Synthesis of imidazo[2,1-b[-1,3,4-thiadiazoles in DABCO as an efficient and recyclable catalyst

Article abstract of DOI:10.1080/00397911.2011.574329

An efficient and general method has been described for the synthesis of imidazo[2,1-b]-1,3,4-thiadiazole by the reaction of 2-aminothiadiazoles with phenacyl bromides in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO). The method is suitable for the synthesis of functionalized imidazothiadiazoles.

Full text of DOI:10.1080/00397911.2011.574329

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Synthesis of Imidazo[2,1-b]-1,3,4-
thiadiazoles in DABCO as an Efficient and
Recyclable Catalyst
Kamleshwar Tiwari a , Pankaj Kumar Verma a , Shyam Babu Singh a &
Jagdamba Singh a
a Environmentally Benign Synthesis Laboratory, Department of
Chemistry, University of Allahabad, Allahabad, India
Accepted author version posted online: 10 Jan 2012. Version of
record first published: 21 Jun 2012
To cite this article: Kamleshwar Tiwari, Pankaj Kumar Verma, Shyam Babu Singh & Jagdamba Singh
(2012): Synthesis of Imidazo[2,1-b]-1,3,4-thiadiazoles in DABCO as an Efficient and Recyclable
Catalyst, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 42:20, 3021-3030
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Synthetic Communications1, 42: 3021–3030, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.574329
SYNTHESIS OF IMIDAZO[2,1-b]-1,3,4-THIADIAZOLES
IN DABCO AS AN EFFICIENT AND RECYCLABLE
CATALYST
Kamleshwar Tiwari, Pankaj Kumar Verma,
Shyam Babu Singh, and Jagdamba Singh
Environmentally Benign Synthesis Laboratory, Department of Chemistry,
University of Allahabad, Allahabad, India
GRAPHICAL ABSTRACT
Abstract An efficient and general method has been described for the synthesis of
imidazo[2,1-b]-1,3,4-thiadiazole by the reaction of 2-aminothiadiazoles with phenacyl
bromides in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO). The method is
suitable for the synthesis of functionalized imidazothiadiazoles.
Keywords 2-Aminothiadiazole; DABCO; imidazothiadiazole; phenacyl bromide
INTRODUCTION
Imidazo[2,1-b]-1,3,4-thiadiazole derivatives have been of great interest among
medicinal chemists for many years because of their anticancer,[1] antitubercular,[2] anti-
bacterial,[3] antifungal,[4] anticonvulsant, analgesic,[5] and antisecretory[6] activities.
Moreover, much interest has also been focused on the anti-inflammatory,[7] cardio-
tonic,[8] diuretic,[9] and herbicidal[10] activities displayed by compounds incorporating
this heterocyclic system. Because the imidazo[2,1-b]-1,3,4-thiadiazole system is similar
in part to levamisole (I), a well-known immunomodulator,[11] the possibility of
reducing the harmful effects of the cytotoxic agents on the immune system is also very
attractive. Biheterocycles containing benzofuran with pyridine, thiadiazoles, and
chromone[12] rings have been found to exhibit antimicrobial, psychotropic, and anti-
inflammatory activities. For example, efaroxan (2-imidazolinyl-2,3-dihydrobenzo-
furan) is a well-known antagonist of the a-2-adrenoreceptor.[13] Many recently
reported benzofuran derivatives are good anti-inflammatory agents.[14,15] Similarly
Received February 1, 2011.
Address correspondence to Shyam Babu Singh, Environmentally Benign Synthesis Laboratory,
Department of Chemistry, University of Allahabad, Allahabad 211002, India. E-mail: shyam.qt@
gmail.com
3021

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K. TIWARI ET AL.
tetramisole (II), a broad-spectrum antithelmintic,[16] also contains imidazo[2,1-b]-
1,3,4-thiadiazole (Fig. 1).
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-thiadiazole is the reaction
of 5-R-2-amino-1,3,4-thiadiazoles with a-haloketones. However, these reactions are
performed in organic solvents at reflux temperatures giving only moderate yields;
therefore, this synthetic methodology does not provide the possibility of synthesizing
a wide range of derivatives of imidazo[2,1-b]-1,3,4-thiadiazole derivatives.
Besides these methods, there are many other methods[17] that provide good
yields. These methods suffer from tedious workup, long reaction time, use of metal
catalyst, and narrow scope of substrates. Moreover, some of the methods have some
drawbacks such as unsatisfactory yields and expensive and detrimental metal reagents.
Recently, use of nonmetallic reagents is an area of growing interest because of
environmental regulations. Among the various organic bases, 1,4-diazabicyclo
[2,2,2]octane (DABCO) has been employed as a organic-hindered base to bring about
various organic transformations such as deprotection of peptides,[18] and as a catalyst
for the Baylis–Hillman reaction,[19] isoxazole preparation,[20] o-alkylations of phe-
nols,[21] and deprotection of benzylic trimethylsilyl ethers,[22] substituted imidazoles,[23]
xanthates,[24] and ethyldiazoacetates.[25] To the best of our knowledge, there is no report
on the synthesis of imidazo[2,1-b]-1,3,4-thiadiazole derivatives using organic bases.
Herein we report a simple, efficient, and general method for the preparation of substi-
tuted imidazo[2,1-b]-1,3,4-thiadiazole (C) derivatives by the reaction of 2-aminothiadia-
zole (A) with phenacyl bromides (B) in the presence of DABCO (Scheme 1).
We have initiated our study with the reaction of phenacyl bromide with
2-aminothiadiazole in the presence of different organic bases such as quinuclidine,
DABCO, urotropine, and Troger’s base in tetrahydrofuran (THF) (Table 1).
It was observed that the reaction proceeded efficiently using DABCO
and resulted in good yield of the desired product in a short reaction time (55 min).
However, with other bases the reaction was comparatively slow and gave less yield
of the product even after stretching the reaction time. In addition to this, we have
screened acyclic tertiary amines such as triethylamine (TEA) and N1,N1,N2-triethyl-
N2-methylethane-1,2-diamine and found that the reaction was very sluggish with
poor yield (10–20%) even with extended reaction time (4–5 h). We have attempted
different ratios of DABCO (10, 15, 20, 25, 30, and 40 mol%) and observed that
20 mol% was suitable for the optimum conversion. The increase in the molar ratio
of DABCO also did not improve the yield.
Figure 1. Levamisole and tetramisole.

IMIDAZO[2,1-b]-1,3,4-THIADIAZOLES
3023
Scheme 1. Synthesis of imidazo[2,1-b]-1,3,4-thiadiazole.
To further optimize the reaction conditions, the reaction was studied in differ-
ent solvents such as benzene, toluene, dichloromethane, and acetonitrile. The reac-
tion proceeded in all the solvents with different degrees of conversion (Table 2).
However, THF was the solvent of choice in terms of reaction time and yield.
The formation of product may be explained by the reaction of phenacyl
bromide (2) with DABCO (1), which forms the quaternary salt (3).[26] Later it reacts
with 2-aminothiadiazole, and subsequent cyclization and dehydration results in
expected product (8) (Scheme 2).
The scope of this DABCO-catalyzed imidazo[2,1-b]-1,3,4-thiadiazole formation
was explored under optimal condition, and the results are summarized in Table 3. We
have studied the electronic effects of the substituent on the rate of the reaction and
the mode of formation of imidazo[2,1-b]-1,3,4-thiadiazole. It was observed that elec-
tron-rich substituent on the 2-aminothiadiazole slightly influence the reaction because
electron-releasing groups slightly increase electron density over NH2 group of
2-aminothiadiazoles. We have also examined phenacyl bromides having different
substituent such as Cl, Br, OMe, and Me. The electron-rich functionalities influence
the reaction and furnish the corresponding imidazo[2,1-b]-1,3,4-thiadiazoles
in good yield, whereas the electron-withdrawing substituent on phenacyl bromide gave
Table 1. Screened bases for the reaction of phenacyl bromide with
2-aminothiadiazole
Entry
1
Base
Conversion (%) Yielda (%)
65
60
2
3
100
50
95
47
4
55
52
aIsolated yields.

3024
K. TIWARI ET AL.
Table 2. Imidazo[2,1-b]-1,3,4-thiadiazole derivatives formation
in different solvent conditions
Entry
Solvent
Yielda (%)
1
2
3
4
5
Benzene
Toluene
THF
65
67
95
75
56
CH3CN
CH2Cl2
aAll the reactions were carried out at 45 ꢀC.
comparatively poor yield of imidazo[2,1-b]-1,3,4-thiadiazole under identical conditions.
It is worth mentioning that the present method provides access for the synthesis of new
functionalized imidazo[2,1-b]-1,3,4-thiadiazoles. These imidazo[2,1-b]-1,3,4-thiadiazoles
may provide scope for further extension to build up pharmaceutically important
molecules.
EXPERIMENTAL
General Procedure for the Synthesis of Target Molecule
A mixture of phenacyl bromide (1 equiv) and DABCO (20 mol%) was stirred at
45 ꢀC for 5 min. Then 2-aminothiadiazole (1 equiv) was added slowly, and the resultant
Scheme 2. Mechanism for the formation of imidazo[2,1-b]-1,3,4-thiadiazole.

3025

3026

IMIDAZO[2,1-b]-1,3,4-THIADIAZOLES
3027
mixture was stirred at the same temperature for 50 min. After completion of the reac-
tion, as indicated by thin-layer chromatography (TLC), the mixture was poured into
water. It was extracted with ethylacetate (3 ꢁ 15 ml), dried over Na2SO4, and evapo-
rated under reduced pressure. The crude product was passed through a small pad of
silica gel to give the pure product (ethyl acetate–hexane 1:4). All the compounds were
characterized by infrared (IR), 1H NMR, mass spectral data, and elemental analysis.
Compound C1
Mp 135–137 ꢀC (lit. mp 135–137 ꢀC).[27] IR (tmax, cmꢂ1, KBr) 2924, 1676, 1587,
1
1534, 1468, 1344; H NMR (d, 300 MHz, CDCl3) 1.27 (s, 3H, CH3), 8.01 (s, 1H,
C5-H imidazole), 7.37–7.95 (m, 5H, Ar-H); HRMS (Mþ) 215.052.
Compound C2
Mp 200–202 ꢀC (lit. mp 200–202 ꢀC).[28] IR (tmax, cmꢂ1, KBr) 2922, 1695, 1573,
1
1499, 1375; H NMR (d, 300 MHz, CDCl3) 1.27 (s, 3H, CH3), 7.99 (s, 1H, C5-H
imidazole), 7.03–7.42 (m, 4H, Ar-H), 3.62 (s, 3H, -OCH3); HRMS (Mþ) 245.064.
Compound C3
Mp 210–212 ꢀC (lit. mp 210–212 ꢀC).[28] IR (tmax, cmꢂ1, KBr) 2922, 1603, 1539,
1
1476, 1345; H NMR (d, 300 MHz, CDCl3) 1.23 (s, 3H, CH3), 8.01 (s, 1H, C5-H
imidazole), 7.38–7.54 (m, 4H, Ar-H); HRMS (Mþ) 292.963.
Compound C4
Mp 169–172 ꢀC. IR (tmax, cmꢂ1, KBr) 2924, 1597, 1504, 1474, 1342; 1H NMR
(d, 300 MHz, CDCl3) 1.27 (s, 3H, CH3), 7.94 (s, 1H, C5-H imidazole), 7.30–7.62 (m,
4H, Ar-H); HRMS (Mþ) 249.013.
Compound C5
Mp 158–160 ꢀC (lit. mp 158–160 ꢀC).]28] IR (tmax, cmꢂ1, KBr) 2922, 1697, 1571,
1
1498, 1318; H NMR (d, 300 MHz, CDCl3) 1.27 (s, 3H, CH3), 2.27 (s, 3H, CH3),
7.03–7.38 (m, 4H, Ar-H), 8.02 (s, 1H, C5-H imidazole); HRMS (Mþ) 229.068.
Compound C6
Mp 206–208 ꢀC (lit. mp 206–208 ꢀC).[27] IR (tmax, cmꢂ1, KBr) 2924, 1679, 1595,
1501, 1486, 1323; 1H NMR (d, 300 MHz, CDCl3) 7.14–7.58 (m, 10H, Ar-H), 8.01 (s,
1H, C5-H imidazole); HRMS (Mþ) 277.069.

3028
K. TIWARI ET AL.
Compound C7
Mp 178–180 ꢀC, IR (tmax, cmꢂ1, KBr) 2924, 1638, 1573, 1506, 1391, 1317; H
1
NMR (d, 300 MHz, CDCl3) 6.94–7.42 (m, 9H, Ar-H), 8.02 (s, 1H, C5-H imidazole),
3.63 (s, 3H, -OCH3); HRMS (Mþ) 307.078.
Compound C8
Mp 220–222 ꢀC. IR (tmax, cmꢂ1, KBr) 2922, 1603, 1537, 1472, 1346; 1H NMR
(d, 300 MHz, CDCl3) 7.34–7.67 (m, 9H, Ar-H), 8.01 (s, 1H, C5-H imidazole); HRMS
(Mþ) 354.978.
Compound C9
Mp 154–156 ꢀC. IR (tmax, cmꢂ1, KBr) 2922, 1614, 1560, 1479, 1337; 1H NMR
(d, 300 MHz, CDCl3) 7.27–7.67 (m, 9H, Ar-H), 8.01 (s, 1H, C5-H imidazole); HRMS
(Mþ) 311.029.
Compound C10
Mp 274–276 ꢀC. IR (tmax, cmꢂ1, KBr) 2922, 1598, 1510, 1482, 1327; 1H NMR
(d, 300 MHz, CDCl3) 1.27 (s, 3H, CH3), 7.25–7.57 (m, 9H, Ar-H), 7.99(s, 1H, C5-H
imidazole); HRMS (Mþ) 368.992.
Compound C11
1
Mp 144–146 ꢀC. IR (tmax, cmꢂ1, KBr) 2924, 1673, 1592, 1537, 1492, 1346; H
NMR (d, 300 MHz, CDCl3) 7.28–7.62 (m, 9H, Ar-H), 8.10(s, 1H, C5-H imidazole);
HRMS (Mþ) 354.977.
Compound C12
1
Mp 260–262 ꢀC. IR (tmax, cmꢂ1, KBr) 2924, 1676, 1587, 1534, 1468, 1344; H
NMR (d, 300 MHz, CDCl3) 7.01–7.69 (m, 9H, Ar-H), 8.02(s, 1H, C5-H imidazole);
HRMS (Mþ) 384.987.
CONCLUSION
In conclusion, we have demonstrated an efficient and mild method for the syn-
thesis of functionalized Imidazo[2,1-b]-1,3,4-thiadiazole derivatives using DABCO
as a catalyst. This method is applicable for a variety of phenacyl bromides and
2-aminothiadiazole. Moreover, this protocol provides access for the synthesis of
functionalized Imidazo[2,1-b]-1,3,4-thiadiazole derivatives.

IMIDAZO[2,1-b]-1,3,4-THIADIAZOLES
3029
ACKNOWLEDGEMENTS
We sincerely thank SAIF, Punjab University, Chandigarh, for providing micro
analyses and spectra. K. T., P. K. V., and S. B. S. are grateful to the University
Grants Commission, New Delhi, for the award of junior research Fellowships.
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