A rapid and high-yielding synthesis of thiazoles and aminothiazoles using tetrabutylammonium salts

Article abstract of DOI:10.3987/COM-10-12067

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. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-12067

HETEROCYCLES, Vol. 81, No. 12, 2010
2849
HETEROCYCLES, Vol. 81, No. 12, 2010, pp. 2849 - 2854. © The Japan Institute of Heterocyclic Chemistry
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 Chemistry, Selcuk University, Konya 42099, Turkey
ekocabas50@gmail.com, absariguney@gmail.com, acoskun42@gmail.com
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.

2850
HETEROCYCLES, Vol. 81, No. 12, 2010
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).
O
S
N
Ar
R
Bu4NPF6, MeOH
rt, 13-15 min.
+
Br
Ar
H2N
R
S
1
2
: R=Me
NH2
3
88-96 %
NMe2
Ph
NHCH2Ph
NHCH2CH2Ph
Scheme 1. Synthesis of thiazole derivatives in the presence of catalyst
The catalyzed reaction time and yield, and also melting points of the obtained products are given in Table
1.
Table 1. Synthesis of 2-amino-4-arylthiazoles and 2-methyl-4-arylthiazoles catalyzed by Bu4NPF6
Entry
Ar
R
Thiazole
3a
Yielda
96
95
94
93
93
89
94
88
91
92
89
95
94
92
89
93
94
92
Time (min)
Mp (oC)
150-151
67-68
101-102
184-185
163-164
111-112
179-181
130-131
124-125
58-60
Lit. mp (oC)
15015
1
2
3
4
5
6
7
8
9
C6H5
C6H5
NH2
Me
NH2
Me
NH2
Me
NH2
Me
NH2
Me
NH2
Me
NH2
Me
NMe2
Ph
14
15
13
14
15
14
15
13
15
15
14
15
15
14
13
15
14
15
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3p
3r
6716
p-F-C6H4
p-F-C6H4
p-Cl-C6H4
p-Cl-C6H4
p-Br-C6H4
p-Br-C6H4
p-Me-C6H4
102-10317
18518
163-16416
11119
180-18116
13020
124-12521
58-5919
200-20319
67-6819
-
10 p-Me-C6H4
11 p-MeO-C6H4
12 p-MeO-C6H4
13 C6H4-O-C6H4
14 C6H4-O-C6H4
15 C6H4-O-C6H4
16 C6H4-O-C6H4
17 C6H4-O-C6H4
18 C6H5
202-203
66-67
65-67
67-68
-
-
-
-
154-155
127-128
137-138
116-117
NHCH2Ph
NHCH2CH2Ph
3s
3t
116-11722
a Isolated yield after column chromatography.

HETEROCYCLES, Vol. 81, No. 12, 2010
2851
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.
Table 2. Convertion of phenacyl bromide using different tetrabutylammonium salts as catalyst
Catalyst
Thiazole 3a
Thiazole 3c
Thiazole 3h
Thiazole 3k
Thiazole 3n
t
y
t
y
t
y
t
y
t
y
Bu4NPF6
Bu4N BF4
Bu4NCl
Bu4NBr
Bu4NI
14
22
22
23
21
96
89
88
86
89
13
21
23
22
24
94
86
88
85
87
13
25
23
24
23
88
81
83
82
80
14
26
24
25
22
89
80
82
81
83
14
28
25
27
24
92
83
81
85
82
* t= time (min), y= yield (%)
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
1
products were characterized by H and 13C NMR spectroscopy, FT-IR, melting point and elemental
analyses.
1
The H 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

2852
HETEROCYCLES, Vol. 81, No. 12, 2010
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)
o
White solid; mp 65–67 C; 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,

HETEROCYCLES, Vol. 81, No. 12, 2010
2853
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)
o
Yellow solid; mp 67–68 C; 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)
o
White solid; mp 154–155 C; FT-IR (KBr): 3209, 3019, 2837, 1605, 1565, 1548, 1488, 1461, 1313, 759
1
cm-1; H 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,
1
753 cm-1; H NMR (CDCl3, 400 MHz): δ= 4.41 (s, 2H, CH2), 5.04 (br s, 1H, NH), 6.62 (s, 1H, thiazole
13
H), 6.89-7.46 (m, 14H, Ar-H); C 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.
2.
R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719.
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.

2854
HETEROCYCLES, Vol. 81, No. 12, 2010
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.
K. Tsuji and H. Ishikawa, Bioorg. Med. Chem. Lett., 1994, 4, 1601.
4.
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.
6.
7.
B. A. Fink, D. S. Mortensen, S. R. Stauffer, Z. D. Aron, and J. A. Katzenellenbogen, Chem. Biol.,
1999, 6, 205.
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.
8.
9.
A. Hantzsch and J. H. Weber, Ber. Dtsch. Chem. Ges., 1887, 20, 3118.
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.
11. M. Narender, M. S. Reddy, R. Sridhar, Y. V. D. Nageswar, and K. R. Rao, Tetrahedron Lett., 2005,
46, 5953.
12. H. L. Siddiqui, A. Iqbal, S. Ahmed, and G. Weaver, Molecules, 2006, 11, 206.
13. T. M. Potewar, S. A. Ingale, and K. V. Srinivasan, Tetrahedron, 2007, 63, 11066.
14. W. K. George and R. M. Arjun, Tetrahedron Lett., 2006, 47, 5171.
15. T. Aoyama, S. Murata, I. Arai, N. Araki, T. Takido, Y. Suzuki, and M. Kodomari, Tetrahedron, 2006,
62, 3201.
16. S. Balalaie, S. Nikoo, and S. Haddadi, Synth. Commun., 2008, 38, 2521.
17. T. M. Potewar, S. A. Ingale, and K. V. Srinivasan, Tetrahedron, 2008, 64, 5019.
18. K. C. Joshi, V. N. Pathak, and P. Arya, Agric. Biol. Chem., 1979, 43, 199.
19. M. Ueno and H. Togo, Synthesis, 2004, 16, 2673.
20. C. R. Barbarín, S. Bernès, F. Sánchez-Viesca, and M. Berros, Acta Cryst. C, 2003, 59, 360.
21. L. C. King and R. J. Hlavacek, J. Am. Chem. Soc., 1950, 72, 3722.
22. M. P. Taterao, A. I. Sachin, and V. S. Kumar, Tetrahedron, 2007, 63, 11066.
23. E. Garcia-Egido, S. Y. F. Wong, and B. H. Warrington, Lab Chip., 2002, 2, 31.