hantzsch thiazole reaction of 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones (4a–e) with
suitably substituted thioureas using microwave heating. The ethanones (4a–e) were prepared by the
reaction of 6-phenylimidazo[2,1-b]thiazoles (3a–e) with chloroacetylchloride in refluxing 1,4-dioxane
whereas the thiazoles (3a–e) were synthesized by the reaction of 2-bromo-1-phenylethanones (2a–e)
with thiazol-2-amine in refluxing acetone.
Received 8 June 2012
Revised 24 June 2012
Accepted 26 June 2012
Available online 4 July 2012
Keywords:
Microwave irradiation
Ó 2012 Elsevier Ltd. All rights reserved.
(6-Phenylimidazo[2,1-b]thiazol-5-
yl)thiazol-2-amine 2-chloro-1-(6-
phenylimidazo[2,1-b]thiazol-5-
yl)ethanones
6-Phenylimidazo[2,1-b]thiazoles
Introduction
cells mediated by TARC.8 Subsequently another research group
identified hydrazone derivatives of imidazo[2,1-b]benzothiazoles
Many natural products and biologically active compounds con-
taining imidazo[2,1-b]thiazole moieties have been synthesized
and shown to exhibit potent biological activity.1 As shown in Figure
1, tetramisole (A) is a strong anthelmintic in the treatment of many
nematodes.2 Thieno[3,2-d]pyrimidinone (B)3 and 5,6-diarylimi-
dazo[2,1-b][1,3]thiazoles (C),4 are excellent antibacterial agents
and C-2 aryl-substituted pilicides [thiazole ring-fused 2-pyridones
(D)]5 exhibit anti-coccidial behavior. 11C-labeled imidazo[2,1-
b]benzothiazole (E)6 has been shown to be a superb fluoroprobe in
PET analysis of Alzheimer’s disease. Milne et al.7 have prepared com-
pound (F) which possesses an imidazo[2,1-b]benzothiazole ring.
Compound F, although unrelated in structure to resveratrol, showed
a 1000-fold greater affinity toward SIRT1 than resveratrol. These
workers also demonstrated that compound F binds to the SIRT1 en-
zyme–peptide substrate complex at an allosteric amino terminal
site to the catalytic domain resulting in lower Michaelis constant
for acetylated substrates. Compound G (Fig. 1) inhibits binding of
radio labeled TARC (Thymus and Activation Regulated Chemokine)
and MDC (Macrophase-derived Chemokine) to CCR4 receptors on
the surface of CEM8 and also inhibits the in vitro migration of CEM
as a potent antitumor agent.9 It has also been reported that imi-
dazo[2,1-b]benzothiazole system acts as a scaffold endowing dihy-
dropyridines with selective cardiodepressant activities.10
For the past few years, our group has, also, been preparing bio-
logically important heterocycles using microwave irradiation11a–g
Of particular importance to this report, is our preparation of novel
bis(2-thioxothiazolidin-4-one) derivatives,11a several of which
possess strong neuroprotecting activities against Alzheimer’s and
Parkinson’s diseases. We have now extended our research to the
microwave-assisted synthesis of potentially biologically active N-
phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2
amine
derivatives (6a–p) in which imidazo[2,1-b]thiazole core moieties
are attached to a variety of 2-aminothiazoles, and report the re-
sults herein. We were attracted to the Hantzsch synthesis since it
has been one of the methods of choice for preparing aminothiaz-
oles.12 Most of these syntheses involve extended conventional
heating and give aminothiazoles in mediocre yields. For example,
N-thiazoyl
a-amino acids were prepared in yields generally rang-
ing from 18% to 55% in a one-pot, two-step, 7–15 h Hantzsch reac-
tion.13 There are only
a few reports on microwave-assisted
Hantzsch reactions.14a–d Thus this study should add to the increas-
ing importance of microwave-assisted reactions in heterocyclic
chemistry.15
⇑
Corresponding author. Tel.: +1 214 768 1280; fax: +1 214 768 4089.
E-mail address: ebiehl@smu.edu (E.R. Biehl).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.116

4922
S. Kamila et al. / Tetrahedron Letters 53 (2012) 4921–4924
R1
O
N
O
N
N
N
S
Cl
N
R2
N
S
S
OCH3
R1
S
N
N
N
COR2
A
O
D
B
F
C
S
N
H
N
11
N
HO
N
CH3
H3CO
N
N
S
N
H
N
HN
S
O
E
G
F
Figure 1. Imidazo[2,1-b]thiazoles and 2-aminothiazoles.
O
R1
Br
N
O
1. Acetone-reflux
N
Cl
NH2
S
Cl
2. 2 (N) HCl- reflux
3. NH4OH
N
R1
S
1
2a-e
1 = H, CH3
OCH3
3a-e
R
1,4-Dioxane
Br, CN
104 ºC
3 h
R2
Cl
R3
R4
O
H
N
R1
R2
R3
NH2
MW irradiarion
HN
N
N
S
N
S
90 ºC, 30 min
Methanol
250 psi
S
R4
R1
4a-e
5a-d
R2 = H, Cl
3 = H, Cl, OCH3,
R4 = H, Cl
N
N
R
S
6a-p
Scheme 1. Schematic representation for the synthesis of compounds 6a–p.
Results and discussion
Table 1
Screening of solvents, reaction time, and temperature for synthesis of 6a
Scheme 1 outlines the synthesis of 6a–p. Optimum conditions
for carrying out the Hantzsch microwave-assisted reactions were
ascertained by carrying out a series of reactions of 2-chloro-1-(6-
phenylimidazo[2,1-b]thiazol-5-yl)ethanones (4a) with N-phenyl-
thiourea. The results, which are summarized in Table 1, showed
that maximum yield of 6a (95%) were obtained by heating at
90 °C for 30 min in methanol.
The results for the reactions of 6a–p are shown in Table 2. Com-
pounds 6a–p were obtained in 89–95% yields and most of them are
powder-like solids. They are insoluble in usual organic solvents
such as, dichloromethane, ethyl acetate, THF, ethanol, or methanol
but soluble in DMF or DMSO. The proposed structures of 6a–p were
confirmed, in part, by the presence of C@N signals around d
164 ppm (indicative of an 2-aminothiazole ring) in the 13C NMR
spectra. The 1H NMR spectra of these compounds showed a broad
singlet (equivalent to 1H) around d 11 ppm which corresponds to
NH functionality. The starting 2-chloro-1-(6-phenylimidazo[2,1-
b]thiazol-5-yl)ethanones (4a–e) were prepared by refluxing
2.5 equiv of chloroacetylchloride and 1 equiv of 6-phenylimi-
dazo[2,1-b]thiazoles (3a–e) in refluxing 1,4-dioxane. Although we
tried other solvents, 1,4-dioxane proved to be superior. The struc-
Condition
Temp (°C)
Time (min)
Yield (%)
No solvent
Ethanol
Ethanol
Methanol
Methanol
Acetonitrile
Water
THF
n-Butanol
DME
Sulfonale
Benzene/toluene
DMF
90–120
90–120
90–120
90
15
15
30
15
Trace
79
85
71
95
90
30
90–100
90–120
70–100
90–110
90–110
90–130
90–110
90–110
15–30
30–45
30–45
30–45
30–45
30–45
30–45
30–45
55
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Reaction condition: microwave irradiation using 4a:5a (1:1 equiv) and 1 mmol of
4a, solvent (2 mL) under 250 psi pressure in a capped specially designed microwave
test tube.
tures of 4a–e were confirmed by the presence of C@O signals
around d 180 ppm and the CH2 signal around d 47 ppm. The 1H
NMR spectra of 4a–e showed characteristic singlets (equivalent
to 2H) around d 4 ppm which corresponds to –CH2 functionality.

S. Kamila et al. / Tetrahedron Letters 53 (2012) 4921–4924
4923
Table 2
The synthesis of N-phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines (6a–p) by the microwave-assisted Hantzsch reaction of ethanone derivatives (4a–e) with
substituted thioureas (5a–d)
R2
R3
Cl
R4
O
HN
H
R1
R2
R3
N
NH2
S
N
MW irradiarion
N
S
N
S
o
R1
90 C, 30 min
R4
N
Methanol
250 psi
4a-e
5a-d
N
S
R2 = H, Cl
R3 = H, Cl, OCH3,
R4 = H, Cl
6a-p
Cl
O
H
N
R2
R3
R4
R2
R3
NH3
R1
S
N
HN
R4
N
S
S
N
5
Entry
Yielda,b
Yielda,c
4
R1
N
N
S
6
1
2
3
4
5
6
7
8
4a, R1 = H
5a, R2 = R3 = R4 = H
5a, R2 = R3 = R4 = H
5a, R2 = R3 = R4 = H
5a, R2 = R3 = R4 = H
5a, R2 = R3 = R4 = H
5b, R2 = R4 = H, R3 = Cl
5c, R2 = R4 = Cl, R3 = H
5d, R2 = R4 = H, R3 = OCH3
5d, R2 = R4 = H, R3 = OCH3
5c, R2 = R4 = Cl, R3 = H
5b, R2 = R4 = H, R3 = Cl
5c, R2 = R4 = Cl, R3 = H
5b, R2 = R4 = H, R3 = Cl
5d, R2 = R4 = H, R3 = OCH3
5c, R2 = R4 = Cl, R3 = H
5c, R2 = R4 = Cl, R3 = H
6a, R1 = R2 = R3 = R4 = H
98
96
92
90
95
93
99
90
89
98
93
96
89
91
98
96
65
45
69
60
78
74
88
53
47
67
81
80
55
58
67
70
4b, R1 = OCH3
4c, R1 = CH3
4d, R1 = CN
4e, R1 = Br
4a, R1 = H
6b, R1 = OCH3, R2 = R3 = R4 = H
6c, R1 = CH3, R2 = R3 = R4 = H
6d, R1 = CN, R2 = R3 = R4 = H
6e, R1 = Br, R2 = R3 = R4 = H
6f, R1 = H, R2 = R4 = H, R3 = Cl
6g, R1 = H, R2 = R4 = Cl, R3 = H
6h, R1 = H, R2 = R4 = H, R3 = OCH3
6i, R1 = CH3, R2 = R4 = H, R3 = OCH3
4a, R1 = H
4a, R1 = H
9
4c, R1 = CH3
4e, R1 = Br
4c, R1 = CH3
4c, R1 = CH3
4e, R1 = Br
4e, R1 = Br
4d, R1 = CN
4b, R1 = OCH3
10
11
12
13
14
15
16
6j, R1 = Br, R2 = R4 = Cl, R3 =
6k, R1 = CH3, R2 = R4 = H, R3 = Cl
6l, R1 = CH3, R2 = R4 = Cl, R3 = H
6m, R1 = Br, R2 = R4 = H, R3 Cl
6n, R1 = Br, R2 = R4 = H, R3 = OCH3
6o, R1 = CN, R2 = R4 = Cl, R3 = H
6p, R1 = OCH3, R2 = R4 = Cl, R3 = H
d 3.6 mmol:23.4 mmol/10 mL MeOH.
a
Isolated yield, all compounds were characterized by 1H NMR, 13C NMR, IR, and HRMS analysis.
MW, 30 min, 90 °C.1 mmol:06 mmol 4:5/2 mL MeOH.
Conventional heating for 8 h at 90 °C; 0.1 mmol:06 mmol 4:5/2 mL MeOH.
b
c
The starting 6-phenylimidazo[2,1-b]thiazoles (3a–e) were synthe-
b]thiazol-5-yl)thiazol-2-amine derivatives. Thus, the mild reaction
condition, easy work up procedure, good to excellent yields, and
readily available starting materials make this reaction an attractive
method for the preparation of title compounds. To the best of our
knowledge, there has been no reported example of synthesis of this
type of biologically important molecule. Efforts directed toward
the synthesis of other important drug molecules with imi-
dazo[2,1-b]thiazol-5-yl)thiazole moieties by microwave irradiation
are ongoing in our laboratory. Also work is in progress to obtain
biological activity (antibacterial, antifungal, anticancer, antitumor,
and neuroprotective kinase inhibitory activity) of these important
compounds. Results in these studies will be presented in due
course.
sized according to a literature16 procedure. All compounds were
characterized by 1H NMR, 13C NMR, DEPT-135, and HRMS analysis.
Interestingly, the same reactions carried out under conventional
reflux conditions using methanol as a solvent gave 6a–p in lower
yields (Table 2), required longer reaction time (8 h), and/or the
products required rigorous purification. However, the microwave
reactions provided 6a–p in higher yields in faster reaction times
(usually less than 30 min) and the pure products were obtained
by simple washing of the crude products with cold ethanol. Our
method compares favorably to that reported for the microwave-as-
sisted synthesis of functionalized simple 2-aminothiazoles14a with
respect to yield and reaction time. However a higher temperature
was needed in our procedure presumably due to the more complex
nature of the phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amine
products.
Acknowledgments
In conclusion, we have successfully developed an easy practical
access to a novel series of N-phenyl-4-(6-phenylimidazo[2,1-
The authors are grateful to NIH (IRC2NS064950) for generous
financial support.

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S. Kamila et al. / Tetrahedron Letters 53 (2012) 4921–4924
9. Andreani, A.; Burnelli, S.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.;
Supplementary data
Rambaldi, M.; Varoli, L.; Calonghi, N.; Cappadone, C.; Farruggia, G.; Zini, M.;
Stefanelli, C.; Masotti, L.; Radin, N. S.; Shoemaker, R. H. J. Med. Chem. 2008, 51,
809.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
06.116.
10. Budriesi, R.; Ioan, P.; Locatelli, A.; Cosconati, S.; Leoni, A.; Ugenti, M. P.;
Andreani, A.; Toro, R. D.; Bedini, A.; Spampinato, S.; Marinelli, L.; Novellino, E.;
Chiarini, A. J. Med. Chem. 2008, 51, 1592.
11. See, for example: (a) Kamila, S.; Biehl, E. R. Tetrahedron Lett. in press.; (b)
Kamila, S.; Ankati, H.; Harry, E.; Biehl, E. R. Tetrahedron Lett. 2012, 53, 2195; (c)
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