received.
assistance of compounds.
Preparation of the intermediates 2-(trifluoromethyl)-6-
arylimidazo [2,1-b][1,3,4]-thiadiazole (IVa-c).
The intermediates IV were prepared according to the literature
References
[
19,20]
method,
as shown in Scheme 1.
[1] Samai, S.; Nandi, G. C.; Singh, P.; Singh, M. S. Tetrahedron 2009, 65,
Synthesis of 5-(trifluoromethyl)-1,3,4-thiadiazol-2- amine (III).
A mixture of thiosemicarbazide (50 mmol), trifluoroacetic
anhydride (50 mmol) was stirred at -5 °C for 1 h under nitrogen
atmosphere, then the reaction was heated at 40 °C for 2 h. After
cooling down, the reaction mixture was diluted with water and
alkalized with ammonia. The crystalline precipitate was filtered and
recrystallized with ethanol to afford intermediate III as white
crystals.
10155.
[
2] Noolvi, M. N.; Patel, H. M.; Singh, N.; Gadad, A. K.; Cameotra, S. S.;
Badiger, A. Eur. J. Med. Chem. 2011, 46, 4411.
[
[
3] Yadav, L. D. S.; Vaish, A. J. Agric. Food Chem. 1992, 40, 294.
4] Utture, S. C.; Banerjee, K.; Dasgupta, S.; Patil, S. H.; Jadhav, M.
R.; Wagh, S. S.; Kolekar, S. S.; Anuse, M. A.; Adsule, P. G. J. Agric. Food
Chem. 2011, 59, 7866.
General
-(trifluoromethyl)-6-arylimidazo
IVa-c).
A mixture of 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine (25
mmol) and an appropriate α-haloaryl ketone (25 mmol) was
refluxed in dry ethanol (200 mL) for 10 h. The excess of solvent was
removed under reduced pressure and the solid (hydrobromide salt)
procedure
for
the
preparation
of
[5] Whelan, M.; Chirollo, C.; Furey, A.; Cortesi, M. L.; Anastasio, A.;
Danaher, M. J. Agric. Food Chem. 2010, 58, 12204.
2
(
[2,1-b][1,3,4]-thiadiazoles
[
[
6] Vaughn, S. F.; Spencer, G. F. J. Agric. Food Chem. 1994, 42, 200.
7] Wang, B.-L.; Liu, X.-H.; Zhang, X.-L.; Zhang, J.-F.; Song, H.-B.; Li, Z.-M.
Chem. Biol. Drug. Des. 2011, 78, 42.
[
[
8] Scott, M. K.; Martin, G. E.; DiStefano, D. L.; Fedde, C. L.; Kukla, M. J.;
Barrett, D. L.; Baldy, W. J.; Elgin, Jr., R. J.; Kesslick, J. M.; Mathiasen, J. R.;
Shank, R. P.; Vaught, J. L. J. Med. Chem. 1992, 35, 552.
2 3
was suspended in water, and neutralized by aqueous Na CO . The
yield precipitate was filtered, washed with water, and recrystallized
from ethanol to give the key intermediate IV.
9] Shi, M.; Zhan, G.; Du, W.; Chen, Y. Acta Chim. Sinica 2017, 75, 998.
General
procedure
for
the
synthesis
of
[
10] Li, F.; Mu, M.; Yang, N.; Zhong, L.; Hu, R.; Li, J.; Bai, L.; Shi, J.; Zhang, M.
Chin. J. Org. Chem. 2016, 36, 1419.
5
-((4-substitutedpiperazin-1-yl)methyl)-6-aryl-2-(trifluorometh
yl)imidazo[2,1-b][1,3,4] thiadiazole Va-o.
[
[
11] Liu, Y.; Wu, Q.; Yin, D.; Li, D. Chin. J. Org. Chem. 2016, 36, 927.
12] Singh, S. K.; Chandna, N.; Jain, N. Org. Lett. 2017, 19, 1322.
To a mixture solution of the intermediate IV (1 mmol) and
1-substitutedpiperazine (1.1 mmol) in ethanol (10 mL) and glacial
acetic acid (10 mL), 37% formalin (4 mmol) was added. The reaction
mixture was stirred at room temperature (for the case of R = OCH ),
or stirred under reflux (for the case of R = H, Cl) for 5 h. After
cooling to the room temperature, the reaction system was added 10
mL of water and the mixture was extracted with ethyl acetate (3 ×
[13] Zhang, L.-Y.; Wang, B.-L.; Zhan, Y.-Z.; Zhang, Y.; Zhang, X.; Li, Z.-M. Chin.
Chem. Lett. 2016, 27, 163.
1
3
1
[
[
[
14] Chen, Y.; Wang, G.; Duan, N.; Cao, T.; Wen, X.; Yin, J.; Wang, W.; Xie, S.;
Huang, W.; Hu, G. Chin. J. Appl. Chem. 2012, 29, 1246.
15] Bayrak, H.; Demirbas, A.; Karaoglu, S. A.; Demirbas, N. Eur. J. Med.
Chem. 2009, 44, 1057.
1
0 mL), the organic phase was combined and dried over anhydrous
Na SO . The solvent was removed under reduced pressure and the
2
4
16] Ahmed, S. A.; Hamdy, M.; Abdel, R. N. Bioorg. Med. Chem. 2006, 14,
1236.
residue was recrystallized from ethanol to afford the title
compounds Va-o.
General
,4-bis((6-aryl-2-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiaz
ol-5-yl)methyl) piperazine VIa-c.
To a mixture solution of the intermediate IV (2 mmol) and
anhydrous piperazine (1 mmol) in ethanol (10 mL) and glacial acetic
acid (10 mL), 37% formalin (4 mmol) was added. The reaction
procedure
for
the
synthesis
of
[17] Bachman, G. B.; Heisey, L. V. J. Am. Chem. Soc. 1946, 68, 2496.
1
[
[
[
18] Stocker, F. B.; Kurtz, J. L.; Gilman, B. L.; Forsyth, D. A. J. Org. Chem. 1970,
5, 883.
19] Gadad, A. K.; Noolvi, M. N.; Karpoormath, R. V. Bioorg. Med. Chem.
004, 12, 5651.
3
2
20] Alegaon, S. G.; Alagawadi, K. R.; Sonkusare, P. V.; Chaudhary, S. M.;
Dadwe, D. H.; Shah, A. S. Bioorg. Med. Chem. Lett. 2012, 22, 1917.
mixture was stirred at room temperature (for the case of R
1 3
= OCH ),
or stirred under reflux (for the case of R = H, Cl) for 5 h. After
1
cooling to the room temperature, the reaction system was added 20
mL of water and the mixture was extracted with ethyl acetate (3 ×
[21] Zhang, Y.; Liu, X.-H.; Zhan, Y.-Z.; Zhang, L.-Y.; Li, Z.-M.; Li, Y.-H.; Zhang, X.;
Wang, B.-L. Bioorg. Med. Chem. Lett. 2016, 26, 4661.
1
5 mL), the organic phase was combined and dried over anhydrous
[
[
[
[
22] Wang, B.-L.; Shi, Y.-X.; Ma, Y.; Liu, X.-H.; Li, Y.-H.; Song, H.-B.; Li, B.-J.; Li,
Z.-M. J. Agric. Food Chem. 2010, 58, 5515.
Na SO . The solvent was removed under reduced pressure and the
2
4
residue was recrystallized from ethanol to afford the title
compounds VIa-c.
23] Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Curr. Top. Med. Chem. 2016, 16,
1
200.
24] Wang, B.-L.; Zhang, L.-Y.; Zhan, Y.-Z.; Zhang, Y.; Zhang, X.; Wang, L.-Z.; Li,
Z.-M. J. Fluorine Chem. 2016, 184, 36.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
25] Wang, B.; Shi, Y.; Zhan, Y.; Zhang, L.; Zhang, Y.; Wang, L.; Zhang, X.; Li, Y.;
Li, Z.; Li, B. Chin. J. Chem. 2015, 33, 1124.
Acknowledgement
Manuscript received: XXXX, 2017
This
the National Key Research and Development Program of China (No.
017YFD0200505), the National Natural Science Foundation of
work
was
supported
by
Revised manuscript received: XXXX, 2017
Accepted manuscript online: XXXX, 2017
Version of record online: XXXX, 2017
2
China (Nos. 21372133 and 21772103), and Tianjin Natural Science
Foundation (No. 17JCYBJC19900). We thank the teachers of the
Biological Assay Center, Nankai University, for kind bioassay
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