Potassium carbonate-mediated green and efficient synthesis of imidazo[2,1-b]-1,3,4-thiadiazoles using PEG as solvent

Article abstract of DOI:10.1002/jhet.1037

Polyethylene glycol (PEG) was found to be an inexpensive nontoxic and effective medium for the synthesis of imidazo[2,1-b]-1,3,4-thiadiazoles in the presence of potassium carbonate as a green base in high yields. In addition, the solvent system can be recovered and reused, making this protocol economically and potentially viable.

Full text of DOI:10.1002/jhet.1037

Month 2013
Potassium Carbonate‐Mediated Green and Efficient Synthesis of Imidazo
[2,1‐b]‐1,3,4‐thiadiazoles Using PEG as Solvent
a
a
a
*
Mazaahir Kidwai, Divya Bhatnagar, and Ritika Chauhan
Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
*
E-mail: kidwai.chemistry@gmail.com
Received January 24, 2011
DOI 10.1002/jhet.1037
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
R
N
O
N
N
K2CO3 (10 mol%)
PEG 400, 80°C, 1hr
S
NH2
N
R1
CH2 Br
R2
S
N
R2
1(a-e)
2(a-c)
3(a-l)
Polyethylene glycol (PEG) was found to be an inexpensive nontoxic and effective medium for the synthe-
sis of imidazo[2,1‐b]‐1,3,4‐thiadiazoles in the presence of potassium carbonate as a green base in high yields.
In addition, the solvent system can be recovered and reused, making this protocol economically and poten-
tially viable.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
Imidazo[2,1‐b]‐1,3,4‐thiadiazole derivatives have been of
interest to the medicinal chemists for many years because of
their anticancer [1], antitubercular [2], antibacterial [3],
antifungal [4], anticonvulsant, analgesic [5], and antisecre-
tory [6] activities. This has generated much interest in the
synthesis of these compounds. The most common method
of synthesis of imidazo[2,1‐b]‐1,3,4‐thiadiazoles is the
reaction of 5‐R‐2‐amino‐1,3,4‐thiadiazoles with α‐halo
ketones [7–9]. However, these reactions are performed in
organic solvents at reflux temperatures giving only moderate
yields; therefore, this synthetic methodology does not meet
the requirement of green chemistry. Also, these methodologies
do not provide the possibility of synthesizing a wide range of
derivatives of imidazo[2,1‐b]‐1,3,4‐thiadiazole derivatives.
Regulatory pressure is increasingly focusing on the use,
manufacture, and disposal of organic solvents, and thus,
the development of nonhazardous alternatives (one of the
several goals of green chemistry and engineering) is vitally
important for the continued and sustainable development
of the chemical enterprise.
Recently, polyethylene glycol (PEG) is found to be an
interesting solvent system. It is being extensively used as a
solvent in organic synthesis [10–14]. It has previously been
suggested that PEGs could be used as complexing solvents
of inorganic salts, to enhance the reactivity of the anion with
the organic substrate [15]. In these systems, the anion could
be brought into solution with higher reactivity.
In continuation of our studies in developing cheap and
environmentally benign methodologies for organic synthe-
sis [16–18], we report our finding that readily available
K2CO3 as the base, in combination with an eco‐friendly
solvent PEG‐400 is an extremely effective catalytic system
for the synthesis of imidazo[2,1‐b]‐1,3,4‐thiadiazoles
(Scheme 1).
In a model reaction, we used phenacyl bromide 1a
(1 mmol) and 2‐aminothiadiazole 2a (1 mmol) as reactants
with ethanol as solvent in the presence of inorganic base such
as K2CO3 at 80°C and found that imidazo[2,1‐b]‐1,3,4‐thia-
diazole 3a could be produced in 62% yield in 6 h (Entry 1,
Table 1). To improve the yield and to optimize the reaction
conditions, the same reaction was carried out in the presence
of PEG‐400 as environmentally friendly medium. A tremen-
dous improvement was observed and the yield of 3a was
increased up to 92% after stirring the mixture at 80°C for
only 1 h (Entry 5, Table 1). A plausible explanation for such
an increase could be that PEGs can be regarded as open‐
chain crown ethers as they are able to form complexes with
alkaline and alkaline‐earth cations in protic and aprotic
solvents [19]. Various other solvents were tried for the same
reaction. The results have been summarized in Table 1.
Our next investigation into an effective synthesis of imi-
dazo[2,1‐b]‐1,3,4‐thiadiazoles began with phenacyl bromide
1a (1 mmol), 2‐aminothiadiazole 2a (1 mmol), and 10 mol %
K2CO3 and an array of solvents combined with PEG 400.
The choice of solvent has a significant impact on the
efficiency of the reaction. When the reaction was carried
out in PEG/DMSO, PEG/H2O, and PEG/DMF at 80°C
for 12 h scarcely afforded the corresponding imidazo[2,1‐
b]‐1,3,4‐thiadiazole. When PEG/C2H5OH, PEG/toluene,
PEG/CH3CN, or PEG/dioxane systems were used as
solvents, the yields of the products were also very low.
Evidently, the best solvent for the reaction was pure PEG,
which produced 92% of imidazo[2,1‐b]‐1,3,4‐thiadiazoles
in only 1 h.
We also screened a range of other bases. Na2CO3, KOH,
and NaOH were found to be effective in the reaction.
K3PO4.3H2O, KOAc, NaOAc, and Cs2CO3 led to acceptable
moderate yields of the product, whereas Et3N was
© 2013 HeteroCorporation

M. Kidwai, D. Bhatnagar, and R. Chauhan
Vol 000
Scheme 1. Synthesis of imidazo[2,1‐b]‐1,3,4‐thiadiazoles.
R
N
O
N
N
K2CO3 (10 mol%)
PEG 400, 80°C, 1hr
S
NH2
N
R1
CH2 Br
R2
S
N
R2
1(a-e)
2(a-c)
3(a-l)
and environmentally friendly with simple work up. We
could reuse our solvent system several times. All these
characteristics of our protocol make the reaction quite suit-
able for scale up and commercialization.
Table 1
Effect of solvents for the synthesis of imidazo[2,1‐b]‐1,3,4‐thiadiazoles.a
Entries
Solvents
Time (h)
Yield (%)b
1
Ethanol
Acetonitrile
Toluene
PEG 200
PEG 400
PEG 600
6
6
7
1
1
1
62
62
60
92
92
92
EXPERIMENTAL
2
3
4
5
6
Materials and methods.
All chemicals were purchased
from Sigma‐Aldrich and were used as such. All reactions and
purity of imidazo[2,1‐b]‐1,3,4‐thiadiazoles were monitored by
thin‐layer chromatography (TLC) using aluminum plates coated
with silica gel F254 plates; (Merck) using 20% ethyl acetate,
80% petroleum ether as an eluent. The spots were detected
either under UV light or by placing in iodine chamber. Melting
points were determined using a Thomas Hoover melting point
apparatus and are uncorrected. IR spectra were recorded on a
PerkinElmer FTIR‐1710 spectrophotometer using KBr as
pastilles. 1H‐NMR were recorded on a Bruker spectrospin 300
MHz FT NMR system using TMS as an internal standard.
Elemental analysis was performed on a Hereaus CHN rapid
analyzer. The temperature of the reaction mixture was measured
through a noncontact infrared mini gun thermometer (AZ
minigun type, model 8868).
aReaction conditions: phenacyl bromide 1a (1 mmol), 2‐aminothiadiazole
2a (1 mmol); base: K2CO3 (10 mol %); temp: 80°C.
bIsolated yields.
completely inactive. Finally, K2CO3 proved to be the most
effective base leading to 92% isolated yield in 1 h (Table 2).
The PEG/K2CO3 system was applied to a wide range of
substrates to give the products with good to excellent yields
(Table 3). A wide array of functional groups were tolerated
in the reaction and were not affected by the system.
To check the eco‐friendliness of PEG, we recycled PEG
400 for several times. The reaction proceeded cleanly with
consistent results, although a weight loss of ∼ 5% of PEG
400 was observed from cycle to cycle due to mechanical loss.
General procedure for the synthesis of imidazo[2,1‐b]‐1,3,4‐
In a 50‐mL round‐bottom flask, phenacyl
bromide 1a (0.1990 g, 1 mmol), 2‐aminothiadiazole 2a (0.1151 g,
thiadiazoles.
1 mmol), and K2CO3 (0.0138 g, 10 mol %) in PEG 400 (1 mL)
CONCLUSIONS
Table 3
In conclusion, we have developed an effective catalytic
system PEG 400/K2CO3 for the synthesis of imidazo[2,1‐
b]‐1,3,4‐thiadiazoles. The methodology is simple, efficient,
Synthesis of various imidazo[2,1‐b]‐1,3,4‐thiadiazoles using PEG/K2CO3
system.a
Yield
Time
(h)
(%)
Table 2
b
Entries
R2
R1
M.P (°C)
Effect of base on the synthesis of imidazo[2,1‐b]‐1,3,4‐thiadiazoles.a
3a
3b
3c
3d
3e
3f
3g
3h
3i
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
H
pOMe
pBr
oCl
pMe
H
pOMe
pBr
oCl
pMe
H
1
1
1.25
1.25
1
1
1
1
1
135–137 [20]
200–202 [21]
210–212 [21]
169–171
158–160 [21]
206–208 [20]
178–180
220–222
154–156
274–276
144–146
92
94
90
90
93
93
96
94
92
92
94
93
Entries
Bases
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
K2CO3
K3PO4.3H2O
KOAc
1
9
3
1.5
1
11
3
1.5
9
14
92
77
81
89
92
62
79
87
72
KOH
Na2CO3
NaHCO3
NaOAc
NaOH
Cs2CO3
Et3N
3j
3k
3l
mBrPh
mBrPh
mBrPh pOMe
1.25
1.25
1.25
9
10
260–262
Trace
aReaction conditions: substituted phenacyl bromide 1(a-e) (1 mmol), 2‐
nothiadiazole 2(a-c) (1 mmol); base: K2CO3 (10 mol %); solvent: PEG
400 (1 mL); temp: 80°C.
aReaction conditions: phenacyl bromide 1a (1 mmol), 2‐aminothiadiazole
2a (1 mmol); solvent: PEG 400 (1 mL); temp: 80°C.
bIsolated yields.
bIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Potassium Carbonate‐Mediated Green and Efficient Synthesis of
Imidazo[2,1‐b]‐1,3,4‐thiadiazoles Using PEG as Solvent
Month 2013
were mixed and stirred at 80°C. The progress of the reaction mixture
was monitored by TLC. After completion of the reaction, the
reaction mixture was cooled with a dry ice‐acetone bath to
precipitate the PEG and extracted with ether (PEG being insoluble
in ether). The ether layer was decanted, dried, and concentrated
under reduced pressure. The product though seen as a single
compound by TLC, was subjected to further purification by silica
gel column chromatography using 15% ethyl acetate and 85%
hexane as an eluent to yield the products 3(a–l). The recovered
PEG can be reused for consecutive runs. The structures of all the
products were unambiguously established based on their spectral
analysis (IR, 1H‐NMR, mass spectral and elemental analyses data).
C16H10BrN3S; C, 53.94; H, 2.83; N, 11.80; found C, 53.89; H,
2.75; N, 11.87.
2‐(3‐Bromo‐phenyl)‐6‐(4‐methoxy‐phenyl)‐imidazo[2,1‐b]
[1,3,4]thiadiazole (3l). Yellow solid; IR (KBr) νmax: 2924, 1676,
1587, 1534, 1468, 1344 cm−1; 1H‐NMR (300 MHz, CDCl3) δ: 3.62
(s, 3H, OMe), 7.01–7.69 (m, 8H, Ar‐H), 8.02 (s, 1H, C5-H
imidazole); MS (EI): m/z calcd for C17H12BrN3OS: 384.99;
found: 384.987; Anal. Calcd. for C17H12BrN3OS; C, 52.86; H,
3.13; N, 10.88; found C, 52.72; H, 3.21; N, 10.92.
Acknowledgments. The authors express their sincere thanks to
Council of Scientific and Industrial Research, India, for financial
assistance.
Spectral data for the novel compounds.
6‐(2‐Chloro‐
Yellow
phenyl)‐2‐methyl‐imidazo[2,1‐b][1,3,4]thiadiazole (3d).
solid; IR (KBr) νmax: 2924, 1597, 1504, 1474, 1342 cm−1
;
1H‐NMR (300 MHz, CDCl3) δ: 1.27 (s, 3H, CH3), 7.94 (s, 1H,
C5-H imidazole), 7.30–7.62 (m, 4H, Ar‐H); MS (EI): m/z calcd
for C11H8ClN3S: 249.01; found: 249.013; Anal. Calcd. for
C11H8ClN3S; C, 52.91; H, 3.23; N, 16.83. Found: C, 52.83; H,
3.19; N, 16.89.
REFERENCES AND NOTES
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6‐(4‐Methoxy‐phenyl)‐2‐phenyl‐imidazo[2,1‐b][1,3,4]thiadiazole
(3g). White solid; IR (KBr) νmax: 2924, 1638, 1573, 1506, 1391,
1317 cm−1; 1H‐NMR (300 MHz, CDCl3) δ: 6.94–7.42 (m, 9H, Ar‐
H), 8.02 (s, 1H, C5-H imidazole), 3.63 (s, 3H, -OCH3); MS (EI): m/
z calcd for C17H13N3OS: 307.08; found: 307.078; Anal. Calcd. for
C17H13N3OS; C, 66.43; H, 4.26; N, 13.67; found: C, 66.51; H,
4.33; N, 13.59.
6‐(4‐Bromo‐phenyl)‐2‐phenyl‐imidazo[2,1‐b][1,3,4]thiadiazole
(3h). Light yellow solid; IR (KBr) νmax: 2922, 1603, 1537, 1472,
1346 cm−1; 1H‐NMR (300 MHz, CDCl3) δ: 7.34–7.67 (m, 9H, Ar‐
H), 8.01 (s, 1H, C5-H imidazole); MS (EI): m/z calcd for
C16H10N3BrS: 354.98; found: 354.978; Anal. Calcd. for
C16H11N3BrS: C, 53.94; H, 2.83; N, 11.80; found: C, 53.99; H,
2.89; N, 11.72.
6‐(2‐Chloro‐phenyl)‐2‐phenyl‐imidazo[2,1‐b][1,3,4]thiadiazole
(3i). Creamy white solid; IR (KBr) νmax: 2922, 1614, 1560, 1479,
1337 cm−1; 1H‐NMR (300 MHz, CDCl3) δ: 7.27–7.66 (m, 9H, Ar‐
H), 8.01 (s, 1H, C5-H imidazole); MS (EI): m/z calcd for
C16H10ClN3S: 311.03; found: 311.029; Anal. Calcd. for
C16H10ClN3S: C, 61.64; H, 3.23; N, 13.48; found C, 61.72; H,
3.19; N, 13.50.
[4] Andotra, C. S.; Langer, T. C.; Kotha, A. J Indian Chem Soc
1997, 74, 125.
[5] Khazi, I. A. M.; Mahajanshetti, C. S.; Gadad, A. K.; Tarnalli,
A. D.; Sultanpur, C. M. Arzneim forsch/Drug Res 1996, 46, 949.
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Simon, W. A.; Senn‐Bilfinger,J. Arzneim forsch/Drug Res 2000, 50, 550.
[7] Pyl, T.; Waschk, F.; Beyer, H. Justus Liebigs Ann Chem 1963,
663, 113.
[8] Wang, X.; Wang, M; Quan, Z.; Li, Z. Synth Commun 2005,
35, 2881.
[9] Paul, H.; Sitte, A.; Wessel, R. Monatsh Chem 1977, 108, 665.
[10] Harris, J. M. Eds. Poly(ethylene Glycol) Chemistry,
Biotechnological Applications; Plenum Press: New York, 1992.
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Biological Application; ACS Books: Washington, DC, 1997.
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6237.
[14] Kouznetsov, V. V.; Merchan Arenas, D. R.; Bohorquez, A. R.
R. Tetrahedron Lett 2008, 49, 3097.
[15] (a) Santaniello, E.; Manzwchi, A.; Sozzani, P. Tetrahedron
Lett 1979, 20, 4581; (b) Brandstrom, A. Acta Chem Scand 1956, 10,
1197; (c) Santaniello, E.; Ferraboschi, P.; Sozzani, P. Synthesis
1980,646.
2‐(3‐Bromo‐phenyl)‐6‐(p‐tolyl)‐imidazo[2,1‐b][1,3,4]thiadiazole
(3j). White solid; IR (KBr) νmax: 2922, 1598, 1510, 1482, 1327
1
cm−1; H‐NMR (300 MHz, CDCl3) δ: 2.23 (s, 3H, CH3), 7.25–
7.57 (m, 8H, Ar‐H), 7.99 (s, 1H, C5-H imidazole); MS (EI): m/z
calcd for C17H12BrN3S: 368.99; found: 368.992; Anal. Calcd. for
C17H12BrN3S: C, 55.14; H, 3.27; N, 11.35; found C, 55.21; H,
3.19; N, 11.42.
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Commun 2008, 9, 2547.
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105, 777.
2‐(3‐Bromo‐phenyl)‐6‐phenyl‐imidazo[2,1‐b][1,3,4]thiadiazole
(3k). Light brown solid; IR (KBr) νmax: 2924, 1673, 1592, 1537,
1
1492, 1346 cm−1; H‐NMR (300 MHz, CDCl3) δ: 7.28–7.62 (m,
9H, Ar‐H), 8.10 (s, 1H, C5-H imidazole); MS (EI): m/z calcd for
C16H10BrN3S: 354.98; found: 354.977; Anal. Calcd. for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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