HETEROCYCLES

Note | Regular issue | Vol. 81, No. 12, 2010, pp. 2849-2854
Received, 18th September, 2010, Accepted, 25th October, 2010, Published online, 4th November, 2010.
DOI: 10.3987/COM-10-12067

■ A Rapid and High-Yielding Synthesis of Thiazoles and Aminothiazoles Using Tetrabutylammonium Salts

Erdal Kocabas,* Ahmet Burak Sarıguney, and Ahmet Coskun

Department of ChemistryM, Selcuk University, Meram 42009, Konya, Turkey

Abstract

A convenient method for the synthesis of thiazoles and aminothiazoles by treatment of phenacyl bromides with thioamides/thiourea in the presence of tetrabutylammonium hexafluorophosphate (Bu4NPF6) at room temperature was developed. The products having high yields were formed rapidly (within 15 min). The method is simple, rapid and practical, generating thiazole derivatives in excellent isolated yields. The structures of the newly synthesized products were identified by FT-IR, 1H NMR, 13C NMR spectroscopy and elemental analysis data.

Thiazole and its derivatives are very useful compounds in various fields of chemistry including medicine and agriculture. For example, the thiazolium ring present in vitamin B1 serves as an electron sink, and its coenzyme form is important for the decarboxylation of α-keto acids.1 This heterocyclic system has a broad application in drug developments for the treatment of inflammation,2 hypertension,3 bacterial,4 and HIV infections.5 Especially, aminothiazoles are known to be ligands of estrogen receptors6 as well as a novel class of adenosine receptor antagonists.7
In view of the importance of thiazole and its derivatives, several methods for the synthesis of thiazole derivatives were developed. The most widely used method is Hantzsch synthesis,8,9 involving the reactions of α-halo carbonyl compounds with thiourea or thioamide derivatives. Recently, many improved methods have been reported for the synthesis of thiazoles by using catalysts such as ammonium-12-molybdophosphate in methanol,10 β-cyclodextrin in water,11 iodine,12 1,3-di-alkylimidazolium salts13 and by the use of microwave in ethanol.14 However, in spite of their potential utility, some of these reported methods suffer from drawbacks such as harsh reaction conditions, unsatisfactory yields and often expensive catalysts.
We, herein, present an improved method for the synthesis of thiazoles, 2-amino and 2-alkyl derivatives, from treatments of phenacyl bromides with thioamide/thiourea derivatives by using Bu4NPF6 as a catalyst. The reactions were carried out at room temperature and the high yield products were formed within 15 min. The obtained structures were settled from their spectral (1H and 13C NMR) data.

Thiazole derivatives in high yield were obtained from the treatments of phenacyl bromides and thiourea/thioamide derivatives with Bu4NPF6 at ambient temperature (Scheme 1).

The catalyzed reaction time and yield, and also melting points of the obtained products are given in Table 1.

We also examined various tetrabutylammonium salts given in Table 2 to investigate the efficiency of the catalyst. When tetrabutylammonium hexafluorophosphate was used, it was observed that conversion of phenacyl halides into thiazoles occurred in a shorter reaction time and higher yield according to other tetrabutylammonium salts.
The significant enhancement in the rate of reaction has been attributed to basicity of anions as depicted in the previous study.22 Indeed, the nature of the anion governing the electrophilicity of the tetrabutylammonium cation led to the remarkable rate accelerations.
The amount of catalysts used in the reaction did not have any significant influence on the overall rate of the reaction and yields of products. This was confirmed by scaling up the concentration from the present 10% solids (w/v) to 15% and 20% solids (w/v) in the case of 3m and 3n compounds, respectively. The reactions went to completion in identical times and with the same isolated yields as for the diluted reaction mixture.

Several phenacyl bromides given in Table 2 exhibited smooth reactions with thiourea and thioacetamide to give substituted 2-amino-4-arylthiazole and 2-methyl-4-arylthiazole, respectively. As can be seen in Table 2, the reactions were efficiently completed at ambient temperature under mild conditions to afford the corresponding thiazoles in excellent yields in all cases. Also, we did not obtain any difference among the phenacyl bromides substituted by electron-donating or electron-withdrawing groups. The obtained products were characterized by 1H and 13C NMR spectroscopy, FT-IR, melting point and elemental analyses.
The 1H NMR spectra of 3s and 3m compounds show peaks as broad singlets at δ 5.04 and 5.12 ppm respectively, which correspond to the amino group. The characteristic peaks appearing at δ 6.48–6.62 ppm correspond to C5–H of the thiazole ring for all compounds. In the 13C NMR spectra, the peaks appearing in the range of δ 169–171 ppm correspond to C2 of the thiazole ring. The FT-IR spectra of 3m and 3s compounds show peaks at 3448 and 3459 cm-1 corresponding to the amino group. In the case of 3n and 3p compounds, the peaks corresponding to the methyl group appeared at 3019-2835 cm-1. For the compounds synthesized previously (compounds 3a-3l and 3t in Table 1), the obtained values were in agreement with those reported in the literature.
Methanol was chosen as the most available solvent for the catalyzed reactions among the polar solvents, because the reaction was sluggish in the others, such as dichloromethane and chloroform. It was also noted that the reaction did not proceed in nonpolar solvents such as hexane and toluene even after stretching the reaction time (24 h).
N-Phenethyl-4-phenylthiazol-2-amine, commonly known as fanetizole is an anti-inflammatory agent that was reported to have reached phase II clinical trails for the treatment of rheumatoid arthritis.23 Generally, fanetizole has been synthesized by using stringent reaction conditions such as microreactors and heating in solvents, such as DMF and NMP. We presented a novel procedure for the synthesis of the anti-inflammatory drug fanetizole (compound 3t). In this procedure, we treated phenacyl bromide with 2-phenylethyl thiourea in methanol by using Bu4NPF6 as a catalyst to afford fanetizole in 92% yield in 15 min at ambient temperature.

EXPERIMENTAL
Materials and methods
1H and 13C NMR spectra were recorded on a Bruker DPX-400 spectrometer in CDCl3 using TMS as internal standard. Infrared spectra were recorded with Perkin-Elmer 1605 FTIR spectrometer using KBr pellets. Elemental analyses were obtained using a LECO-CHNS-932 instrument. Melting points were measured by using a EZ-Melt Automated MPA 120 melting point apparatus. All solvents and chemicals were of research grade and were used as obtained from Merck, Fluka and Sigma. Column chromatography was performed using silica gel (60–120 mesh size).

General procedure for the synthesis of thiazole derivatives
A mixture of phenacyl bromide 1 (1 mmol), thioamide/thiourea 2 (1.2 mmol) and Bu4NPF6 (10 mol%) was stirred in MeOH (5 mL) at room temperature under vigorous magnetic stirring. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was filtered. The filtrate was concentrated and the residue was subjected to column chromatography over silica gel using hexane-EtOAc (4:1) as eluent to afford pure product.
4-(4-Phenoxyphenyl)thiazol-2-amine (3m)
White solid; mp 65–67 oC; FT-IR (KBr): 3459, 3244, 3016, 2202, 2048, 1673, 1626, 1543, 1522, 1491, 1456, 1329, 973, 761 cm-1; 1H NMR (CDCl3, 400 MHz): δ= 5.12 (br s, 2H, NH2), 6.55 (s, 1H, thiazole H), 7.14-7.72 (m, 9H, Ar-H); 13C NMR (CDCl3, 100 MHz): δ= 98.6, 119.2, 119.7, 124.0, 125.6, 127.9, 130.2, 145.6, 156.4, 158.5, 171.3. Anal. Calcd for C15H12N2OS: C, 67.14; H, 4.51; N, 10.44%. Found: C, 67.49; H, 4.72; N, 10.34%.
2-Methyl-4-(4-phenoxyphenyl)thiazole (3n)
Yellow solid; mp 67–68 oC; FT-IR (KBr): 3235, 3017, 2835, 2200, 1669, 1619, 1541, 1488, 1461, 1301, 977, 756 cm-1; 1H NMR (CDCl3, 400 MHz): δ= 2.77 (s, 3H, CH3), 6.51 (s, 1H, thiazole H), 7.17-7.64 (m, 9H, Ar-H); 13C NMR (CDCl3, 100 MHz): δ= 19.7, 108.4, 118.0, 118.8, 121.9, 124.1, 126.2, 127.1, 128.5, 153.4, 157.0, 169.2. Anal. Calcd for C16H13NOS: C, 71.88; H, 4.90; N, 5.24%. Found: C, 71.76; H, 4.77; N, 5.09%.
N,N-Dimethyl-4-(4-phenoxyphenyl)thiazol-2-amine (3p)
White solid; mp 154–155 oC; FT-IR (KBr): 3209, 3019, 2837, 1605, 1565, 1548, 1488, 1461, 1313, 759 cm-1; 1H NMR (CDCl3, 400 MHz): δ= 3.12 (s, 6H, CH3), 6.48 (s, 1H, thiazole H), 7.11-7.66 (m, 9H, Ar-H); 13C NMR (CDCl3, 100 MHz): δ= 41.0, 105.0, 117.6, 117.9, 121.5, 124.0, 125.4, 127.2, 127.9, 150.2, 157.0, 170.1. Anal. Calcd for C17H16N2OS: C, 68.89; H, 5.44; N, 9.45%. Found: C, 69.09; H, 5.06; N, 9.13%.
4-(4-Phenoxyphenyl)-2-phenylthiazole (3r)
Yellow solid; mp 127-128 oC; FT-IR (KBr): 3221, 3009, 1611, 1543, 1521, 1479, 1449, 759 cm-1; 1H NMR (CDCl3, 400 MHz): δ= 6.46 (s, 1H, thiazole H), 7.09-7.69 (m, 14H, Ar-H); 13C NMR (CDCl3, 100 MHz): δ= 100.3, 111.4, 118.7, 119.6, 123.9, 125.4, 127.6, 129.1, 130.8, 144.9, 153.2, 156.1, 158.2, 170.4. Anal. Calcd for C21H15NOS: C, 76.57; H, 4.59; N, 4.25%. Found: C, 76.35; H, 4.83; N, 4.03%.
N-Benzyl-4-(4-phenoxyphenyl)thiazol-2-amine (3s)
Yellow solid; mp 137-138 oC; FT-IR (KBr): 3448, 3196, 3010, 2824, 1618, 1552, 1539, 1477, 1454, 1318, 753 cm-1; 1H NMR (CDCl3, 400 MHz): δ= 4.41 (s, 2H, CH2), 5.04 (br s, 1H, NH), 6.62 (s, 1H, thiazole H), 6.89-7.46 (m, 14H, Ar-H); 13C NMR (CDCl3, 100 MHz): δ= 49.0, 114.3, 116.1, 118.7, 121.4, 126.8, 128.4, 139.9, 152.4, 152.6, 157.1, 170.2. Anal. Calcd for C22H18N2OS: C, 73.71; H, 5.06; N, 7.82%. Found: C, 73.34; H, 4.99; N, 7.39%.

ACKNOWLEDGEMENTS
The authors are please to acknowledge the Scientific Research Projects (BAP) of Selcuk University for grant with grant number (No. 2008/08401063).

References

1. R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719. CrossRef
2. F. Haviv, J. D. Ratajczyk, R. W. DeNet, F. A. Kerdesky, R. L. Walters, S. P. Schmidt, J. H. Holms, P. R. Young, and G. W. Carter, J. Med. Chem., 1988, 31, 1719. CrossRef
3. W. C. Patt, H. W. Hamilton, M. D. Taylor, M. J. Ryan, D. G. Taylor, C. J. C. Connolly, A. M. Doherty, S. R. Klutchko, I. Sircar, B. A. Steinbaugh, B. L. Batley, C. A. Painchaud, S. T. Rapundalo, B. M. Michniewicz, and S. C. J. Olson, J. Med. Chem., 1992, 35, 2562. CrossRef
4. K. Tsuji and H. Ishikawa, Bioorg. Med. Chem. Lett., 1994, 4, 1601. CrossRef
5. F. W. Bell, A. S. Cantrell, M. Hoegberg, S. R. Jaskunas, N. G. Johansson, C. L. Jordon, M. D. Kinnick, P. Lind, J. M. Morin, R. O. B. Noreen, J. A. Palkowitz, C. A. Parrish, P. Pranc, C. Sahlberg, R. J. Ternansky, R. T. Vasileff, L. Vrang, S. J. West, H. Zhang, and X.-X. Zhou, J. Med. Chem., 1995, 38, 4929. CrossRef
6. B. A. Fink, D. S. Mortensen, S. R. Stauffer, Z. D. Aron, and J. A. Katzenellenbogen, Chem. Biol., 1999, 6, 205. CrossRef
7. J. E. van Muijlwijk-Koezen, H. Timmerman, R. C. Vollinga, J. F. von Drabbe Künzel, M. de Groote, S. Visser, and A. P. Ijzerman, J. Med. Chem., 2001, 44, 749. CrossRef
8. A. Hantzsch and J. H. Weber, Ber. Dtsch. Chem. Ges., 1887, 20, 3118. CrossRef
9. J. V. Metzger In: R. Katritzky and C. W. Rees, Editors, Comprehensive Heterocyclic Chemistry Vol. 6, Pergamon, New York, NY (1984), pp. 235–332.
10. B. Das, V. Saidi Reddy, and R. Ramu, J. Mol. Catal. A: Chem., 2006, 252, 235. CrossRef
11. M. Narender, M. S. Reddy, R. Sridhar, Y. V. D. Nageswar, and K. R. Rao, Tetrahedron Lett., 2005, 46, 5953. CrossRef
12. H. L. Siddiqui, A. Iqbal, S. Ahmed, and G. Weaver, Molecules, 2006, 11, 206. CrossRef
13. T. M. Potewar, S. A. Ingale, and K. V. Srinivasan, Tetrahedron, 2007, 63, 11066. CrossRef
14. W. K. George and R. M. Arjun, Tetrahedron Lett., 2006, 47, 5171. CrossRef
15. T. Aoyama, S. Murata, I. Arai, N. Araki, T. Takido, Y. Suzuki, and M. Kodomari, Tetrahedron, 2006, 62, 3201. CrossRef
16. S. Balalaie, S. Nikoo, and S. Haddadi, Synth. Commun., 2008, 38, 2521. CrossRef
17. T. M. Potewar, S. A. Ingale, and K. V. Srinivasan, Tetrahedron, 2008, 64, 5019. CrossRef
18. K. C. Joshi, V. N. Pathak, and P. Arya, Agric. Biol. Chem., 1979, 43, 199. CrossRef
19. M. Ueno and H. Togo, Synthesis, 2004, 16, 2673. CrossRef
20. C. R. Barbarín, S. Bernès, F. Sánchez-Viesca, and M. Berros, Acta Cryst. C, 2003, 59, 360. CrossRef
21. L. C. King and R. J. Hlavacek, J. Am. Chem. Soc., 1950, 72, 3722. CrossRef
22. M. P. Taterao, A. I. Sachin, and V. S. Kumar, Tetrahedron, 2007, 63, 11066. CrossRef
23. E. Garcia-Egido, S. Y. F. Wong, and B. H. Warrington, Lab Chip., 2002, 2, 31. CrossRef