Hypervalent iodine(iii) sulfonate mediated synthesis of 6-arylimidazo[2,1-b]thiazoles in liquid PEG-400

Article abstract of DOI:10.1002/jccs.201190103

PEG-400[poly(ethylene glycol-400)] is used as reaction medium in the one-pot synthesis of 6-arylimidazo[ 2,1-b]thiazoles by reaction with aryl ketones, hypervalent iodine(III) sulfonate and 2-aminothiazole. Significant rate enhancements and improved yield

Full text of DOI:10.1002/jccs.201190103

Journal of the Chinese Chemical Society, 2011, 58, 663-666
663
Hypervalent Iodine(III) Sulfonate Mediated Synthesis of
6-Arylimidazo[2,1-b]thiazoles in Liquid PEG-400
Fang-Wen Wu,a Rei-Sheu Hou,b* Huey-Min Wang,b Iou-Jiun Kangc and Ling-Ching Chena*
aGraduate Institute of Pharmaceutical Sciences, College of Pharmacy, Kaohsiung Medical University,
Kaohsiung 807, Taiwan, R.O.C.
bChung Hwa College of Medical Technology, Tainan 717, Taiwan, R.O.C.
cDivision of Biotechnology and Pharmaceutical Research, National Health Research Institutes,
Miaoli County 350, Taiwan, R.O.C.
Received February 18, 2011; Accepted April 25, 2011; Published Online May 9, 2011
PEG-400[poly(ethylene glycol-400)] is used as reaction medium in the one-pot synthesis of 6-aryl-
imidazo[2,1-b]thiazoles by reaction with aryl ketones, hypervalent iodine(III) sulfonate and 2-amino-
thiazole. Significant rate enhancements and improved yields have been observed.
Keywords: Hypervalent iodine; 6-Arylimidazo[2,1-b]thiazoles; Poly(ethylene golycol).
INTRODUCTION
Imidazo[2,1-b]thiazoles are inhibitors of mitochon-
still debated. Compared with PEG, however, toxicity and
environmental burden of ionic liquids are for the most part
unknown. Furthermore, the cost of ionic liquids is often
more expensive than that of PEG.13 To date some of the
more important reactions have been carried out and investi-
gated in PEG, for example, Heck reaction,14 Lindlar catalytic
hydrogenation,15 asymmetric dihydroxylation,16 Baylis-
Hillman reaction,17 Biginelli reaction,18 Suzuki-Miyaura
reaction, Stille cross-coupling reaction,19 Wacker reac-
tion,20 and asymmetric aldol reaction,21 etc.
drial NADH dehydrogenase,1 specific inhibitors of the
NADH-ubiquinone reductase activity in mitochondrial
membranes,2 and also display broad spectrum anthelmin-
tic,3 and cardiotonic,4 bacteriostatic, fungistatic,5 antiin-
flammatory,6 and antitumor7 activities.
There are two important routes reported in the litera-
ture, which are commonly employed for the synthesis of
the title compounds. The first one involves the condensa-
tion of 2-aminothiazole with a-halocarbonyl compounds,8
and the second method commences with the reaction of ap-
propriate a-haloketones with 2-mercaptoimidazole deriva-
tives, followed by construction of the thiazole ring.9 Unfor-
tunately, a-haloketones are lachrymatory, toxic, and not
readily available. Therefore, the development of a mild, ef-
ficient, environmentally friendly method to prepare 6-aryl-
imidazo[2,1-b]thiazoles is still presently significant in
organic synthesis.
Poly(ethylene golycol) (PEG),10 a biologically ac-
ceptable polymer used extensively in drug delivery and in
bioconjugates as tools for diagnostics has been used as a
solvent medium support for various transformations. 11 In
recent times ionic liquids have been in the forefront of re-
search, and several publications and reviews have already
appeared.12 Even though ionic liquids offer some advan-
tages, the tedious preparation of ionic liquids (and raw ma-
terials for ionic liquids) and their environmental safety is
Recently, hypervalent iodine(III) reagents have been
used extensively in organic synthesis due to their low tox-
icity, ready availability and easy handling.22 In continua-
tion of our efforts to develop greener organic reaction pro-
cedures, we now report [hydroxyl(2,4-dinitrobenzenesul-
fonyloxy)iodo]benzene (HDNIB) mediated facile and effi-
cient synthesis of 6-arylimidazo[2,1-b]thiazoles. The re-
quired HDNIB was prepared in satisfactory yields from the
reaction 2,4-dinitrobenzenesulfonic acid with phenylido-
dine(III) diacetate (PIDA).23 Treatment of aromatic ke-
tones with HDNIB in PEG-400 produced the a-[(2,4-di-
nitrobenzene)sulfonyl]oxy ketone intermediates (2). Sub-
sequent cyclocondensation by 2-aminothiazole in PEG-
400 gave the corresponding 6-arylimidazo[2,1-b]thiazoles
(3) in good yields (Scheme I).
RESULTS AND DISCUSSION
The 2,4-dinitrobenzenesulfonyloxy group located at

664 J. Chin. Chem. Soc., Vol. 58, No. 5, 2011
Wu et al.
Scheme I
N
R
O
N
O
S
NH2
HDNIB
R
R
Ar
Ar
S
N
Ar
Na2CO3
PEG-400
PEG-400
ODNs
3
2
1
O2N
O
HDNIB = HO
I
O S
O
NO2
DNs = 2,4-dinitrobenzenesulfonyl
the a position to a carbonyl group represents an increas-
ingly important entity in both mechanistic and synthetic or-
ganic chemistry. One reason for this importance is that
2,4-dinitrobenzenesulfonyloxy group is a good leaving
group, and this accounts for the considerable synthetic util-
ity associated with this group in functionalization of car-
bonyl compounds.
Table 1. Preparation of 6-arylimidazo[2,1-b]thiazoles 3a-l
Entry
Ar
R
Yield (%)
3a
3b
3c
3d
3e
3f
Ph
H
H
85
78
83
80
82
84
76
83
82
78
76
81
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
3,4-Cl2C6H3
Ph
H
H
H
H
As shown in Scheme I, our experiments involving a
one-pot procedure for the preparation of 6-arylimidazo-
[2,1-b]thiazoles (3) by cyclocondensation of 2-amino-
thiazole with a-sulfonyloxy aryl ketone (2) in PEG-400
was successful. The results are summarized in the Table 1.
An array of aryl ketones having electron-donating and
-withdrawing substituents on the aromatic ring attached to
carbonyl carbon reacted with HDNIB to afford 6-arylimi-
dazo[2,1-b]thiazoles (3b-3h) in good yields. When the re-
action was conducted in the classical molecular solvent,
such as acetonitrile, the preparation of 6-arylimidazo[2,1-
b]thiazoles (3a) needs refluxing for 3 h; however, in PEG-
400, the reaction took place at 80 °C for 0.5 h and gave a
higher yield.
3g
3h
3i
H
H
Me
H
3j
2-Furyl
3k
3l
2-Thienyl
2-Naphthy
H
H
spect to TMS. MS were obtained on a JEOL JMS D-300 in-
strument.
General procedure for the synthesis of quinoxalines
(3)
To a solution of aryl ketone (1) (1.0 mmol) in PEG (2
g), was added HDNIB (1.2 mmol) and stirred at 60 °C for 1
h. Then 2-aminothiazole (1.0 mmol) and sodium carbonate
(0.6 mmol) were added to the reaction mixture and was
In conclusion, we have described a novel and effi-
cient method for the synthesis of 6-arylimidazo[2,1-b]thia-
zoles from aryl ketones, hypervalent(III) sulfonate and
2-aminothiazole in PEG-400. The important features of
this procedure are enhanced reaction rate, mild reaction
condition, high yield and green aspects such as avoiding
hazardous organic solvents.
stirred at 80 °C for 0.5 h to complete the reaction. Subse
-
quently, the reaction mixture was extracted with Et2O (3 ´
5 mL). The remaining PEG suspension was filtered and re-
used for further runs. The combined ethereal solution was
evaporated under reduced pressure. The resulting residue
was chromatographed on silica gel using ethyl acetate:
n-hexan (1:1) as eluent to give 3.
EXPERIMENTAL SECTION
6-Phenylimidazo[2,1-b]thiazole (3a)
mp 143-144 °C (Lit.24 144-146 °C). IR (KBr) n: 3118,
1533, 1466 cm-1; 1H NMR (CDCl3) d: 6.82 (d, J = 3.3 Hz,
1H), 7.26-7.30 (m, 1H), 7.38-7.42 (m, 2H), 7.43 (d, J = 3.3
Hz, 1H), 7.74 (s, 1H), 7.82-7.84 (m, 2H); EI-MS m/z (rela-
All melting points are uncorrected. The IR spectra
were recorded on a Shimadzu IR-27 G spectrophotometer.
1H NMR spectra was recorded on a Varian Unity Plus 400
MHz. Chemical shifts (d) were measured in ppm with re-

Synthesis of 6-Arylimidazo[2,1-b]thiazoles
J. Chin. Chem. Soc., Vol. 58, No. 5, 2011 665
tive intensity) 200 (M+), 199, 174.
cm-1; 1H NMR (CDCl3) d: 2.60 (s, 3H), 6.83 (d, J = 4.5 Hz,
1H), 7.29-7.32 (m, 1H), 7.30 (d, J = 4.5 Hz, 1H), 7.40-7.46
(m, 2H), 7.70-7.73 (m, 2H); EI-MS m/z (relative intensity)
214 (M+), 186, 115; Anal. Calcd for C12H10N2S: C, 67.26;
H, 4.07; N, 13.07. Found: C, 67.34; H, 4.85; N, 13.21.
6-(2-Furanyl)imidazo[2,1-b]thiazole (3j)
mp 91-93 °C. IR (KBr) n: 3124, 1553, 1472 cm-1; 1H
NMR (CDCl3) d: 6.46-6.48 (m, 1H), 6.47 (m, 1H), 6.72 (d,
J = 3.3 Hz, 1H), 6.82 (d, J = 3.3 Hz, 1H), 7.41-7.43 (m, 2H),
7.63 (s, 1H); EI-MS m/z (relative intensity) 190 (M+), 161,
136; Anal. Calcd for C9H6N2OS: C, 56.83; H, 3.18; N,
14.73. Found: C, 56.75; H, 3.24; N, 14.62.
6-(4-Methyphenyl)imidazo[2,1-b]thiazole (3b)
mp 156-157 °C (Lit.24 157 °C). IR (KBr) n: 3114,
1544, 1461 cm-1; 1H NMR (CDCl3) d: 2.40 (s, 3H), 6.80 (d,
J = 3.45 Hz, 1H), 7.20 (d, J = 5.4 Hz, 2H), 7.40 (d, J = 3.45
Hz, 1H), 7.69 (s, 1H), 7.70 (d, J = 5.5 Hz, 2H); EI-MS m/z
(relative intensity) 214 (M+), 186, 130, 115.
6-(4-Methoxyphenyl)imidazo[2,1-b]thiazole (3c)
mp 159 °C (Lit.24 158 °C). IR (KBr) n: 3113, 1605,
1545, 1463 cm-1; 1H NMR (CDCl3) d: 3.86 (d, 3H), 6.80 (d,
J = 5.7 Hz, 1H), 7.42 (d, J = 5.7 Hz, 1H), 7.65 (s, 1H), 7.75
(d, J = 7.2 Hz, 2H), 7.97 (d, J = 7.2 Hz, 2H); EI-MS m/z
(relative intensity) 230 (M+), 215, 187.
6-(2-Thiophenyl)imidazo[2,1-b]thiazole (3k)
6-(4-Fluorophenyl)imidazo[2,1-b]thiazole (3d)
mp 127 °C (Lit.24 126-127 °C). IR (KBr) n: 3138,
1597, 1542, 1461 cm-1; 1H NMR (CDCl3) d: 6.83 (d, J = 3.3
Hz, 1H), 7.07-7.11 (m, 2H), 7.43 (d, J = 3.3 Hz, 1H), 7.69
(s, 1H) , 7.77-7.80 (m, 2H); EI-MS m/z (relative intensity)
218 (M+), 219, 192.
mp 132 °C (Lit.24 130 °C). IR (KBr) n: 3109, 1552,
1458 cm-1; 1H NMR (CDCl3) d: 6.82 (d, J = 4.5 Hz, 1H),
7.04-7.07 (m, 1H), 7.23-7.25 (m, 1H), 7.33-7.34 (m, 1H),
7.41 (d, J = 4.5 Hz, 1H), 7.66 (s, 1H); EI-MS m/z (relative
intensity) 206 (M+), 183, 152, 108.
6-(2-Naphthyl)imidazo[2,1-b]thiazole (3l)
6-(4-Chlorophenyl)imidazo[2,1-b]thiazole (3e)
mp 169 °C (Lit.24 167 °C). IR (KBr) n: 3137, 1532,
1459 cm-1; 1H NMR (CDCl3) d: 6.84 (d, J = 3.6 Hz, 1H),
7.36 (d, J = 6.3 Hz, 2H), 7.43 (d, J = 3.3 Hz, 1H), 7.72 (s,
1H), 7.75 (d, J = 6.3 Hz, 2H); EI-MS m/z (relative inten-
sity) 234 (M+), 236, 234, 199.
mp 114-116 °C. IR (KBr) n: 3113, 1541, 1466 cm-1;
1H NMR (CDCl3) d: 6.85 (d, J = 3.3 Hz, 1H), 7.44-7.48 (m,
3H), 7.47 (d, J = 3.3 Hz, 1H), 7.82-7.90 (m, 4H), 8.38 (s,
1H); EI-MS m/z (relative intensity) 250 (M+), 191, 166;
Anal. Calcd for C15H10N2S: C, 71.97; H, 4.03; N, 11.19.
Found: C, 71.84; H, 4.18; N, 11.05.
6-(4-Bromophenyl)imidazo[2,1-b]thiazole (3f)
mp 179 °C (Lit.24 179-180 °C). IR (KBr) n: 3137,
1532, 1458 cm-1; 1H NMR (CDCl3) d: 6.84 (d, J = 3.6 Hz,
1H), 7.43 (d, J = 3.3 Hz, 1H), 7.52 (d, J = 6.3 Hz, 2H), 7.69
(d, J = 6.3 Hz, 2H), 7.73 (s, 1H); EI-MS m/z (relative inten-
sity) 277 (M+), 199, 172.
ACKNOWLEDGEMENT
We gratefully acknowledge the National Council Sci-
ence of Republic of China for financial support of this
work.
6-(4-Nitrophenyl)imidazo[2,1-b]thiazole (3g)
mp 280-281 °C (Lit.24 280 °C). IR (KBr) n: 3106,
1597, 1502, 1339 cm-1; 1H NMR (CDCl3) d: 6.91 (d, J = 3.6
Hz, 1H), 7.48 (d, J = 3.6 Hz, 1H), 7.96 (s, 1H), 7.98 (d, J =
8.1 Hz, 2H), 8.27 (d, J = 8.1 Hz, 2H); EI-MS m/z (relative
intensity) 245 (M+), 215, 199, 187.
REFERENCES
1. Andreani, A.; Rambaldi, M.; Leoni, A.; Locatelli, A.; Ghelli,
A.; Ratta, M.; Benelli, B.; Esposti, M. D. J. Med. Chem.
1995, 38, 1090.
2. Andreani, A.; Granaiola, M.; Leoni, A.; Locatelli, A.;
Morigi, R.; Rambaldi, M.; Recanatini, M.; Lenaz, G.; Fato,
R.; Bergamini, C. Bioorg. Med. Chem. 2004, 12, 5525.
3. Amarouch, H.; Loiseau, P. R.; Bacha, C.; Caujolle, R.;
Payard, M.; Loiseau, P. M.; Bories, C.; Gayral, P. Eur. J.
Med. Chem. 1987, 22, 463.
6-(3,4-Dichlorophenyl)imidazo[2,1-b]thiazole (3h)
mp 116-118 °C. IR (KBr) n: 3114, 1551, 1461 cm-1;
1H NMR (CDCl3) d: 6.86 (d, J = 4.5 Hz, 1H) , 7.44 (s, 1H),
7.46 (d, J = 4.5 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.74 (s,
1H), 7.93 (d, J = 2.1 Hz, 1H); EI-MS m/z (relative inten-
sity) 269 (M+), 273; Anal. Calcd for C11H6Cl2N2S: C,
49.09; H, 2.25; N, 10.41. Found: C, 49.16; H, 2.12; N,
10.25.
4. Andreani, A.; Rambaldi, M.; Leoni, A.; Locatelli, A.; Bossa,
R.; Chiericozzi, M.; Galatulas, I.; Salvatore, G. J. Med.
Chem. 1996, 31, 383.
5. Tartler, G.; Weuffen, W. Pharmazie 1966, 21, 425.
6. Moser, R. E.; Powers, L. J.; Ariyan, Z. S. Can. CA 1,127,084,
July 6, 1982; Chem. Abstr. 1982, 97, 208380.
5-Methyl-6-phenylimidazo[2,1-b]thiazole (3i)
mp 109-111 °C. IR (KBr) n: 3096, 1598, 1536, 1468
7. Andreani, A.; Bonazzi, D.; Rambaldi, M. Arch. Pharm.
1982, 315, 451-456; Chem. Abstr. 1982, 97, 72289.

666 J. Chin. Chem. Soc., Vol. 58, No. 5, 2011
Wu et al.
8. Meakins, G. D.; Musk, S. R. R.; Robertson, C. A.; Wood-
house, L. S. J. Chem. Soc., Perkin Trans. 1 1989, 3, 643.
9. Mazur, I. A.; Kochergin, P. M. Khim. Geterotsikl. Soedin.
1970, 4, 512; Chem. Abstr. 1970, 73, 87855.
S. Tetrahedron Lett. 2004, 45, 5865.
18. Xia, M.; Wang, Y.-G. Tetrahedron Lett. 2002, 43, 7703.
19. Li, J.-H.; Hu, X.-C.; Liang, Y.; Xie, Y.-X. Tetrahedron 2006,
62, 31.
10. Harris, J. M.; Zalipsky, S. Poly(ethylene glycol): Chemistry
and Biological Applications; ACS Books: Washington, DC,
1997.
20. Haimov, A.; Neumann, R. Chem. Commun. 2002, 876.
21. Chandrasekhar, S.; Narsihmulu, Ch.; Reddy, N. R. K.; Sul-
tana, S. S. Tetrahedron Lett. 2004, 45, 4581.
11. (a) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. Rev.
2002, 102, 3325. (b) Ahn, J.-M.; Wentworth, Jr., P.; Janda, K.
D. Chem. Commun. 2003, 4, 480.
22. (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
(b) Kita, Y.; Takada, T.; Tohma, H. Pure. Appl. Chem. 1996,
68, 627. (c) Varvoglis, A., Hypervalent Iodine in Organic
Synthesis; Academic Press: San Diego, 1997. (d) Kitamura,
T.; Fujiwara, Y. Org. Prep. Proced. Int. 1997, 29, 409. (e)
OChiai, M. In Chemistry in Hypervalent Compounds; Akiba,
K., Eds.; Wiley-VCH: New York, 1999; Chapter 12. (f)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523. (g)
Wirth, T. Hypervalent Iodine Chemistry; Springer-Verlag:
Berlin, Heidelberg, 2003. (h) Moriarty, R. M. J. Org. Chem.
2005, 70, 2893. (i) Wirth, T. Angew. Chem. Int. Ed. 2005, 44,
3656.
12. (a) Welton, T. Chem Rev. 1999, 99, 2071. (b) Freemoutle, M.
Chem. Eng. News 2000, 78(15), 37. (c) Wassercheid, P.;
Keim, W. Angew. Chem. Int. Ed. 2000, 39, 3772. (d)
Freemoulte, M. Chem.Eng. News 2001, 79 (1), 21.
13. Ji, C.; Scott, K. S.; Jonathan, G. H.; Robin, D. R. Green
Chem. 2005, 7, 64.
14. Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S.; Reddy,
N. R. K. Org. Lett. 2002, 4, 4399.
15. Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S.; Reddy,
N. R. K. Chem. Commun. 2003, 1716.
23. Hou, R. S.; Wang, H. M.; Haung, H. Y.; Chen, L. C. Org.
Prep. Proced. Int. 2004, 36, 491.
16. Chandrasekhar, S.; Narsihmulu, Ch.; Chandrasekhar, G.;
Shyamsunder, T. Tetrahedron Lett. 2004, 45, 2421.
17. Chandrasekhar, S.; Narsihmulu, Ch.; Saritha, B.; Sultana, S.
24. Aggarwal, R.; Sumran, G. Synth. Commun. 2006, 36, 875.