D. Cáceres-Castillo et al. / Tetrahedron Letters 53 (2012) 3934–3936
3935
Table 2
Synthesis of 2-amino-4-arylthiazole from p-substituted acetophenones, thiourea and iodine
R
R
I2, neat
S
O
CH3
N
S
+
H2N NH2
NH2
MW, 130-150 °C,
50 W, 10 min
1
2
3a-h
R = H, Me, OMe, OH, NH2,
Cl, Br, NO2
Entry
R
Producta
Temp (°C)
140
Microwave yieldb (%)
Conventional yieldc (%)
1
2
3
4
5
6
7
8
H
3a
3b
3c
3d
3e
3f
88
80
80
62
40
91
99
99
65
64
Me
OMe
OH
NH2
Cl
150
140
140
130
150
150
145
54
d
d
81
85
91
Br
NO2
3g
3h
a
b
c
Spectroscopic data are consistent with those reported in the literature.21
Yield after 10 min of irradiation time.
Yield after 120 min under conventional heating.
No product observed.
d
mixture. In accordance with the literature,17 two moles of thiourea
must be present for each mole of halogen. Varying the proportion
of thiourea, it was found that at lower concentration the yield of
thiazole was poor (Table 1, entries 6 and 7). King and Ryden re-
ported that the formation of a thiazole from acetophenones and
thiourea can be accomplished by an oxidative process. So, when
the reaction is promoted by iodine it appears to proceed through
a dimer of thiourea.18 This fact explains partially the need of two
equivalents of thiourea. In order to determine the most appropriate
iodine concentration towards the synthesis of 2-aminothiazoles,
different iodine amounts were examined. A significant reduction
in yields was observed when using less than one equivalent of io-
dine (Table 1, entries 8 and 9). Thus, it was found that two equiv-
alents of thiourea 2 and one equivalent of iodine afforded the
corresponding 2-amino-4-phenylthiazole with the better yields
(88%, see Table 1, entry 10).
the technique has the advantage of being simple and allows the
synthesis of thiazole compounds in a minimum of time.
Acknowledgments
Financial support was provided by Facultad de Química of the
Universidad Autónoma de Yucatán through the PIFI-2008. The
authors are grateful to Dr. Leovigildo Quijano for the critical review
of the Letter.
References and notes
1. Dighe, N. S.; Pattan, S. R.; Musmade, D. S.; Gaware, V. M.; Kale, S. H.; Shinde, H.
V.; Shirote, P. J. Pharmacology online 2010, 1, 70–84.
2. Bekhit, A. A.; Fahmy, H. T. Y.; Rostom, S. A. F.; Bekhit, A. E. D. A. Eur. J. Med.
Chem. 2010, 45, 6027–6038.
3. Prasanna, P.; Balamurugan, K.; Perumal, S.; Yogeeswari, Pe.; Sriram, D. Eur. J.
Med. Chem. 2010, 45, 5653–5661.
With these results in hand, we extended our studies using dif-
ferent p-substituted acetophenones (Table 2).19 It is possible to
appreciate that both the temperature as well as the thiazole ring
formation depend on the electronic effects of the p-phenyl substi-
tuent. Thus electro-releasing groups decrease the yield of the reac-
tion (Table 2, entries 2–5) as they increase the electron density on
the carbonyl group, hindering the cyclocondensation mechanism.
Accordingly, acetophenones with p-substitution by slightly elec-
tron donors gave acceptable yields (Table 2, entries 1–3) and
strong electron-releasing groups with protic hydrogens gave lower
yields (entries 4 and 5). On the other hand excellent yields were
obtained with p-substituted acetophenones with electron-with-
drawing substituents (Table 2, entries 6–8).
For comparison purposes, the reactions were also carried out
using a thermostated oil-bath under the same conditions but for
a longer (optimized) period of time20 to ascertain whether the
microwave heating improves the yield. It was found that lower
yields were obtained using oil-bath heating rather than the micro-
wave activated method (Table 2). In addition the reaction time for
microwave-assisted reactions was twelve times shorter than the
same reactions in all of our studied substrates. As a result when
the reaction time was shortened, thermal decomposition was also
minimized, resulting in higher isolated yields.
4. Maruyama, T.; Kano, Y.; Yamamoto, Y.; Kurazono, M.; Iwamatsu, K.; Atsumi, K.;
Shitara, E. Bioorg. Med. Chem. 2007, 15, 392–402.
5. Eliazyan, K. A.; Avetisyan, F. V.; Jivanshiryan, T. L.; Pivazyan, V. A.; Ghazaryan, E.
A.; Shahbazyan, L. V.; Harutyunyan, S. V.; Yengoyan, A. P. J. Heterocycl. Chem.
2011, 48, 118–123.
6. Badiger, N. P.; Khan, A.; Kalashetti, M. B.; Khazi, I. M. Med. Chem. Res., in press.
7. Paronikyan, E. G.; Noravyan, A. S.; Dzhagatspanyan, I. A.; Nazaryan, I. M. Pharm.
Chem. J. 2006, 40, 407–409.
8. Gupta, R.; Sharma, D.; Singh, S. Phosphorus Sulfur 2010, 185, 1321–1331.
9. Morales-Bonilla, P.; Perez-Cardeña, A.; Quintero-Marmol, E.; Arias-Tellez, J. L.;
Mena-Rejon, G. J. Heteroat. Chem. 2006, 17, 254–260.
10. Choi, M.-J.; Jung, K. H.; Kim, D.; Lee, H.; Zheng, H.-M.; Park, B. H.; Hong, S.-W.;
Kim, M.-H.; Hong, S.; Hong, S.-S. Cancer Lett. 2011, 306, 190–196.
11. Andreani, A.; Rambaldi, M.; Mascellani, G.; Rugarli, P. Eur. J. Med. Chem. 1987,
22, 19–22.
12. (a) King, L. C.; Hlavek, R. J. J. Am. Chem. Soc. 1950, 72, 3722–3725; (b) Schwarz,
G. Org. Synth., Coll. Vol. III 1955, 332–333; (c) Van Leusen, A. M.; Wildeman, J.
Synthesis 1977, 7, 501–502; (d) Brandsma, L.; de Jong, R. L. P.; VerKruijsse, H. D.
Synthesis 1985, 10, 948–949; (e) Moriarty, R. M.; Vaid, B. K.; Duncan, M. P.; Ley,
S. G.; Prakash, O.; Goyal, S. Synthesis 1992, 9, 845–846; (f) Kim, H.-S.; Kwon, L.-
C.; Kim, O.-H. J. Heterocycl. Chem. 1995, 32, 937–939; (g) Kim, H.-S.; Kwon, L.-C.;
Kim, O.-H. J. Heterocycl. Chem. 1995, 32, 937–939; (h) Kamproudi, H.;
Spyroudis, S.; Tarantili, P. J. Heterocycl. Chem. 1996, 33, 575–578; (i) Flaig, R.;
Hartmann, H. Heterocycles 1997, 45, 875–888.
13. Hantzsch, A.; Webber, J. H. Ber. Dtsch. Chem. Ges. 1887, 20, 3118–3132.
14. (a) Kabalka, G. W.; Mereddy, A. R. Tetrahedron Lett. 2006, 47, 5171–5172; (b)
Narender, M.; Reddy, M. S.; Sridhar, R.; Nageswar, Y. V. D.; Rao, K. R.
Tetrahedron Lett. 2005, 46, 5953–5955; (c) Potewar, T. M.; Ingale, S. A.;
Srinivasan, K. V. Tetrahedron 2008, 64(22), 5019–5022.
15. (a) Zav’yalov, S. I.; Dorofeeva, O. V.; Rumyantseva, E. E.; Kulikova, L. B.; Ezhova,
G. I.; Kravchenko, N. E.; Zavosin, A. G. Pharm. Chem. J. 2001, 35, 96–98; (b)
Giridhar, T.; Buchi Reddy, R.; Sunil Kumar, A.; Chandra Mouli, G. V. P.
Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 2058–2072; (c) Kidwai, M.;
Bhatnagar, D.; Mothsra, P.; Singh, A. K.; Dey, S. J. Sulfur Chem. 2009, 30, 29–36;
(d) Ignat, A.; Zaharia, V.; Mogosan, C.; Palibroda, N.; Cristea, C.; Silaghi-
In conclusion, there was an improvement in yields of the con-
densation of p-substituted acetophenones with thiourea and io-
dine to obtain 2-amino-4-(p-substituted-phenyl)-1,3-thiazoles
using microwave heating under solvent-free conditions. Besides,