Microwave promoted synthesis of functionalized 2-aminothiazoles

Article abstract of DOI:10.1016/j.tetlet.2006.05.053

Microwave irradiation promotes the rapid one-pot synthesis of 2-aminothiazoles fromed via the condensation of α-bromoketones with thiourea.

Full text of DOI:10.1016/j.tetlet.2006.05.053

Tetrahedron Letters 47 (2006) 5171–5172
Microwave promoted synthesis of functionalized 2-aminothiazoles
George W. Kabalka* and Arjun R. Mereddy
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37966-1600, USA
Received 6 December 2005; revised 9 May 2006; accepted 10 May 2006
Abstract—Microwave irradiation promotes the rapid one-pot synthesis of 2-aminothiazoles fromed via the condensation of a-bromo-
ketones with thiourea.
Ó 2006 Elsevier Ltd. All rights reserved.
Table 1. Synthesis of 2-(N-substituted)aminothiazoles from a-bromo-
The biological activity of aminothiazoles has been well
ketonesa
documented.1 They have broad application in the treat-
ment of allergies,2 hypertension,3 schizophrenia,4
O
R
S
EtOH, MW
5 min
N
inflammation,5 bacterial infections,6 and HIV.7 Recently
they have been utilized for the treatment of pain,8 as
fibrinogen receptor antagonists with anti-thrombotic
activity,9 as inhibitors of bacterial DNA gyrase B,6
and in the development of cyclin-dependent kinase
(CDK) inhibitors.10
2
Br
NHR
2
R
NH
NHR
2
S
1
R
1
R
1
2
3
Substrates 1 and 2
Yieldb
(%)
R
R1
R2
H
CH3
C6H5
H
CH3
C6H5
H
CH3
C6H5
H
CH3
C6H5
H
CH3
C6H5
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3C6H4
CH3C6H4
CH3C6H4
NO2C6H4
NO2C6H4
NO2C6H4
CH3SC6H4
CH3SO2C6H4
C6H5
C6H5
C6H5
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
98
96
98
96
88
97
99
98
98
98
98
98
98
97
97
95
87
Among the various methodologies reported for the
preparation of thiazoles, solid supported syntheses have
been used to generate small organic libraries11 and solu-
tion phase preparations of combinatorial libraries have
been prepared in DMF12 as well as in 1,4-dioxane.13
These methods require high temperatures, long reaction
times, hazardous solvents, and often produce low yields.
The use of microwaves in organic synthesis has recently
gained in importance.14 Microwave systems provide the
opportunity to complete complex reactions in minutes.
In this letter, we report the use of microwave irradiation
to enhance condensation reactions between a-bromo-
ketones and thiourea. We have found that the condensa-
tion of a-bromoketones with thioureas furnish the
desired products within 5 min under microwave (MW)
irradiation in the absence of catalysts. The results of
the study are summarized in the Table 1.
H
1
a All products were identified by H, 13C NMR, and comparison with
authentic samples.
b Isolated yields.
In a typical procedure, a mixture of a-bromoketone 1
(1.0 mmol) and a thiourea 3 (1.0 mmol) were placed in
a MW test tube (10 mL) containing a magnetic stirring
bar, rubber cap, and 4 mL of ethanol. The test tube
was placed in the microwave cavity (CEM, Discover)
and subjected to MW irradiation at 50 °C (100 W) for
5 min. After completion of the reaction, the tube was
removed, cooled to room temperature, and the contents
added to water (10 mL). The product 3 was extracted
Keywords: Microwave; Aminothiazole; Green chemistry; a-Bromo
ketone; Thiourea.
*
Corresponding author. Tel.: +1 865 974 3260; fax: +1 865 974
2997; e-mail: kabalka@utk.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.053

5172
G. W. Kabalka, A. R. Mereddy / Tetrahedron Letters 47 (2006) 5171–5172
6. Rudolph, J.; Theis, H.; Hanke, R.; Endermann, R.;
Johannsen, L.; Geschke, F.-U. J. Med. Chem. 2001, 44,
619.
into methylene chloride (15 mL), which was filtered
though a short silica column to afford the 2-aminothiazole
after the solvent was removed under reduced pressure.
7. Venkatachalam, T. K.; Sudbeck, E. A.; Mao, C.; Uckum,
F. M. Bioorg. Med. Chem. Lett. 2001, 11, 523.
8. Wilson, K. J.; Illig, C. R.; Subasinghe, N.; Hoffman, J. B.;
Jonathan Rudolph, M.; Soll, R.; Molloy, C.; Bone, R.;
Green, D.; Randall, T.; Zhang, M.; Lewandowski, F. A.;
Zhou, Z.; Sharp, C.; Maguire, D.; Grasberger, B.;
DesJarlais, R. L.; Spurlino, J. Bioorg. Med. Chem. Lett.
2001, 11, 915.
In conclusion, microwave irradiation promotes the
condensation of a-bromoketones with thioureas to
provide an excellent route to highly functionalized
2-aminothiazoles.
9. Badorc, A.; Borders, M.-F.; Cointet, P. de.; Savi, P.;
Bernat, A.; Lale, A.; Petitou, M.; Maffrand, J.-P.; Herbert,
J.-M. J. Med. Chem. 1997, 40, 3393.
Acknowledgements
We wish to thank the US Department of Energy and
the Robert H. Cole foundation for support of this
research.
10. (a) Kim, K. S.; Kimball, S. D.; Misra, R. N.; Rawlins, D.
B.; Hunt, J. T.; Xiao, H.-Y.; Lu, S.; Qian, L.; Han, W.-C.;
Shan, W.; Mitt, T.; Cai, Z.-W.; Poss, M. A. .; Zhu, H.;
Sack, J. S.; Tokarski, J. S.; Chang, C. Y.; Pavletich, N.;
Kamath, A.; Humphreys, W. G.; Marathe, P.; Bursuker,
I.; Kellar, K. A.; Roongta, U.; Batorsky, R.; Mulheron, J.
G.; Bol, D.; Fairchild, C. R.; Lee, F. Y.; Webster, K. R. J.
Med. Chem. 2002, 45, 3905; (b) Misra, R. N.; Xiao, H.-Y.;
Kim, K. S.; Lu, S.; Han, W.-C.; Barbosa, S. A.; Hunt, J.
T.; Rawlins, D. B.; Shan, W.; Ahmed, S. Z.; Qian, L.;
Chen, B.-C.; Zhao, R.; Bednarz, M. S.; Kellar, K. A.;
Mulheron, J. G.; Batorsky, R.; Roongta, U.; Kamath, A.;
Marathe, P.; Ranadive, S. A.; Sack, J. S.; Tokarski, J. S.;
Pavletich, N. P.; Lee, F. Y. F.; Webster, K. R.; Kimball, S.
D. J. Med. Chem. 2004, 47, 1719.
11. Kazzouli, S. EI.; Raboin, S. B.; Mouadbib, A.; Guillau-
met, G. Tetrahedron Lett. 1999, 40, 423.
12. Bailey, N.; Dean, A. W.; Judd, D. B.; Middlemiss, D.;
Storer, R.; Stephen, P. W. Bioorg. Med. Chem. Lett. 1996,
6, 1409.
13. Kearney, P. C.; Fernandez, M.; Flygare, J. A. J. Org.
Chem. 1998, 62, 196.
14. Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9925.
References and notes
1. (a) Barone, R.; Chanon, M.; Gallo, R. Aminothiazoles
and their derivatives. In The Chemistry of Heterocyclic
Compounds, Part 2; Metzger, J. V., Ed.; Wiley: New York,
1979; Vol. 34, (b) Gorczynski, M. J.; Leal, R. M.;
Mooberry, S. L.; Bushweller, J. H.; Brown, M. L. Bioorg.
Med. Chem. 2004, 12, 1029.
2. Ohkubo, M.; Kuno, A.; Nakanishi, I.; Takasugi, H.
Chem. Pharm. Bull. 1995, 43, 1497.
3. Patt, W. C.; Hamilton, H. W.; Taylor, M. D.; Ryan, M. J.;
Taylor, D. G., Jr.; Connolly, C. J. C.; Doherty, A. M.;
Klutchko, S. R.; Sircar, I.; Steinbaugh, B. A.; Batley, B.
L.; Painchaud, C. A.; Rapundalo, S. T.; Michniewicz, B.
M.; Olson, S. C. J. J. Med. Chem. 1992, 35, 2562.
4. Hallas, G.; Choi, J. Dyes Pigments 1999, 42, 249.
5. Jayashree, B. S.; Anuradha, D.; Venugopala, N. K. Asian.
J. Chem. 2005, 17, 2093.