Microwave assisted synthesis of novel imidazo [2,1-b]thiazole derivative attached to quinoxalinones

Article abstract of DOI:10.1016/j.tetlet.2012.08.093

3-(6-Phenylimidazo[2,1-b]thiazol-5-yl)quinoxalin-2(1H)-ones (qunoxalinone) (6a-q) have been synthesized by the reaction of ethyl 2-oxo-2-(6- phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) with suitably substituted o-phenylenediamines (5a-f) under microw

Full text of DOI:10.1016/j.tetlet.2012.08.093

Tetrahedron Letters 53 (2012) 6008–6014
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted synthesis of novel imidazo [2,1-b]thiazole derivative
attached to quinoxalinones
⇑
Chandrani Mukherjee, Kenneth T. Watanabe, 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:
3-(6-Phenylimidazo[2,1-b]thiazol-5-yl)quinoxalin-2(1H)-ones (qunoxalinone) (6a–q) have been synthe-
sized by the reaction of ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a–e) with suitably
substituted o-phenylenediamines (5a–f) under microwave heating. The ethyl 2-oxo-2-(6-phenylimi-
dazo[2,1-b]thiazol-5-yl)acetates (4a–e) were prepared by the reaction of 6-phenylimidazo[2,1-b]thia-
zoles (3a–e) with ethyl chlorooxoacetate 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 August 2012
Revised 22 August 2012
Accepted 23 August 2012
Available online 31 August 2012
Keywords:
Microwave irradiation
3-(6-Phenylimidazo[2,1-b]thiazol-5-
yl)quinoxalin-2(1H)-ones
Ethyl 2-oxo-2-(6-phenylimidazo[2,1-
b]thiazol-5-yl)acetate
Ó 2012 Elsevier Ltd. All rights reserved.
o-Phenylenediamine
6-Phenylimidazo[2,1-b]thiazoles
Introduction
treatment of thrombotic diseases and is being investigated for
these uses. In addition, these quinoxalinone derivatives are
Cardiovascular disease has been the leading cause of death in
the United States, with coronary heart disease and stroke as the
predominant sources of mortality.1 Each year, 795,000 people
experience a new or recurrent stroke. Approximately 610,000 of
these are first attacks, and 185,000 are recurrent attacks. Mortality
data from 2008 indicate that stroke accounted for 1 of every 18
deaths in the United States. On average, every 40 s, someone in
the United States has a stroke. In 2012, myocardial infarction,
stroke, deep vein thrombosis, and pulmonary embolism accounted
for approximately two million deaths in United States alone.1,2
Inappropriate thrombus formation is a common cause of the above
clinical conditions, and therefore there has been a large effort de-
voted to the discovery of new antithrombotic therapies.3 The coag-
ulation cascade is composed of a complex series of plasma
proteins, serine proteases, and cellular receptors. Each of these
helps play a delicate balancing act, through positive and negative
controls, between thrombosis and homeostasis.
versatile scaffolds for drug related molecules.6 They possess a wide
variety of biological activities such as anti-inflammatory, antimi-
crobial,7 and antidiabetic activities.8 In addition they have been
shown to have antiviral activity against retroviruses including
HIV.9 Moreover, these quinoxalinones have been identified as
platforms for diversity-oriented synthesis in solid phase,10 and
they have been established as inhibitors of aldose reductase,11
and agonist of c-aminobuanoic acid (GABA)/benzodiazepine recep-
tor complex.12 On the other hand, imidazo[2,1-b]thiazole moieties
have been synthesized and have been shown to exhibit potent
biological activity.13
Also shown in Figure 1, tetramisole (B) is a strong anthelmintic
in the treatment of many nemotods.14 Thieno[3,2-d]pyrimidinone
(C)15 and 5,6-diarylimidazo[2,1-b][1,3]thiazoles (D)16 are excellent
antibacterial agents and C-2 aryl-substituted pilicides [thiazole
ring-fused 2-pyridones (E)]17 exhibit anti-coccidial behavior. 11C-
labeled imidazo[2,1-b]benzothiazole (F)18 has been shown to be
a superb fluoroprobe in PET analysis of Alzheimer’s disease. Milne
et al.19 have prepared compound (G) which possesses an imi-
dazo[2,1-b]benzothiazole ring. Compound G, although unrelated
in structure to resveratrol, shows a 1000-fold greater affinity to-
ward SIRT1 than resveratrol. These workers also demonstrated that
compound G binds to the SIRT1 enzyme–peptide substrate com-
plex at an allosteric site amino terminal to the catalytic domain
resulting in lower Michaelis constant for acetylated substrates.
Compound H inhibits binding of radio labeled TARC (Thymus and
Recently, significant efforts have been put forth to develop
inhibitors of the key serine proteases that are part of the coagula-
tion cascade. Thrombin was the initial target, and many small
molecule inhibitors have been reported.4 Recent studies5 revealed
quinoxalinone A (shown in Fig. 1) to be a selective inhibitor of
coagulation FXa and also shows promise for the parenteral
⇑
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.2012.08.093

C. Mukherjee et al. / Tetrahedron Letters 53 (2012) 6008–6014
6009
HO
N
N
NH2
NH
O
A
N
R1
N
N
O
O
N
N
S
Cl
N
R2
N
S
S
OCH3
R1
S
N
N
N
COR2
B
O
C
F
D
E
S
N
H
N
11
N
HO
N
CH3
H3CO
N
N
S
N
HN
H
S
N
O
F
H
G
Figure 1. Imidazo[2,1-b]thiazoles and 2-aminothiazole derivative with biological and medicinal activities.
Activation Regulated Chemokine) and MDC (Macrophase-derived
Chemokine) to CCR4 receptors on the surface of CEM20 and also
inhibits the in vitro migration of CEM cells mediated by TARC.20
Subsequently another group identified hydrazone derivatives of
imidazo[2,1-b]benzothiazoles as a potent antitumor agent.21 It
has also been reported that imidazo[2,1-b]benzothiazole system
acts as a scaffold endowing dihydropyridines with selective cardi-
odepressant activity.22
For the past few years, our group has also been preparing and
evaluating biologically important compounds using microwave
irradiation.23a–k Of particular importance in this report, is our prep-
aration of N-phenyl-4-(6-phenylimidazo[2,1-b] thiazol-5-yl)thia-
zol-2-amines,23a 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
biologically active imidazo[2,1-b]thiazole core moieties attached
to a variety of quinoxalinone molecule, and report the results herein.
Results and discussion
Quinoxalinones (6a–q) were prepared via the Hinsberg reaction
of ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates
(4a–e) with suitably substituted o-phenylenediamines (5a–f) un-
der microwave conditions in acetonitrile (Scheme 1). The optimum
temperature and condition for Hinsberg MW assisted reactions
were determined by a series of reactions of ethyl 2-oxo-2-(6-
phenylimidazo[2,1-b]thiazol-5-yl)acetate (4a) and o-phenylenedi-
amine (5a). The results, which are summarized in Table 1,
show that using MW irradiation at 200 °C for 35 min in acetoni-
trile is the optimum condition for the synthesis of these
compounds.
The results of synthesis of the quinoxalinones 6a–q using MW
irradiation and conventional heating are shown in Table 2. The
MW-assisted reactions gave 6a–q in excellent yields (89–99%)
using a 35 min reaction time and the crude products were readily
O
R1
Br
O
N
1. Acetone-reflux
N
O
Cl
NH2
2. 2 (N) HCl- reflux
3. NH4OH
N
S
R1
S
O
2a-e
1 = H, CH3
OCH3, CN
1
3a-e
70-80%
1,4-Dioxane
R
104 °C
3 h
R2
O
R3
O
N
O
R2
NH2
NH2
R1
MW irradiarion
HN
R3
N
200 °C, 35 min
CH3CN (2 mL)
250 psi
N
O
S
R1
4a-d
80-85%
5a-f
N
R2 = H, Cl, NO2, CH3,
R3 = H, Cl, CH3
N
S
6a-q
89-98
Scheme 1. Schematic representation for the synthesis of quinoxalinones 6a–q.

6010
C. Mukherjee et al. / Tetrahedron Letters 53 (2012) 6008–6014
Table 1
purified by washing with cold acetonitrile. The same reactions
using conventional refluxing in 1,4-dioxane solvent gave 5a–f in
lower yields (47–88%), required a longer reaction time (8 h), and/
or compounds required rigorous purification of molecules.
Screening of solvents, reaction times, and temperatures for the synthesis of 6a
Solvent
Conditions
Temp (°C)
Time (min)
Yield (%)
There are ample examples for the formation of quinoxaline moi-
ety via Hinsberg reaction in the literature.24a,b Fernandez and co-
workers reported the kinetic study on Hinsberg reaction by reacting
unsymmetrical benzene-1,2-diamines with pyruvate (2-oxopro-
panoate) derivatives and explained the positional isomer.24a To im-
prove the regioselectivity in the positional isomerism, Lumma et al.
synthesized the related compounds in acidic medium.24b Recently,
Ballini et al. developed a one pot synthesis of polyfunctionalized
dihydroquinoxalinone derivatives via an anti-Michael reaction.24c
Moglioni and co-workers prepared several chemotherapeutic
quinoxalinone derivatives by using Saccharomyces cerevisiae as
biocatalyst and also by means of microwave-assisted organic
No solvent
No solvent
Ethanol
90–120
120–200
90–120
120–200
120–200
90–100
200
120–200
120–200
120–200
120–200
120–200
120–200
120–200
30–35
30–35
30–35
30–35
30–35
30–35
35
30–35
30–35
30–35
30–35
30–35
30–35
30–35
Trace
Trace
Trace
71
75
35
98
65
66
Trace
Trace
Trace
40
Ethanol
Methanol
Acetonitrile
Acetonitrile
THF
n-Butanol
DMF
Sulfonate
Benzene/Toluene
DMF
Water
50
Table 2
The synthesis of 3-(6-phenylimidazo[2,1-b]thiazol-5-yl)quinoxalin-2(1H)-ones (6a–q) by the microwave-assisted reaction of the ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-
5-yl)acetate derivatives (4a–e) with substituted o-phenylenediamine (5a–d)
R2
R3
O
O
N
HN
O
R2
R3
NH2
NH2
MW irradiarion
R1
N
O
R1
200 °C, 35 min
CH3CN (2 mL)
250 psi
N
N
S
N
S
4a-d
5a-f
6a-q
R2 = H, Cl, NO2, CH3,
R3 = H, Cl, CH3
R2
R3
NH2
NH2
R2
O
R3
O
N
O
HN
R1
N
5
O
Entry
Yielda
Yieldb
N
R1
S
N
4
N
S
6a-p
6
HN
N
O
1
4a, R1 = H
5a, R2 = R3 = H
98
65
N
N
S
6a, R1 = R2 = R3= H
CH3
CH3
HN
N
2
4a, R1 = H
5b, R2 = R3 = CH3
96
45
O
N
N
S
6b, R1 = H,, R2 = R3 = CH3

C. Mukherjee et al. / Tetrahedron Letters 53 (2012) 6008–6014
6011
Table 2 (continued)
R2
R3
NH2
NH2
R2
N
O
R3
O
N
O
HN
R1
5
O
Entry
Yielda
Yieldb
N
R1
S
N
4
N
S
6a-p
6
Cl
Cl
HN
N
3
4a, R1 = H
5c, R2 = R3 = Cl
92
69
O
N
N
S
6c, R1 = H,, R2 = R3 = Cl
CN
HN
N
O
4
4a, R1 = H
5d, R2 = CN, R3 = H
90
60
N
N
S
6d, R1 = H, R2 = CN, R3 = H
NO2
HN
N
O
5
4a, R1 = H
5e, R2 = NO2, R3 = H
95
78
N
N
S
6e, R1 = H, R2 = NO2, R3 = H
CN
CN
HN
N
O
6
4a, R1 = H
5f, R2 = R3 = CN
89
78
N
N
S
6f, R1 = H, R2 = R3 = CN
HN
N
7
4a, R1 = H
5g, R2 = R3 = Ph
99
88
O
N
N
S
6g, R1 = H, R2 = R3 = Ph
(continued on next page)
synthesis.24d Most recently Nageswar and his co-workers24e
reported a green synthetic protocol for the synthesis of this qui-
noxalinone core moiety. But to our knowledge no regioselectivity
of this reaction has been reported. We have extended this reaction
under microwave condition in the case of unsymmetrically substi-
tuted benzene-1,2-diamines (Table 2, entries 4, 5, and 15). The

6012
C. Mukherjee et al. / Tetrahedron Letters 53 (2012) 6008–6014
Table 2 (continued)
R2
R3
NH2
NH2
R2
N
O
R3
O
N
O
HN
R1
5
O
Entry
Yielda
Yieldb
N
R1
S
N
4
N
S
6a-p
6
HN
N
O
8
4b, R1 = CH3
5a, R2 = R3 = H
5b, R2 = R3 = CH3
5a, R2 = R3 = H
5b, R2 = R3 = CH3
CH3
90
89
98
93
53
47
67
81
N
N
S
6h, R1 = CH3, R2 = R3 = H
CH3
CH3
HN
N
9
4b, R1 = CH3
O
CH3
N
N
S
6i, R1 = R2 = R3 = CH3
HN
N
O
10
4c, R1 = OCH3
OCH3
N
N
S
6j, R1 = OCH3, R2 = R3 = H
CH3
CH3
HN
N
11
4c, R1 = OCH3
O
OCH3
N
N
S
6k, R1 = OCH3, R2 = R3 = CH3
HN
N
12
4c, R1 = OCH3
5g, R2 = R3 = Ph
96
80
O
OCH3
N
N
S
6l, R1 = OCH3, R2 = R3 = Ph
products were subjected to LC/MS, GC, and NMR analyses which
clearly indicated the presence of one isomer. For example in case
of compound 6o (entry 15) 1H NMR spectra show singlet at d
7.10 ppm which corresponds to an aromatic-6-proton adjacent to
5-methyl functionality which is in accordance with the similar
structure reported in the literature.24e
Quinoxalinones 6a–q were obtained25 as high melting (mp
>300 °C) solids. Most of them are insoluble in usual organic sol-

C. Mukherjee et al. / Tetrahedron Letters 53 (2012) 6008–6014
6013
Table 2 (continued)
R2
R3
NH2
NH2
R2
N
O
R3
O
N
O
HN
R1
5
O
Entry
Yielda
Yieldb
N
R1
S
N
4
N
S
6a-p
6
HN
N
O
13
4d, R1 = CN
5a, R2 = R3 = H
89
55
CN
N
N
S
6m, R1 = CN, R2 = R3 = H
CH3
CH3
HN
N
14
4d, R1 = CN
5b, R2 = R3 = CH3
91
58
O
CN
N
N
S
6n, R1 = CN, R2 = R3 = CH3
CH3
HN
N
O
15
4d, R1 = CN
5b, R2 = CH3, R3 = H
98
67
CN
N
N
S
6o, R1 = CN, R2 = CH3, R3 = H
CN
CN
HN
N
O
CN
16
4d, R1 = CN
5f, R2 = R3 = CN
96
70
N
N
S
6p, R1 = R2 = R3 = CN
HN
N
17
4d, R1 = CN
5g, R2 = R3 = Ph
93
81
O
CN
N
N
S
6q, R1 = CN, R2 = R3 = Ph
a
Isolated yield for microwave heating 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.
Isolated yield for conventional heating for 8 h at 104 °C using 4a:5a (1:1 equiv) and 1 mmol of 4a, solvent (1,4-dioxane, 10 mL).
b
vents such as, dichloromethane, ethyl acetate, THF, ethanol, or
around d 12.5 ppm which corresponds to NH functionality. The
starting ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)ace-
tates (4a–e) were prepared by refluxing 2.5 equiv of ethyl chloro-
oxoacetate and 1 equiv of 6-phenylimidazo[2,1-b]thiazoles (3a–e)
in refluxing 1,4-dioxane.26 Although we tried other solvents, 1,
methanol but soluble in DMF or DMSO. The proposed structures
of 6a–q were confirmed, in part, by the presence of C@O signals
around d 154 ppm in the 13C NMR spectra. The 1H NMR spectra
of these compounds showed a broad singlet (equivalent to 1H)

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C. Mukherjee et al. / Tetrahedron Letters 53 (2012) 6008–6014
10. Lee, J.; Murray, W. V.; Rivero, R. A. J. Org. Chem. 1997, 62, 3874; Zaragoza, F.;
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4-dioxane proved to be the best. The structures of 4a–e were con-
firmed by the presence of two C@O signals around d 175 ppm and
163 ppm and the OCH2 signal around d 62 ppm. The starting 6-
phenylimidazo[2,1-b]thiazoles (3a–e) were synthesized according
to a literature21 procedure. All compounds were characterized by
1H NMR, 13C NMR, DEPT-135, LC/MS, and HRMS analyses.
Reaction condition: microwave irradiation using 4a:5a
(1:1 equiv) and 1 mmol of 4a, solvent (2 mL) under 250 psi pres-
sure in a capped specially designed microwave test tube.
12. (a) TenBrink, R. E.; Im, W. B.; Sethy, V. H.; Tang, A. H.; Careter, D. B. J. Med.
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In conclusion, we have successfully developed an easy practical
access to novel series of 3-(6-phenylimidazo[2,1-b]thiazol-5-
yl)quinoxalin-2(1H)-one (qunoxalinone) derivatives. The easy
work up procedure, good to excellent yields with selectivity, and
readily available starting materials make this reaction an attractive
method for the preparation of titled compounds. To the best of our
knowledge, there has been no reported example of the synthesis of
this type of biologically important molecule. Efforts directed to-
ward the synthesis of other important drug molecules with imi-
14. Raeymaekers, A. H. M.; Allewijn, F. T. N.; Vandenberk, J.; Demoen, P. J. A.;
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C.; Speake, J. D.; Witty, D. R. WO03033476, 2003.
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A.; Brown, C.; Mathew, J.; Thompson, D.; Schmatz, D.; Biftu, T. Bioorg. Med.
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L.; Boss, O.; Perni, R. B.; Vu, C. B.; Bemis, J. E.; Xie, R.; Disch, J. S.; Ng, P. Y.;
Nunes, J. J.; Lynch, A. V.; Yang, H. Y.; Galonek, H.; Israelian, K.; Choy, W.; Iffland,
A.; Lavu, S.; Medvedik, O.; Sinclair, D. A.; Olefsky, J. M.; Jirousek, M. R.; Elliott, P.
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Tang, L.; McMaster, B. E.; Dairaghi, D. J.; Schall, T. J.; Collins, T. L.; Medina, J. C.
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dazo
[2,1-b]thiazol-5-yl)thiazol
moieties
by
microwave
irradiation are ongoing in our laboratory. Also work is in progress
to obtain biological activities (antibacterial, antifungal, anticancer,
antitumor, neuroprotective kinase inhibitory , and anti-thrombotic
activities) of these important compounds. Results in this area will
be presented in due course.
Acknowledgments
22. 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.
The authors are grateful to the NIH (IRC2NS064950) for gener-
ous financial support. Thanks are due to Emily Harry of Omm Sci-
entific Inc for LC/MS analysis and Dr. John L. Tan for helpful
discussion.
23. See, for example: (a) Kamila, S.; Mendoza, K.; Biehl, E. R. Tetrahedron Lett. 2012,
53, 3998; (b) Kamila, S.; Biehl, E. R. Tetrahedron Lett. 2012, 53, 3998; (c) Kamila,
S.; Ankati, H.; Harry, E.; Biehl, E. R. Tetrahedron Lett. 2012, 53, 2195; (d) Kamila,
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
08.093.
24. For example: (a) Abasolo, M. I.; Gaozza, C. H.; Fernandez, B. M. J. Heterocycl.
Chem. 1987, 24, 1771; (b) Lumma, W. C.; Hartman, R. D.; Saari, W. S.;
Engelhardt, E. L.; Lotti, V. J.; Stone, C. A. J. Med. Chem. 1981, 24, 93; (c) Ballini, R.;
Gabrielli, S.; Palmieri, A. Synlett 2009, 14, 3455; (d) Gris, J.; Glisoni, R.; Fabian,
L.; Fernandez, B.; Moglioni, A. G. Tetrahedron Lett. 2008, 49, 1053; (e) Murthy, S.
N.; Madhav, B.; Nageswar, Y. V. D. Helv. Chim. Acta 2010, 93, 1216.
25. Representative example for the synthesis of 6a. Ethyl-2-oxo-2-(6-
phenylimidazo[2,1-b]thiazol-5-yl)acetate (4a, 0.3 g, 0.9 mole) and O-
phenylenediamine (5a, 0.108 g, 0.9 mole) were mixed properly and was
References and notes
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charged into
a specially designed microwave test tube and acetonitrile
(5 mL) was added to this mixture and was irradiated for 35 min at 200 °C
and 250 psi pressure. After cooling, the solid mass was crushed into 50 ml cold
acetonitrile. The solid mass was filtered and the filtrate was discarded. After
washing several times with cold acetonitrile, the solid mass was dried under
vacuum to get the 3-(6-phenylimidazo[2,1-b]thiazol-5-yl)quinoxalin-2(1H)-
ones (6a). The related compounds (6b–q) were prepared in the same way.
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Mykhailiuk, P.; Tolmachev, A. A. Synthesis 2010, 10, 1692.
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